Favorable human dosing regimens for administering INX-315

Abstract

Dosage and regimens based on the discovery of unexpectedly high and persistent exposure to INX-315 in individuals requiring medication, which increase efficacy per dose and C max vs C min Dosage and regimen that minimize adverse events during treatment by minimizing the ratio and reducing the initial drug spike after administration. TIFF2026518846000063.tif62170

Description

[Technical Field]

[0001] [Cross-reference of related applications] This application claims the benefits of U.S. Provisional Application No. 63 / 460,201 filed on 18 April 2023, U.S. Provisional Application No. 63 / 470,621 filed on 2 June 2023, International Application PCT / US2023 / 025791 filed on 20 June 2023, U.S. Provisional Application No. 63 / 540,884 filed on 27 September 2023, and U.S. Provisional Application No. 63 / 612,840 filed on 20 December 2023. These applications in whole constitute part of this specification by reference for any purpose.

[0002] This invention provides dosages and regimens based on the discovery of unexpectedly high and persistent exposure to INX-315 after administration to humans requiring administration. The surprisingly high and persistent exposure to INX-315 would not have been predictable before administration to humans. This surprising pharmacokinetic behavior increases the efficacy per dose and the initial spike during administration, i.e., C at administration. max and C min By minimizing the ratio of [specific factors], adverse events during treatment can be minimized. [Background technology]

[0003] Cell division is regulated by the cell cycle, which is divided into four phases: G1 phase (cell growth and mechanism synthesis), S phase (DNA replication to produce two identical sets of chromosomes), G2 phase (cell growth and auxiliary mechanism synthesis), and M phase (division of a single cell into two identical daughter cells). The progression between phases of the cell cycle is primarily controlled by cyclins and cyclin-dependent kinases (CDKs) (Non-Patent Literature 1), which are activated or inhibited in response to a complex system of cellular signaling networks that interpret extracellular signals.

[0004] Cyclin-dependent kinase 2 (CDK2), which is activated after binding to cyclin E, is required for cells to enter the S phase of the cell cycle (Non-Patent Literature 2). The CDK2 / cyclin E protein complex, like the CDK4 / 6 / cyclin D protein complex, phosphorylates retinoblastoma protein (Rb) and releases the G1 transcription factor E2F, thereby promoting the completion of the S phase (Non-Patent Literature 3, Non-Patent Literature 1). In addition to regulating G1 / S transition, the CDK2 / cyclin E protein complex mediates histone biosynthesis and centrosome replication (Non-Patent Literature 4, Non-Patent Literature 5).

[0005] CDK2-mediated hyperphosphorylation leads to complete inactivation of the Rb protein, which is necessary to facilitate the completion of the S phase. Therefore, retinoblastoma protein is considered to be a key protein in the cell cycle system, including the CDK2 / cyclin E protein complex. Evidence suggests that CDK2 fundamentally modulates cell proliferation and CDK4 / 6 inhibitor resistance mechanisms, highlighting the potential of targeting CDK2 in cancer (Non-Patent Literature 6).

[0006] Currently, several CDK2 inhibitors are undergoing human clinical trials for the treatment of cancer (including, for example, BLU-222, Blueprint Medicines Corporation; PF-07104091, Pfizer; INX-315, Incyclix Bio; INCB123667, Incyte Medical; and AVZO-021, Avenzo Therapeutics).

[0007] Administration of either BLU-222 or PF-07104091 to humans may result in plasma concentration spikes that could cause adverse effects. For example, in an open-label, first-in-human, phase 1 / 2 clinical trial (NCT05252416) evaluating the CDK2 inhibitor BLU-222 in patients with progressive solid tumors, several ocular adverse events (AEs) affecting vision were observed in 5 patients (19%). These ocular AEs included transient and reversible cases of photosensitivity, blurred vision, photophobia, and changes in visual acuity. Most ocular AEs were mild, but there was one case of grade 3 blurred vision / photophobia in a patient receiving 600 mg of BLU-222 twice daily (BID). Due to these ocular-related AEs, the U.S. Food and Drug Administration (FDA) imposed a temporary suspension of the clinical trial for patient enrollment in February 2023 (Non-Patent Literature 7), which was lifted after a mitigation plan.

[0008] BLU-222 has the following structure: [ka]

[0009] Pfizer's CDK2 inhibitor PF-07104091 is currently being evaluated in a Phase 1 trial for advanced or metastatic solid tumors (NCT04553133; Non-Patent Literature 8).

[0010] PF-07104091 has the following structure: [ka]

[0011] The most common treatment-related adverse events (AEs) observed with PF-07104091 included nausea (77.1%; 14.3% grade 3), diarrhea (48.6%; 8.6% grade 3), vomiting (48.6%; 2.9% grade 3), fatigue (45.7%; 20.0% grade 3), and anemia (45.7%; 8.6% grade 3).

[0012] Another CDK2 inhibitor that has just entered Phase I clinical trials is INX-315, which was initially disclosed in Patent Document 1 filed by G1 Therapeutics, Inc. and is exclusively licensed to Incyclix Bio (see also Patent Document 2 filed by Incyclix Bio). [ka]

[0013] There is a continuing need for improved treatment and dosing regimes that are useful for treating patients with cancer, including CDK4 / 6-resistant tumors, while minimizing non-target toxicity. [Prior art documents] [Patent Documents]

[0014] [Patent Document 1] International Publication No. 2021 / 236650 [Patent Document 2] International Publication No. 2023 / 249974 [Non-patent literature]

[0015] [Non-Patent Document 1] Asghar et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 14(2):130-146(2015) [Non-Patent Document 2] Merrick, KA et al. Switching Cdk2 on or off with small molecules to reveal requirements in human cell proliferation. Mol Cell. 42:624-636(2011) [Non-Patent Document 3] Sherr, CJ Mammalian G1 cyclins. Cell. 73(6):1059-65(1993 Jun 18) [Non-Patent Document 4] Matsumoto, YK et al. CDK2 is required for centrosome duplication in mammalian cells. Curr Biol. 9:429-432(1999) [Non-Patent Document 5] Nelson, DM et al. Coupling of DNA synthesis and histone synthesis in S phase independent of cyclin / cdk2 activity. Mol Cell Biol. 22(21):7459-7472(2002 Nov) [Non-Patent Document 6] Tadesse, S. et al. Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update. J Med Chem. 62(9):4233-4251(2019 May 9) [Non-Patent Document 7] Blueprint Medicines announces partial clinical hold for phase 1 / 2 VELA trial of BLU-222. News release (2023 Feb 10) [Non-Patent Document 8] Yap, TA et al. First-in-human phase 1 / 2a study of a potent and novel CDK2-selective inhibitor PF-07104091 in patients (pts) with advanced solid tumors, enriched for CDK4 / 6 inhibitor resistant HR+ / HER2- breast cancer. 2023 ASCO Annual Meeting I - Developmental Therapeutics-Molecularly Targeted Agents and Tumor Biology. Meeting Abstract 3010. 41(16):suppl(2023)

[0016] [Detailed explanation] The present invention is a CDK2 inhibitor having the following structure: [ka] (INX-315) Based on the surprising findings resulting from the initial administration of this compound to humans, namely, the discovery that this compound has a unique and highly unexpected pharmacokinetic profile that does not significantly agree with predictive mathematical pharmacokinetic models extrapolated from other mammalian species (dogs, rats, and mice), we provide dosage and regimens.

[0017] In one aspect of the present invention, a favorable pharmaceutical composition of INX-315 or a pharmaceutically acceptable salt thereof is provided, which, when administered to humans, results in i) a reduction or minimization of spikes in plasma concentrations of INX-315 over time, and ii) sustained release of INX-315 into the plasma, enabling an extension of the drug's half-life. While we do not wish to be bound by any single theory, it is proposed that INX-315 binds to human blood cells in vivo to a much higher degree than observed in other tested mammals or than predicted before administration to humans. This increases the amount of drug available in human blood, creating a depot effect for sustained availability of certain drugs as the drug is released over time from red blood cells into plasma and then to the site of treatment.

[0018] In another aspect of the present invention, a pharmaceutical formulation in solid dosage form of INX-315 or a pharmaceutically acceptable salt thereof is provided, which improves the bioavailability and release properties of the drug or a pharmaceutically acceptable salt thereof. It has been found that advantageous delivery is achieved when INX-315 is administered in an amorphous spray-dried dispersion (ASD) of INX-315 together with a compound that acts as a precipitation inhibitor. INX-315 is highly insoluble and readily crystallizes. This compound has a tendency to self-aggregate and crystallize in solid form. This can occur during manufacturing, storage, or even after administration to humans. As a result of formulation studies, it has been found that the efficacy of the drug is improved when a pharmaceutically acceptable precipitation inhibitor is included in the amorphous spray-dried dispersion. Some specific suitable precipitation preventer agents include, but are not limited to, polyvinylpyrrolidone, polymethacrylate, and pharmaceutically acceptable cellulose derivatives such as hydroxypropyl methylcellulose acetate succinate (HPMCAS), which effectively prevent precipitation of INX-315, as will be further described in the detailed description. ASD can be granulated with appropriate excipients. In certain embodiments, the pharmaceutical composition is a tablet comprising a blend of INX-315 ASD granules containing a sufficient amount of a precipitation enhancer and one or more extragranular excipients (i.e., excipients added after granulation but before compression or tableting). This pharmaceutical composition has been well tolerated in human patients and has been successfully administered in exemplary solid dosage forms, such as tablets with 100 mg, 200 mg, and 300 mg active ingredient strengths.

[0019] Surprisingly, INX-315 was also found to be effective in treating Rb-independent (Rb-negative) cancers in humans, based on human data. As shown in the background of the invention, INX-315 is a CDK2 inhibitor that is activated after binding to its binding partner, cyclin E. When cyclin E is amplified, cells enter the S phase of the cell cycle, leading to uncontrolled replication in the case of cancer. CDK2-mediated hyperphosphorylation leads to inactivation of the Rb protein, which is necessary to facilitate the completion of the S phase. However, it was found here that INX-315 can also inhibit uncontrolled replication in several specific cancers that do not proceed via the cyclin E / retinoblastoma protein mechanism. INX-315 may also be able to inhibit cyclin A-mediated replication that occurs downstream of the retinoblastoma protein pathway. By utilizing this alternative pathway, effective doses of INX-315 can be used to treat Rb-independent cancers, including but not limited to small cell lung cancer (SCLC) (see, for example, Figures 15C and 15D). Other tumors include Rb-independent tumors selected from triple-negative breast cancer (TNBC), prostate cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, stomach cancer, esophageal cancer, head and neck cancer, glioblastoma, retinoblastoma, osteosarcoma, or lymphoma.

[0020] This discovery represents a step forward in cancer treatment by providing a CDK2 inhibitor useful for treating both Rb-dependent and Rb-independent tumors (which may include heterogeneous tumors of both types). Furthermore, INX-315 can be used in combination with CDK4 / 6 inhibitors, including but not limited to ribociclib (Novartis), abemaciclib (Eli Lilly), palbociclib (Pfizer Inc.), or rerocyclib (G1 Therapeutics, Inc.). In some embodiments, INX-315 is administered daily, and the CDK4 / 6 inhibitor is administered for 21 days during a typical 28-day cycle, with a 7-day rest period.

[0021] It is also highly unexpected that administration of INX-315 does not result in a spike in drug concentration at the first administration, as is often seen with other drugs such as BLU-222 and PF-07104091. The spike effect is shown by the large initial C max versus C min ratio, which decays after administration (see Figures 2 and 3). Conversely, when the C max versus C min ratio is small, it is shown that there is no spike. As a non-limiting example, the C max versus C min ratio of INX-315 in the first two humans administered 100 mg of INX-315 once daily was measured to be approximately 2.2, whereas the estimated C max versus C min ratio of BLU-222 (400 mg twice daily) based on published human results was 9.3 and 22 for BLU-222 (600 mg twice daily). Similarly, the estimated C max versus C min ratio of PF-07104091 was 16 - 64 based on published human data (see Table 5 and Figures 2 and 3). The presence of a spike after administration means that there is an excess amount of drug in the blood in the short term, which can lead to side effects and is generally not preferred. Based on this finding in humans, a method for treating CDK2-mediated cancer is provided, which includes administering an effective amount of INX-315 such that the C max versus C min ratio does not exceed 6, 5, 4, or even 3.

[0022] INX-315 exhibits a very high AUC, lasting from day 1 to day 15 of administration, which is much larger than predicted based on profiles observed in non-human mammalian models. It was not foreseeable in advance that the human pharmacokinetic parameters would be superior to those in other tested mammals, as will be more fully described in the detailed description of the invention. The non-limiting range of AUC in humans is such that a single daily administration of INX-315 in the range of 100 mg to 300 mg results in plasma AUCs of 1000 ng·hr / mL to 40000 ng·hr / mL. Naturally, AUC increases with dosage and varies somewhat from person to person based on individual metabolic patterns and individual differences.

[0023] INX-315 binds to red blood cells at a higher level than in plasma, and the ratio of red blood cells to plasma (K) RBC / P The ratio (K) in humans could range from approximately 12 to 30, 15 to 30, or approximately 12.0 to 20.0, which was found to be higher than in other mammals tested (see Example 2, Table 7). Furthermore, the ratio (K) of INX-315 in whole blood to plasma in humans was found to be higher than in other mammals tested. WB / P The values ​​are approximately 4-10, 5-10, or 6-10, which are also higher than those of other mammals (Table 7).

[0024] For example, as described in Example 10, the predicted AUC of INX-315 with a 100 mg dose once daily based on a mammalian model was approximately 740 (ng·hr / mL), while the measured AUC was 2020 on day 1 (average of 5 human patients) and 3290 on day 15. These results exceeded the prediction by more than 2.7 and 4.4 times, respectively. Similarly, the predicted C for a 100 mg dose once daily was also exceeded. max (ng / mL) is 39.3, but the measured C max The result was 148 on day 1 and 211 on day 15. These results exceeded the prediction by more than 3.7 times and 5.3 times, respectively. In addition, the prediction C for the same dosage was also higher. min The value was 19.1 (ng / mL), but the actual C minThe value was 103 on day 1 and 177 on day 15. The C calculated based on that dosage was min free The (ng / mL) value was 0.997, but the observed value was 5.4 on day 1 and 9.2 on day 15 (see Example 2, Table 2 for general information).

[0025] As an additional example, as described in Example 10, the predicted AUC of INX-315 with a 200 mg once daily dose based on a mammalian model was 1380 (ng·hr / mL), while the measured AUC was 8940 on day 1 (average of 5 human patients) and 12200 on day 15. These results exceeded the prediction by more than 6.4 and 8.8 times, respectively. Similarly, the predicted C for a 200 mg once daily dose was 1380 (ng·hr / mL). max (ng / mL) is 72.3, but the measured C max The figure was 590 on day 1 and 922 on day 15. These results exceeded the predictions by more than 8.1 times and 12.7 times, respectively.

[0026] In addition, INX-315 has a blood-to-plasma distribution ratio (K) of 25-29 in the range of 0.03 μM to 10 μM. RBC / P ) shows the ratio (K) of whole blood to plasma. WB / P The values ​​were 10-16, and on average, all of these were significantly higher than those of the mammals tested (Table 8).

[0027] In whole blood, the predicted AUC based on the mammalian model was 5560 (ng·hr / mL), but the actual AUC in humans was surprisingly 50550 on day 1 and 116350 on day 15 (Table 9). This was more than 9 times higher than the model on day 1 and more than 20 times higher on day 15 (Table 9).

[0028] As reported in this specification, AUC, C max , C min , and C min freeAll of the profiles were approximately 2 to 3 times larger in plasma and more than 9 times larger in whole blood than predicted from studies in three non-human animal models. This is likely because the drugs bind disproportionately to human red blood cells compared to red blood cells of non-human mammals.

[0029] The inventions described herein also include amorphous spray-dried dispersion (ASD) formulations of INX-315. As described above and herein, INX-315 is highly insoluble in water (Table 12), and free INX-315 is crystalline (Figures 5A-6C). It has been found that INX-315 can be mixed in a solvent with a precipitation inhibitor, such as a polymeric precipitation inhibitor, to produce advantageous amorphous spray-dried dispersion (ASD) formulations. The precipitation inhibitor minimizes crystallization of INX-315 in the ASD formulation. In non-limiting embodiments, the mixed solvent may be, for example, a mixture of THF and water, and in non-limiting embodiments, 90% THF and 10% water. In some embodiments, the mixed solvent is a mixture of THF and water, for example, 92% THF and 8% water. In some embodiments, THF is stabilized with butylated hydroxytoluene (BHT). As a non-limiting example of Example 3, the INX-315 ASD formulation disperses INX-315 throughout a polymer matrix (e.g., an anti-precipitation agent such as HPMCAS) and has high T g and low T m / T g As shown by the ratio, crystallization of INX-315 in the ASD formulation is prevented (Figures 9A and 9B).

[0030] The present invention comprises an amorphous spray-dried dispersion of INX-315 or a pharmaceutically acceptable salt thereof, having a substantial amount of a precipitation enhancer, for example, 20% to 60% by weight of INX-315 of ASD. In some embodiments, amorphous INX-315 is included in a range of, for example, about 25% to about 60% by weight of ASD, or for example, about 35% to 45% by weight, or even 40% by weight of ASD (Tables 17 and 20). In some embodiments, INX-315 is spray-dried together with a precipitation inhibitor, for example, but not limited to hydroxypropyl methylcellulose acetate succinate - high substitution (HPMCAS-HG), or other precipitation inhibitors further described herein. The precipitation inhibitor may be included, for example, in an amount of about 50% to 70% by weight of ASD, or in an amount of about 55% to 65% by weight of ASD, or even in an amount of about 60% by weight of ASD (Tables 17 and 20).

[0031] In additional embodiments, advantageous pharmaceutical compositions comprising an ASD formulation added with one or more additional pharmaceutically acceptable excipients are described herein. As a non-limiting example of Example 4, the INX-315 ASD formulation is dry-granulated, dry-mixed, and then tableted with one or more additional pharmaceutically acceptable excipients, including but not limited to microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, and stearyl fumarate sodium, to produce a pharmaceutical composition to be administered to a subject requiring it (Tables 21 and 23).

[0032] In some embodiments, amorphous INX-315 is included in the pharmaceutical composition in an amount ranging from about 10% to about 30% by weight, or from about 15% to about 35% by weight, or, for example, about 20% by weight (Tables 17 and 20). Precipitation inhibitors may be included in an amount ranging from about 20% to about 50% by weight, or, for example, from about 25% to about 45% by weight, or, for example, about 30% by weight (Tables 17 and 20).

[0033] Pharmaceutical compositions containing the INX-315 ASD formulations described herein exhibit favorable total and soluble drug concentrations over extended periods (Figures 8A–8C), suggesting that the majority of INX-315 exists as micelles, small colloids, small self-assembled drug aggregates, or molecularly free drug (Figures 7, 10A–13B). While we do not wish to be bound by any single theory, sustained absorption of INX-315 is facilitated by the shuttleping of the drug across the intestinal mucous boundary, which is rapidly replaced by free drug as it is absorbed, while the free drug is continuously replaced by intermittently soluble INX-315 drug / polymer colloids. The formation of various INX-315 drug / polymer and micelle structures in vivo leads to sustained dissolution and absorption of INX-315, creating a “depot effect” phenomenon where drug levels rise and are prolonged for longer periods than would have been predicted based on prior preclinical animal studies. In the case of INX-315, this compound is advantageously and rapidly produced in humans without a "spike effect" in its C max It reaches, for example, as seen in Figure 1, C max and C min A small difference between them (i.e., a lower C) max vs C min Maintain the ratio for several hours.

[0034] INX-315 is used here to treat humans with tumors that have intact and functional retinoblastoma protein. Examples of cancers that have intact and functional retinoblastoma protein include, but are not limited to, breast cancer, ovarian cancer, non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, or glioblastoma. In some embodiments, Rb-positive cancer is breast cancer. In some embodiments, Rb-positive breast cancer is HR+ / HER2- breast cancer. In some embodiments, Rb-positive breast cancer is ER+ / HER2- breast cancer. In some embodiments, Rb-positive cancer is ovarian cancer. In some embodiments, Rb-positive ovarian cancer is high-grade serous ovarian cancer (HGSOC).

[0035] Unexpectedly, INX-315 was also found to effectively treat Rb-independent cancers through an Rb-independent mechanism (see, for example, Figures 15C and 15D). In some embodiments, the Rb-independent cancer is selected from small cell lung cancer (SCLC), retinoblastoma, triple-negative breast cancer (TNBC), human papillomavirus (HPV)-positive head and neck cancer, HPV-positive cervical cancer, or bladder cancer. In some embodiments, the Rb-independent cancer is SCLC. In some embodiments, the Rb-independent cancer is TNBC. In some embodiments, the Rb-independent cancer is bladder cancer.

[0036] In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof in the ASD formulations described herein provides an additive or synergistic effect on the anticancer or antiproliferative activity of an additional therapeutic agent. In some embodiments, the additional therapeutic agent is selected from CDK4 / 6 inhibitors, endocrine therapies, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example, Figures 15C and 15D and Figure 16B). This improvement represents a significant advance in the technological level of cancer treatment. In some embodiments, the additional therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocyclib, or darpiciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Pfizer Inc.). In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Novartis). In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is rerocyclib (G1 Therapeutics, Inc.).

[0037] INX-315 can be advantageously administered to patients with CDK4 / 6-resistant tumors or cyclin E-overexpressing tumors, as shown, for example, in Figure 16B. INX-315 can also be administered in combination with a selective CDK4 inhibitor. In certain embodiments, INX-315 can be administered in combination with a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocyclib, or dalpiciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Pfizer Inc.). In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Novartis). In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is rerocyclib (G1 Therapeutics, Inc.).

[0038] Surprisingly, it was discovered that administering INX-315 in several specific dosing regimens achieved improved pharmacokinetic parameters compared to predictions generated using preclinical mammalian-based models. These dosing regimens are sufficient to treat human patients in need of treatment, such as those with cancers sensitive to CDK2 inhibitors.

[0039] Non-limiting examples of aspects of the present invention include: 1. A pharmaceutical composition comprising an amorphous spray-dried dispersion (ASD) of INX-315 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the ASD further comprises an anti-precipitation agent. 2. The pharmaceutical composition of Embodiment 1, wherein INX-315 is present in an amount of approximately 20% to approximately 60% by weight of ASD. 3. The pharmaceutical composition of Embodiment 1, wherein INX-315 is present in an amount of approximately 30% to approximately 50% by weight of ASD. 4. The pharmaceutical composition of Embodiment 1, wherein INX-315 is approximately 40% by weight of ASD. 5. A pharmaceutical composition according to any one of Embodiments 1 to 4, wherein the pharmaceutical composition contains approximately 100 mg to approximately 500 mg of INX-315. 6. The precipitation inhibitor is a cellulose derivative, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethylcellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP A pharmaceutical composition selected from VA37, one of any four embodiments (1 to 4). 7. The pharmaceutical composition of Embodiment 6, wherein the precipitation inhibitor is HPMCAS-HG. 8. A pharmaceutical composition according to any one of Embodiments 1 to 7, wherein the precipitation inhibitor in ASD is approximately 40% to approximately 80% by weight of ASD. 9. A pharmaceutical composition according to any one of Embodiments 1 to 7, wherein the precipitation inhibitor in ASD is approximately 60% by weight of ASD. 10. A pharmaceutical composition according to any one of Embodiments 1 to 9, wherein ASD is present in an amount of approximately 40% to approximately 60% by weight of the pharmaceutical composition. 11. A pharmaceutical composition according to any one of Embodiments 1 to 9, wherein ASD is present in an amount of approximately 50% by weight of the pharmaceutical composition. 12. A pharmaceutical composition according to any one of Embodiments 1 to 11, comprising an insoluble diluent. 13. The pharmaceutical composition of Embodiment 12, wherein the insoluble diluent is microcrystalline cellulose. 14. The pharmaceutical composition according to claim 12 or 13, wherein the insoluble diluent is present in an amount of about 15% to about 25% by weight of the pharmaceutical composition. 15. A pharmaceutical composition according to any one of Embodiments 1 to 14, comprising a soluble diluent. 16. The pharmaceutical composition of Embodiment 15, wherein the soluble diluent is mannitol. 17. The pharmaceutical composition according to claim 15 or 16, wherein the soluble diluent is present in an amount of about 15% to about 25% by weight of the pharmaceutical composition. 18. A pharmaceutical composition comprising any one of Embodiments 1 to 17, comprising a disintegrant. 19. The pharmaceutical composition of Embodiment 18, wherein the disintegrant is croscarmellose sodium. 20. The pharmaceutical composition of Embodiment 18 or Embodiment 19, wherein the disintegrant is present in an amount of about 1% to about 10% by weight of the pharmaceutical composition. 21. A pharmaceutical composition comprising any one of Embodiments 1 to 20, comprising a fluidizing agent. 22. The pharmaceutical composition of Embodiment 21, wherein the fluidizing agent is colloidal silicon dioxide. 23. A pharmaceutical composition according to Embodiment 21 or Embodiment 22, wherein the fluidizing agent is present in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition. 24. A pharmaceutical composition comprising any one of Embodiments 1 to 20, comprising a lubricant. 25. The pharmaceutical composition of Embodiment 24, wherein the lubricant is sodium stearyl fumarate. 26. The pharmaceutical composition of Embodiment 24 or Embodiment 25, wherein the lubricant is present in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition. 27. A method for treating a person having heterogeneous CDK2-mediated cancer, comprising administering an effective dose of INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment. A method for heterogeneous CDK2-mediated cancer comprising a mixture of retinoblastoma protein (Rb)-dependent cells and Rb-independent cells. 28. INX-315 or a pharmaceutically acceptable salt thereof is administered as a component of a pharmaceutical composition, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. The method of Embodiment 27, wherein the amount of INX-315 in ASD is 20% to 60% by weight. 29. A method for treating a person having CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, which yields an average plasma area under the curve (AUC) (ng·hr / mL) of approximately 1250 to approximately 50000 when measured on day 1 of administration. The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 30. Any one of Embodiments 27 to 29, wherein the mean plasma AUC measured on day 1 of administration is 6,000 to 50,000. 31. Any one of the methods from Embodiments 27 to 29, wherein the mean plasma AUC measured on day 1 of administration is 9000 to 50000. 32. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average peak plasma concentration (C) measured on day 1 of administration is approximately 75 to approximately 2400. max ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 33. Mean plasma 14C measured on day 1 of administration max A method according to any one of Embodiments 27 to 32, wherein the value is between 350 and 2400. 34. Mean plasma 14C measured on day 1 of administration max One of the methods from Embodiments 27 to 32, wherein the value is between 525 and 2400. 35. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average minimum plasma concentration (C) measured on day 1 of administration is approximately 20 to approximately 1000. min) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 36. Mean plasma 14C measured on day 1 of administration min One of the methods from Embodiments 27 to 35, wherein the value is between 120 and 1000. 37. Mean plasma 14C measured on day 1 of administration min One of the methods from Embodiments 27 to 35, wherein the value is between 180 and 1000. 38. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average minimum free plasma concentration (C) measured on day 1 of administration is approximately 4.0 to approximately 48.0. min free ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 39. Average C measured on day 1 of administration min free One of the methods from Embodiments 27 to 38, wherein the value is 10 to 48. 40. Average C measured on day 1 of administration min free One of the methods from Embodiments 27 to 38, wherein the value is 15 to 48. 41. A method for treating a human with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a human patient in need of treatment, which yields a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 1250 to approximately 56000 when measured on day 15 of administration. The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 42. Any one of the methods from Embodiments 27 to 41, wherein the mean plasma AUC measured on day 15 of administration is 11,000 to 56,000. 43. Any one of Embodiments 27 to 41, wherein the mean plasma AUC measured on day 15 of administration is 16,500 to 56,000. 44. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average peak plasma concentration (C) measured on day 15 of administration is approximately 90 to approximately 4000. max ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 45. Mean plasma C measured on day 15 of administration max One of the methods of Embodiments 27 to 44, wherein the value is between 700 and 4000. 46. ​​Mean plasma C measured on day 15 of administration max One of the methods from Embodiments 27 to 44, wherein the value is between 1050 and 4000. 47. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average minimum plasma concentration (C) measured on day 15 of administration is approximately 100 to approximately 2000. min ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 48. Mean plasma C measured on day 15 of administration min A method from any one of Embodiments 27 to 47, wherein the value is between 250 and 2000. 49. Mean plasma 15% C measured on day 15 of administration min One of the methods from Embodiments 27 to 47, wherein the value is between 375 and 2000. 50. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average minimum free plasma concentration (C) measured on day 15 of administration is approximately 6.0 to approximately 80.0. min free ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 51. Average C measured on day 15 of administration min free One of the methods from Embodiments 27 to 50, wherein the value is 14 to 80. 52. Average C measured on day 15 of administration min free One of the methods from Embodiments 27 to 50, wherein the value is 21 to 80. 53. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, which results in an average whole blood area under the curve (AUC) (ng·hr / mL) of approximately 25,000 to approximately 480,000 when measured on day 1 of administration. The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 54. Any one of Embodiments 27 to 53, wherein the mean whole blood AUC measured on day 1 of administration is 80,000 to 480,000. 55. Any one of Embodiments 27 to 53, wherein the mean whole blood AUC measured on day 1 of administration is 120,000 to 480,000. 56. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average peak whole blood concentration (C) measured on day 1 of administration is approximately 2000 to approximately 28000. max ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 57. Mean whole blood C12 measured on day 1 of administration max A method according to any one of Embodiments 27 to 56, wherein the value is between 4500 and 28000. 58. Mean whole blood C12 measured on day 1 of administration max A method according to any one of Embodiments 27 to 56, wherein the value is between 6750 and 28000. 59. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average minimum whole blood concentration (C) measured on day 1 of administration is approximately 500 to approximately 14400. min ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 60. Mean whole blood C12 measured on day 1 of administration min One of the methods from Embodiments 27 to 59, wherein the value is between 1800 and 14400. 61. Mean whole blood C12 measured on day 1 of administration min One of the methods from Embodiments 27 to 59, wherein the value is between 2700 and 14400. 62. A method for administering a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person requiring administration, wherein this results in an average whole blood area under the curve (AUC) (ng·hr / mL) of approximately 25,000 to approximately 800,000 when measured on day 15 of administration. The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 63. Any one of Embodiments 27 to 62, wherein the mean whole blood AUC measured on day 15 of administration is between 120,000 and 800,000. 64. Any one of Embodiments 27 to 62, wherein the mean whole blood AUC measured on day 15 of administration is between 180,000 and 800,000. 65. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average peak whole blood concentration (C) measured on day 15 of administration is approximately 3000 to approximately 56000. max ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 66. Mean whole blood C12 measured on day 15 of administration max A method according to any one of Embodiments 27 to 65, wherein the value is between 7000 and 56000. 67. Mean whole blood C12 measured on day 15 of administration max A method according to any one of Embodiments 27 to 65, wherein the value is between 10500 and 56000. 68. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average minimum whole blood concentration (C) measured on day 15 of administration is approximately 1000 to approximately 24000. min ) (ng / mL) results in The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 69. Average whole blood C min One of the methods of Embodiments 27 to 68, wherein the value is between 2600 and 24000. 70. Average whole blood C min A method from any one of Embodiments 27 to 68, wherein the value is between 3900 and 24000. 71.a) Average plasma C1.25-5 max C relative to plasma min Ratio, and / or b) mean whole blood C12 of 1.25-5 max C in whole blood min Any one of embodiments 27 to 70 further yields one of the ratios. Average plasma C72.3-72.5 max C relative to plasma min Any one of embodiments 27 to 70 further brings about the ratio. Average whole blood C7 of 73.3-75 max C in whole blood min Any one of embodiments 27 to 70 further brings about the ratio. 74. A method for treating a person with CDK2-mediated cancer, comprising administering an effective dose of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, wherein the average plasma C is less than about 5 but greater than about 1.25. max vs C min Bringing about a ratio, The pharmaceutical composition contains an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method in which the amount of INX-315 in ASD is 20% to 60% by weight. 75.C max vs C min The method of Embodiment 74, wherein the ratio is less than 3. 76.C max vs C min The method of Embodiment 74, wherein the ratio is less than 2.25. 77.C max vs. C min Any one of the methods of Embodiments 74 to 76, wherein the ratio is measured in plasma. 78.C max vs. C min Any one of the methods of Embodiments 74 to 76, wherein the ratio is measured in whole blood. 79. A t of about 5 hours to about 32 hours 1 / 2 Any one of the methods of Embodiments 27 to 78, which results in 80. A t of about 8 hours to about 28 hours 1 / 2 Any one of the methods of Embodiments 27 to 78, which results in 81. A t of about 12 hours to about 18 hours 1 / 2 Any one of the methods of Embodiments 27 to 78, which results in 82.t 1 / 2 Any one of the methods of Embodiments 79 to 81, wherein t is about 14 hours. 83.t 1 / 2 Any one of the methods of Embodiments 79 to 81, wherein t is about 15 hours. 84.t 1 / 2 Any one of the methods of Embodiments 79 to 81, wherein t is about 16 hours. 85. Any one of the methods of Embodiments 27 to 84, wherein INX-315 is administered once a day. 86. Any one of the methods of Embodiments 27 to 85, wherein INX-315 is administered orally. 87. Any one of the methods of Embodiments 28 to 86, wherein the amount of INX-315 in the ASD is about 40%. 88. Any one of the methods of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 100 mg. 89. Any one of the methods of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 125 mg. 90. Any one of the methods of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 150 mg. 91. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 175 mg. 92. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 200 mg. 93. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 225 mg. 94. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 250 mg. 95. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 275 mg. 96. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 300 mg. 97. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 325 mg. 98. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 350 mg. 99. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 375 mg. 100. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 400 mg. 101. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 425 mg. 102. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 450 mg. 103. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 475 mg. 104. Any one of Embodiments 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is approximately 500 mg. 105. Any one of Embodiments 28 to 104, wherein the pharmaceutical composition further comprises a precipitation inhibitor. 106. The method of Embodiment 105, wherein the amount of precipitation inhibitor in ASD is 40% to 70% by weight. 107. The method of Embodiment 105 or Embodiment 106, wherein the amount of precipitation inhibitor in the ASD is approximately 60% by weight. 108. Precipitation inhibitors include cellulose derivatives, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethylcellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, PVP K 30, PVP K 25, PVP VA64, or PVP One method selected from VA37, from Embodiments 105 to 107. 109. The method of Embodiment 108, wherein the precipitation inhibitor is HPMCAS. 110. Any one of Embodiments 28 to 109, wherein the pharmaceutical composition further comprises one or more additional pharmaceutically acceptable excipients. 111. A method of any one of Embodiments 27 to 110 in which a human patient has a tumor. 112. Any one of Embodiments 29 to 110, wherein the CDK2-mediated cancer is selected from bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, glioblastoma multiforme (GBM), head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, peritoneal cancer, prostate cancer, sarcoma, skin cancer, gastric cancer, and uterine cancer. 113. The method of Embodiment 112, wherein the CDK2-mediated cancer is lung cancer. 114. The method of Embodiment 113, wherein the lung cancer is small cell lung cancer (SCLC). 115. The method of Embodiment 112, wherein the CDK2-mediated cancer is breast cancer. 116. The method of Embodiment 115, wherein the breast cancer is hormone receptor-positive (HR+). 117. The method of Embodiment 115 or Embodiment 116, wherein the breast cancer is estrogen receptor positive (ER+). 118. A method according to any one of Embodiments 115 to 117, wherein the breast cancer is progesterone receptor positive (PR+). 119. A method according to any one of Embodiments 115 to 118, wherein the breast cancer is HER2-negative (HER2-). 120. The method of Embodiment 115, wherein the breast cancer is triple-negative breast cancer. 121. The method of Embodiment 112, wherein the CDK2-mediated cancer is bladder cancer. 122. The method of Embodiment 112, wherein the CDK2-mediated cancer is ovarian cancer. 123. The method of Embodiment 112, wherein the CDK2-mediated cancer is prostate cancer. 124. The method of Embodiment 112, wherein the CDK2-mediated carcinoma is a sarcoma. 125. The method of Embodiment 112, wherein the CDK2-mediated cancer is uterine cancer. 126. Any one of Embodiments 29 to 125, wherein the CDK2-mediated cancer is advanced unresectable cancer and / or metastatic cancer. 127. Any one of Embodiments 29 to 126, wherein CDK2-mediated cancer amplifies or overexpresses cyclin E. 128. The method of Embodiment 127, which uses next-generation sequencing (NGS) panel testing to confirm the state of cyclin E overexpression or amplification. 129. Any one of Embodiments 29 to 128, wherein the CDK2-mediated cancer is Rb-positive cancer. 130. The method of Embodiment 129, wherein the Rb-positive cancer is selected from Rb-positive HR+ / HER2- breast cancer, ER+ / HER2- breast cancer, high-grade serous ovarian cancer (HGSOC), non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, or glioblastoma. 131. The method of Embodiment 130, wherein the Rb-positive cancer is HR+ / HER2- breast cancer. 132. The method of Embodiment 130, wherein the Rb-positive cancer is ER+ / HER2- breast cancer. 133. The method of Embodiment 130, wherein the Rb-positive cancer is high-grade serous ovarian cancer (HGSOC). 134. The method of Embodiment 130, wherein the Rb-positive cancer is non-small cell lung cancer (NSCLC). 135. Any one of Embodiments 29 to 128, wherein the CDK2-mediated cancer is Rb-independent. 136. The method of Embodiment 135, wherein the Rb-independent cancer is selected from breast cancer, lung cancer, prostate cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, retinoblastoma, osteosarcoma, or lymphoma. 137. The method of Embodiment 135, wherein the Rb-independent cancer is selected from small cell lung cancer (SCLC), retinoblastoma, triple-negative breast cancer (TNBC), human papillomavirus (HPV)-positive head and neck cancer, HPV-positive cervical cancer, or neuroendocrine prostate cancer. 138. The method of Embodiment 137, wherein the Rb-independent cancer is SCLC. 139. The method of Embodiment 137 in which Rb-independent cancer is TNBC. 140. Any one of Embodiments 27 to 139, wherein a human has previously received at least one preceding line of chemotherapy. 141. Any one of Embodiments 27 to 140, wherein a human has previously received at least two preceding lines of chemotherapy. 142. Any one of Embodiments 27 to 141, wherein a human has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. 143. Any one of Embodiments 27 to 142, wherein a human has previously received at least one preceding line of endocrine therapy. 144. A method for which CDK2-mediated cancer is recurrent, any one of Embodiments 27 to 143. 145. Any one of Embodiments 27 to 144, wherein CDK2-mediated cancer is resistant to CDK4 / 6 inhibitors. 146. A method for any one of Embodiments 27 to 145 in which CDK2-mediated cancer has progressed after a prior regimen including endocrine therapy. 147. Any one of Embodiments 27 to 146 for a CDK2-mediated cancer that is resistant to endocrine therapy. 148. Any one of Embodiments 27 to 147, wherein the treatment results in a reduction in the incidence of treatment-emergent adverse events compared to the predicted incidence of treatment-emergent adverse events in subjects receiving CDK2 treatment other than INX-315. 149. Any one of Embodiments 27 to 148, wherein the treatment results in a reduction in the incidence of abnormal clinical laboratory values ​​compared to the predicted incidence of abnormal clinical laboratory values ​​in subjects receiving CDK2 treatment other than INX-315. 150. Any one of Embodiments 27 to 149, wherein the treatment results in improved overall survival (OS) compared to the predicted overall survival (OS) in subjects receiving CDK2 treatment other than INX-315. 151. Any one of Embodiments 27 to 150, wherein the treatment results in an improved overall response rate (ORR) compared to the predicted overall response rate (ORR) in subjects receiving CDK2 therapy other than INX-315. 152. Any one of Embodiments 27 to 151, wherein the treatment results in an improved disease control rate (DCR) compared to the predicted disease control rate (DCR) in subjects receiving CDK2 treatment other than INX-315. 153. Any one of Embodiments 27 to 152, wherein the treatment results in improved progression-free survival (PFS) compared to the predicted PFS in subjects receiving CDK2 treatment other than INX-315. 154. Any one of Embodiments 27 to 153, wherein the treatment results in an improved duration of response (DOR) compared to the predicted duration of response (DOR) in subjects receiving CDK2 treatment other than INX-315. 155. Any one of Embodiments 27 to 154, wherein the treatment results in an extension of the time to progression (TTP) compared to the time to progression (TTP) in subjects receiving CDK2 therapy other than INX-315. 156. Any one of Embodiments 148 to 155, wherein CDK2 treatment other than INX-315 includes the administration of a CDK2 inhibitor selected from BLU-222 or PF-07104091. 157. The method of Embodiment 156, wherein the CDK2 inhibitor is BLU-222. 158. The method of Embodiment 156, wherein the CDK2 inhibitor is PF-07104091. 159. Any one of Embodiments 148 to 158, wherein a CDK2 inhibitor other than INX-315 is administered at the same dose and frequency as INX-315. 160. A process for producing any one of Embodiments 1 to 26 of a pharmaceutical composition, (i) A solution containing INX-315 or a pharmaceutically acceptable salt thereof and a precipitation inhibitor is spray-dried to obtain an amorphous spray-dried dispersion (ASD), (ii) To provide granules by granulating ASD together with one or more pharmaceutically acceptable excipients, (iii) Dry mixing of the granules with one or more additional pharmaceutically acceptable excipients, (iv) Tablet compression of dry-mixed granules, A process that includes this. 161. The process of Embodiment 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of approximately 100 mg to approximately 500 mg. 162. The process of Embodiment 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of approximately 100 mg. 163. The process of Embodiment 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of approximately 200 mg. 164. The process of Embodiment 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of approximately 300 mg. 165. The process of Embodiment 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of approximately 400 mg. [Brief explanation of the drawing]

[0040] [Figure 1A] This graph shows the plasma INX-315 concentration measured on day 1 (circles) and day 15 (squares) after oral administration of 100 mg of INX-315 once daily (QD). The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 1B] This graph shows the results of measuring the free concentration of unbound INX-315 from plasma proteins obtained after oral administration of 100 mg of INX-315 once daily (QD) on day 1 (circles) and day 15 (squares). The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the free concentration of INX-315 in plasma, measured in nanograms per milliliter (ng / mL). [Figure 2] This graph compares the plasma concentration of INX-315 (round) administered once daily (QD) at 100 mg with the concentration of the commercial CDK2 inhibitor BLU-222 (triangle) administered twice daily (BID) at 50 mg, 100 mg, 200 mg, 400 mg, or 600 mg. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the plasma concentration of INX-315 or BLU-222 measured in nanograms per milliliter (ng / mL). [Figure 3]This graph shows the plasma concentrations of INX-315 (round) administered once daily (QD) at 100 mg, and the commercial CDK2 inhibitor PF-07104091 (triangle) administered twice daily (BID) at 75 mg, 150 mg, 225 mg, 300 mg, or 500 mg, after 15 consecutive days of administration. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the plasma concentration of INX-315 or PF-07104091, measured in nanograms per milliliter (ng / mL). [Figure 4] This graph shows the results of measuring the INX-315 concentration in whole blood obtained after oral administration of 100 mg of INX-315 once daily (QD) on day 1 (d1) and day 15 (d15). The x-axis represents the time since the start of administration measured in hours, and the y-axis represents the INX-315 concentration in whole blood measured in nanograms per milliliter (ng / mL). [Figure 5A] This is an SEM image of the INX-315 free base described in Example 3. [Figure 5B] This is an SEM image of the INX-315 free base described in Example 3. [Figure 5C] This is an SEM image of the INX-315 free base described in Example 3. [Figure 6A] This is an SEM image of the INX-315 HCl salt described in Example 3. [Figure 6B] This is an SEM image of the INX-315 HCl salt described in Example 3. [Figure 6C] This is an SEM image of the INX-315 HCl salt described in Example 3. [Figure 7] This figure shows the micelle distribution of the free INX-315 drug described in Example 3. The x-axis shows the volume fraction of micelles (Vm), and the y-axis shows the Dt / Df ratio. [Figure 8A] This figure shows the setup for the non-sink dissolution method described in Example 3. [Figure 8B]This figure shows the results of a non-sink dissolution method in which samples of free INX-315 and spray-dried INX-315 amorphous solid dispersion formulations described in Example 3 were microcentrifuged at various time lengths shown on the x-axis, and the total INX-315 drug concentration shown on the y-axis was measured. [Figure 8C] This figure shows the results of a non-sink dissolution method in which samples of free INX-315 and spray-dried INX-315 amorphous solid dispersion formulations described in Example 3 were ultracentrifuged at various time lengths shown on the x-axis, and the dissolved INX-315 drug concentration shown on the y-axis was measured. [Figure 9A] This is a differential scanning calorimetry (DSC) thermogram of the INX-315 during the initial scan (before quenching), with temperature on the x-axis and normalized heat flow (W / g) on ​​the y-axis. The DSC thermogram was obtained as described in Example 3. [Figure 9B] This is a differential scanning calorimetry (DSC) thermogram of the INX-315 during the second scan (after quenching), showing normalized reversible heat flow and normalized irreversible heat flow. The x-axis represents temperature, and the y-axis represents normalized heat flow (W / g). The DSC thermogram was obtained as described in Example 3. [Figure 10A] This is an SEM image of the 25% INX-315:HPMCAS-H spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 10B] This is an SEM image of the 25% INX-315:HPMCAS-H spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 11A] This is an SEM image of the 40% INX-315:HPMCAS-H spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 11B] This is an SEM image of the 40% INX-315:HPMCAS-H spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 12A] This is an SEM image of the 25% INX-315:HPMCAS-M spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 12B] This is an SEM image of the 25% INX-315:HPMCAS-M spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 13A] This is an SEM image of the 40% INX-315:HPMC-E3 spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 13B] This is an SEM image of the 40% INX-315:HPMC-E3 spray-dried amorphous solid dispersion formulation described in Example 3. [Figure 14] This is a powder X-ray diffraction (PXRD) diffractogram plot of various spray-dried INX-315 amorphous solid dispersion formulations described in Example 3. [Figure 15A] This graph shows the body weight measurements for the six treatment groups in Cohort 1 described in Example 5. The y-axis represents the body weight (mean value plus or minus standard error) measured over time on the x-axis, corresponding to the number of test days, in grams (g). The term "mpk" refers to milligrams per kilogram (mg / kg). [Figure 15B] This graph shows the body weight measurements for the six treatment groups in Cohort 2 described in Example 5. The y-axis represents the body weight (mean value plus or minus standard error) measured over time on the x-axis, corresponding to the number of test days, in grams (g). The term "mpk" refers to milligrams per kilogram (mg / kg). [Figure 15C] This graph shows the tumor volume measurements for the six treatment groups in Cohort 1 described in Example 5. The y-axis represents the mean tumor volume (standard error plus or minus of the sample) measured over time, as measured on the x-axis (test days), in cubic millimeters (mm3). The term "mpk" refers to milligrams per kilogram (mg / kg). [Figure 15D] This graph shows the tumor volume measurements for the six treatment groups in Cohort 2 described in Example 5. The y-axis represents the mean tumor volume (standard error plus or minus of the sample) measured over time, corresponding to the number of test days on the x-axis, in cubic millimeters (mm3). The term "mpk" refers to milligrams per kilogram (mg / kg). [Figure 16A]This graph shows the body weight measurements for the various treatment groups described in Example 6. The y-axis represents the body weight (standard deviation plus or minus) measured in grams (g) over time, corresponding to the number of test days on the x-axis. [Figure 16B] This graph shows the tumor volume measurements for the various treatment groups described in Example 6. The y-axis represents the average tumor volume (standard error plus or minus the mean value) measured in cubic millimeters (mm3) over time, corresponding to the number of test days on the x-axis. [Figure 17A] As described in Example 7, this graph shows the whole blood INX-315 concentration obtained from oral administration of 100 mg of INX-315 once daily (QD) on day 1 for six individual subjects in Cohort 1. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the whole blood INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 17B] As described in Example 7, this graph shows the whole blood INX-315 concentration obtained from oral administration of 100 mg of INX-315 once daily (QD) on day 15 for six individual subjects in Cohort 1. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the whole blood INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 17C] As described in Example 7, this graph shows the plasma INX-315 concentrations obtained from oral administration of 100 mg of INX-315 once daily (QD) on day 1 for six individual subjects in Cohort 1. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 17D]As described in Example 7, this graph shows the plasma INX-315 concentrations obtained from oral administration of 100 mg of INX-315 once daily (QD) on day 15 for six individual subjects in Cohort 1. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 17E] As described in Example 7, this graph shows the whole blood and plasma concentrations of INX-315 obtained from oral administration of 100 mg of INX-315 once daily (QD) on days 1 and 15, separately for each of the six subjects in Cohort 1. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the INX-315 concentration in either whole blood or plasma, measured in nanograms per milliliter (ng / mL). [Figure 18A] This graph shows the plasma concentrations of INX-315 administered once daily (QD) at doses of 100 mg (gray) versus 200 mg (black), as described in Example 8. The x-axis represents the time since the start of administration, measured in hours, and the y-axis represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 18B] This graph shows the plasma concentrations of INX-315 administered once daily (QD) at doses of 100 mg (gray) versus 200 mg (black), as described in Example 8. The x-axis represents time points indicated by cycle numbers (C#) and day numbers (D#) starting from C1D1, and the y-axis represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 18C] This graph shows the plasma free concentrations of INX-315 administered once daily (QD) at doses of 100 mg (gray) versus 200 mg (black), as described in Example 8. The x-axis represents days 1 and 7, and the y-axis represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). [Figure 19A]This graph shows the preliminary plasma INX-315 concentration-time profile for Cohort 1 (100 mg QD) described in Example 10. The x-axis represents the time after dose administration on day 1 (black line) and day 15 (gray line) in hours (h). The y-axis is a linear scale and represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). The dose is shown in the top header row, and the subject ID is shown in the second header row. [Figure 19B] This graph shows the preliminary plasma INX-315 concentration-time profile for Cohort 1 (100 mg QD) described in Example 10. The x-axis represents the time after dose administration on day 1 (black line) and day 15 (gray line) in hours (h). The y-axis is on a logarithmic scale and represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). The dose is shown in the top header row, and the subject ID is shown in the second header row. [Figure 19C] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for Cohort 1 (100 mg QD) on day 1 after administration, as described in Example 10. The gray lines represent individual concentration-time profiles, and the solid black line represents the mean concentration-time profile for the entire cohort. [Figure 19D] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for Cohort 1 (100 mg QD) on day 15 after administration, as described in Example 10. The gray lines represent individual concentration-time profiles, and the solid black line represents the mean ± SD concentration-time profile for the entire cohort. [Figure 20A] This graph shows the preliminary plasma INX-315 concentration-time profile for Cohort 2 (200 mg QD) described in Example 10. The x-axis represents the time after dose administration on day 1 (black line) and day 15 (gray line) in hours (h). The y-axis is a linear scale and represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). The dose is shown in the top header row, and the subject ID is shown in the second header row. [Figure 20B]This graph shows the preliminary plasma INX-315 concentration-time profile for Cohort 2 (200 mg QD) described in Example 10. The x-axis represents the time after dose administration on day 1 (black line) and day 15 (gray line) in hours (h). The y-axis is on a logarithmic scale and represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). The dose is shown in the top header row, and the subject ID is shown in the second header row. [Figure 20C] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for Cohort 2 (200 mg QD) on day 1 after administration, as described in Example 10. The gray lines represent individual concentration-time profiles, and the solid black line represents the mean concentration-time profile for the entire cohort. [Figure 20D] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for Cohort 2 (200 mg QD) on day 15 after administration, as described in Example 10. The gray lines represent individual concentration-time profiles, and the solid black line represents the mean concentration-time profile for the entire cohort. [Figure 21A] This graph shows the preliminary plasma INX-315 concentration-time profile for Cohort 3 (300 mg QD) described in Example 10. The x-axis represents the time after dose administration in hours (h) on day 1 (black line) and day 15 (gray line). The y-axis is a linear scale and represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). The dose is shown in the top header row, and the subject ID is shown in the second header row. [Figure 21B] This graph shows the preliminary plasma INX-315 concentration-time profile for Cohort 3 (300 mg QD) described in Example 10. The x-axis represents the time after dose administration on day 1 (black line) and day 15 (gray line) in hours (h). The y-axis is on a logarithmic scale and represents the plasma INX-315 concentration measured in nanograms per milliliter (ng / mL). The dose is shown in the top header row, and the subject ID is shown in the second header row. [Figure 21C]This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for Cohort 3 (300 mg QD) on day 1 after administration, as described in Example 10. The gray lines represent individual concentration-time profiles, and the solid black line represents the mean concentration-time profile for the entire cohort. [Figure 21D] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for Cohort 3 (300 mg QD) on day 15 after administration, as described in Example 10. The gray lines represent individual concentration-time profiles, and the solid black line represents the mean concentration-time profile for the entire cohort. [Figure 22A] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for the entire cohort on day 1 after administration, as described in Example 10. The dotted lines represent the individual concentration-time profiles. The solid lines represent the mean ± SD concentration-time profiles for Cohort 1 (black line), Cohort 2 (dark gray line), and Cohort 3 (light gray line). [Figure 22B] This graph shows the individual and mean (SD) plasma INX-315 concentration-time profiles for the entire cohort 15 days after administration, as described in Example 10. The dotted lines represent individual concentration-time profiles. The solid lines represent the mean ± SD concentration-time profiles for Cohort 1 (black line) and Cohort 2 (dark gray line), and the median concentration-time profile for Cohort 3 (light gray line). [Figure 23] This is a diagram showing the chemical structure of INX-315. [Modes for carrying out the invention]

[0041] As a result of the initial administration of INX-315 to humans, it was surprisingly discovered that this compound has a unique and highly unexpected pharmacokinetic profile that does not significantly agree with predictive mathematical pharmacokinetic models extrapolated from other mammalian species (dogs, rats, and mice). While we do not wish to be bound by any single theory, it is proposed that INX-315 binds to human blood cells in vivo to a much higher degree than observed in other tested mammals and than predicted from these other mammalian models, thereby increasing the amount of drug available in the blood and creating a depot effect for sustained drug availability as the drug is released over time from red blood cells into the plasma and then to the site of treatment.

[0042] Surprisingly, INX-315 was also found to be effective in treating Rb-independent (i.e., Rb-negative) cancers. This specification shows that the CDK2 inhibitor INX-315 can be used in effective doses to treat Rb-independent cancers, including but not limited to Rb-independent small cell lung cancer (SCLC) (see, for example, Figures 15C and 15D). Other Rb-independent tumors include Rb-independent triple-negative breast cancer (TNBC), prostate cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, retinoblastoma, osteosarcoma, or lymphoma.

[0043] This discovery represents an advance in the field of cancer therapy technology by providing a CDK2 inhibitor useful for treating both Rb-dependent and Rb-independent tumors (which may include heterogeneous tumors of both types). In some embodiments, INX-315 is administered in combination with a CDK4 / 6 inhibitor, including but not limited to ribociclib (Novartis), abemaciclib (Eli Lilly), palbociclib (Pfizer Inc.), or rerocyclib (G1 Therapeutics, Inc.). In some embodiments, INX-315 is administered daily, and the CDK4 / 6 inhibitor is administered for 21 days, typically within a 28-day cycle, with a 7-day rest period. In some embodiments, INX-315 is administered daily, and the CDK4 / 6 inhibitor is administered continuously.

[0044] According to the present invention, INX-315 can be used to treat tumors having intact and functional retinoblastoma protein (Rb-positive). In some embodiments, the Rb-positive cancer is selected from Rb-positive HR+ / HER2-breast cancer, ER+ / HER2-breast cancer, high-grade serous ovarian cancer (HGSOC), non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, or glioblastoma. In some embodiments, the Rb-positive cancer is HR+ / HER2-breast cancer. In some embodiments, the Rb-positive cancer is ER+ / HER2-breast cancer. In some embodiments, the Rb-positive cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, the Rb-positive cancer is non-small cell lung cancer (NSCLC). In some embodiments, INX-315 or its pharmaceutically acceptable salts or ASD formulations described herein provide an additive or synergistic effect on the anticancer or antiproliferative activity of an additional therapeutic agent for the treatment of Rb-positive cancer. In some embodiments, the additional therapeutic agent is selected from CDK4 / 6 inhibitors, endocrine therapies, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example, Figures 15C and 15D and Figure 16B). In some embodiments, the additional therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocyclib, or darpiciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Pfizer Inc.). In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Novartis). In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is rerocyclib (G1 Therapeutics, Inc.).

[0045] Unexpectedly, it was also discovered that INX-315 can effectively treat Rb-independent cancers (see, for example, Figures 15C and 15D). In some embodiments, Rb-independent cancers are selected from small cell lung cancer (SCLC), retinoblastoma, triple-negative breast cancer (TNBC), human papillomavirus (HPV)-positive head and neck cancer, HPV-positive cervical cancer, or bladder cancer. In some embodiments, the Rb-independent cancer is SCLC. In some embodiments, the Rb-independent cancer is TNBC. In some embodiments, the Rb-independent cancer is bladder cancer. In some embodiments, INX-315 or its pharmaceutically acceptable salts or ASD formulations described herein provide additive or synergistic effects on the anticancer or antiproliferative activity of additional therapeutic agents for the treatment of Rb-independent cancers. In some embodiments, the additional therapeutic agent is selected from CDK4 / 6 inhibitors, endocrine therapies, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example, Figures 15C and 15D and Figure 16B). In some embodiments, the additional therapeutic agent is a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocyclib, or darpiciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib (Pfizer Inc.). In some embodiments, the CDK4 / 6 inhibitor is ribociclib (Novartis). In some embodiments, the CDK4 / 6 inhibitor is abemaciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is rerocyclib (G1 Therapeutics, Inc.).

[0046] It is also quite unexpected that administration of INX-315 does not result in the initial drug concentration spike often seen with other drugs such as BLU-222 and PF-07104091. The spike effect is due to a large initial C at the start. max vs C min This is shown by a ratio, which decays after administration (see Figures 2 and 3). Conversely, C max vs C minA small ratio indicates the absence of spikes. C in the first two humans who received 100 mg of INX-315 once daily. max vs C min The ratio was measured at approximately 2.2, compared to the estimated C of BLU-222 (400 mg twice daily) based on published human results. max vs C min The ratio was 9.3, while it was 22 for BLU-222 (600 mg twice daily). Similarly, the estimated C for PF-07104091 max vs C min The ratio ranged from 16 to 64 based on publicly available human data (see Table 5 and Figures 2 and 3). The presence of spikes during administration indicates a short-term excess of drug in the bloodstream, which can lead to side effects and is generally undesirable.

[0047] It was surprisingly and unexpectedly discovered that administration of INX-315 or a pharmaceutically acceptable salt thereof provides particularly improved plasma and whole blood pharmacokinetic parameters compared to values ​​predicted based on non-human preclinical model studies. In some embodiments, cancers amplify or overexpress cyclin E and are resistant to CDK4 / 6 inhibitors via either acquired resistance or endogenous resistance (e.g., SCLC) (see, e.g., Figures 15C and 15D) (see, e.g., Figure 16B), and / or resistant to endocrine therapies such as estrogen receptor degraders. Dosage regimes comprising administration of INX-315 or a pharmaceutically acceptable salt thereof as described herein can be used to treat Rb-positive cancers and Rb-independent cancers such as SCLC (see, e.g., Figures 15C and 15D). The improved dosage regimes described herein can be used to treat difficult-to-treat cyclin E-amplifying cancers, including CCNE1-amplified unresectable solid tumors and CCNE1-amplified platinum-resistant or platinum-refractory cancers. Non-limiting examples of the favorable properties demonstrated by the dosing regimes including the administration of INX-315 described herein include improved area under the curve (AUC) (ng·hr / mL) and mean peak concentration (C) compared to those predicted based on non-human mammalian preclinical models. max(ng / mL) value, improved average minimum concentration (C min (ng / mL) value, improved mean minimum free plasma concentration (C min free ) (ng / mL) value, and improved C max vs C min The ratio can be cited. These improved PK profiles, compared to CDK2 inhibitors in clinical development, show extended duration of concentrations above the therapeutic threshold, superior exposure profile, and half-life (t 1 / 2 This provides an extension of the on-target drug activity and a reduction in off-target activity. Sustained steady-state levels of INX-315 in plasma lead to sustained on-target drug activity and a tumor microenvironment favorable to resensitizing tumors to other therapeutic agents, including but not limited to CDK4 / 6 inhibitors, endocrine therapies such as SERD, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, e.g., Figures 15C and 15D and 16B). This improvement represents a significant advance in the technological level of cancer treatment.

[0048] As described herein, INX-315 is highly insoluble in water (Table 12), and free INX-315 is crystalline (Figures 5A-6C). It has been found that INX-315 can be mixed with a polymeric precipitation inhibitor in a solvent to produce advantageous amorphous spray-dried dispersion (ASD) formulations. The precipitation inhibitor minimizes crystallization of INX-315 in the ASD formulation. In non-limiting embodiments, the solvent is a mixture of THF and water, e.g., 90% THF and 10% water (see, e.g., Table 20). In some embodiments, the solvent is a mixture of THF and water, e.g., 92% THF and 8% water (see, e.g., Table 33). In some embodiments, THF is stabilized with butylated hydroxytoluene (BHT). As a non-limiting example of Example 3, the INX-315 ASD formulation disperses INX-315 throughout a polymer matrix (e.g., a precipitation inhibitor such as HPMCAS), and high T g and low T m / T g As shown by the ratio, crystallization of INX-315 in the ASD formulation is prevented (Figures 9A and 9B).

[0049] In some embodiments, amorphous INX-315 is included in an amount of about 20% to about 50% by weight of ASD, for example, in the range of about 25% to about 45% by weight of ASD, or for example, in an amount of about 40% by weight of ASD (Tables 17 and 20). In some embodiments, INX-315 is spray-dried together with a precipitation inhibitor, for example, but not limited to hydroxypropyl methylcellulose acetate succinate-high substitution (HPMCAS-HG), or other precipitation inhibitors further described herein. The precipitation inhibitor may be included in an amount of about 50% to about 70% by weight of ASD, for example, in the range of about 55% to about 65% by weight of ASD, or for example, in an amount of about 60% by weight of ASD (Tables 17 and 20).

[0050] In further embodiments, advantageous pharmaceutical compositions comprising ASD formulations added together with one or more additional pharmaceutically acceptable excipients are described herein. As a non-limiting example of Example 4, the INX-315 ASD formulation is dry-granulated, dry-mixed, and then tableted together with one or more additional pharmaceutically acceptable excipients, including but not limited to microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silicon dioxide, and stearyl fumarate sodium, to produce a pharmaceutical composition to be administered to a subject requiring it (Tables 21 and 23).

[0051] In some embodiments, amorphous INX-315 is included in the pharmaceutical composition in an amount ranging from about 10% to about 30% by weight, or from about 15% to about 35% by weight, or, for example, about 20% by weight (Tables 17 and 20). Precipitation inhibitors may be included in an amount ranging from about 20% to about 50% by weight, or from about 25% to about 45% by weight, or, for example, about 30% by weight (Tables 17 and 20).

[0052] term Unless otherwise specified, all technical and scientific terms used herein have the same meaning as those generally understood by those skilled in the art to which the present invention pertains. The present invention can be carried out using methods and materials similar to or equivalent to those described herein, but preferred methods and materials are described below. All publications, patent applications, patents, and other references referenced herein constitute part of this specification by citation. In the event of any conflict, this specification shall prevail, including definitions. Furthermore, materials, methods, and examples are for illustrative purposes only and are not intended to limit the scope of the invention.

[0053] The terms "a" and "an" do not indicate a limitation of quantity, but rather indicate the presence of at least one of the items mentioned. The term "or" means "and / or". Unless otherwise specified herein, the enumeration of value ranges is intended to serve merely as a simple way to refer individually to each distinct value contained within that range, and each distinct value constitutes part of this specification as if they were individually enumerated herein. The endpoints of all ranges are contained within that range and can be combined independently. All methods described herein can be performed in a preferred order unless otherwise specified herein or clearly rejected by the context. The use of example or illustrative words (e.g., "such as") is intended merely to better illustrate the invention and does not indicate a limitation of the scope of the invention unless otherwise asserted. Unless otherwise specified, the technical and scientific terms used herein have the same meanings as commonly understood by those skilled in the art to which the invention pertains.

[0054] In certain embodiments, the term "approximately" means ±10%.

[0055] The “patient,” “subject,” or “participant” being treated is typically a human patient unless otherwise specified. In alternative embodiments, the methods described herein may be used to treat or test mammals, such as those used in preclinical studies, including, for example, mice, rats, monkeys, dogs, pigs, and rabbits, as well as other similarly responsive animals, such as domestic pigs (pigs and hogs), ruminants, horses, poultry, felines, cattle, mice, and dogs.

[0056] As used herein, “effective dose” means the amount that produces a therapeutic benefit.

[0057] As used herein, the term “mean” is synonymous with the average value, for example, the middle numerical point in a set of values. In some embodiments, a skewed distribution is assumed for the PK parameter (e.g., C max Regarding AUC, the mean refers to the geometric mean, taking into account the combined effects.

[0058] As used herein, the term "adverse event occurring under treatment" means an adverse event that occurs or worsens after the initial dose or during treatment.

[0059] As used herein, the term "overall survival (OS)" means the time from the first dose of medication to death from any cause.

[0060] As used herein, the term "overall response rate (ORR)" means that the best overall response, whether complete response (CR) or partial response (PR), is confirmed to be as determined by the RECIST v1.1 criteria.

[0061] As used herein, the term "disease control rate (DCR)" means that the best overall response is confirmed to be complete response (CR), partial response (PR), or stable disease (SD), as determined by the RECIST v1.1 criteria.

[0062] As used herein, the term “progression-free survival (PFS)” means the period from the first dose of medication to the first recorded occurrence of disease progression or death from any cause, whichever comes first.

[0063] As used herein, the term “DOR (Duration of Response)” means the time from the first recorded instance of the best overall response (CR) or PR to the first recorded instance of disease progression or death from any cause, whichever comes first.

[0064] As used herein, the term “time to progression (TTP)” means the time from the first dose of medication to the first recorded progression of the disease.

[0065] As used herein, the term "MTD" refers to the maximum tolerated dose of a compound, for example, INX-315.

[0066] As used herein, the term "AUC" refers to the area under the concentration-time curve of a compound in whole blood or plasma.

[0067] When used herein, "AUC" 0-t " or "AUC last The term "AUC" refers to the AUC of a compound, such as INX-315, up to the last measurable concentration point.

[0068] When used herein, "AUC" 0-∞ The term "AUC" refers to the AUC of a compound, such as INX-315, up to infinite time.

[0069] As used herein, the term "Cl" refers to the clearance of a compound, such as INX-315.

[0070] When used herein, "C max The term "highest concentration" refers to the highest concentration of a compound, such as INX-315, in whole blood or plasma.

[0071] When used herein, "C last The term "last quantifiable concentration" refers to the last quantifiable concentration of a compound, such as INX-315, in whole blood or plasma.

[0072] When used herein, "IC" 50 The term "IC" refers to the median inhibitory concentration of a compound, such as INX-315. IC is a measure of the potency of a drug. 50 This indicates the concentration of the target compound that inhibits a specific biological process by half compared to the control compound.

[0073] When used herein, "t 1 / 2 The term "half-life" refers to the half-life of a compound, such as INX-315.

[0074] When used herein, "t max The term "compounds in whole blood or plasma, compounds such as INX-315 C" refers to compounds in whole blood or plasma. max This refers to the time it takes to reach a certain point.

[0075] When used herein, "t last The term "time" refers to the time it takes for a compound, such as INX-315, to reach its final measurable concentration.

[0076] As used herein, the term “precipitation inhibitor” refers to a polymer used in amorphous spray-dried dispersion (ASD) formulations to increase the solubility of INX-315 in the ASD formulation and / or to prevent crystallization of INX-315 in the ASD formulation. Non-limiting examples of precipitation inhibitors include, but are not limited to, hydroxypropyl methylcellulose, e.g., HPMCAS, or other agents further described herein.

[0077] As used herein, “intrinsic resistance” is also known as primary resistance and refers to a condition in which cancer does not respond, or does not respond adequately, to the inhibitory effects of initial anticancer treatment, not limited to, for example, CDK4 / 6 inhibitor therapy or endocrine therapy. In some embodiments of the treatment methods described herein, the treated cancer exhibits intrinsic resistance to CDK4 / 6 inhibitors. Examples of mutations and conditions associated with intrinsic resistance to CDK4 / 6 inhibitors include, but are not limited to, increased activity of cyclin-dependent kinase 1 (CDK1); increased activity of cyclin-dependent kinase 2 (CDK2); loss, deficiency, or absence (Rb null) of retinoblastoma tumor suppressor protein (Rb); high levels of p16Ink4a expression; high levels of MYC expression; increased expression of cyclin E1, cyclin E2, and cyclin A; and combinations thereof. Cancers that are intrinsically resistant to CDK4 / 6 inhibitors may be characterized by reduced expression of retinoblastoma tumor suppressor proteins or retinoblastoma family member proteins (one or more) (but not limited to p107 and p130). In certain embodiments, a tumor or cancer that is intrinsically resistant to selective CDK4 / 6 inhibitor inhibition is a tumor or cancer whose cell population as a whole does not experience substantial G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor. In certain embodiments, a tumor or cancer that is intrinsically resistant to CDK4 / 6 inhibitor inhibition is a tumor or cancer having a cell population in which less than 25%, 20%, 15%, 10%, or 5% of its cells experience G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor. In some alternative embodiments of the therapeutic methods described herein, the cancer being treated is intrinsically resistant to endocrine therapy, estrogen inhibitor therapy such as SERD. In some alternative embodiments of the treatment methods described herein, the cancer being treated is intrinsically resistant to the therapeutic agent or other anticancer therapies.

[0078] As used herein, “acquired resistance” refers to a condition in which cancer that was initially sensitive to or is sensitive to the inhibitory effects of anticancer therapy becomes unresponsive or less responsive to the effects of the administration of that anticancer therapy over time. In some embodiments of the methods described herein, the treated cancer has acquired resistance to selective CDK4 / 6 inhibitors. While we do not wish to be bound by any theory, acquired resistance to CDK4 / 6 inhibitors is thought to result from one or more additional mutations or genetic alterations in bypass signaling that occur after the initiation of a CDK4 / 6 inhibitor treatment regimen. For example, non-exclusive exemplary causes of acquired resistance to CDK4 / 6 inhibitors may be the result of the expression of one or more genetic abnormalities associated with “endogenous resistance.” Furthermore, other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors include increased cyclin E expression; CCNE1 / 2 amplification; E2F amplification; CDK2 amplification; CDK6 amplification; CDK4 amplification; p16 amplification; WEE1 overexpression; MDM2 overexpression; CDK7 overexpression; FZR1 deficiency; HDAC activation; FGFR pathway activation; PI3K / AKT / mTOR pathway activation; loss of ER or PR expression; increased AP-1 transcriptional activity; epithelial-mesenchymal transition; Smad3 suppression; autophagy activation; Rb1 deficiency or inactivated RB1 mutation; or combinations thereof. A review of CDK4 / 6 resistance mechanisms can be found, for example, in Pandey et al., Molecular mechanisms of resistance to CDK4 / 6 inhibitors in breast cancer: A review. Int. J. Cancer:00,1-10 (2019), which is incorporated herein by reference. In some embodiments, a tumor or cancer that has acquired resistance to selective CDK4 / 6 inhibitor inhibition is a tumor or cancer in which the cell population as a whole no longer experiences substantial G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, resulting in disease progression.In some embodiments, a tumor or cancer that has acquired resistance to CDK4 / 6 inhibitor inhibition is a tumor or cancer having a cell population in which 50%, 40%, 30%, 20%, 15%, 10%, or less than 5% of its cells experience G1 cell cycle arrest upon exposure to a selective CDK4 / 6 inhibitor, leading to disease progression. In some embodiments, the cancer has progressed after a prior treatment regimen including administration of a CDK4 / 6 inhibitor. In some alternative embodiments of the treatment methods described herein, the cancer being treated has acquired resistance to estrogen inhibitor therapy, such as SERD, for example, fulvestrant or elastrant, for example, but not limited to. In some alternative embodiments of the treatment methods described herein, the cancer being treated has acquired resistance to further anticancer therapy.

[0079] The retinoblastoma susceptibility gene (RB1) was the first molecularly defined tumor suppressor gene. The protein encoded by RB1, retinoblastoma protein (Rb), is frequently mutated or deleted in retinoblastoma and osteosarcoma, and is also mutated or deleted in various ways in several other specific tumors or cancer types, including but not limited to prostate cancer, neuroendocrine prostate cancer, breast cancer, triple-negative breast cancer (TNBC), lung cancer, small cell lung cancer (SCLC), liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, and lymphoma. In some cancers, Rb may be neutralized by binding partners such as the human papillomavirus-E7 protein in cervical cancer (Ishiji, T. J Dermatol. 27:73-86 (2000)) or through dysregulation of the Rb pathway.

[0080] The term "Rb pathway" refers to the entire molecular signaling pathway that includes retinoblastoma protein (Rb) and other proteins and protein families in the pathway, including but not limited to CDK2, CDK4, CDK6, E2f, atypical protein kinase C, and Skp2.

[0081] The terms “Rb-plus,” “Rb+,” “Rb-proficient,” “Rb-dependent,” or “Rb-positive” refer to certain types of cells, tumors, or cancers in which functional Rb is expressed in detectable amounts. In some embodiments, Rb-positive cells, tumors, or cancers include cells, tumors, or cancers containing a functional RB1 gene. In some embodiments, Rb-positive cells, tumors, or cancers include cells, tumors, or cancers encoding a functional Rb protein. In some embodiments, Rb-positive cells, tumors, or cancers include cells, tumors, or cancers expressing detectable amounts of RB1 or Rb.

[0082] The presence or normal function of retinoblastoma (Rb) tumor suppressor protein (Rb-positive) can be determined via any of the standard assays known to those skilled in the art, including but not limited to Western blotting, ELISA (enzyme-linked immunosorbent assay), IHC (immunohistochemistry), and FACS (fluorescence-activated cell sorting). The choice of assay depends on the tissue, cell line, or surrogate tissue sample used; for example, Western blotting and ELISA can be used with any or all types of tissues, cell lines, or surrogate tissues, while IHC would be more appropriate if the tissue used in the method of the present invention was tumor biopsy material. FACS analysis would be most applicable to samples that were cell lines and single-cell suspensions such as isolated peripheral blood mononuclear cells. See, for example, U.S. Patent Application Publication No. 20070212736, “Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer.” Alternatively, molecular genetic testing may be used to determine the status of the retinoblastoma gene. Molecular genetic testing for retinoblastoma includes those described in Lohmann and Gallie, "Retinoblastoma. Gene Reviews" (2010), or Parsam et al., "A comprehensive, sensitive and economical approach for the detection of mutations in the RB1 gene in retinoblastoma," Journal of Genetics, 88(4), 517-527 (2009).

[0083] The terms “Rb-independent,” “Rb-negative,” “Rb-deficient,” “Rb-minus,” “Rb-null,” or “Rb-” refer to certain types of cells, tumors, or cancers in which the function of Rb is disrupted, and in some cases include cells, tumors, or cancers in which Rb is deleted or absent in undetectable amounts of Rb. In some embodiments, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers that do not contain a functional RB1 gene. In some embodiments, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers that encode a dysfunctional Rb protein. In some embodiments, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers that are deficient in Rb. In some embodiments, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers characterized by loss-of-function mutations in RB1, which may include missense mutations (i.e., encoding incorrect amino acids) or nonsense mutations (i.e., encoding stop codons). In some embodiments, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers characterized by the deletion of all or part of the RB1 gene.

[0084] INX-315 Dosing Regimes The inventions described herein provide a method for treating human patients in need of treatment, for example, human patients having CDK2-mediated cancers including but not limited to hormone receptor-positive (HR+), HER2- breast cancer, ovarian cancer, or small cell lung cancer (SCLC), the method comprising the administration of INX-315 or a pharmaceutically acceptable salt thereof, which provides a plasma and whole blood profile range of INX-315 in humans. In another embodiment, the invention comprises administering INX-315 to human patients having CDK2-mediated cancers that are sensitive to CDK2 inhibitors. In yet another embodiment, the invention comprises administering INX-315 to human patients having CDK2-mediated cancers that overexpress cyclin E.

[0085] In one embodiment, the herein provides a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective amount of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, which yields a mean plasma area under the curve (AUC) (ng·hr / mL) of at least about 1250 to about 50000 when measured on day 1 of administration, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, and the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the mean AUC is at least about 6000. In some embodiments, the mean AUC is at least about 9000.

[0086] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the average peak plasma concentration (C) measured on day 1 of administration is at least about 75 to about 2400. max The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C max It is at least about 350. In some embodiments, the average C max It is at least approximately 525.

[0087] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the mean minimum plasma concentration (C) measured on day 1 of administration is at least about 20 to about 1000. minThe method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C min It is at least about 120. In some embodiments, the average C min It is at least approximately 180.

[0088] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the mean minimum free plasma concentration (C) measured on day 1 of administration ranges from at least about 4.0 to about 48.0. min free The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C min free It is at least about 10.0. In some embodiments, the average C min free It is at least approximately 15.0.

[0089] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, which yields a mean plasma area under the curve (AUC) (ng·hr / mL) of at least about 1250 to about 56000 when measured on day 15 of administration, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, and the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the mean AUC is at least about 11000. In some embodiments, the mean AUC is at least about 16500.

[0090] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the average peak plasma concentration (C) measured on day 15 of administration is at least about 90 to about 4000. max The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C max It is at least about 700. In some embodiments, the average C max It is at least approximately 1050.

[0091] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the mean minimum plasma concentration (C) measured on day 15 of administration is at least about 100 to about 2000. minThe method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C min It is at least about 250. In some embodiments, the average C min It is at least approximately 375.

[0092] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the mean minimum free plasma concentration (C) measured on day 15 of administration ranges from at least about 6.0 to about 80.0. min free The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C min free It is at least about 14.0. In some embodiments, the average C min free It is at least approximately 21.0.

[0093] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective amount of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, which results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of at least about 25,000 to about 480,000 when measured on day 1 of administration, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, and the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the mean AUC is at least about 80,000. In some embodiments, the mean AUC is at least about 120,000.

[0094] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the average peak whole blood concentration (C) is at least about 2000 to about 28000 as measured on day 1 of administration. max The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C max It is at least about 4500. In some embodiments, the average C max It is at least approximately 6750.

[0095] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the mean minimum whole blood concentration (C) is at least about 500 to about 14400 as measured on day 1 of administration. minThe method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C min It is at least about 1800. In some embodiments, the average C min It is at least approximately 2700.

[0096] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, which results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of at least about 25,000 to about 800,000 when measured on day 15 of administration, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, and the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the mean AUC is at least about 120,000. In some embodiments, the mean AUC is at least about 180,000.

[0097] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the average peak whole blood concentration (C) is at least about 3000 to about 56000, as measured on day 15 of administration. max The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C max It is at least about 7000. In some embodiments, the average C max It is at least approximately 10,500.

[0098] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective dose of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the average minimum whole blood concentration (C) is at least about 1000 to about 24000, as measured on day 15 of administration. min The method yields (ng / mL) and the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, the average C min It is at least about 2600. In some embodiments, the average C min It is at least approximately 3900.

[0099] In another embodiment, provided herein is a method for treating a person having CDK2-mediated cancer, comprising administering to a person in need of treatment an effective amount of a pharmaceutical composition comprising a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, wherein the average plasma C is less than about 5 but greater than about 1.25. max vs C min The method yields a ratio in which the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315, wherein the amount of INX-315 in the ASD is 20% to 50% by weight. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25. In some embodiments, C max vs C min The ratio is measured in plasma. In some embodiments, C max vs C min The ratio is measured in whole blood.

[0100] In some embodiments, t 1 / 2 This ranges from approximately 5 hours to approximately 32 hours. In some embodiments, t 1 / 2This is approximately 8 to 28 hours. In some embodiments, t 1 / 2 This is approximately 12 to 18 hours. In some embodiments, t 1 / 2 This is approximately 14 hours. In some embodiments, t 1 / 2 This is approximately 15 hours. In some embodiments, t 1 / 2 The time interval is approximately 16 hours. In some embodiments, INX-315 is administered once daily. In some embodiments, INX-315 is administered orally. In some embodiments, the amount of INX-315 in ASD is approximately 40%. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 100 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 125 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 150 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 175 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 200 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 225 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is approximately 250 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 275 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 300 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 325 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 350 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 375 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 400 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 425 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 450 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 475 mg. In some embodiments, the total amount of INX-315 in the pharmaceutical composition is about 500 mg.

[0101] In some embodiments, the pharmaceutical composition further comprises an anti-precipitation agent. In some embodiments, the amount of anti-precipitation agent in the ASD is 40% to 70% by weight. In some embodiments, the amount of anti-precipitation agent in the ASD is about 60% by weight. In some embodiments, the anti-precipitation agent comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) selected from HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, or HPMCAS-E3. In some embodiments, HPMCAS is HPMCAS-HG. In some embodiments, the pharmaceutical composition further comprises one or more additional pharmaceutically acceptable excipients.

[0102] In some embodiments, INX-315 is administered in doses of approximately 100, 125, 150, or 175 mg. In some embodiments, INX-315 is administered in doses of approximately 200 mg, 225 mg, 250 mg, or 275 mg. In other embodiments, INX-315 is administered in doses of approximately 300 mg, 325 mg, 350 mg, or 375 mg. In some embodiments, INX-315 is administered in doses of approximately 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0103] In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average C value less than approximately 5 but greater than approximately 1.25. max vs C min This results in a ratio of approximately 4.75 but greater than approximately 1.5 in human patients requiring administration of INX-315 or its pharmaceutically acceptable salt. max vs C minThis results in a ratio of approximately 4.5 but greater than approximately 1.75 in human patients requiring administration of INX-315 or its pharmaceutically acceptable salt. max vs C min This results in a ratio of approximately 4.25 but greater than approximately 2 in human patients requiring administration of INX-315 or its pharmaceutically acceptable salt. max vs C min This results in a ratio of approximately 2.2 C in human patients requiring administration. max vs C min It brings about a ratio. In some embodiments, INX-315 is administered once daily. In some embodiments, INX-315 is administered in doses of about 100 mg to about 500 mg. In some embodiments, INX-315 is administered in doses of about 100 mg, about 125 mg, or about 150 mg. In some embodiments, INX-315 is administered in doses of about 200 mg, about 225 mg, or about 250 mg. In some embodiments, INX-315 is administered in doses of about 300 mg, about 325 mg, or about 350 mg. In some embodiments, INX-315 is administered in doses of about 400 mg, about 425 mg, or about 450 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as a spray-dried dispersion. In some embodiments, C max vs C min The ratio is measured in plasma. In some embodiments, C max vs C min The ratio is measured in whole blood.

[0104] In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration is performed over a period of approximately 12 to 24 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 12 to 18 hours.1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a duration of approximately 12.5 to 17.5 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 13 to 17 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a duration of approximately 13.5 to 16.5 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 14 to 16 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 14 hours of t 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 15 hours of t 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 16 hours of t 1 / 2 This brings about the INX-315's t 1 / 2 This is measured for INX-315 in plasma. In some embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in whole blood.

[0105] In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration is performed over a period of approximately 8 to 28 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a duration of approximately 10 to 26 hours. 1 / 2In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 12 to 26 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a duration of approximately 13 to 25 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 14 to 24 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 15 to 23 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 14 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 15 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 16 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 17 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 18 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 19 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 20 hours of t 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 21 hours of t 1 / 2In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in approximately 22 hours of t 1 / 2 This brings about the INX-315's t 1 / 2 This is measured for INX-315 in plasma. In some embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in whole blood.

[0106] In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration is performed over a period of approximately 5 to 32 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 8 to 28 hours. 1 / 2 In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 12 to 24 hours. 1 / 2 This brings about the INX-315's t 1 / 2 This is measured for INX-315 in plasma. In some embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in whole blood.

[0107] In some embodiments, the treatment method involves a ratio (K) of red blood cells to plasma that is greater than about 12 but less than about 50. RBC / P ) provides. In some embodiments, K RBC / P It is approximately 15 to approximately 45. In some embodiments, K RBC / P It is approximately 20 to approximately 40. In some embodiments, the treatment method is K greater than approximately 12 but less than 40. RBC / P The treatment method provides a K value greater than about 15 but less than 40. RBC / P The treatment method provides a K value greater than about 20 but less than 40. RBC / P The treatment method provides a K value greater than about 25 but less than 40. RBC / PTo provide.

[0108] In some embodiments, the treatment method involves a ratio (K) of whole blood to plasma that is greater than approximately 4 and less than approximately 20. WB / P ) provides. In some embodiments, K WB / P It is approximately 6 to approximately 18. In some embodiments, K WB / P It is approximately 10 to approximately 14. In some embodiments, the treatment method is K greater than approximately 4 but less than 14. WB / P The treatment method provides a K value greater than about 6 but less than 14. WB / P The treatment method provides a K value greater than about 8 but less than 14. WB / P The treatment method provides a K value greater than about 10 but less than 14. WB / P To provide.

[0109] Importantly, these PK / PD parameters indicate that drug levels of INX-315 sufficient to treat CDK2 inhibitor-sensitive cancers can be achieved with once-daily oral administration without significant drug spikes at human administration, minimizing adverse and / or off-target events as seen with other CDK2 inhibitors currently under development. The INX-315 administration regime has been identified in a Phase I human clinical trial conducted in the United States under the supervision of the U.S. Food and Drug Administration (FDA) for the treatment of recurrent, advanced, or metastatic cancers in humans with hormone receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) breast cancer, including cancers that have progressed on prior cyclin-dependent kinase 4 / 6 inhibitor (CDK4 / 6i) regimens and solid tumors (with and without CCNE1 amplification) that have progressed on standard of care treatment. INX-315 can also be used to treat other cancers that can be treated with CDK2 inhibitors, particularly cancers that exhibit cyclin E overexpression, or cancers that are otherwise resistant to CDK4 / 6 inhibitors (see, for example, Figure 16B).

[0110] The results described herein show that two other selective CDK2 inhibitors currently in clinical development, BLU-222 and PF-07104091, most notably, showed significantly higher peak plasma drug concentrations (C) during a once-daily administration regime. max It is surprising that it has a value of ) and cannot achieve the pharmacokinetic parameters of INX-315 described herein. This method provides a remarkable treatment for cancer while significantly reducing off-target side effects that limit treatment, such as diarrhea and vomiting associated with other CDK2 inhibitors. These dosing regimes for human administration are particularly useful, for example, in treatment regimens for HR+ / HER2- breast cancer, ovarian cancer, and for the long-term treatment of solid tumors (with and without CCNE1 amplification) that have progressed with CDK4 / 6i regimens and / or prior standard treatment. These improved dosing regimes have a longer half-life (t) of INX-315 compared to other CDK2 inhibitors (due to the red blood cell depot effect) without significant accumulation. 1 / 2 ) is promoted by low C max vs C min This allows for the continuous administration of INX-315 over a long period while reaping the benefits of the ratio.

[0111] Low C max vs C min For comparison, INX-315 may be administered for a longer period, such as two, three, four, five, six months, or longer, or even indefinitely, as permitted by the healthcare provider, until the cancer or other disorder is successfully treated or other treatments are used. In some embodiments, INX-315 may be administered daily for a longer period, such as once daily, as prescribed by a healthcare professional, to improve patient compliance. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered orally once daily (QD) in doses of approximately 100 mg to 400 mg or 500 mg (e.g., 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 250 mg, 300 mg, or 400 mg per day), to enhance patient compliance with the administration regimens described herein.

[0112] In one embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 2750 ng·hr / mL to approximately 28000 ng·hr / mL when measured on day 1 of administration. In a different embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 1250 ng·hr / mL to approximately 20000 ng·hr / mL when measured on day 1 of administration. In a different embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 5000 ng·hr / mL to approximately 50000 ng·hr / mL when measured on day 1 of administration. In some embodiments, the mean plasma AUC is approximately 2750 ng·hr / mL or greater than 2750 ng·hr / mL, approximately 3000 ng·hr / mL or greater than 3000 ng·hr / mL, or approximately 3250 ng·hr / mL or greater than 3250 ng·hr / mL, but less than approximately 7000 ng·hr / mL. In some embodiments, the mean AUC is approximately 2750 ng·hr / mL or greater than 2750 ng·hr / mL, but less than approximately 7000 ng·hr / mL. In some embodiments, the mean AUC is approximately 3000 ng·hr / mL or greater than 3000 ng·hr / mL, but less than approximately 7000 ng·hr / mL. In some embodiments, the mean AUC is approximately 3250 ng·hr / mL or greater than 3250 ng·hr / mL, but less than approximately 7000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 1250 ng·hr / mL or greater than 1250 ng·hr / mL, approximately 1500 ng·hr / mL or greater than 1500 ng·hr / mL, or approximately 1750 ng·hr / mL or greater than 1750 ng·hr / mL, but less than approximately 5000 ng·hr / mL. In different embodiments, the mean AUC is approximately 1250 ng·hr / mL or greater than 1250 ng·hr / mL, but less than approximately 5000 ng·hr / mL.In different embodiments, the mean AUC is approximately 1500 ng·hr / mL or greater than 1500 ng·hr / mL but less than approximately 5000 ng·hr / mL. In different embodiments, the mean AUC is approximately 1750 ng·hr / mL or greater than 1750 ng·hr / mL but less than approximately 5000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL, approximately 6000 ng·hr / mL or greater than 6000 ng·hr / mL, or approximately 7000 ng·hr / mL or greater than 7000 ng·hr / mL but less than approximately 12500 ng·hr / mL. In different embodiments, the mean AUC is approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL but less than approximately 12500 ng·hr / mL. In different embodiments, the mean AUC is approximately 6000 ng·hr / mL or greater than 6000 ng·hr / mL but less than approximately 12500 ng·hr / mL. In different embodiments, the mean AUC is approximately 7000 ng·hr / mL or greater than 7000 ng·hr / mL but less than approximately 12500 ng·hr / mL. In some embodiments, the mean plasma AUC is approximately 5500 ng·hr / mL or greater than 5500 ng·hr / mL, approximately 6000 ng·hr / mL or greater than 6000 ng·hr / mL, or approximately 6500 ng·hr / mL or greater than 6500 ng·hr / mL but less than approximately 14000 ng·hr / mL. In some embodiments, the mean AUC is approximately 5500 ng·hr / mL or greater than 5500 ng·hr / mL but less than approximately 14000 ng·hr / mL. In some embodiments, the mean AUC is approximately 6000 ng·hr / mL or greater than 6000 ng·hr / mL but less than approximately 14000 ng·hr / mL. In some embodiments, the mean AUC is approximately 6500 ng·hr / mL or greater than 6500 ng·hr / mL but less than approximately 14000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 2500 ng·hr / mL or greater than 2500 ng·hr / mL, approximately 3000 ng·hr / mL or greater than 3000 ng·hr / mL, or approximately 3500 ng·hr / mL or greater than 3500 ng·hr / mL but less than approximately 10000 ng·hr / mL.In different embodiments, the mean AUC is approximately 2500 ng·hr / mL or greater than 2500 ng·hr / mL but less than approximately 10000 ng·hr / mL. In different embodiments, the mean AUC is approximately 3000 ng·hr / mL or greater than 3000 ng·hr / mL but less than approximately 10000 ng·hr / mL. In different embodiments, the mean AUC is approximately 3500 ng·hr / mL or greater than 3500 ng·hr / mL but less than approximately 10000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 10000 ng·hr / mL or greater than 10000 ng·hr / mL, approximately 12000 ng·hr / mL or greater than 12000 ng·hr / mL, or approximately 14000 ng·hr / mL or greater than 14000 ng·hr / mL but less than approximately 25000 ng·hr / mL. In different embodiments, the mean AUC is approximately 10,000 ng·hr / mL or greater than 10,000 ng·hr / mL but less than approximately 25,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 12,000 ng·hr / mL or greater than 12,000 ng·hr / mL but less than approximately 25,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 14,000 ng·hr / mL or greater than 14,000 ng·hr / mL but less than approximately 25,000 ng·hr / mL. In some embodiments, the mean plasma AUC is approximately 8,250 ng·hr / mL or greater than 8,250 ng·hr / mL, approximately 9,000 ng·hr / mL or greater than 9,000 ng·hr / mL, or approximately 9,750 ng·hr / mL or greater than 9,750 ng·hr / mL but less than approximately 21,000 ng·hr / mL. In some embodiments, the average AUC is about 8250 ng·hr / mL or greater than 8250 ng·hr / mL but less than about 21000 ng·hr / mL. In some embodiments, the average AUC is about 9000 ng·hr / mL or greater than 9000 ng·hr / mL but less than about 21000 ng·hr / mL. In some embodiments, the average AUC is about 9750 ng·hr / mL or greater than 9750 ng·hr / mL but less than about 21000 ng·hr / mL.In different embodiments, the mean plasma AUC is approximately 3750 ng·hr / mL or greater than 3750 ng·hr / mL, approximately 4500 ng·hr / mL or greater than 4500 ng·hr / mL, or approximately 5250 ng·hr / mL or greater than 5250 ng·hr / mL, but less than approximately 15000 ng·hr / mL. In different embodiments, the mean AUC is approximately 3750 ng·hr / mL or greater than 3750 ng·hr / mL, but less than approximately 15000 ng·hr / mL. In different embodiments, the mean AUC is approximately 4500 ng·hr / mL or greater than 4500 ng·hr / mL, but less than approximately 15000 ng·hr / mL. In different embodiments, the mean AUC is approximately 5250 ng·hr / mL or greater than 5250 ng·hr / mL, but less than approximately 15000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 15,000 ng·hr / mL or greater than 15,000 ng·hr / mL, approximately 18,000 ng·hr / mL or greater than 18,000 ng·hr / mL, or approximately 21,000 ng·hr / mL or greater than 21,000 ng·hr / mL, but less than approximately 37,500 ng·hr / mL. In different embodiments, the mean AUC is approximately 15,000 ng·hr / mL or greater than 15,000 ng·hr / mL, but less than approximately 37,500 ng·hr / mL. In different embodiments, the mean AUC is approximately 18,000 ng·hr / mL or greater than 18,000 ng·hr / mL, but less than approximately 37,500 ng·hr / mL. In different embodiments, the mean AUC is approximately 21,000 ng·hr / mL or greater than 21,000 ng·hr / mL, but less than approximately 37,500 ng·hr / mL. In some embodiments, the mean plasma AUC is approximately 11,000 ng·hr / mL or greater than 11,000 ng·hr / mL, approximately 12,000 ng·hr / mL or greater than 12,000 ng·hr / mL, or approximately 13,000 ng·hr / mL or greater than 13,000 ng·hr / mL, but less than approximately 28,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 11,000 ng·hr / mL or greater than 11,000 ng·hr / mL, but less than approximately 28,000 ng·hr / mL.In some embodiments, the mean AUC is approximately 12,000 ng·hr / mL or greater than 12,000 ng·hr / mL but less than approximately 28,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 13,000 ng·hr / mL or greater than 13,000 ng·hr / mL but less than approximately 28,000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 5,000 ng·hr / mL or greater than 5,000 ng·hr / mL, approximately 5,750 ng·hr / mL or greater than 5,750 ng·hr / mL, or approximately 6,500 ng·hr / mL or greater than 6,500 ng·hr / mL but less than approximately 20,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 5,000 ng·hr / mL or greater than 5,000 ng·hr / mL but less than approximately 20,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 5750 ng·hr / mL or greater than 5750 ng·hr / mL but less than approximately 20000 ng·hr / mL. In different embodiments, the mean AUC is approximately 6500 ng·hr / mL or greater than 6500 ng·hr / mL but less than approximately 20000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 20000 ng·hr / mL or greater than 20000 ng·hr / mL, approximately 24000 ng·hr / mL or greater than 24000 ng·hr / mL, or approximately 28000 ng·hr / mL or greater than 28000 ng·hr / mL but less than approximately 50000 ng·hr / mL. In different embodiments, the mean AUC is approximately 20000 ng·hr / mL or greater than 20000 ng·hr / mL but less than approximately 50000 ng·hr / mL. In different embodiments, the mean AUC is approximately 24,000 ng·hr / mL or greater than 24,000 ng·hr / mL but less than approximately 50,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 28,000 ng·hr / mL or greater than 28,000 ng·hr / mL but less than approximately 50,000 ng·hr / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg.In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma C level less than 5 but greater than approximately 1.25. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0113] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean peak plasma concentration (C) of approximately 150 ng / mL to approximately 2000 ng / mL in humans, as measured on day 1 of administration. max In a different embodiment, administration of INX-315 or its pharmaceutically acceptable salts to human patients requiring administration results in mean peak plasma concentrations in humans of approximately 100 ng / mL to approximately 1600 ng / mL (C) when measured on day 1 of administration. max In a different embodiment, administration of INX-315 or its pharmaceutically acceptable salts to human patients requiring administration results in mean peak plasma concentrations in humans of approximately 75 ng / mL to approximately 2400 ng / mL (C) when measured on day 1 of administration. max This results in (ng / mL). In some embodiments, the average C max This is approximately 150 ng / mL or greater than 150 ng / mL, approximately 175 ng / mL or greater than 175 ng / mL, or approximately 200 ng / mL or greater than 200 ng / mL, but less than approximately 500 ng / mL. In some embodiments, C max It is approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 500 ng / mL. In some embodiments, C max It is approximately 175 ng / mL or greater than 175 ng / mL, but less than approximately 500 ng / mL. In some embodiments, C max The average C is approximately 200 ng / mL or greater than 200 ng / mL, but less than approximately 500 ng / mL. In different embodiments, the average Cmax This is approximately 100 ng / mL or greater than 100 ng / mL, approximately 125 ng / mL or greater than 125 ng / mL, or approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 400 ng / mL. In different embodiments, C max It is approximately 100 ng / mL or greater than 100 ng / mL, but less than approximately 400 ng / mL. In different embodiments, C max It is approximately 125 ng / mL or greater than 125 ng / mL, but less than approximately 400 ng / mL. In different embodiments, C max The average C is approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 400 ng / mL. In different embodiments, the average C max This is approximately 75 ng / mL or greater than 75 ng / mL, approximately 180 ng / mL or greater than 180 ng / mL, or approximately 210 ng / mL or greater than 210 ng / mL, but less than approximately 600 ng / mL. In different embodiments, C max It is approximately 75 ng / mL or greater than 75 ng / mL, but less than approximately 600 ng / mL. In different embodiments, C max It is approximately 180 ng / mL or greater than 180 ng / mL, but less than approximately 600 ng / mL. In different embodiments, C max The average C is approximately 210 ng / mL or greater than 210 ng / mL, but less than approximately 600 ng / mL. In some embodiments, the average C max This is approximately 300 ng / mL or greater than 300 ng / mL, approximately 350 ng / mL or greater than 350 ng / mL, or approximately 400 ng / mL or greater than 400 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, C max It is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, C max It is approximately 350 ng / mL or greater than 350 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, C max The average C is approximately 400 ng / mL or greater than 400 ng / mL, but less than approximately 1000 ng / mL. In different embodiments, the average C maxThis is approximately 200 ng / mL or greater than 200 ng / mL, approximately 250 ng / mL or greater than 250 ng / mL, or approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 800 ng / mL. In different embodiments, C max It is approximately 200 ng / mL or greater than 200 ng / mL, but less than approximately 800 ng / mL. In different embodiments, C max It is approximately 250 ng / mL or greater than 250 ng / mL, but less than approximately 800 ng / mL. In different embodiments, C max The average C is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 800 ng / mL. In different embodiments, the average C max This is approximately 150 ng / mL or greater than 150 ng / mL, approximately 360 ng / mL or greater than 360 ng / mL, or approximately 420 ng / mL or greater than 420 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, C max It is approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, C max It is approximately 360 ng / mL or greater than 360 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, C max The average C is approximately 420 ng / mL or greater than 420 ng / mL, but less than approximately 1200 ng / mL. In some embodiments, the average C max This is approximately 450 ng / mL or greater than 450 ng / mL, approximately 525 ng / mL or greater than 525 ng / mL, or approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, C max It is approximately 450 ng / mL or greater than 450 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, C max It is approximately 525 ng / mL or greater than 525 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, C max The average C is approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 1500 ng / mL. In different embodiments, the average C maxThis is approximately 300 ng / mL or greater than 300 ng / mL, approximately 375 ng / mL or greater than 375 ng / mL, or approximately 450 ng / mL or greater than 450 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, C max It is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, C max It is approximately 375 ng / mL or greater than 375 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, C max The average C is approximately 450 ng / mL or greater than 450 ng / mL, but less than approximately 1200 ng / mL. In different embodiments, the average C max This is approximately 225 ng / mL or greater than 225 ng / mL, approximately 540 ng / mL or greater than 540 ng / mL, or approximately 630 ng / mL or greater than 630 ng / mL, but less than approximately 1800 ng / mL. In different embodiments, C max It is approximately 225 ng / mL or greater than 225 ng / mL, but less than approximately 1800 ng / mL. In different embodiments, C max It is approximately 540 ng / mL or greater than 540 ng / mL, but less than approximately 1800 ng / mL. In different embodiments, C max The average C is approximately 630 ng / mL or greater than 630 ng / mL, but less than approximately 1800 ng / mL. In some embodiments, the average C max This is approximately 600 ng / mL or greater than 600 ng / mL, approximately 700 ng / mL or greater than 700 ng / mL, or approximately 800 ng / mL or greater than 800 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, C max It is approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, C max It is approximately 700 ng / mL or greater than 700 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, C max The average C is approximately 800 ng / mL or greater than 800 ng / mL, but less than approximately 2000 ng / mL. In different embodiments, the average C maxThis is approximately 400 ng / mL or greater than 400 ng / mL, approximately 500 ng / mL or greater than 500 ng / mL, or approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 1600 ng / mL. In different embodiments, C max It is approximately 400 ng / mL or greater than 400 ng / mL, but less than approximately 1600 ng / mL. In different embodiments, C max It is approximately 500 ng / mL or greater than 500 ng / mL, but less than approximately 1600 ng / mL. In different embodiments, C max The average C is approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 1600 ng / mL. In different embodiments, the average C max This is approximately 300 ng / mL or greater than 300 ng / mL, approximately 720 ng / mL or greater than 720 ng / mL, or approximately 840 ng / mL or greater than 840 ng / mL, but less than approximately 2400 ng / mL. In different embodiments, C max It is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 2400 ng / mL. In different embodiments, C max It is approximately 720 ng / mL or greater than 720 ng / mL, but less than approximately 2400 ng / mL. In different embodiments, C max The glycemic index (C) is approximately 840 ng / mL or greater than 840 ng / mL but less than approximately 2400 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0114] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum plasma concentration (C) of approximately 50 ng / mL to approximately 1000 ng / mL, as measured on day 1 of administration. min In a different embodiment, administration of INX-315 or its pharmaceutically acceptable salts to human patients requiring administration results in an average minimum plasma concentration (C) of approximately 20 ng / mL to approximately 600 ng / mL, as measured on day 1 of administration. min This results in (ng / mL). In some embodiments, the mean plasma C min This is approximately 50 ng / mL or greater than 50 ng / mL, approximately 60 ng / mL or greater than 60 ng / mL, or approximately 75 ng / mL or greater than 75 ng / mL, but less than approximately 250 ng / mL. In some embodiments, C min It is approximately 50 ng / mL or greater than 50 ng / mL, but less than approximately 250 ng / mL. In some embodiments, C min It is approximately 60 ng / mL or greater than 60 ng / mL, but less than approximately 250 ng / mL. In some embodiments, C min The mean plasma C is approximately 75 ng / mL or greater than 75 ng / mL, but less than approximately 250 ng / mL. In different embodiments, the mean plasma C is approximately 75 ng / mL or greater than 75 ng / mL. min This is approximately 20 ng / mL or greater than 20 ng / mL, approximately 40 ng / mL or greater than 40 ng / mL, or approximately 60 ng / mL or greater than 60 ng / mL, but less than approximately 150 ng / mL. In different embodiments, C min It is approximately 20 ng / mL or greater than 20 ng / mL, but less than approximately 150 ng / mL. In different embodiments, C min It is approximately 40 ng / mL or greater than 40 ng / mL but less than approximately 150 ng / mL. In different embodiments, C min The mean plasma C is approximately 60 ng / mL or greater than 60 ng / mL, but less than approximately 150 ng / mL. In some embodiments, the mean plasma C is approximately 60 ng / mL. minThis is approximately 100 ng / mL or greater than 100 ng / mL, approximately 120 ng / mL or greater than 120 ng / mL, or approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 500 ng / mL. In some embodiments, C min It is approximately 100 ng / mL or greater than 100 ng / mL, but less than approximately 500 ng / mL. In some embodiments, C min It is approximately 120 ng / mL or greater than 120 ng / mL, but less than approximately 500 ng / mL. In some embodiments, C min The mean plasma C is approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 500 ng / mL. In different embodiments, the mean plasma C is approximately 150 ng / mL or greater than 150 ng / mL. min This is approximately 40 ng / mL or greater than 40 ng / mL, approximately 80 ng / mL or greater than 80 ng / mL, or approximately 120 ng / mL or greater than 120 ng / mL, but less than approximately 300 ng / mL. In different embodiments, C min It is approximately 40 ng / mL or greater than 40 ng / mL but less than approximately 300 ng / mL. In different embodiments, C min It is approximately 80 ng / mL or greater than 80 ng / mL, but less than approximately 300 ng / mL. In different embodiments, C min The mean plasma C is approximately 120 ng / mL or greater than 120 ng / mL, but less than approximately 300 ng / mL. In some embodiments, the mean plasma C is approximately 120 ng / mL or greater than 120 ng / mL. min This is approximately 150 ng / mL or greater than 150 ng / mL, approximately 180 ng / mL or greater than 180 ng / mL, or approximately 225 ng / mL or greater than 225 ng / mL, but less than approximately 750 ng / mL. In some embodiments, C min It is approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 750 ng / mL. In some embodiments, C min It is approximately 180 ng / mL or greater than 180 ng / mL, but less than approximately 750 ng / mL. In some embodiments, C min The mean plasma C is approximately 225 ng / mL or greater than 225 ng / mL, but less than approximately 750 ng / mL. In different embodiments, the mean plasma C is approximately 225 ng / mL or greater than 225 ng / mL. minThis is approximately 60 ng / mL or greater than 60 ng / mL, approximately 120 ng / mL or greater than 120 ng / mL, or approximately 180 ng / mL or greater than 180 ng / mL, but less than approximately 450 ng / mL. In different embodiments, C min It is approximately 60 ng / mL or greater than 60 ng / mL, but less than approximately 450 ng / mL. In different embodiments, C min It is approximately 120 ng / mL or greater than 120 ng / mL, but less than approximately 450 ng / mL. In different embodiments, C min The mean plasma C is approximately 180 ng / mL or greater than 180 ng / mL, but less than approximately 450 ng / mL. In some embodiments, the mean plasma C is approximately 180 ng / mL or greater than 180 ng / mL. min This is approximately 200 ng / mL or greater than 200 ng / mL, approximately 240 ng / mL or greater than 240 ng / mL, or approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, C min It is approximately 200 ng / mL or greater than 200 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, C min It is approximately 240 ng / mL or greater than 240 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, C min The mean plasma C is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1000 ng / mL. In different embodiments, the mean plasma C is approximately 300 ng / mL. min This is approximately 80 ng / mL or greater than 80 ng / mL, approximately 160 ng / mL or greater than 160 ng / mL, or approximately 240 ng / mL or greater than 240 ng / mL, but less than approximately 600 ng / mL. In different embodiments, C min It is approximately 80 ng / mL or greater than 80 ng / mL, but less than approximately 600 ng / mL. In different embodiments, C min It is approximately 160 ng / mL or greater than 160 ng / mL, but less than approximately 600 ng / mL. In different embodiments, C minThe glycemic index (C) is approximately 240 ng / mL or greater than 240 ng / mL but less than approximately 600 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is such that the mean plasma C is less than 5 but greater than approximately 1.25. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0115] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum free plasma concentration (C) of approximately 4.0 ng / mL to approximately 48.0 ng / mL, as measured on day 1 of administration. min free This results in (ng / mL). In some embodiments, the average C min free The average C is approximately 4.0 ng / mL or greater than 4.0 ng / mL, approximately 5.0 ng / mL or greater than 5.0 ng / mL, or approximately 6.0 ng / mL or greater than 6.0 ng / mL, but less than approximately 12.0 ng / mL. In some embodiments, the average C min free The average C is approximately 4.0 ng / mL or greater than 4.0 ng / mL, but less than approximately 12.0 ng / mL. In some embodiments, the average C min free The average C is approximately 5.0 ng / mL or greater than 5.0 ng / mL, but less than approximately 12.0 ng / mL. In some embodiments, the average C min free The average C is approximately 6.0 ng / mL or greater than 6.0 ng / mL, but less than approximately 12.0 ng / mL. In some embodiments, the average C min freeThe average C is approximately 8.0 ng / mL or greater than 8.0 ng / mL, approximately 10.0 ng / mL or greater than 10.0 ng / mL, or approximately 12.0 ng / mL or greater than 12.0 ng / mL, but less than approximately 24.0 ng / mL. In some embodiments, the average C min free The average C is approximately 8.0 ng / mL or greater than 8.0 ng / mL, but less than approximately 24.0 ng / mL. In some embodiments, the average C min free The average C is approximately 10.0 ng / mL or greater than 10.0 ng / mL, but less than approximately 24.0 ng / mL. In some embodiments, the average C min free The average C is approximately 12.0 ng / mL or greater than 12.0 ng / mL, but less than approximately 24.0 ng / mL. In some embodiments, the average C min free The average C is approximately 12.0 ng / mL or greater than 12.0 ng / mL, approximately 15.0 ng / mL or greater than 15.0 ng / mL, or approximately 18.0 ng / mL or greater than 18.0 ng / mL, but less than approximately 36.0 ng / mL. In some embodiments, the average C min free The average C is approximately 12.0 ng / mL or greater than 12.0 ng / mL, but less than approximately 36.0 ng / mL. In some embodiments, the average C min free The average C is approximately 15.0 ng / mL or greater than 15.0 ng / mL, but less than approximately 36.0 ng / mL. In some embodiments, the average C min free The average C is approximately 18.0 ng / mL or greater than 18.0 ng / mL, but less than approximately 36.0 ng / mL. In some embodiments, the average C min free The average C is approximately 16.0 ng / mL or greater than 16.0 ng / mL, approximately 20.0 ng / mL or greater than 20.0 ng / mL, or approximately 24.0 ng / mL or greater than 24.0 ng / mL, but less than approximately 48.0 ng / mL. In some embodiments, the average C min freeThe average C is approximately 16.0 ng / mL or greater than 16.0 ng / mL, but less than approximately 48.0 ng / mL. In some embodiments, the average C min free The average C is approximately 20.0 ng / mL or greater than 20.0 ng / mL, but less than approximately 48.0 ng / mL. In some embodiments, the average C min free The glycemic index (C) is approximately 24.0 ng / mL or greater than 24.0 ng / mL but less than approximately 48.0 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is such that the mean plasma C is less than 5 but greater than approximately 1.25. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0116] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 5000 ng·hr / mL to approximately 56000 ng·hr / mL when measured on day 15 of administration. In a different embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 1250 ng·hr / mL to approximately 28000 ng·hr / mL when measured on day 15 of administration. In some embodiments, the mean plasma AUC is approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL, approximately 5500 ng·hr / mL or greater than 5500 ng·hr / mL, or approximately 6000 ng·hr / mL or greater than 6000 ng·hr / mL, but less than approximately 14000 ng·hr / mL. In some embodiments, the mean AUC is about 5000 ng·hr / mL or greater than 5000 ng·hr / mL but less than about 14000 ng·hr / mL. In some embodiments, the mean AUC is about 5500 ng·hr / mL or greater than 5500 ng·hr / mL but less than about 14000 ng·hr / mL. In some embodiments, the mean AUC is about 6000 ng·hr / mL or greater than 6000 ng·hr / mL but less than about 14000 ng·hr / mL. In different embodiments, the mean plasma AUC is about 1250 ng·hr / mL or greater than 1250 ng·hr / mL, about 2100 ng·hr / mL or greater than 2100 ng·hr / mL, or about 2450 ng·hr / mL or greater than 2450 ng·hr / mL but less than about 7000 ng·hr / mL. In different embodiments, the average AUC is approximately 1250 ng·hr / mL or greater than 1250 ng·hr / mL but less than approximately 7000 ng·hr / mL. In different embodiments, the average AUC is approximately 2100 ng·hr / mL or greater than 2100 ng·hr / mL but less than approximately 7000 ng·hr / mL. In different embodiments, the average AUC is approximately 2450 ng·hr / mL or greater than 2450 ng·hr / mL but less than approximately 7000 ng·hr / mL.In some embodiments, the mean plasma AUC is approximately 10,000 ng·hr / mL or greater than 10,000 ng·hr / mL, approximately 11,000 ng·hr / mL or greater than 11,000 ng·hr / mL, or approximately 12,000 ng·hr / mL or greater than 12,000 ng·hr / mL, but less than approximately 28,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 10,000 ng·hr / mL or greater than 10,000 ng·hr / mL, but less than approximately 28,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 11,000 ng·hr / mL or greater than 11,000 ng·hr / mL, but less than approximately 28,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 12,000 ng·hr / mL or greater than 12,000 ng·hr / mL, but less than approximately 28,000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 2,500 ng·hr / mL or greater than 2,500 ng·hr / mL, approximately 4,200 ng·hr / mL or greater than 4,200 ng·hr / mL, or approximately 4,900 ng·hr / mL or greater than 4,900 ng·hr / mL, but less than approximately 14,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 2,500 ng·hr / mL or greater than 2,500 ng·hr / mL, but less than approximately 14,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 4,200 ng·hr / mL or greater than 4,200 ng·hr / mL, but less than approximately 14,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 4900 ng·hr / mL or greater than 4900 ng·hr / mL but less than approximately 14000 ng·hr / mL. In some embodiments, the mean plasma AUC is approximately 15000 ng·hr / mL or greater than 15000 ng·hr / mL, approximately 16500 ng·hr / mL or greater than 16500 ng·hr / mL, or approximately 18000 ng·hr / mL or greater than 18000 ng·hr / mL but less than approximately 42000 ng·hr / mL. In some embodiments, the mean AUC is approximately 15000 ng·hr / mL or greater than 15000 ng·hr / mL but less than approximately 42000 ng·hr / mL.In some embodiments, the mean AUC is approximately 16,500 ng·hr / mL or greater than 16,500 ng·hr / mL but less than approximately 42,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 18,000 ng·hr / mL or greater than 18,000 ng·hr / mL but less than approximately 42,000 ng·hr / mL. In different embodiments, the mean plasma AUC is approximately 3,750 ng·hr / mL or greater than 3,750 ng·hr / mL, approximately 6,300 ng·hr / mL or greater than 6,300 ng·hr / mL, or approximately 7,350 ng·hr / mL or greater than 7,350 ng·hr / mL but less than approximately 21,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 3,750 ng·hr / mL or greater than 3,750 ng·hr / mL but less than approximately 21,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 6300 ng·hr / mL or greater than 6300 ng·hr / mL but less than approximately 21000 ng·hr / mL. In different embodiments, the mean AUC is approximately 7350 ng·hr / mL or greater than 7350 ng·hr / mL but less than approximately 21000 ng·hr / mL. In some embodiments, the mean plasma AUC is approximately 20000 ng·hr / mL or greater than 20000 ng·hr / mL, approximately 22000 ng·hr / mL or greater than 22000 ng·hr / mL, or approximately 24000 ng·hr / mL or greater than 24000 ng·hr / mL but less than approximately 56000 ng·hr / mL. In some embodiments, the mean AUC is approximately 20000 ng·hr / mL or greater than 20000 ng·hr / mL but less than approximately 56000 ng·hr / mL. In some embodiments, the average AUC is approximately 22,000 ng·hr / mL or greater than 22,000 ng·hr / mL, but less than approximately 56,000 ng·hr / mL. In some embodiments, the average AUC is approximately 24,000 ng·hr / mL or greater than 24,000 ng·hr / mL, but less than approximately 56,000 ng·hr / mL.In different embodiments, the mean plasma AUC is approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL, approximately 8400 ng·hr / mL or greater than 8400 ng·hr / mL, or approximately 9800 ng·hr / mL or greater than 9800 ng·hr / mL, but less than approximately 28000 ng·hr / mL. In different embodiments, the mean AUC is approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL, but less than approximately 28000 ng·hr / mL. In different embodiments, the mean AUC is approximately 8400 ng·hr / mL or greater than 8400 ng·hr / mL, but less than approximately 28000 ng·hr / mL. In different embodiments, the mean AUC is approximately 9800 ng·hr / mL or greater than 9800 ng·hr / mL, but less than approximately 28000 ng·hr / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the dose of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0117] In an alternative embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean peak plasma concentration (C) of approximately 300 ng / mL to approximately 4000 ng / mL in humans, as measured on day 15 of administration. max In a different embodiment, administration of INX-315 or its pharmaceutically acceptable salts to human patients requiring administration results in mean peak plasma concentrations in humans of approximately 90 ng / mL to approximately 2800 ng / mL (C) when measured on day 15 of administration. max This results in (ng / mL). In some embodiments, the mean plasma C maxThe average C is approximately 300 ng / mL or greater than 300 ng / mL, approximately 300 ng / mL or greater than 300 ng / mL, or approximately 350 ng / mL or greater than 350 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C max The average C is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C max The average C is approximately 350 ng / mL or greater than 350 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C max The mean plasma C is approximately 400 ng / mL or greater than 400 ng / mL, but less than approximately 1000 ng / mL. In different embodiments, the mean plasma C is approximately 400 ng / mL or greater than 400 ng / mL. max The average C is approximately 90 ng / mL or greater than 90 ng / mL, approximately 210 ng / mL or greater than 210 ng / mL, or approximately 245 ng / mL or greater than 245 ng / mL, but less than approximately 700 ng / mL. In different embodiments, the average C max The average C is approximately 90 ng / mL or greater than 90 ng / mL, but less than approximately 700 ng / mL. In different embodiments, the average C max The average C is approximately 210 ng / mL or greater than 210 ng / mL, but less than approximately 700 ng / mL. In different embodiments, the average C max The mean plasma C is approximately 245 ng / mL or greater than 245 ng / mL, but less than approximately 700 ng / mL. In some embodiments, the mean plasma C is max The average C is approximately 600 ng / mL or greater than 600 ng / mL, approximately 700 ng / mL or greater than 700 ng / mL, or approximately 800 ng / mL or greater than 800 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C max The average C is approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C max The average C is approximately 700 ng / mL or greater than 700 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C max The mean plasma C is approximately 800 ng / mL or greater than 800 ng / mL, but less than approximately 2000 ng / mL. In different embodiments, the mean plasma C is approximately 800 ng / mL or greater than 800 ng / mL.max The average C is approximately 180 ng / mL or greater than 180 ng / mL, approximately 420 ng / mL or greater than 420 ng / mL, or approximately 490 ng / mL or greater than 490 ng / mL, but less than approximately 1400 ng / mL. In different embodiments, the average C max The average C is approximately 180 ng / mL or greater than 180 ng / mL, but less than approximately 1400 ng / mL. In different embodiments, the average C max The average C is approximately 420 ng / mL or greater than 420 ng / mL, but less than approximately 1400 ng / mL. In different embodiments, the average C max The mean plasma C is approximately 490 ng / mL or greater than 490 ng / mL, but less than approximately 1400 ng / mL. In some embodiments, the mean plasma C is max The average C is approximately 900 ng / mL or greater than 900 ng / mL, approximately 1050 ng / mL or greater than 1050 ng / mL, or approximately 1200 ng / mL or greater than 1200 ng / mL, but less than approximately 3000 ng / mL. In some embodiments, the average C max The average C is approximately 900 ng / mL or greater than 900 ng / mL, but less than approximately 3000 ng / mL. In some embodiments, the average C max The average C is approximately 1050 ng / mL or greater than 1050 ng / mL, but less than approximately 3000 ng / mL. In some embodiments, the average C max The mean plasma C is approximately 1200 ng / mL or greater than 1200 ng / mL, but less than approximately 3000 ng / mL. In different embodiments, the mean plasma C is approximately 1200 ng / mL. max The average C is approximately 270 ng / mL or greater than 270 ng / mL, approximately 630 ng / mL or greater than 630 ng / mL, or approximately 735 ng / mL or greater than 735 ng / mL, but less than approximately 2100 ng / mL. In different embodiments, the average C max The average C is approximately 270 ng / mL or greater than 270 ng / mL, but less than approximately 2100 ng / mL. In different embodiments, the average C max The average C is approximately 630 ng / mL or greater than 630 ng / mL, but less than approximately 2100 ng / mL. In different embodiments, the average C maxThe mean plasma C is approximately 735 ng / mL or greater than 735 ng / mL, but less than approximately 2100 ng / mL. In some embodiments, the mean plasma C is approximately 735 ng / mL or greater than 735 ng / mL. max The average C is approximately 1200 ng / mL or greater than 1200 ng / mL, approximately 1400 ng / mL or greater than 1400 ng / mL, or approximately 1600 ng / mL or greater than 1600 ng / mL, but less than approximately 4000 ng / mL. In some embodiments, the average C max The average C is approximately 1200 ng / mL or greater than 1200 ng / mL, but less than approximately 4000 ng / mL. In some embodiments, the average C max The average C is approximately 1400 ng / mL or greater than 1400 ng / mL, but less than approximately 4000 ng / mL. In some embodiments, the average C max The mean plasma C is approximately 1600 ng / mL or greater than 1600 ng / mL, but less than approximately 4000 ng / mL. In different embodiments, the mean plasma C is approximately 1600 ng / mL. max The average C is approximately 360 ng / mL or greater than 360 ng / mL, approximately 840 ng / mL or greater than 840 ng / mL, or approximately 980 ng / mL or greater than 980 ng / mL, but less than approximately 2800 ng / mL. In different embodiments, the average C max The average C is approximately 360 ng / mL or greater than 360 ng / mL, but less than approximately 2800 ng / mL. In different embodiments, the average C max The average C is approximately 840 ng / mL or greater than 840 ng / mL, but less than approximately 2800 ng / mL. In different embodiments, the average C max The glycemic index (C) is approximately 980 ng / mL or greater than 980 ng / mL, but less than approximately 2800 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is such that the mean plasma C is less than 5 but greater than approximately 1.25. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C minThe ratio is less than 2.25.

[0118] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean minimum plasma concentration (C) of approximately 100 ng / mL to approximately 2000 ng / mL, as measured on day 15 of administration. min This results in (ng / mL). In some embodiments, the average C min The average C is approximately 100 ng / mL or greater than 100 ng / mL, approximately 125 ng / mL or greater than 125 ng / mL, or approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 500 ng / mL. In some embodiments, the average C min The average C is approximately 100 ng / mL or greater than 100 ng / mL, but less than approximately 500 ng / mL. In some embodiments, the average C min The average C is approximately 125 ng / mL or greater than 125 ng / mL, but less than approximately 500 ng / mL. In some embodiments, the average C min The average C is approximately 150 ng / mL or greater than 150 ng / mL, but less than approximately 500 ng / mL. In some embodiments, the average C min The average C is approximately 200 ng / mL or greater than 200 ng / mL, approximately 250 ng / mL or greater than 250 ng / mL, or approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C min The average C is approximately 200 ng / mL or greater than 200 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C min The average C is approximately 250 ng / mL or greater than 250 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C min The average C is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1000 ng / mL. In some embodiments, the average C min The average C is approximately 300 ng / mL or greater than 300 ng / mL, approximately 375 ng / mL or greater than 375 ng / mL, or approximately 450 ng / mL or greater than 450 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, the average C minThe average C is approximately 300 ng / mL or greater than 300 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, the average C min The average C is approximately 375 ng / mL or greater than 375 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, the average C min The average C is approximately 450 ng / mL or greater than 450 ng / mL, but less than approximately 1500 ng / mL. In some embodiments, the average C min The average C is approximately 400 ng / mL or greater than 400 ng / mL, approximately 500 ng / mL or greater than 500 ng / mL, or approximately 600 ng / mL or greater than 600 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C min The average C is approximately 400 ng / mL or greater than 400 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C min The average C is approximately 500 ng / mL or greater than 500 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C min The glycemic index (C) is approximately 600 ng / mL or greater than 600 ng / mL but less than approximately 2000 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0119] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum free plasma concentration (C) of approximately 6.0 ng / mL to approximately 80.0 ng / mL, as measured on day 15 of administration. min free This results in (ng / mL). In some embodiments, the average Cmin free The average C is approximately 6.0 ng / mL or greater than 6.0 ng / mL, approximately 7.0 ng / mL or greater than 7.0 ng / mL, approximately 8.0 ng / mL or greater than 8.0 ng / mL, but less than approximately 20.0 ng / mL. In some embodiments, the average C min free The average C is approximately 6.0 ng / mL or greater than 6.0 ng / mL, but less than approximately 20.0 ng / mL. In some embodiments, the average C min free The average C is approximately 7.0 ng / mL or greater than 7.0 ng / mL, but less than approximately 20.0 ng / mL. In some embodiments, the average C min free The average C is approximately 8.0 ng / mL or greater than 8.0 ng / mL, but less than approximately 20.0 ng / mL. In some embodiments, the average C min free The average C is approximately 12.0 ng / mL or greater than 12.0 ng / mL, approximately 14.0 ng / mL or greater than 14.0 ng / mL, approximately 16.0 ng / mL or greater than 16.0 ng / mL, but less than approximately 40.0 ng / mL. In some embodiments, the average C min free The average C is approximately 12.0 ng / mL or greater than 12.0 ng / mL, but less than approximately 40.0 ng / mL. In some embodiments, the average C min free The average C is approximately 14.0 ng / mL or greater than 14.0 ng / mL, but less than approximately 40.0 ng / mL. In some embodiments, the average C min free The average C is approximately 16.0 ng / mL or greater than 16.0 ng / mL, but less than approximately 40.0 ng / mL. In some embodiments, the average C min free The average C is approximately 18.0 ng / mL or greater than 18.0 ng / mL, approximately 21.0 ng / mL or greater than 21.0 ng / mL, approximately 24.0 ng / mL or greater than 24.0 ng / mL, but less than approximately 60.0 ng / mL. In some embodiments, the average C min free The average C is approximately 18.0 ng / mL or greater than 18.0 ng / mL, but less than approximately 60.0 ng / mL. In some embodiments, the average Cmin free The average C is approximately 21.0 ng / mL or greater than 21.0 ng / mL, but less than approximately 60.0 ng / mL. In some embodiments, the average C min free This is approximately 24.0 ng / mL or greater than 24.0 ng / mL However, it is less than approximately 60.0 ng / mL. In some embodiments, the average C min free The average C is approximately 24.0 ng / mL or greater than 24.0 ng / mL, approximately 28.0 ng / mL or greater than 28.0 ng / mL, approximately 32.0 ng / mL or greater than 32.0 ng / mL, but less than approximately 80.0 ng / mL. In some embodiments, the average C min free The average C is approximately 24.0 ng / mL or greater than 24.0 ng / mL, but less than approximately 80.0 ng / mL. In some embodiments, the average C min free The average C is approximately 28.0 ng / mL or greater than 28.0 ng / mL, but less than approximately 80.0 ng / mL. In some embodiments, the average C min free The glycemic index (C) is approximately 32.0 ng / mL or greater than 32.0 ng / mL but less than approximately 80.0 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration results in a mean plasma C value less than 5 but greater than approximately 1.25. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0120] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 30,000 ng·hr / mL to approximately 480,000 ng·hr / mL when measured on day 1 of administration. In a different embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 25,000 ng·hr / mL to approximately 400,000 ng·hr / mL when measured on day 1 of administration. In some embodiments, the mean whole blood AUC is approximately 30,000 ng·hr / mL or greater than 30,000 ng·hr / mL, approximately 40,000 ng·hr / mL or greater than 40,000 ng·hr / mL, or approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL, but less than approximately 120,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 30,000 ng·hr / mL or greater than 30,000 ng·hr / mL, but less than approximately 120,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 40,000 ng·hr / mL or greater than 40,000 ng·hr / mL, but less than approximately 120,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL, but less than approximately 120,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 25,000 ng·hr / mL or greater than 25,000 ng·hr / mL, approximately 27,500 ng·hr / mL or greater than 27,500 ng·hr / mL, or approximately 30,000 ng·hr / mL or greater than 30,000 ng·hr / mL, but less than approximately 100,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 25,000 ng·hr / mL or greater than 25,000 ng·hr / mL, but less than approximately 100,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 27,500 ng·hr / mL or greater than 27,500 ng·hr / mL, but less than approximately 100,000 ng·hr / mL.In different embodiments, the mean AUC is approximately 30,000 ng·hr / mL or greater than 30,000 ng·hr / mL, but less than approximately 100,000 ng·hr / mL. In some embodiments, the mean whole blood AUC is approximately 60,000 ng·hr / mL or greater than 60,000 ng·hr / mL, approximately 80,000 ng·hr / mL or greater than 80,000 ng·hr / mL, or approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, but less than approximately 240,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 60,000 ng·hr / mL or greater than 60,000 ng·hr / mL, but less than approximately 240,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 80,000 ng·hr / mL or greater than 80,000 ng·hr / mL, but less than approximately 240,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, but less than approximately 240,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL, approximately 55,000 ng·hr / mL or greater than 55,000 ng·hr / mL, or approximately 60,000 ng·hr / mL or greater than 60,000 ng·hr / mL, but less than approximately 200,000 ng·hr / mL. In different embodiments, the average AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL but less than approximately 200,000 ng·hr / mL. In different embodiments, the average AUC is approximately 55,000 ng·hr / mL or greater than 55,000 ng·hr / mL but less than approximately 200,000 ng·hr / mL. In different embodiments, the average AUC is approximately 60,000 ng·hr / mL or greater than 60,000 ng·hr / mL but less than approximately 200,000 ng·hr / mL. In some embodiments, the mean whole blood AUC is approximately 90,000 ng·hr / mL or greater than 90,000 ng·hr / mL, approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL, or approximately 150,000 ng·hr / mL or greater than 150,000 ng·hr / mL, but less than approximately 360,000 ng·hr / mL.In some embodiments, the average AUC is about 90,000 ng·hr / mL or greater than 90,000 ng·hr / mL but less than about 360,000 ng·hr / mL. In some embodiments, the average AUC is about 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL but less than about 360,000 ng·hr / mL. In some embodiments, the average AUC is about 150,000 ng·hr / mL or greater than 150,000 ng·hr / mL but less than about 360,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 75,000 ng·hr / mL or greater than 75,000 ng·hr / mL, approximately 82,500 ng·hr / mL or greater than 82,500 ng·hr / mL, or approximately 90,000 ng·hr / mL or greater than 90,000 ng·hr / mL, but less than approximately 300,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 75,000 ng·hr / mL or greater than 75,000 ng·hr / mL, but less than approximately 300,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 82,500 ng·hr / mL or greater than 82,500 ng·hr / mL, but less than approximately 300,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 90,000 ng·hr / mL or greater than 90,000 ng·hr / mL, but less than approximately 300,000 ng·hr / mL. In some embodiments, the mean whole blood AUC is approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL, approximately 160,000 ng·hr / mL or greater than 160,000 ng·hr / mL, or approximately 200,000 ng·hr / mL or greater than 200,000 ng·hr / mL, but less than approximately 480,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL, but less than approximately 480,000 ng·hr / mL. In some embodiments, the average AUC is approximately 160,000 ng·hr / mL or greater than 160,000 ng·hr / mL but less than approximately 480,000 ng·hr / mL. In some embodiments, the average AUC is approximately 200,000 ng·hr / mL or greater than 200,000 ng·hr / mL but less than approximately 480,000 ng·hr / mL.In different embodiments, the mean whole blood AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, approximately 110,000 ng·hr / mL or greater than 110,000 ng·hr / mL, or approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL, but less than approximately 400,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, but less than approximately 400,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 110,000 ng·hr / mL or greater than 110,000 ng·hr / mL, but less than approximately 400,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL but less than approximately 400,000 ng·hr / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at doses of 100 mg to 500 mg. In some embodiments, the dose of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0121] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean peak whole blood concentration (C) of approximately 2000 ng / mL to approximately 28000 ng / mL in humans, as measured on day 1 of administration. max This results in (ng / mL). In some embodiments, the mean whole blood C max The average C is approximately 2000 ng / mL or greater than 2000 ng / mL, approximately 2250 ng / mL or greater than 2250 ng / mL, or approximately 2500 ng / mL or greater than 2500 ng / mL, but less than approximately 7000 ng / mL. In some embodiments, the average C maxThe average C is approximately 2000 ng / mL or greater than 2000 ng / mL, but less than approximately 7000 ng / mL. In some embodiments, the average C max The average C is approximately 2250 ng / mL or greater than 2250 ng / mL, but less than approximately 7000 ng / mL. In some embodiments, the average C max It is approximately 2500 ng / mL or greater than 2500 ng / mL, but less than approximately 7000 ng / mL. In some embodiments, mean whole blood C max The average C is approximately 4000 ng / mL or greater than 4000 ng / mL, approximately 4500 ng / mL or greater than 4500 ng / mL, or approximately 5000 ng / mL or greater than 5000 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, the average C max The average C is approximately 4000 ng / mL or greater than 4000 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, the average C max The average C is approximately 4500 ng / mL or greater than 4500 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, the average C max It is approximately 5000 ng / mL or greater than 5000 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, mean whole blood C max The average C is approximately 6000 ng / mL or greater than 6000 ng / mL, approximately 6750 ng / mL or greater than 6750 ng / mL, or approximately 7500 ng / mL or greater than 7500 ng / mL, but less than approximately 21000 ng / mL. In some embodiments, the average C max The average C is approximately 6000 ng / mL or greater than 6000 ng / mL, but less than approximately 21000 ng / mL. In some embodiments, the average C max The average C is approximately 6750 ng / mL or greater than 6750 ng / mL, but less than approximately 21000 ng / mL. In some embodiments, the average C max It is approximately 7500 ng / mL or greater than 7500 ng / mL, but less than approximately 21000 ng / mL. In some embodiments, mean whole blood C maxThe average C is approximately 8000 ng / mL or greater than 8000 ng / mL, approximately 9000 ng / mL or greater than 9000 ng / mL, or approximately 10000 ng / mL or greater than 10000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, the average C max The average C is approximately 8000 ng / mL or greater than 8000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, the average C max The average C is approximately 9000 ng / mL or greater than 9000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, the average C max The glycemic index (C) is approximately 10,000 ng / mL or greater than 10,000 ng / mL, but less than approximately 28,000 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0122] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum whole blood concentration (C) of approximately 800 ng / mL to approximately 14400 ng / mL, as measured on day 1 of administration. min In a different embodiment, administration of INX-315 or its pharmaceutically acceptable salts to human patients requiring administration results in an average minimum whole blood concentration (C) of approximately 500 ng / mL to approximately 8000 ng / mL, as measured on day 1 of administration. min This results in (ng / mL). In some embodiments, the average C minThe average C is approximately 800 ng / mL or greater than 800 ng / mL, approximately 900 ng / mL or greater than 900 ng / mL, or approximately 1000 ng / mL or greater than 1000 ng / mL, but less than approximately 3600 ng / mL. In some embodiments, the average C min The average C is approximately 800 ng / mL or greater than 800 ng / mL, but less than approximately 3600 ng / mL. In some embodiments, the average C min The average C is approximately 900 ng / mL or greater than 900 ng / mL, but less than approximately 3600 ng / mL. In some embodiments, the average C min The average C is approximately 1000 ng / mL or greater than 1000 ng / mL, but less than approximately 3600 ng / mL. In different embodiments, the average C min The average C is approximately 500 ng / mL or greater than 500 ng / mL, approximately 575 ng / mL or greater than 575 ng / mL, or approximately 650 ng / mL or greater than 650 ng / mL, but less than approximately 2000 ng / mL. In different embodiments, the average C min The average C is approximately 500 ng / mL or greater than 500 ng / mL, but less than approximately 2000 ng / mL. In different embodiments, the average C min The average C is approximately 575 ng / mL or greater than 575 ng / mL, but less than approximately 2000 ng / mL. In different embodiments, the average C min The average C is approximately 650 ng / mL or greater than 650 ng / mL, but less than approximately 2000 ng / mL. In some embodiments, the average C min The average C is approximately 1600 ng / mL or greater than 1600 ng / mL, approximately 1800 ng / mL or greater than 1800 ng / mL, or approximately 2000 ng / mL or greater than 2000 ng / mL, but less than approximately 7200 ng / mL. In some embodiments, the average C min The average C is approximately 1600 ng / mL or greater than 1600 ng / mL, but less than approximately 7200 ng / mL. In some embodiments, the average C min The average C is approximately 1800 ng / mL or greater than 1800 ng / mL, but less than approximately 7200 ng / mL. In some embodiments, the average C minThe average C is approximately 2000 ng / mL or greater than 2000 ng / mL, but less than approximately 7200 ng / mL. In different embodiments, the average C min The average C is approximately 1000 ng / mL or greater than 1000 ng / mL, approximately 1150 ng / mL or greater than 1150 ng / mL, or approximately 1300 ng / mL or greater than 1300 ng / mL, but less than approximately 4000 ng / mL. In different embodiments, the average C min The average C is approximately 1000 ng / mL or greater than 1000 ng / mL, but less than approximately 4000 ng / mL. In different embodiments, the average C min The average C is approximately 1150 ng / mL or greater than 1150 ng / mL, but less than approximately 4000 ng / mL. In different embodiments, the average C min The average C is approximately 1300 ng / mL or greater than 1300 ng / mL, but less than approximately 4000 ng / mL. In some embodiments, the average C min The average C is approximately 2400 ng / mL or greater than 2400 ng / mL, approximately 2700 ng / mL or greater than 2700 ng / mL, or approximately 3000 ng / mL or greater than 3000 ng / mL, but less than approximately 10800 ng / mL. In some embodiments, the average C min The average C is approximately 2400 ng / mL or greater than 2400 ng / mL, but less than approximately 10800 ng / mL. In some embodiments, the average C min The average C is approximately 2700 ng / mL or greater than 2700 ng / mL, but less than approximately 10800 ng / mL. In some embodiments, the average C min The average C is approximately 3000 ng / mL or greater than 3000 ng / mL, but less than approximately 10800 ng / mL. In different embodiments, the average C min The average C is approximately 1500 ng / mL or greater than 1500 ng / mL, approximately 1725 ng / mL or greater than 1725 ng / mL, or approximately 1950 ng / mL or greater than 1950 ng / mL, but less than approximately 6000 ng / mL. In different embodiments, the average C min The average C is approximately 1500 ng / mL or greater than 1500 ng / mL, but less than approximately 6000 ng / mL. In different embodiments, the average C minThe average C is approximately 1725 ng / mL or greater than 1725 ng / mL, but less than approximately 6000 ng / mL. In different embodiments, the average C min The average C is approximately 1950 ng / mL or greater than 1950 ng / mL, but less than approximately 6000 ng / mL. In some embodiments, the average C min The average C is approximately 3200 ng / mL or greater than 3200 ng / mL, approximately 3600 ng / mL or greater than 3600 ng / mL, or approximately 4000 ng / mL or greater than 4000 ng / mL, but less than approximately 14400 ng / mL. In some embodiments, the average C min The average C is approximately 3200 ng / mL or greater than 3200 ng / mL, but less than approximately 14400 ng / mL. In some embodiments, the average C min The average C is approximately 3600 ng / mL or greater than 3600 ng / mL, but less than approximately 14400 ng / mL. In some embodiments, the average C min The average C is approximately 4000 ng / mL or greater than 4000 ng / mL, but less than approximately 14400 ng / mL. In different embodiments, the average C min The average C is approximately 2000 ng / mL or greater than 2000 ng / mL, approximately 2300 ng / mL or greater than 2300 ng / mL, or approximately 2600 ng / mL or greater than 2600 ng / mL, but less than approximately 8000 ng / mL. In different embodiments, the average C min The average C is approximately 2000 ng / mL or greater than 2000 ng / mL, but less than approximately 8000 ng / mL. In different embodiments, the average C min The average C is approximately 2300 ng / mL or greater than 2300 ng / mL, but less than approximately 8000 ng / mL. In different embodiments, the average C min The C5 level is approximately 2600 ng / mL or greater than 2600 ng / mL but less than approximately 8000 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C5. max vs C minIt brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0123] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 50,000 ng·hr / mL to approximately 800,000 ng·hr / mL when measured on day 15 of administration. In a different embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 25,000 ng·hr / mL to approximately 600,000 ng·hr / mL when measured on day 15 of administration. In some embodiments, the mean whole blood AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL, approximately 60,000 ng·hr / mL or greater than 60,000 ng·hr / mL, or approximately 70,000 ng·hr / mL or greater than 70,000 ng·hr / mL, but less than approximately 200,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL, but less than approximately 200,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 60,000 ng·hr / mL or greater than 60,000 ng·hr / mL, but less than approximately 200,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 70,000 ng·hr / mL or greater than 70,000 ng·hr / mL, but less than approximately 200,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 25,000 ng·hr / mL or greater than 25,000 ng·hr / mL, approximately 45,000 ng·hr / mL or greater than 45,000 ng·hr / mL, or approximately 52,500 ng·hr / mL or greater than 52,500 ng·hr / mL, but less than approximately 150,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 25,000 ng·hr / mL or greater than 25,000 ng·hr / mL, but less than approximately 150,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 45,000 ng·hr / mL or greater than 45,000 ng·hr / mL, but less than approximately 150,000 ng·hr / mL.In different embodiments, the mean AUC is approximately 52,500 ng·hr / mL or greater than 52,500 ng·hr / mL, but less than approximately 150,000 ng·hr / mL. In some embodiments, the mean whole blood AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL, or approximately 140,000 ng·hr / mL or greater than 140,000 ng·hr / mL, but less than approximately 400,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, but less than approximately 400,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL but less than approximately 400,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 140,000 ng·hr / mL or greater than 140,000 ng·hr / mL but less than approximately 400,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL, approximately 90,000 ng·hr / mL or greater than 90,000 ng·hr / mL, or approximately 105,000 ng·hr / mL or greater than 105,000 ng·hr / mL but less than approximately 300,000 ng·hr / mL. In different embodiments, the average AUC is approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL but less than approximately 300,000 ng·hr / mL. In different embodiments, the average AUC is approximately 90,000 ng·hr / mL or greater than 90,000 ng·hr / mL but less than approximately 300,000 ng·hr / mL. In different embodiments, the average AUC is approximately 105,000 ng·hr / mL or greater than 105,000 ng·hr / mL but less than approximately 300,000 ng·hr / mL. In some embodiments, the mean whole blood AUC is approximately 150,000 ng·hr / mL or greater than 150,000 ng·hr / mL, approximately 120,000 ng·hr / mL or greater than 120,000 ng·hr / mL, or approximately 140,000 ng·hr / mL or greater than 140,000 ng·hr / mL, but less than approximately 600,000 ng·hr / mL.In some embodiments, the average AUC is approximately 150,000 ng·hr / mL or greater than 150,000 ng·hr / mL but less than approximately 600,000 ng·hr / mL. In some embodiments, the average AUC is approximately 180,000 ng·hr / mL or greater than 180,000 ng·hr / mL but less than approximately 600,000 ng·hr / mL. In some embodiments, the average AUC is approximately 210,000 ng·hr / mL or greater than 210,000 ng·hr / mL but less than approximately 600,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 75,000 ng·hr / mL or greater than 75,000 ng·hr / mL, approximately 135,000 ng·hr / mL or greater than 135,000 ng·hr / mL, or approximately 157,500 ng·hr / mL or greater than 157,500 ng·hr / mL, but less than approximately 450,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 75,000 ng·hr / mL or greater than 75,000 ng·hr / mL, but less than approximately 450,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 135,000 ng·hr / mL or greater than 135,000 ng·hr / mL, but less than approximately 450,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 157,500 ng·hr / mL or greater than 157,500 ng·hr / mL but less than approximately 450,000 ng·hr / mL. In some embodiments, the mean whole blood AUC is approximately 200,000 ng·hr / mL or greater than 200,000 ng·hr / mL, approximately 240,000 ng·hr / mL or greater than 240,000 ng·hr / mL, or approximately 280,000 ng·hr / mL or greater than 280,000 ng·hr / mL but less than approximately 800,000 ng·hr / mL. In some embodiments, the mean AUC is approximately 200,000 ng·hr / mL or greater than 200,000 ng·hr / mL but less than approximately 800,000 ng·hr / mL. In some embodiments, the average AUC is approximately 240,000 ng·hr / mL or greater than 240,000 ng·hr / mL, but less than approximately 800,000 ng·hr / mL.In some embodiments, the mean AUC is approximately 280,000 ng·hr / mL or greater than 280,000 ng·hr / mL, but less than approximately 800,000 ng·hr / mL. In different embodiments, the mean whole blood AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, approximately 180,000 ng·hr / mL or greater than 180,000 ng·hr / mL, or approximately 210,000 ng·hr / mL or greater than 210,000 ng·hr / mL, but less than approximately 600,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 100,000 ng·hr / mL or greater than 100,000 ng·hr / mL, but less than approximately 600,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 180,000 ng·hr / mL or greater than 180,000 ng·hr / mL but less than approximately 600,000 ng·hr / mL. In different embodiments, the mean AUC is approximately 210,000 ng·hr / mL or greater than 210,000 ng·hr / mL but less than approximately 600,000 ng·hr / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the dose of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 mean plasma C. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0124] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean peak whole blood concentration (C) of approximately 3000 ng / mL to approximately 56000 ng / mL in humans, as measured on day 15 of administration. max This results in (ng / mL). In some embodiments, the mean whole blood C maxThe average C is approximately 3000 ng / mL or greater than 3000 ng / mL, approximately 3500 ng / mL or greater than 3500 ng / mL, or approximately 4000 ng / mL or greater than 4000 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, the average C max The average C is approximately 3000 ng / mL or greater than 3000 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, the average C max The average C is approximately 3500 ng / mL or greater than 3500 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, the average C max It is approximately 4000 ng / mL or greater than 4000 ng / mL, but less than approximately 14000 ng / mL. In some embodiments, mean whole blood C max The average C is approximately 6000 ng / mL or greater than 6000 ng / mL, approximately 7000 ng / mL or greater than 7000 ng / mL, or approximately 8000 ng / mL or greater than 8000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, the average C max The average C is approximately 6000 ng / mL or greater than 6000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, the average C max The average C is approximately 7000 ng / mL or greater than 7000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, the average C max It is approximately 8000 ng / mL or greater than 8000 ng / mL, but less than approximately 28000 ng / mL. In some embodiments, mean whole blood C max The average C is approximately 9000 ng / mL or greater than 9000 ng / mL, approximately 10500 ng / mL or greater than 10500 ng / mL, or approximately 12000 ng / mL or greater than 12000 ng / mL, but less than approximately 42000 ng / mL. In some embodiments, the average C max The average C is approximately 9000 ng / mL or greater than 9000 ng / mL, but less than approximately 42000 ng / mL. In some embodiments, the average C max The average C is approximately 10,500 ng / mL or greater than 10,500 ng / mL, but less than approximately 42,000 ng / mL. In some embodiments, the average C maxIt is approximately 12,000 ng / mL or greater than 12,000 ng / mL, but less than approximately 42,000 ng / mL. In some embodiments, mean whole blood C max The average C is approximately 12,000 ng / mL or greater than 12,000 ng / mL, approximately 14,000 ng / mL or greater than 14,000 ng / mL, or approximately 16,000 ng / mL or greater than 16,000 ng / mL, but less than approximately 56,000 ng / mL. In some embodiments, the average C max The average C is approximately 12,000 ng / mL or greater than 12,000 ng / mL, but less than approximately 56,000 ng / mL. In some embodiments, the average C max The average C is approximately 14,000 ng / mL or greater than 14,000 ng / mL, but less than approximately 56,000 ng / mL. In some embodiments, the average C max The C5 level is approximately 16,000 ng / mL or greater than 16,000 ng / mL, but less than approximately 56,000 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5, but greater than approximately 1.25, resulting in a mean plasma C5 level of less than 5. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0125] In another embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum whole blood concentration (C) of approximately 1000 ng / mL to approximately 24000 ng / mL, as measured on day 15 of administration. min This results in (ng / mL). In some embodiments, the mean whole blood C minThe average C is approximately 1000 ng / mL or greater than 1000 ng / mL, approximately 1300 ng / mL or greater than 1300 ng / mL, or approximately 1600 ng / mL or greater than 1600 ng / mL, but less than approximately 6000 ng / mL. In some embodiments, the average C min The average C is approximately 1000 ng / mL or greater than 1000 ng / mL, but less than approximately 6000 ng / mL. In some embodiments, the average C min The average C is approximately 1300 ng / mL or greater than 1300 ng / mL, but less than approximately 6000 ng / mL. In some embodiments, the average C min It is approximately 1600 ng / mL or greater than 1600 ng / mL, but less than approximately 6000 ng / mL. In some embodiments, mean whole blood C min The average C is approximately 2000 ng / mL or greater than 2000 ng / mL, approximately 2600 ng / mL or greater than 2600 ng / mL, or approximately 3200 ng / mL or greater than 3200 ng / mL, but less than approximately 12000 ng / mL. In some embodiments, the average C min The average C is approximately 2000 ng / mL or greater than 2000 ng / mL, but less than approximately 12000 ng / mL. In some embodiments, the average C min The average C is approximately 2600 ng / mL or greater than 2600 ng / mL, but less than approximately 12000 ng / mL. In some embodiments, the average C min It is approximately 3200 ng / mL or greater than 3200 ng / mL, but less than approximately 12000 ng / mL. In some embodiments, mean whole blood C min The average C is approximately 3000 ng / mL or greater than 3000 ng / mL, approximately 3900 ng / mL or greater than 3900 ng / mL, or approximately 4800 ng / mL or greater than 4800 ng / mL, but less than approximately 18000 ng / mL. In some embodiments, the average C min The average C is approximately 3000 ng / mL or greater than 3000 ng / mL, but less than approximately 18000 ng / mL. In some embodiments, the average C min The average C is approximately 3900 ng / mL or greater than 3900 ng / mL, but less than approximately 18000 ng / mL. In some embodiments, the average C minIt is approximately 4800 ng / mL or greater than 4800 ng / mL, but less than approximately 18000 ng / mL. In some embodiments, mean whole blood C min The average C is approximately 4000 ng / mL or greater than 4000 ng / mL, approximately 5200 ng / mL or greater than 5200 ng / mL, or approximately 6400 ng / mL or greater than 6400 ng / mL, but less than approximately 24000 ng / mL. In some embodiments, the average C min The average C is approximately 4000 ng / mL or greater than 4000 ng / mL, but less than approximately 24000 ng / mL. In some embodiments, the average C min The average C is approximately 5200 ng / mL or greater than 5200 ng / mL, but less than approximately 24000 ng / mL. In some embodiments, the average C min The C5 level is approximately 6400 ng / mL or greater than 6400 ng / mL but less than approximately 24000 ng / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg. In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than approximately 1.25 in mean plasma C5. max vs C min It brings about a ratio. In some embodiments, C max vs C min The ratio is less than 3. In some embodiments, C max vs C min The ratio is less than 2.25.

[0126] In one embodiment, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration is characterized by an average C25 of less than 5, less than 4, less than 3, or less than 2.25 but greater than approximately 1.25. max vs C min It yields a ratio. In some embodiments, the mean C max vs C min The ratio is less than 5 but greater than approximately 1.25. In some embodiments, the mean C max vs C min The ratio is less than 4 but greater than approximately 1.25. In some embodiments, the average C maxvs C min The ratio is less than 3 but greater than approximately 1.25. In some embodiments, the average C max vs C min The ratio is less than 2.25 but greater than approximately 1.25. In some embodiments, C max vs C min The ratio is approximately 2.2. In some embodiments, C max vs C min The ratio is measured in plasma. In some embodiments, C max vs C min The ratio is measured in whole blood. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg.

[0127] In one embodiment, treatment of a person with CDK2-mediated cancer, comprising administering an effective dose of INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, results in a whole blood-to-plasma area under the curve (AUC) ratio of at least about 6 to about 22 when measured on day 1 of administration. In some embodiments, the whole blood-to-plasma AUC ratio is at least about 12 to about 20 when measured on day 1 of administration.

[0128] In another embodiment, treatment of a person with CDK2-mediated cancer, comprising administering an effective dose of INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, results in a whole blood-to-plasma area under-curve (AUC) ratio of at least about 6 to about 40 when measured on day 15 of administration. In some embodiments, the whole blood-to-plasma AUC ratio is at least about 8 to about 18 when measured on day 15 of administration.

[0129] In a different embodiment, treatment of a person with CDK2-mediated cancer, comprising administering an effective dose of INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, is performed with a ratio of RBCs to plasma (K) of at least about 10.0 to about 20.0. RBC / P ) results in a different embodiment, the ratio of RBCs to plasma (K RBC / P) is at least from about 20.0 to about 50.0.

[0130] In a different embodiment, the treatment of a person with CDK2-mediated cancer, comprising administering an effective dose of INX-315 or a pharmaceutically acceptable salt thereof to a person in need of treatment, is performed with a whole blood to plasma ratio (K) of at least about 4.0 to about 10.0. WB / P ) results in a ratio (K) of whole blood to plasma in different embodiments. WB / P ) ranges from at least approximately 8.0 to approximately 20.0.

[0131] In another embodiment, the treatment method involves the t of INX-315 in humans for approximately 12 to 24 hours. 1 / 2 It provides. In some embodiments, t 1 / 2 It is longer than about 12 hours but less than about 18 hours. In some embodiments, t 1 / 2 This is approximately 12 hours or more than approximately 12 hours, approximately 13 hours or more than approximately 13 hours, approximately 14 hours or more than approximately 14 hours, approximately 15 hours or more than approximately 15 hours, approximately 16 hours or more than approximately 16 hours, approximately 17 hours or more than approximately 17 hours, or approximately 18 hours. In some embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours, longer than approximately 16 hours, longer than approximately 16.5 hours, longer than approximately 17 hours, longer than approximately 17.5 hours, or longer than approximately 18 hours. In some embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours. In some embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours. In some embodiments, t 1 / 2 This is approximately 16 hours or more than approximately 16 hours. In some embodiments, the INX-315's t 1 / 2 This is measured for INX-315 in plasma. In some embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in whole blood. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg.

[0132] In a different embodiment, the treatment method involves the t of INX-315 in humans for approximately 8 to 28 hours. 1 / 2 It provides. In different embodiments, t 1 / 2 It is longer than about 10 hours but less than about 26 hours. In different embodiments, t 1 / 2 This is approximately 8 hours or more than approximately 8 hours, approximately 10 hours or more than approximately 10 hours, approximately 12 hours or more than approximately 12 hours, approximately 14 hours or more than approximately 14 hours, approximately 15 hours or more than approximately 15 hours, approximately 16 hours or more than approximately 16 hours, approximately 18 hours or more than approximately 18 hours, or approximately 20 hours. In different embodiments, t 1 / 2 This is approximately 12 hours or more than approximately 12 hours, longer than approximately 14 hours, longer than approximately 16 hours, longer than approximately 18 hours, longer than approximately 20 hours, or longer than approximately 20 hours. In different embodiments, t 1 / 2 This is approximately 9 hours or more than approximately 9 hours. In some embodiments, t 1 / 2 This is approximately 10 hours or more than approximately 10 hours. In different embodiments, t 1 / 2 This is approximately 11 hours or more than approximately 11 hours. In different embodiments, t 1 / 2 This is approximately 12 hours or more than approximately 12 hours. In different embodiments, t 1 / 2 This is approximately 13 hours or more than approximately 13 hours. In different embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours. In different embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours. In different embodiments, t 1 / 2 This is approximately 16 hours or more than approximately 16 hours. In different embodiments, t 1 / 2 This is approximately 17 hours or more than approximately 17 hours. In different embodiments, t 1 / 2 This is approximately 18 hours or more than approximately 18 hours. In different embodiments, t 1 / 2 This is approximately 19 hours or more than approximately 19 hours. In different embodiments, t 1 / 2 This is approximately 20 hours or more than approximately 20 hours. In different embodiments, t 1 / 2 This is approximately 21 hours or more than approximately 21 hours. In different embodiments, t 1 / 2 This is approximately 22 hours or more than approximately 22 hours. In different embodiments, t1 / 2 This is approximately 23 hours or more than approximately 23 hours. In different embodiments, t 1 / 2 This is approximately 24 hours or more than approximately 24 hours. In different embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in plasma. In different embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in whole blood. In different embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg.

[0133] In a different aspect, the treatment method involves the t of INX-315 in humans for approximately 5 to 32 hours. 1 / 2 It provides. In different embodiments, t 1 / 2 It is longer than about 8 hours but less than about 28 hours. In different embodiments, t 1 / 2 This is approximately 5 hours or more than approximately 5 hours, approximately 8 hours or more than approximately 8 hours, approximately 10 hours or more than approximately 10 hours, approximately 12 hours or more than approximately 12 hours, approximately 14 hours or more than approximately 14 hours, approximately 15 hours or more than approximately 15 hours, approximately 16 hours or more than approximately 16 hours, approximately 18 hours or more than approximately 18 hours, or approximately 20 hours. In different embodiments, t 1 / 2 This is approximately 8 hours or more than approximately 8 hours, approximately 12 hours or more than approximately 12 hours, longer than approximately 14 hours, longer than approximately 16 hours, longer than approximately 18 hours, longer than approximately 20 hours, or longer than approximately 20 hours. In different embodiments, t 1 / 2 This is approximately 5 hours or more than approximately 5 hours. In different embodiments, t 1 / 2 This is approximately 6 hours or more than approximately 6 hours. In different embodiments, t 1 / 2 This is approximately 7 hours or more than approximately 7 hours. In different embodiments, t 1 / 2 This is approximately 8 hours or more than approximately 8 hours. In different embodiments, t 1 / 2 This is approximately 9 hours or more than approximately 9 hours. In some embodiments, t 1 / 2 This is approximately 10 hours or more than approximately 10 hours. In different embodiments, t 1 / 2 This is approximately 11 hours or more than approximately 11 hours. In different embodiments, t 1 / 2This is approximately 12 hours or more than approximately 12 hours. In different embodiments, t 1 / 2 This is approximately 13 hours or more than approximately 13 hours. In different embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours. In different embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours. In different embodiments, t 1 / 2 This is approximately 16 hours or more than approximately 16 hours. In different embodiments, t 1 / 2 This is approximately 17 hours or more than approximately 17 hours. In different embodiments, t 1 / 2 This is approximately 18 hours or more than approximately 18 hours. In different embodiments, t 1 / 2 This is approximately 19 hours or more than approximately 19 hours. In different embodiments, t 1 / 2 This is approximately 20 hours or more than approximately 20 hours. In different embodiments, t 1 / 2 This is approximately 21 hours or more than approximately 21 hours. In different embodiments, t 1 / 2 This is approximately 22 hours or more than approximately 22 hours. In different embodiments, t 1 / 2 This is approximately 23 hours or more than approximately 23 hours. In different embodiments, t 1 / 2 This is approximately 24 hours or more than approximately 24 hours. In different embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in plasma. In different embodiments, the t of INX-315 1 / 2 This is measured for INX-315 in whole blood. In different embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose of 100 mg to 500 mg.

[0134] Treatment method As intended herein, or treating a patient (including a human) in need of treatment, involves administering an effective dose of INX-315 or a pharmaceutically acceptable salt thereof, which provides a substantially improved hemopharmacological (PK) or pharmacodynamic (PD) profile, resulting in higher and longer-lasting blood and plasma levels than expected, without a significant spike immediately after administration.

[0135] In one embodiment, the patient has cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor-positive (HR+) breast cancer. In some embodiments, the breast cancer is estrogen receptor-positive (ER+) breast cancer. In some embodiments, the breast cancer is progesterone receptor-positive (PR+) breast cancer. In some embodiments, the breast cancer is human epidermal growth factor receptor 2-negative (HER2-). In some embodiments, the breast cancer is HR+ / HER2- breast cancer. In some embodiments, the breast cancer is ER+ / HER2- breast cancer. In some embodiments, the breast cancer is triple-negative breast cancer (TNBC). In some embodiments, the TNBC is Rb-independent. In some embodiments, the breast cancer has cyclin E amplification or overexpression. In some embodiments, the breast cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the breast cancer has progressed with a prior CDK4 / 6 inhibitor regimen. In some embodiments, the breast cancer is endocrine therapy resistant. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration is performed with an average C value less than 5 but greater than approximately 1.25. max vs C min This results in a ratio. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration takes approximately 12 to 18 hours. 1 / 2 This brings about... In some embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours. In some embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours. In some embodiments, t 1 / 2The response time is approximately 16 hours or more than approximately 16 hours. In some embodiments, INX-315 is administered in doses of approximately 100 mg to approximately 500 mg. In some embodiments, INX-315 is administered in doses of approximately 100 mg, approximately 125 mg, or approximately 150 mg. In some embodiments, INX-315 is administered in doses of approximately 200 mg, approximately 225 mg, or approximately 250 mg. In some embodiments, INX-315 is administered in doses of approximately 300 mg, approximately 325 mg, or approximately 350 mg. In some embodiments, INX-315 is administered in doses of approximately 400 mg, approximately 425 mg, or approximately 450 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0136] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer has cyclin E amplification or overexpression. In some embodiments, the ovarian cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the ovarian cancer is endocrine therapy resistant. In some embodiments, the ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, the administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients requiring administration is less than 5 but greater than about 1.25 mean C max vs C min In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients with lung cancer results in a ratio of approximately 12 to 24 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 12 to 18 hours. 1 / 2 This brings about... In some embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours but less than approximately 18 hours. In some embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours but less than approximately 18 hours. In some embodiments, t 1 / 2The response time is approximately 16 hours or more than approximately 16 hours but less than approximately 18 hours. In some embodiments, INX-315 is administered in doses of approximately 100 mg to approximately 500 mg. In some embodiments, INX-315 is administered in doses of approximately 100 mg, approximately 125 mg, or approximately 150 mg. In some embodiments, INX-315 is administered in doses of approximately 200 mg, approximately 225 mg, or approximately 250 mg. In some embodiments, INX-315 is administered in doses of approximately 300 mg, approximately 325 mg, or approximately 350 mg. In some embodiments, INX-315 is administered in doses of approximately 400 mg, approximately 425 mg, or approximately 450 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0137] In some embodiments, the cancer is lung cancer. In some embodiments, the lung cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the lung cancer is small cell lung cancer (SCLC). In some embodiments, SCLC has cyclin E amplification or overexpression. In some embodiments, SCLC is Rb-independent. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients with lung cancer results in a mean C15 less than 5 but greater than approximately 1.25. max vs C min In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients with lung cancer results in a ratio of approximately 12 to 24 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients with lung cancer results in a t of approximately 12 to 18 hours. 1 / 2 This brings about... In some embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours but less than approximately 18 hours. In some embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours but less than approximately 18 hours. In some embodiments, t 1 / 2The response time is approximately 16 hours or more than approximately 16 hours but less than approximately 18 hours. In some embodiments, INX-315 is administered in doses of approximately 100 mg to approximately 500 mg. In some embodiments, INX-315 is administered in doses of approximately 100 mg, approximately 125 mg, or approximately 150 mg. In some embodiments, INX-315 is administered in doses of approximately 200 mg, approximately 225 mg, or approximately 250 mg. In some embodiments, INX-315 is administered in doses of approximately 300 mg, approximately 325 mg, or approximately 350 mg. In some embodiments, INX-315 is administered in doses of approximately 400 mg, approximately 425 mg, or approximately 450 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0138] In some embodiments, the cancer is prostate cancer.

[0139] In some embodiments, the cancer is bladder cancer.

[0140] In some embodiments, cancer is a sarcoma.

[0141] In some embodiments, the cancer is uterine cancer. In some embodiments, the uterine cancer is endometrial cancer.

[0142] In some embodiments, the therapeutic methods described herein are used to treat solid tumors. In some embodiments, the solid tumors have amplified or overexpressed cyclin E. In some embodiments, the solid tumors progressed with standard treatment.

[0143] In some specific embodiments, the cancer treated using the method herein is selected from bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, glioblastoma multiforme (GBM), head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, peritoneal cancer, prostate cancer, sarcoma, skin cancer, gastric cancer, or uterine cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is small cell lung cancer (SCLC). In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor-positive (HR+) and HER2-negative. In some embodiments, the breast cancer is estrogen receptor-positive (ER+). In some embodiments, the breast cancer is progesterone receptor-positive (PR+). In some embodiments, the breast cancer is HER2-negative (HER2-). In some embodiments, the breast cancer is triple-negative breast cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, cancer is esophageal cancer. In some embodiments, esophageal cancer includes esophageal adenocarcinoma. In some embodiments, ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, cancer is prostate cancer. In some embodiments, cancer is sarcoma. In some embodiments, cancer is uterine cancer. In some embodiments, cancer is advanced unresectable cancer and / or metastatic cancer. In some embodiments, cancer amplifies or overexpresses cyclin E. In some embodiments, next-generation sequencing (NGS) panel testing is used to confirm the state of cyclin E overexpression or amplification. In some embodiments, the person has previously received at least one prior line of chemotherapy. In some embodiments, the person has previously received at least two prior lines of chemotherapy. In some embodiments, the person has previously received at least one prior line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one prior line of endocrine therapy. In some embodiments, the cancer was recurrent. In some embodiments, the cancer progressed after prior standard treatment.In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer was intolerant to or unsuitable for standard treatment. In some embodiments, the cancer was refractory. In some embodiments, the cancer progressed after a prior regimen containing a platinum analog. In some embodiments, the cancer was platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a prior regimen containing a CDK4 / 6 inhibitor. In some embodiments, the cancer was CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after a prior regimen containing endocrine therapy. In some embodiments, the cancer was endocrine therapy-resistant.

[0144] In one aspect, the cancer treated using the method described herein is Rb-positive cancer. In some embodiments, Rb-positive cancer is selected from Rb-positive lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, cutaneous melanoma or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, anal cancer, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small intestine cancer, endocrine cancer, thyroid cancer, parathyroid cancer, adrenal gland cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureter cancer, renal cell carcinoma, renal pelvis carcinoma, central nervous system (CNS) neoplasm, primary CNS lymphoma, spinal axial tumor, brainstem glioma, or pituitary adenoma. In some embodiments, Rb-positive cancer is selected from Rb-positive HR+ / HER2- breast cancer, ER+ / HER2- breast cancer, high-grade serous ovarian cancer (HGSOC), non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, or glioblastoma. In some embodiments, Rb-positive cancer is HR+ / HER2- breast cancer. In some embodiments, Rb-positive cancer is ER+ / HER2- breast cancer. In some embodiments, Rb-positive cancer is high-grade serous ovarian cancer (HGSOC). In some embodiments, Rb-positive cancer is non-small cell lung cancer (NSCLC).

[0145] In some embodiments, INX-315 or its pharmaceutically acceptable salts or ASD formulations described herein provide an additive or synergistic effect on the effect of CDK4 / 6 inhibitors for the treatment of Rb-positive cancer. In some embodiments, the CDK4 / 6 inhibitor is a selective CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocilib, or darpiciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is rerocilib. In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birocilib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the method further includes administering an effective amount of selective CDK4 inhibitor. In some embodiments, the selective CDK4 inhibitor is PF-07220060. In some embodiments, the CDK4 / 6 inhibitor is administered in a regimen of standard dose and frequency. In some embodiments, the CDK4 / 6 inhibitor is administered at at least about 80%, at least about 75%, at least about 70%, at least about 66.7%, at least about 65%, at least about 60%, at least about 50%, or about 50% of the standard dose. In some embodiments, the CDK4 / 6 inhibitor is administered at 75% of the standard dose. In some embodiments, the CDK4 / 6 inhibitor is administered at 66.7% of the standard dose. In some embodiments, the CDK4 / 6 inhibitor is administered at 50% of the standard dose. In some embodiments, the method further includes administering a chemotherapeutic agent.In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the method further includes administering endocrine therapy. In some embodiments, the endocrine therapy includes SERD. In some embodiments, SERD is selected from fulvestrant or elastrant. In some embodiments, the person has previously received at least one preceding line of standard treatment. In some embodiments, the person has previously received at least two preceding lines of standard treatment. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after prior standard treatment. In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard treatment. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after prior regimens containing platinum analogs. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after prior regimens containing CDK4 / 6 inhibitors. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after prior regimens containing endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0146] In different embodiments, cancers treated using the methods described herein are Rb-independent cancers. In some embodiments, Rb-independent cancers are selected from breast cancer, lung cancer, prostate cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, retinoblastoma, osteosarcoma, or lymphoma. In some embodiments, Rb-independent cancers are selected from small cell lung cancer (SCLC), retinoblastoma, triple-negative breast cancer (TNBC), human papillomavirus (HPV)-positive head and neck cancer, HPV-positive cervical cancer, or neuroendocrine prostate cancer. In some embodiments, Rb-independent cancer is SCLC. In some embodiments, Rb-independent cancer is TNBC. In some embodiments, Rb-independent cancer is bladder cancer.

[0147] In some embodiments, INX-315 or its pharmaceutically acceptable salts or ASD formulations described herein provide an additive or synergistic effect on the effects of CDK4 / 6 inhibitors for the treatment of Rb-independent cancers. In some embodiments, the CDK4 / 6 inhibitor is a selective CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocilib, or darpiciclib. In some embodiments, the CDK4 / 6 inhibitor is palbociclib. In some embodiments, the CDK4 / 6 inhibitor is ribociclib. In some embodiments, the CDK4 / 6 inhibitor is rerocilib. In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, birocilib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the method further includes administering an effective amount of selective CDK4 inhibitor. In some embodiments, the selective CDK4 inhibitor is PF-07220060. In some embodiments, the CDK4 / 6 inhibitor is administered in a regimen of standard dose and frequency. In some embodiments, the CDK4 / 6 inhibitor is administered at at least about 80%, at least about 75%, at least about 70%, at least about 66.7%, at least about 65%, at least about 60%, at least about 50%, or about 50% of the standard dose. In some embodiments, the CDK4 / 6 inhibitor is administered at 75% of the standard dose. In some embodiments, the CDK4 / 6 inhibitor is administered at 66.7% of the standard dose. In some embodiments, the CDK4 / 6 inhibitor is administered at 50% of the standard dose. In some embodiments, the method further includes administering a chemotherapeutic agent.In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the method further includes administering endocrine therapy. In some embodiments, the endocrine therapy includes SERD. In some embodiments, SERD is selected from fulvestrant or elastrant. In some embodiments, the person has previously received at least one preceding line of standard treatment. In some embodiments, the person has previously received at least two preceding lines of standard treatment. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after prior standard treatment. In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard treatment. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after prior regimens containing platinum analogs. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after prior regimens containing CDK4 / 6 inhibitors. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after prior regimens containing endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0148] In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation described herein is used in combination with palbociclib for the treatment of subjects with cancer. In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation is administered in combination with palbociclib, which is administered for 21 days in a 28-day cycle with a 7-day rest period. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor-positive (HR+) and HER2-negative. In some embodiments, the breast cancer is estrogen receptor-positive (ER+). In some embodiments, the breast cancer is progesterone receptor-positive (PR+). In some embodiments, the breast cancer is HER2-negative (HER2-). In some embodiments, the cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, cancer is endometrial cancer. In some embodiments, cancer is esophageal cancer. In some embodiments, esophageal cancer includes esophageal adenocarcinoma. In some embodiments, ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, cancer is prostate cancer. In some embodiments, cancer is sarcoma. In some embodiments, cancer is uterine cancer. In some embodiments, cancer is gastric cancer. In some embodiments, cancer is advanced unresectable cancer and / or metastatic cancer. In some embodiments, cancer includes Rb-independent cancer. In some embodiments, Rb-independent cancer is SCLC. In some embodiments, Rb-independent cancer is TNBC. In some embodiments, the method further includes administering a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin.In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the method further includes administering endocrine therapy. In some embodiments, the endocrine therapy includes SERD. In some embodiments, SERD is selected from fulvestrant or elastrant. In some embodiments, the person has previously received at least one preceding line of standard treatment. In some embodiments, the person has previously received at least two preceding lines of standard treatment. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer has progressed after preceding standard treatment. In some embodiments, the cancer has progressed after preceding systemic therapy. In some embodiments, the cancer is intolerant or unsuitable for standard treatment. In some embodiments, the cancer is refractory. In some embodiments, the cancer has progressed after a preceding regimen containing a platinum analog. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a prior regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after a prior regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0149] In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation described herein is used in combination with ribociclib for the treatment of subjects with cancer. In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation is administered in combination with ribociclib, which is administered for 21 days in a 28-day cycle with a 7-day rest period. In some embodiments, the cancer is breast cancer. In some embodiments, the breast cancer is hormone receptor-positive (HR+) and HER2-negative. In some embodiments, the breast cancer is estrogen receptor-positive (ER+). In some embodiments, the breast cancer is progesterone receptor-positive (PR+). In some embodiments, the breast cancer is HER2-negative (HER2-). In some embodiments, the cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, cancer is endometrial cancer. In some embodiments, cancer is esophageal cancer. In some embodiments, esophageal cancer includes esophageal adenocarcinoma. In some embodiments, ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, cancer is prostate cancer. In some embodiments, cancer is sarcoma. In some embodiments, cancer is uterine cancer. In some embodiments, cancer is gastric cancer. In some embodiments, cancer is advanced unresectable cancer and / or metastatic cancer. In some embodiments, cancer includes Rb-independent cancer. In some embodiments, Rb-independent cancer is SCLC. In some embodiments, Rb-independent cancer is TNBC. In some embodiments, the method further includes administering a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin.In some embodiments, the chemotherapeutic agent is cisplatin. In some embodiments, the method further includes administering endocrine therapy. In some embodiments, the endocrine therapy includes SERD. In some embodiments, SERD is selected from fulvestrant or elastrant. In some embodiments, the person has previously received at least one preceding line of standard treatment. In some embodiments, the person has previously received at least two preceding lines of standard treatment. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer has progressed after preceding standard treatment. In some embodiments, the cancer has progressed after preceding systemic therapy. In some embodiments, the cancer is intolerant or unsuitable for standard treatment. In some embodiments, the cancer is refractory. In some embodiments, the cancer has progressed after a preceding regimen containing a platinum analog. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a prior regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after a prior regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0150] In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation described herein is used in combination with abemaciclib for the treatment of subjects with cancer. In some embodiments, the cancer is breast cancer. In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation is administered in combination with continuously administered abemaciclib. In some embodiments, the breast cancer is hormone receptor-positive (HR+) and HER2-negative. In some embodiments, the breast cancer is estrogen receptor-positive (ER+). In some embodiments, the breast cancer is progesterone receptor-positive (PR+). In some embodiments, the breast cancer is HER2-negative (HER2-). In some embodiments, the cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, cancer is esophageal cancer. In some embodiments, esophageal cancer includes esophageal adenocarcinoma. In some embodiments, ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, cancer is prostate cancer. In some embodiments, cancer is sarcoma. In some embodiments, cancer is uterine cancer. In some embodiments, cancer is gastric cancer. In some embodiments, cancer is advanced unresectable cancer and / or metastatic cancer. In some embodiments, cancer includes Rb-independent cancer. In some embodiments, Rb-independent cancer is SCLC. In some embodiments, Rb-independent cancer is TNBC. In some embodiments, the method further includes administering a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is cisplatin.In some embodiments, the method further includes administering endocrine therapy. In some embodiments, the endocrine therapy includes SERD. In some embodiments, SERD is selected from fulvestrant or elastrant. In some embodiments, the person has previously received at least one preceding line of standard treatment. In some embodiments, the person has previously received at least two preceding lines of standard treatment. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer has progressed after preceding standard treatment. In some embodiments, the cancer has progressed after preceding systemic therapy. In some embodiments, the cancer is intolerant or unsuitable for standard treatment. In some embodiments, the cancer is refractory. In some embodiments, the cancer has progressed after a preceding regimen containing a platinum analog. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a prior regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after a prior regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0151] In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation described herein is used in combination with rerocyclib for the treatment of subjects with cancer. In some embodiments, the cancer is breast cancer. In some embodiments, INX-315 or its pharmaceutically acceptable salt or ASD formulation is administered in combination with continuously administered rerocyclib. In some embodiments, the breast cancer is hormone receptor-positive (HR+) and HER2-negative. In some embodiments, the breast cancer is estrogen receptor-positive (ER+). In some embodiments, the breast cancer is progesterone receptor-positive (PR+). In some embodiments, the breast cancer is HER2-negative (HER2-). In some embodiments, the cancer is ER+ / HER2- breast cancer. In some embodiments, the cancer is lung cancer. In some embodiments, the cancer is bladder cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is endometrial cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, esophageal cancer includes esophageal adenocarcinoma. In some embodiments, ovarian cancer includes high-grade serous ovarian carcinoma (HGSOC). In some embodiments, cancer is prostate cancer. In some embodiments, cancer is sarcoma. In some embodiments, cancer is uterine cancer. In some embodiments, cancer is gastric cancer. In some embodiments, cancer is advanced unresectable cancer and / or metastatic cancer. In some embodiments, cancer includes Rb-independent cancer. In some embodiments, Rb-independent cancer is SCLC. In some embodiments, Rb-independent cancer is TNBC. In some embodiments, the method further includes administering a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the chemotherapeutic agent is carboplatin. In some embodiments, the chemotherapeutic agent is cisplatin.In some embodiments, the method further includes administering endocrine therapy. In some embodiments, the endocrine therapy includes SERD. In some embodiments, SERD is selected from fulvestrant or elastrant. In some embodiments, the person has previously received at least one preceding line of standard treatment. In some embodiments, the person has previously received at least two preceding lines of standard treatment. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer has progressed after preceding standard treatment. In some embodiments, the cancer has progressed after preceding systemic therapy. In some embodiments, the cancer is intolerant or unsuitable for standard treatment. In some embodiments, the cancer is refractory. In some embodiments, the cancer has progressed after a preceding regimen containing a platinum analog. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a prior regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after a prior regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0152] In some embodiments, INX-315 or its pharmaceutically acceptable salts or ASD formulations described herein provide additive or synergistic effects on the anticancer or antiproliferative activity of chemotherapeutic agents for the treatment of Rb-independent cancer. In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or a combination thereof. In some embodiments, the person has previously received at least one preceding line of chemotherapy. In some embodiments, the person has previously received at least two preceding lines of chemotherapy. In some embodiments, the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one preceding line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer has progressed after prior standard treatment. In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer was intolerant to or unsuitable for standard treatment. In some embodiments, the cancer was refractory. In some embodiments, the cancer progressed after a prior regimen containing a platinum analog. In some embodiments, the cancer was platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a prior regimen containing a CDK4 / 6 inhibitor. In some embodiments, the cancer was CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after a prior regimen containing endocrine therapy. In some embodiments, the cancer was endocrine therapy-resistant.

[0153] In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 2750 ng·hr / mL or greater than 2750 ng·hr / mL but less than approximately 28000 ng·hr / mL, as measured on day 1 of administration. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 1250 ng·hr / mL or greater than 1250 ng·hr / mL but less than approximately 20000 ng·hr / mL, as measured on day 1 of administration. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL but less than approximately 50000 ng·hr / mL, as measured on day 1 of administration. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean peak plasma concentration (C) in humans of approximately 150 ng / mL or greater than 150 ng / mL but less than approximately 2000 ng / mL, as measured on day 1 of administration. max In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a mean peak plasma concentration (C) of approximately 100 ng / mL or greater than 100 ng / mL but less than approximately 1600 ng / mL, as measured on day 1 of administration. max In different embodiments, administration of INX-315 or its pharmaceutically acceptable salt to human patients requiring administration results in a mean peak plasma concentration (C) of approximately 75 ng / mL or greater than 75 ng / mL but less than approximately 2400 ng / mL, as measured on day 1 of administration. maxIn some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum plasma concentration (C) of approximately 50 ng / mL or greater than 50 ng / mL but less than approximately 1000 ng / mL, as measured on day 1 of administration. min In different embodiments, administration of INX-315 or its pharmaceutically acceptable salt to human patients requiring administration results in a mean minimum plasma concentration (C) of approximately 20 ng / mL or greater than 20 ng / mL but less than approximately 600 ng / mL, as measured on day 1 of administration. min In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum free plasma concentration (C) of approximately 4.0 ng / mL or greater than 4.0 ng / mL but less than approximately 48.0 ng / mL, as measured on day 1 of administration. min free In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 5000 ng·hr / mL or greater than 5000 ng·hr / mL but less than approximately 56000 ng·hr / mL, as measured on day 15 of administration. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean plasma area under the curve (AUC) (ng·hr / mL) of approximately 1250 ng·hr / mL or greater than 1250 ng·hr / mL but less than approximately 28000 ng·hr / mL, as measured on day 15 of administration. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration resulted in a mean peak plasma concentration (C) of approximately 300 ng / mL or greater than 300 ng / mL but less than approximately 4000 ng / mL, as measured on day 15 of administration. maxIn different embodiments, administration of INX-315 or its pharmaceutically acceptable salt to human patients requiring administration results in a mean peak plasma concentration (C) of approximately 90 ng / mL or greater than 90 ng / mL but less than approximately 2800 ng / mL, as measured on day 15 of administration. max In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean lowest plasma concentration (C) of approximately 100 ng / mL or greater than 100 ng / mL but less than approximately 2000 ng / mL, as measured on day 15 of administration. min In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum free plasma concentration (C) of approximately 6.0 ng / mL or greater than 6.0 ng / mL but less than approximately 80.0 ng / mL, as measured on day 15 of administration. min free In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 30,000 ng·hr / mL or greater than 30,000 ng·hr / mL but less than approximately 480,000 ng·hr / mL when measured on day 1 of administration. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 25,000 ng·hr / mL or greater than 25,000 ng·hr / mL but less than approximately 400,000 ng·hr / mL when measured on day 1 of administration. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean peak whole blood concentration (C) of approximately 2000 ng / mL or greater than 2000 ng / mL but less than approximately 28000 ng / mL, as measured on day 1 of administration. maxIn some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum whole blood concentration (C) of approximately 800 ng / mL or greater than 800 ng / mL but less than approximately 14400 ng / mL, as measured on day 1 of administration. min In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum whole blood concentration (C) of approximately 500 ng / mL or greater than 500 ng / mL but less than approximately 8000 ng / mL, as measured on day 1 of administration. min In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 50,000 ng·hr / mL or greater than 50,000 ng·hr / mL but less than approximately 800,000 ng·hr / mL when measured on day 15 of administration. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean whole blood area under the curve (AUC) (ng·hr / mL) of approximately 25,000 ng·hr / mL or greater than 25,000 ng·hr / mL but less than approximately 600,000 ng·hr / mL when measured on day 15 of administration. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration resulted in a mean peak whole blood concentration (C) of approximately 3000 ng / mL or greater than 3000 ng / mL but less than approximately 56000 ng / mL, as measured on day 15 of administration. max In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in an average minimum whole blood concentration (C) of approximately 1000 ng / mL or greater than 1000 ng / mL but less than approximately 24000 ng / mL, as measured on day 15 of administration. minThis results in a (ng / mL) ratio. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a whole blood to plasma area under curve (AUC) ratio of approximately 6 or greater than 6 but less than 22, as measured on day 1 of administration. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a whole blood to plasma area under curve (AUC) ratio of approximately 6 or greater than 6 but less than 40, as measured on day 15 of administration. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients requiring administration results in a mean C2 ratio of less than 5 but greater than approximately 1.25. max vs C min In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof in human patients with lung cancer results in a ratio of approximately 12 to 24 hours. 1 / 2 In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient requiring administration results in a time interval of approximately 12 to 18 hours. 1 / 2 This brings about... In some embodiments, t 1 / 2 This is approximately 14 hours or more than approximately 14 hours but less than approximately 18 hours. In some embodiments, t 1 / 2 This is approximately 15 hours or more than approximately 15 hours but less than approximately 18 hours. In some embodiments, t 1 / 2The response time is approximately 16 hours or more than approximately 16 hours but less than approximately 18 hours. In some embodiments, INX-315 is administered in doses of approximately 100 mg to approximately 500 mg. In some embodiments, INX-315 is administered in doses of approximately 100 mg, approximately 125 mg, or approximately 150 mg. In some embodiments, INX-315 is administered in doses of approximately 200 mg, approximately 225 mg, or approximately 250 mg. In some embodiments, INX-315 is administered in doses of approximately 300 mg, approximately 325 mg, or approximately 350 mg. In some embodiments, INX-315 is administered in doses of approximately 400 mg, approximately 425 mg, or approximately 450 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0154] In some specific embodiments, disclosed herein is a method for treating a human having cancer having overexpression and / or activation of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) compared to a control sample, wherein the overexpression and / or activation of CCNE1 and / or CCNE2 constitutes cancer that amplifies or overexpresses cyclin E. In some embodiments, cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) in a sample of the subject to be treated are overexpressed and / or activated by at least 1.5 times, at least 2.0 times, at least 2.5 times, at least 3.0 times, at least 3.5 times, at least 4.0 times, at least 4.5 times, at least 5.0 times, or more than 5.0 times compared to a control sample. In some embodiments, the method further comprises administering an effective amount of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is a selective CDK4 / 6 inhibitor. In some embodiments, the additional CDK4 / 6 inhibitor is selected from palbociclib, ribociclib, abemaciclib, trilaciclib, rerocyclib, or dalpiciclib. In some embodiments, the additional CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, bilociclib (XZP-3287), LY5219, PF-07220060, or ON-123300. In some embodiments, the method further includes administering an effective amount of a selective CDK4 inhibitor. In some embodiments, the selective CDK4 inhibitor is PF-07220060. In some embodiments, an NGS panel test is used to confirm the state of CCNE1 or CCNE2 overexpression or amplification.In some embodiments, the NGS panel test to confirm the overexpression or amplification of CCNE1 or CCNE2 is selected from Foundation One® CDx, Foundation One® Liquid CDx, Tempus xT (Solid Tumor), Tempus xF (Liquid Biopsy), Caris® Life Sciences Molecular Profiling, or OncoHelix Solid Tumor NGS. In some embodiments, the patient sample is selected from tumor tissue, formalin-fixed paraffin-embedded (FFPE) tumor tissue, blood, or plasma.

[0155] In some embodiments, INX-315 is administered in doses ranging from approximately 100 mg to approximately 500 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses ranging from approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, or approximately 500 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses ranging from approximately 100 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses ranging from approximately 200 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 300 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 400 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in a dose of approximately 500 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0156] Pharmaceutical compositions and dosage forms INX-315 or its pharmaceutically acceptable salts may be administered to a host in an effective dose according to the methods described herein to treat any disorder described herein using any preferred approach to achieve the desired therapeutic outcome. The dose and timing of INX-315 administration will naturally depend on the host being treated, the instructions of the supervising healthcare professional, the time course of exposure, the method of administration, the pharmacokinetic properties, and the judgment of the prescribing physician. Therefore, due to variability among hosts, the dosages shown below are guidelines, and physicians may adjust the dose of the compound to achieve the treatment they deem appropriate for the host. When considering the desired degree of treatment, physicians may balance various factors such as the host's age and weight, the presence of pre-existing diseases, and the presence of other diseases.

[0157] Amorphous solid dispersion spray-dried formulation In some embodiments, INX-315 is co-spray dried as an amorphous spray-dried dispersion (ASD) with a precipitation inhibitor in a solvent to achieve the desired functionality of the ASD for the final pharmaceutical composition.

[0158] Spray drying is the process of converting a fluid feed into a dry, particulate form by spraying the feed into a high-temperature drying medium. A spray drying process used in the manufacture of ASD typically includes (i) a feed atomization step, which atomizes the feed into a fine spray; (ii) a step of drying the atomized feed droplets with a high-temperature drying gas to form solid particles; and (iii) a step of separating the dry particles from the gas.

[0159] In some embodiments, the spray-dried solution comprises INX-315, a precipitation inhibitor, and a solvent. In some embodiments, the precipitation inhibitor is selected from cellulose derivatives, polyvinylpyrrolidone (PVP) and PVP / VA (vinyl acetate), or polymethacrylate. In some embodiments, the precipitation inhibitor is selected from hypromellose, e.g., HPMC 2910, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethylcellulose (Na-CMC), polyacrylic acid, polyethylene glycol, e.g., PEG 4000, PEG 6000, PEG 8000, and PEG 20000, and polyvinylpyrrolidone, e.g., PVP K 30, PVP K 25, PVP VA64, and PVP VA37. In some embodiments, HPMCAS is selected from HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, or HPMCAS-E3. In some embodiments, HPMCAS is HPMCAS-H. In some embodiments, HPMCAS is HPMCAS-HF. In some embodiments, HPMCAS is HPMCAS-HG. In some embodiments, the precipitation inhibitor is selected from erythritol, maltodextrin, mannitol, crospovidone, colloidal silicon dioxide, polysorbate 80, lactose, PVP, PVP-VA, chitosan chlorhydrate, meglumine, copovidone, HPMC, sodium alginate, or carmellose sodium.

[0160] In some embodiments, INX-315 is about 20% to about 50% by weight of ASD. In some embodiments, INX-315 is about 25% to about 45% by weight of ASD. In some embodiments, INX-315 is about 40% by weight of ASD. In some embodiments, the preservation inhibitor in ASD is about 40% to about 70% by weight of ASD. In some embodiments, the preservation inhibitor in ASD is about 45% to about 65% by weight of ASD. In some embodiments, the preservation inhibitor in ASD is about 60% by weight of ASD.

[0161] The liquid feed used for spray drying may be a suspension, solution, or emulsion. The liquid solution, suspension, or emulsion can be pumped from the feed container through the atomizing nozzle to the drying chamber. In some embodiments, water is used as the solvent in the liquid feed. In some embodiments, a moderately non-toxic organic solvent and / or co-solvent or aqueous suspension suitable for the pharmaceutical formulation is used to prepare the liquid feed. In some embodiments, the solvent is selected from water, ethanol, isopropanol, dioxane, chloroform, THF, butylated hydroxytoluene (BHT) stabilized THF, methanol, siRNA, acetone, dichloromethane, or mixtures thereof. In some embodiments, the solvent is selected from water, acetic acid, acetone, anisole, 1-butanol, 2-butanol, butyl acetate, tert-butyl methyl ether, 1,1-diethoxypropane, 1,1-dimethoxymethane, 2,2-dimethoxypropane, dimethyl sulfoxide, ethanol, ethyl acetate, ethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isooctane, isopropyl ether, methyl acetate, methyl isopropyl ketone, methyl tetrahydrofuran, 3-methyl-1-butanol, methyl ethyl ketone, 2-methyl-1-propanol, pentane, 1-pentanol, petroleum ether, 1-propanol, 2-propanol, propyl acetate, trichloroacetic acid, trifluoroacetic acid, triethylamine, or mixtures thereof. In some embodiments, the solvent includes or consists of methanol and water. In some embodiments, the solvent includes or consists of THF and water. In some embodiments, the solvent includes or consists of 80% THF and 20% water. In some embodiments, the solvent comprises or consists of 90% THF and 10% water. In some embodiments, the solvent comprises or consists of 92% THF and 8% water. Atomization is typically achieved using either a pressurized nozzle or a rotating disc atomizer. In alternative embodiments, an ultrasonic nozzle or a two-fluid nozzle may be used.

[0162] When the liquid feed is atomized, the fine spray comes into contact with a hot drying gas. In some embodiments, the hot drying gas is nitrogen. The feed and gas flows can be counterflow, parallel, or mixed. In the drying process, the liquid evaporates almost instantaneously, producing solid particles. In the spray drying process, the feed can be atomized into a fine spray or mist with a huge surface area that facilitates the evaporation of the solvent, so the drying rate of the feed is extremely fast. The solid particles obtained from spray drying can be granules, powders, or aggregates.

[0163] The final step in the spray drying process is to separate the dry particles from the gas. This can be done, for example, using a filter or a cyclone.

[0164] In some embodiments, the pharmaceutical composition is prepared from an ASD formulation as described herein. For example, in some embodiments, the pharmaceutical composition is prepared from an ASD formulation comprising amorphous INX-315 and an anti-precipitation agent, where the ASD formulation is dry-granulated, dry-mixed, and then tableted with one or more pharmaceutically acceptable excipients. In some embodiments, the use of a pharmaceutical composition comprising an INX-315 ASD formulation as described herein provides improved PK parameters, including, for example, sustained and elevated drug exposure in plasma and whole blood.

[0165] In one embodiment, the herein provides a pharmaceutical composition comprising an amorphous spray-dried dispersion (ASD) of a compound having the structure of INX-315 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the ASD further comprises an anti-precipitation agent. In some embodiments, the amount of INX-315 is about 20% to about 60% by weight of the ASD. In some embodiments, the amount of INX-315 is about 30% to about 50% by weight of the ASD. In some embodiments, the amount of INX-315 is about 40% by weight of the ASD. In some embodiments, the pharmaceutical composition contains about 100 mg to about 500 mg of INX-315. In some embodiments, the anti-precipitation agent is hydroxypropyl methylcellulose acetate succinate (HPMCAS). In some embodiments, the anti-precipitation agent is HPMCAS-HG. In some embodiments, the amount of the anti-precipitation agent in the ASD is about 40% to about 80% by weight of the ASD. In some embodiments, the precipitation inhibitor in the ASD is about 60% by weight of the ASD. In some embodiments, the ASD is about 40% to about 60% by weight of the pharmaceutical composition. In some embodiments, the ASD is about 50% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes an insoluble diluent. In some embodiments, the insoluble diluent is microcrystalline cellulose. In some embodiments, the insoluble diluent is about 15% to about 25% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a soluble diluent. In some embodiments, the soluble diluent is mannitol. In some embodiments, the soluble diluent is about 15% to about 25% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a disintegrant. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is about 1% to about 10% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a fluidizing agent. In some embodiments, the fluidizing agent is colloidal silicon dioxide. In some embodiments, the fluidizing agent is present in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition includes a lubricant.In some embodiments, the lubricant is sodium stearyl fumarate. In some embodiments, the lubricant is present in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition.

[0166] Pharmaceutical compositions may be formulated in any pharmaceutically useful form, such as liquid oral dosage forms, solid oral dosage forms, semi-solid oral dosage forms, aerosols, creams, gels, pills, solutions for injection or infusion, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation preparations, in-medical devices, suppositories, buccal preparations, or sublingual preparations, parenteral preparations, or eye drops. Some dosage forms, such as tablets and capsules, are divided into appropriate unit doses of appropriate size containing an appropriate amount of active components, for example, an effective amount to achieve the desired purpose.

[0167] INX-315 or a pharmaceutically acceptable salt thereof, as used as described herein, may be administered orally, topically, parenterally, by inhalation or spray, sublingually, implanted (including intraocular implants), transdermally, buccally, rectally, in ophthalmic solution, injection (including intraocular injection), intramuscularly, by inhalation, subaortically, intracranially, intradermally, intraperitoneally, subcutaneously, nasally, sublingually, or rectally, or by other means, in unit dosage forms containing conventionally pharmaceutically acceptable carriers. For delivery to the eye, the compound may be administered, as desired, for example, intravitreous, intrastromal, anterior chamber, sub-Tenon's capsule, subretinal, retrobulbar, peribulbar, superchoroidal, conjunctiva, subconjunctival, episclera, periophthalmos, transscleral, retrobulbar, near the posterior sclera, periliac duct injection, or via mucus, mucin, or the mucosal barrier, in an immediate-release or controlled-release manner, or via an intraocular device.

[0168] In some embodiments, pharmaceutical compositions comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof in ASD are administered orally. For example, in some embodiments, pharmaceutical compositions comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof and an anti-precipitation agent in ASD are administered orally.

[0169] The therapeutically effective dose of INX-315 or its pharmaceutically acceptable salt may be determined by a healthcare professional depending on the patient's condition, size, and age, as well as the route of delivery. In some specific non-limiting embodiments, doses ranging from about 0.1 mg / kg to about 200 mg / kg are therapeutically effective, and all weights are calculated based on the weight of INX-315, including when salts are used. In some embodiments, the dose is about 0.1 mg / kg or greater than 0.1 mg / kg, about 0.5 mg / kg or greater than 0.5 mg / kg, about 1 mg / kg or greater than 1 mg / kg, about 5 mg / kg or greater than 5 mg / kg, about 10 mg / kg or greater than 10 mg / kg, or about 25 mg / kg or greater than 25 mg / kg.

[0170] In some embodiments, the pharmaceutical composition is a dosage form containing about 50 mg to 500 mg of INX-315 in a unit dosage form, for example, 100 mg to 400 mg or 500 mg, or more specifically, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg, 225 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, or 500 mg of INX-315. In some embodiments, the pharmaceutical composition is a dosage form containing about 100 mg or 150 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a dosage form containing about 200 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a dosage form containing about 300 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a dosage form containing about 400 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is a dosage form containing about 500 mg of INX-315 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may also contain INX-315 or a pharmaceutically acceptable salt thereof in a molar ratio that achieves the desired result, and an additional activator (e.g., a selective CDK4 inhibitor).

[0171] In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered once daily (QD). In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered twice daily (QD). In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered at least once daily for a period of at least 21 days, at least 24 days, at least 28 days, at least 35 days, at least 45 days, at least 60 days, at least 75 days, at least 90 days, at least 120 days, at least 180 days, at least 1 year, or longer, including indefinitely, or until the healthcare provider determines that the drug is no longer needed.

[0172] According to the methods of this disclosure, oral administration can take any desired form, such as a solid, gel, or liquid, including a solution, suspension, or emulsion. In some embodiments, INX-315 or a salt thereof is administered by inhalation or intramuscular administration as a liposome suspension. When administered by inhalation, INX-315 or a salt thereof may be in the form of a plurality of solid particles or droplets having any desired particle size, and for example, about 0.01 microns, 0.1 microns, or 0.5 microns to about 5 microns, 10 microns, 20 microns or more, and optionally about 1 micron to about 2 microns.

[0173] Pharmaceutical formulations may contain INX-315 or a pharmaceutically acceptable salt thereof in any pharmaceutically acceptable carrier. If a solution is desired, water may be a suitable carrier for water-soluble compounds or salts. For water-soluble compounds or salts, organic vehicles such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof may be suitable. In the latter case, the organic vehicle may contain a substantial amount of water. In either case, the solution can be sterilized by a suitable method known to those skilled in the art, for example, by filtration through a 0.22 micron filter.

[0174] The carrier, comprising excipients and diluents, must be of sufficiently high purity and sufficiently low toxicity to be suitable for administration to the patient being treated. The carrier may be inert or may have pharmaceutically beneficial properties of its own. The amount of carrier used in conjunction with INX-315 is sufficient to provide a practical amount of material for administration per unit dose of INX-315.

[0175] Examples of carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavorings, fluidizers, lubricants, preservatives, stabilizers, surfactants, tablet compressors, and wetting agents. Some carriers may be of two or more types; for example, vegetable oil may be used as a lubricant in some formulations and as a diluent in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, cellulose, tragacanth powder, malt, gelatin, talc, and vegetable oils. Pharmaceutical compositions may contain any active ingredients, which do not substantially interfere with the activity of INX-315.

[0176] Furthermore, auxiliary substances such as wetting agents or emulsifiers, biological buffers, and surfactants may be present in such vehicles. The biological buffer can be any pharmacologically acceptable solution that provides the formulation with a desired pH, i.e., a physiologically acceptable pH range. Examples of buffers include physiological saline, phosphate-buffered saline, Tris-buffered saline, and Hank's-buffered saline.

[0177] Depending on the intended mode of administration, the pharmaceutical composition may be in solid, semi-solid, or liquid form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably in a unit dosage form suitable for a single dose of a precise amount. The composition contains an effective amount of INX-315 combined with a pharmaceutically acceptable carrier, and may further contain other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0178] In some specific independent embodiments of the present invention, there are provided: i) an ASD formulation of the present invention comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof spray-dried with a precipitation inhibitor; and ii) a pharmaceutical composition optionally further comprising one or more pharmaceutically acceptable excipients, wherein the ASD formulation is dry-granulated, dry-mixed, and then tableted with one or more optional pharmaceutically acceptable excipients. In some embodiments, the precipitation inhibitor in the ASD comprises hydroxypropyl methylcellulose acetate succinate (HPMCAS) selected from HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, or HPMCAS-E3. In some embodiments, the amount of INX-315 is about 10% to about 30% by weight of the pharmaceutical composition, or about 15% to about 25% by weight of the pharmaceutical composition. In some embodiments, INX-315 is present in about 20% by weight of the pharmaceutical composition. In some embodiments, the precipitation inhibitor in ASD is present in about 20% to about 50% by weight of the pharmaceutical composition. In some embodiments, the precipitation inhibitor in ASD is present in about 25% to about 45% by weight of the pharmaceutical composition. In some embodiments, the precipitation inhibitor in ASD is present in about 30% by weight of the pharmaceutical composition.

[0179] In some embodiments, amorphous INX-315 or a pharmaceutically acceptable salt thereof, and the precipitation inhibitor, in the ASD formulations and pharmaceutical compositions described herein, are within the following weight / weight percentage ranges:

[0180] TIFF2026518846000006.tif44170

[0181] In some embodiments, the pharmaceutical composition comprises amorphous INX-315 or a pharmaceutically acceptable salt thereof and an anti-precipitation agent spray-dried together in an ASD formulation, after which one or more pharmaceutically acceptable excipients selected from insoluble diluents, soluble diluents, disintegrants, fluidizers, and / or lubricants are dry-granulated, dry-mixed, and then compressed together into tablets. Non-limiting examples of one or more pharmaceutically acceptable excipients include vitamin E (e.g., d-α-tocopheryl polyethylene glycol succinate), mannitol, cellulose (e.g., microcrystalline cellulose), croscarmellose sodium, silicon dioxide (e.g., untreated fumed colloid), and stearyl fumarate sodium. In some embodiments, the pharmaceutical composition according to the present invention is formulated into unit dosage forms such as oral unit dosage forms. In some embodiments, the pharmaceutical composition according to the present invention is formulated into tablet dosage forms.

[0182] In some embodiments, a pharmaceutical composition comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof comprises one or more of the following pharmaceutically acceptable excipients:

[0183] TIFF2026518846000007.tif61170

[0184] In some embodiments, the process for producing a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient comprises: (i) spray-drying a solution comprising INX-315 or a pharmaceutically acceptable salt thereof and an anti-precipitation agent to obtain an amorphous spray-dried dispersion (ASD) comprising INX-315 or a pharmaceutically acceptable salt thereof; (ii) granulating the ASD together with one or more pharmaceutically acceptable excipients to provide granules; (iii) dry-mixing the granules together with one or more pharmaceutically acceptable excipients; and (iv) tablet-compressing the dry-mixed granules to provide a pharmaceutical composition comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in oral unit dosage form. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 100 mg to about 500 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 100 mg to about 300 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 100 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 150 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 200 mg to about 400 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 200 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 250 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 300 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 350 mg. In some embodiments, the oral unit dosage form has a nominal tablet active ingredient content of about 400 mg.

[0185] Accordingly, the compositions of this disclosure can be administered as pharmaceutical preparations, including those suitable for oral (including buccal and sublingual) administration, rectal administration, nasal administration, topical administration, pulmonary administration, vaginal administration, or parenteral (including intramuscular, intrathecal, and subcutaneous) administration, or in forms suitable for administration by inhalation or airflow. The preferred method of administration is oral administration using a simple daily dosage regimen that can be adjusted according to the degree of the disease.

[0186] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, and magnesium carbonate. Liquid pharmaceutically administerable compositions can be prepared, for example, by dissolving and dispersing INX-315 or a pharmaceutically acceptable salt thereof and any pharmaceutical adjuvant in an excipient such as water, physiological saline, aqueous dextrose, glycerol, or ethanol, thereby forming a solution or suspension. Optionally, the administered pharmaceutical composition may also contain small amounts of non-toxic auxiliary substances such as wetting agents or emulsifiers, pH buffers, etc., such as sodium acetate, sorbitan monolaurate, sodium triethanolamine acetate, and triethanolamine oleate. Practical methods for preparing such dosage forms may be known or obvious to those skilled in the art. For example, see Remington's Pharmaceutical Sciences, 23rd Edition, A. Adejare, Editor, Academic Press (2020); Handbook of Pharmaceutical Excipients, 6th Edition, RC Rowe, PJ Sheskey, ME Quinn, Editors, American Pharmaceutical Association, and Pharmaceutical Press (2009); and Handbook of Pharmaceutical Additives, 3rd Edition, compiled by Michael and Irene Ash, Synapse Information Resources (2007).

[0187] In yet another embodiment, permeation-promoting excipients containing polymers ar...

Claims

1. A pharmaceutical composition comprising an amorphous spray-dried dispersion (ASD) of INX-315 and a pharmaceutically acceptable excipient, INX-315 has the following structure: 【Chemistry 1】 A compound of or a pharmaceutically acceptable salt thereof, A pharmaceutical composition comprising the ASD further containing a precipitation inhibitor.

2. The pharmaceutical composition according to claim 1, wherein INX-315 is present in an amount of about 20% to about 60% by weight of the ASD.

3. The pharmaceutical composition according to claim 1, wherein INX-315 is present in an amount of about 30% to about 50% by weight of the ASD.

4. The pharmaceutical composition according to claim 1, wherein INX-315 is approximately 40% by weight of the ASD.

5. A pharmaceutical composition according to any one of claims 1 to 4, comprising approximately 100 mg to approximately 500 mg of INX-315.

6. The aforementioned precipitation inhibitors include cellulose derivatives, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethylcellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, and PVP. A pharmaceutical composition according to any one of claims 1 to 4, selected from K 30, PVP K 25, PVP VA 64, or PVP VA 37.

7. The pharmaceutical composition according to claim 6, wherein the precipitation inhibitor is HPMCAS-HG.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the precipitation inhibitor in the ASD is in an amount of about 40% to about 80% by weight of the ASD.

9. The pharmaceutical composition according to any one of claims 1 to 7, wherein the precipitation inhibitor in the ASD is approximately 60% by weight of the ASD.

10. The pharmaceutical composition according to any one of claims 1 to 9, wherein the ASD is in an amount of about 40% to about 60% by weight of the pharmaceutical composition.

11. The pharmaceutical composition according to any one of claims 1 to 9, wherein the ASD is approximately 50% by weight of the pharmaceutical composition.

12. A pharmaceutical composition according to any one of claims 1 to 11, comprising an insoluble diluent.

13. The pharmaceutical composition according to claim 12, wherein the insoluble diluent is microcrystalline cellulose.

14. The pharmaceutical composition according to claim 12 or 13, wherein the insoluble diluent is in an amount of about 15% to about 25% by weight of the pharmaceutical composition.

15. A pharmaceutical composition according to any one of claims 1 to 14, comprising a soluble diluent.

16. The pharmaceutical composition according to claim 15, wherein the soluble diluent is mannitol.

17. The pharmaceutical composition according to claim 15 or 16, wherein the soluble diluent is in an amount of about 15% to about 25% by weight of the pharmaceutical composition.

18. A pharmaceutical composition according to any one of claims 1 to 17, comprising a disintegrant.

19. The pharmaceutical composition according to claim 18, wherein the disintegrant is croscarmellose sodium.

20. The pharmaceutical composition according to claim 18 or 19, wherein the disintegrant is in an amount of about 1% to about 10% by weight of the pharmaceutical composition.

21. A pharmaceutical composition according to any one of claims 1 to 20, comprising a fluidizing agent.

22. The pharmaceutical composition according to claim 21, wherein the fluidizing agent is colloidal silicon dioxide.

23. The pharmaceutical composition according to claim 21 or 22, wherein the fluidizing agent is in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition.

24. A pharmaceutical composition according to any one of claims 1 to 20, comprising a lubricant.

25. The pharmaceutical composition according to claim 24, wherein the lubricant is sodium stearyl fumarate.

26. The pharmaceutical composition according to claim 24 or 25, wherein the lubricant is present in an amount of about 0.1% to about 5% by weight of the pharmaceutical composition.

27. A method for treating a person having heterogeneous CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 2】 (INX-315) This includes administering an effective amount of the compound or a pharmaceutically acceptable salt thereof. A method wherein the heterogeneous CDK2-mediated cancer comprises a mixture of retinoblastoma protein (Rb)-dependent cells and Rb-independent cells.

28. INX-315 or a pharmaceutically acceptable salt thereof is administered as a component of a pharmaceutical composition, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing about 100 mg to about 500 mg of INX-315. The method according to claim 27, wherein the amount of INX-315 in the ASD is 20% by weight to 60% by weight.

29. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Transformation 3】 (INX-315) The process involves administering an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, which results in an average plasma area under the curve (AUC) (ng・hr / mL) of approximately 1250 to approximately 50000 when measured on day 1 of administration. The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

30. The method according to any one of claims 27 to 29, wherein the mean plasma AUC measured on day 1 of administration is 6,000 to 50,000.

31. The method according to any one of claims 27 to 29, wherein the mean plasma AUC measured on day 1 of administration is 9,000 to 50,000.

32. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 4】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average peak plasma concentration (C) measured on day 1 is approximately 75 to approximately 2400. ｍａｘ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

33. The average plasma C measured on day 1 of administration ｍａｘ The method according to any one of claims 27 to 32, wherein is 350 to 2400.

34. The average plasma C measured on day 1 of administration ｍａｘ The method according to any one of claims 27 to 32, wherein is 525 to 2400.

35. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Transformation 5】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average minimum plasma concentration (C) measured on day 1 is approximately 20 to approximately 1000. ｍｉｎ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

36. The average plasma C measured on day 1 of administration ｍｉｎ The method according to any one of claims 27 to 35, wherein is 120 to 1000.

37. The average plasma C measured on day 1 of administration ｍｉｎ The method according to any one of claims 27 to 35, wherein is 180 to 1000.

38. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Transformation 6】 (INX-315) The process involves administering an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average minimum free plasma concentration (C) measured on day 1 is approximately 4.0 to approximately 48.

0. ｍｉｎ ｆｒｅｅ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

39. The average C measured on the first day of administration ｍｉｎ ｆｒｅｅ is 10 to 48, and the method according to any one of claims 27 to 38.

40. The average C measured on day 1 of administration. ｍｉｎ ｆｒｅｅ The method according to any one of claims 27 to 38, wherein is 15 to 48.

41. A method for treating a human patient with CDK2-mediated cancer, comprising: 【Transformation 7】 (INX-315) The process involves administering an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, which results in an average plasma area under the curve (AUC) (ng・hr / mL) of approximately 1250 to approximately 56000 when measured on day 15 of administration. The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

42. The method according to any one of claims 27 to 41, wherein the mean plasma AUC measured on day 15 of administration is 11,000 to 56,000.

43. The method according to any one of claims 27 to 41, wherein the mean plasma AUC measured on day 15 of administration is 16,500 to 56,000.

44. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Transformation 8】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average peak plasma concentration (C) measured on day 15 of administration is approximately 90 to approximately 4000. ｍａｘ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

45. The average plasma C measured on day 15 of administration. ｍａｘ The method according to any one of claims 27 to 44, wherein is 700 to 4000.

46. The average plasma C measured on day 15 of administration. ｍａｘ The method according to any one of claims 27 to 44, wherein is 1050 to 4000.

47. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 9】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average minimum plasma concentration (C) measured on day 15 of administration is approximately 100 to approximately 2000. ｍｉｎ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

48. The average plasma C measured on day 15 of administration. ｍｉｎ The method according to any one of claims 27 to 47, wherein is 250 to 2000.

49. The average plasma C measured on day 15 of administration. ｍｉｎ The method according to any one of claims 27 to 47, wherein is 375 to 2000.

50. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 10】 (INX-315) The process involves administering an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average minimum free plasma concentration (C) measured on day 15 of administration is approximately 6.0 to approximately 80.

0. ｍｉｎ ｆｒｅｅ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

51. The average C measured on the 15th day of administration. ｍｉｎ ｆｒｅｅ The method according to any one of claims 27 to 50, wherein is 14 to 80.

52. The average C measured on the 15th day of administration. ｍｉｎ ｆｒｅｅ The method according to any one of claims 27 to 50, wherein is 21 to 80.

53. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 11】 (INX-315) The process involves administering an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, which results in an average whole blood area under the curve (AUC) (ng・hr / mL) of approximately 25,000 to approximately 480,000 when measured on day 1 of administration. The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

54. The method according to any one of claims 27 to 53, wherein the mean whole blood AUC measured on day 1 of administration is 80,000 to 480,000.

55. The method according to any one of claims 27 to 53, wherein the mean whole blood AUC measured on day 1 of administration is 120,000 to 480,000.

56. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 12】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average peak whole blood concentration (C) measured on day 1 is approximately 2000 to approximately 28000. ｍａｘ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

57. The average whole blood C measured on day 1 of administration ｍａｘ The method according to any one of claims 27 to 56, wherein is 4500 to 28000.

58. The average whole blood C measured on day 1 of administration ｍａｘ The method according to any one of claims 27 to 56, wherein is 6750 to 28000.

59. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 13】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average minimum whole blood concentration (C) measured on day 1 is approximately 500 to approximately 14400. ｍｉｎ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

60. The average whole blood C measured on day 1 of administration ｍｉｎ The method according to any one of claims 27 to 59, wherein is 1800 to 14400.

61. The average whole blood C measured on day 1 of administration ｍｉｎ The method according to any one of claims 27 to 59, wherein is 2700 to 14400.

62. For humans requiring administration, structure: 【Chemistry 14】 (INX-315) A method of administering a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein, when measured on day 15 of administration, this results in an average whole blood area under the curve (AUC) (ng・hr / mL) of approximately 25,000 to approximately 800,000. The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

63. The method according to any one of claims 27 to 62, wherein the mean whole blood AUC measured on the 15th day after administration is 120,000 to 800,000.

64. The method according to any one of claims 27 to 62, wherein the mean whole blood AUC measured on the 15th day after administration is 180,000 to 800,000.

65. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 15】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average peak whole blood concentration (C) measured on day 15 of administration is approximately 3,000 to approximately 56,000. ｍａｘ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

66. The average whole blood C measured on day 15 of administration. ｍａｘ The method according to any one of claims 27 to 65, wherein is 7000 to 56000.

67. The average whole blood C measured on day 15 of administration. ｍａｘ The method according to any one of claims 27 to 65, wherein is 10500 to 56000.

68. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 16】 (INX-315) The administration of an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average minimum whole blood concentration (C) measured on day 15 of administration is approximately 1,000 to approximately 24,000. ｍｉｎ ) (ng / mL) results in The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

69. The average whole blood C ｍｉｎ The method according to any one of claims 27 to 68, wherein is 2600 to 24000.

70. The average whole blood C ｍｉｎ The method according to any one of claims 27 to 68, wherein is 3900 to 24000.

71. a) Mean plasma C1.25–5 ｍａｘ C in plasma ｍｉｎ Ratio, and / or b) Mean whole blood C12 of 1.25–5 ｍａｘ C in whole blood ｍｉｎ The method according to any one of claims 27 to 70, further yielding any of the ratios.

72. Average plasma C levels for 3-5 ｍａｘ C in plasma ｍｉｎ The method according to any one of claims 27 to 70, further providing a ratio.

73. Average whole blood C in 3-5 year olds ｍａｘ C in whole blood ｍｉｎ The method according to any one of claims 27 to 70, further providing a ratio.

74. A method for treating a person having CDK2-mediated cancer, wherein the person requiring treatment has a structure: 【Chemistry 17】 (INX-315) The method involves administering an effective dose of a pharmaceutical composition containing the compound or a pharmaceutically acceptable salt thereof, wherein the average plasma C is less than about 5 but greater than about 1.

25. ｍａｘ C in plasma ｍｉｎ Bringing about a ratio, The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing approximately 100 mg to approximately 500 mg of INX-315. A method wherein the amount of INX-315 in the ASD is 20% to 60% by weight.

75. Said C ｍａｘ vs C ｍｉｎ The method according to claim 74, wherein the ratio is less than 3.

76. Said C ｍａｘ vs C ｍｉｎ The method according to claim 74, wherein the ratio is less than 2.

25.

77. Said C ｍａｘ vs C ｍｉｎ The method according to any one of claims 74 to 76, wherein the ratio is measured in plasma.

78. Said C ｍａｘ vs C ｍｉｎ The method according to any one of claims 74 to 76, wherein the ratio is measured in whole blood.

79. Approximately 5 hours to approximately 32 hours １／２ The method according to any one of claims 27 to 78, which brings about the following:

80. Approximately 8 hours to approximately 28 hours １／２ The method according to any one of claims 27 to 78, which brings about the following:

81. Approximately 12 to 18 hours １／２ The method according to any one of claims 27 to 78, which brings about the following:

82. Said t １／２ The method according to any one of claims 79 to 81, wherein the time is approximately 14 hours.

83. Said t １／２ The method according to any one of claims 79 to 81, wherein the time is approximately 15 hours.

84. Said t １／２ The method according to any one of claims 79 to 81, wherein the time is approximately 16 hours.

85. The method according to any one of claims 27 to 84, wherein INX-315 is administered once daily.

86. The method according to any one of claims 27 to 85, wherein INX-315 is administered orally.

87. The method according to any one of claims 28 to 86, wherein the amount of INX-315 in the ASD is about 40%.

88. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 100 mg.

89. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 125 mg.

90. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 150 mg.

91. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 175 mg.

92. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 200 mg.

93. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 225 mg.

94. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 250 mg.

95. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 275 mg.

96. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 300 mg.

97. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 325 mg.

98. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 350 mg.

99. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 375 mg.

100. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 400 mg.

101. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 425 mg.

102. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 450 mg.

103. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 475 mg.

104. The method according to any one of claims 28 to 87, wherein the total amount of INX-315 in the pharmaceutical composition is about 500 mg.

105. The method according to any one of claims 28 to 104, wherein the pharmaceutical composition further comprises a precipitation inhibitor.

106. The method according to claim 105, wherein the amount of the preservation inhibitor in the ASD is 40% to 70% by weight.

107. The method according to claim 105 or 106, wherein the amount of the precipitation inhibitor in the ASD is about 60% by weight.

108. The aforementioned precipitation inhibitors include cellulose derivatives, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethacrylate, hypromellose, HPMC 2910, hydroxyethylcellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), HPMCAS-L, HPMCAS-LF, HPMCAS-LG, HPMCAS-M, HPMCAS-MF, HPMCAS-MG, HPMCAS-H, HPMCAS-HF, HPMCAS-HG, HPMCAS-E3, hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethylcellulose (Na-CMC), polyacrylic acid, polyethylene glycol, PEG 4000, PEG 6000, PEG 8000, PEG 20000, polyvinylpyrrolidone, and PVP. The method according to any one of claims 105 to 107, selected from K 30, PVP K 25, PVP VA 64, or PVP VA 37.

109. The method according to claim 108, wherein the precipitation inhibitor is HPMCAS.

110. The method according to any one of claims 28 to 109, wherein the pharmaceutical composition further comprises one or more additional pharmaceutically acceptable excipients.

111. The method according to any one of claims 27 to 110, wherein the human patient has a tumor.

112. The method according to any one of claims 29 to 110, wherein the CDK2-mediated cancer is selected from bladder cancer, breast cancer, cervical cancer, colon cancer, endometrial cancer, esophageal cancer, fallopian tube cancer, glioblastoma multiforme (GBM), head and neck cancer, kidney cancer, liver cancer, lung cancer, ovarian cancer, peritoneal cancer, prostate cancer, sarcoma, skin cancer, gastric cancer, and uterine cancer.

113. The method according to claim 112, wherein the CDK2-mediated cancer is lung cancer.

114. The method according to claim 113, wherein the lung cancer is small cell lung cancer (SCLC).

115. The method according to claim 112, wherein the CDK2-mediated cancer is breast cancer.

116. The method according to claim 115, wherein the breast cancer is hormone receptor positive (HR+).

117. The method according to claim 115 or 116, wherein the breast cancer is estrogen receptor positive (ER+).

118. The method according to any one of claims 115 to 117, wherein the breast cancer is progesterone receptor positive (PR+).

119. The method according to any one of claims 115 to 118, wherein the breast cancer is HER2-negative.

120. The method according to claim 115, wherein the breast cancer is triple-negative breast cancer.

121. The method according to claim 112, wherein the CDK2-mediated cancer is bladder cancer.

122. The method according to claim 112, wherein the CDK2-mediated cancer is ovarian cancer.

123. The method according to claim 112, wherein the CDK2-mediated cancer is prostate cancer.

124. The method according to claim 112, wherein the CDK2-mediated carcinoma is a sarcoma.

125. The method according to claim 112, wherein the CDK2-mediated cancer is uterine cancer.

126. The method according to any one of claims 111 to 125, wherein the CDK2-mediated cancer is advanced unresectable cancer and / or metastatic cancer.

127. The method according to any one of claims 111 to 126, wherein the CDK2-mediated cancer amplifies or overexpresses cyclin E.

128. The method according to claim 127, wherein the state of cyclin E overexpression or amplification is confirmed using next-generation sequencing (NGS) panel testing.

129. The method according to any one of claims 111 to 128, wherein the CDK2-mediated cancer is Rb-positive cancer.

130. The method according to claim 129, wherein the Rb-positive cancer is selected from Rb-positive HR+ / HER2- breast cancer, ER+ / HER2- breast cancer, high-grade serous ovarian cancer (HGSOC), non-small cell lung cancer (NSCLC), colon cancer, prostate cancer, or glioblastoma.

131. The method according to claim 130, wherein the Rb-positive cancer is HR+ / HER2- breast cancer.

132. The method according to claim 130, wherein the Rb-positive cancer is ER+ / HER2- breast cancer.

133. The method according to claim 130, wherein the Rb-positive cancer is high-grade serous ovarian cancer (HGSOC).

134. The method according to claim 130, wherein the Rb-positive cancer is non-small cell lung cancer (NSCLC).

135. The method according to any one of claims 111 to 128, wherein the CDK2-mediated cancer is Rb-independent cancer.

136. The method according to claim 135, wherein the Rb-independent cancer is selected from breast cancer, lung cancer, prostate cancer, liver cancer, bladder cancer, ovarian cancer, uterine cancer, cervical cancer, gastric cancer, esophageal cancer, head and neck cancer, glioblastoma, retinoblastoma, osteosarcoma, or lymphoma.

137. The method according to claim 135, wherein the Rb-independent cancer is selected from small cell lung cancer (SCLC), retinoblastoma, triple-negative breast cancer (TNBC), human papillomavirus (HPV)-positive head and neck cancer, HPV-positive cervical cancer, or neuroendocrine prostate cancer.

138. The method according to claim 137, wherein the Rb-independent cancer is SCLC.

139. The method according to claim 137, wherein the Rb-independent cancer is TNBC.

140. The method according to any one of claims 27 to 139, wherein the human has previously received at least one preceding line of chemotherapy.

141. The method according to any one of claims 27 to 140, wherein the human has previously received at least two preceding lines of chemotherapy.

142. The method according to any one of claims 27 to 141, wherein the person has previously received at least one preceding line of CDK4 / 6 inhibitor therapy.

143. The method according to any one of claims 27 to 142, wherein the person has previously received at least one preceding line of endocrine therapy.

144. The method according to any one of claims 27 to 143, wherein the CDK2-mediated cancer is recurrent.

145. The method according to any one of claims 27 to 144, wherein the CDK2-mediated cancer is resistant to CDK4 / 6 inhibitors.

146. The method according to any one of claims 27 to 145, wherein the CDK2-mediated cancer progresses after a prior regimen including endocrine therapy.

147. The method according to any one of claims 27 to 146, wherein the CDK2-mediated cancer is resistant to endocrine therapy.

148. The method according to any one of claims 27 to 147, wherein the treatment results in a reduction in the occurrence of adverse events during treatment compared to the predicted number of adverse events during treatment in subjects receiving CDK2 treatment other than INX-315.

149. The method according to any one of claims 27 to 148, wherein the treatment results in a reduction in the occurrence of abnormal clinical laboratory values ​​compared to the predicted number of abnormal clinical laboratory values ​​in subjects receiving CDK2 treatment other than INX-315.

150. The method according to any one of claims 27 to 149, wherein the treatment results in improved overall survival (OS) compared to the predicted overall survival (OS) in subjects receiving CDK2 treatment other than INX-315.

151. The method according to any one of claims 27 to 150, wherein the treatment results in an improved overall response rate (ORR) compared to the predicted overall response rate (ORR) in subjects receiving CDK2 treatment other than INX-315.

152. The method according to any one of claims 27 to 151, wherein the treatment results in an improved disease control rate (DCR) compared to the DCR in subjects receiving CDK2 treatment other than INX-315.

153. The method according to any one of claims 27 to 152, wherein the treatment results in improved progression-free survival (PFS) compared to the predicted PFS in subjects receiving CDK2 treatment other than INX-315.

154. The method according to any one of claims 27 to 153, wherein the treatment results in an improved duration of response (DOR) compared to the predicted duration of response (DOR) in subjects receiving CDK2 treatment other than INX-315.

155. The method according to any one of claims 27 to 154, wherein the treatment results in an extension of the predicted progression-free period (TTP) compared to the time to progression (TTP) in subjects receiving CDK2 treatment other than INX-315.

156. The method according to any one of claims 148 to 155, wherein the CDK2 treatment other than INX-315 comprises the administration of a CDK2 inhibitor selected from BLU-222 or PF-07104091.

157. The method according to claim 156, wherein the CDK2 inhibitor is BLU-222.

158. The method according to claim 156, wherein the CDK2 inhibitor is PF-07104091.

159. The method according to any one of claims 148 to 158, wherein the CDK2 inhibitor other than INX-315 is administered in the same dose and frequency as INX-315.

160. A process for producing a pharmaceutical composition according to any one of claims 1 to 26, (v) A solution containing INX-315 or a pharmaceutically acceptable salt thereof and an anti-precipitation agent is spray-dried to obtain an amorphous spray-dried dispersion (ASD), (vi) Granulating the ASD together with one or more pharmaceutically acceptable excipients to provide a granulated product, (vii) Dry mixing the granules with one or more additional pharmaceutically acceptable excipients, (viiii) Compressing the dry-mixed granules into tablets, A process that includes this.

161. The process according to claim 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of about 100 mg to about 500 mg.

162. The process according to claim 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of about 100 mg.

163. The process according to claim 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of about 200 mg.

164. The process according to claim 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of about 300 mg.

165. The process according to claim 160, wherein the pharmaceutical composition has a nominal tablet active ingredient content of about 400 mg.

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