Advantageous human dosage regimen for administration of INX-315

Abstract

Doses and regimens are based on the discovery of unexpectedly high and sustained INX-315 exposure in a person in need thereof, which results in increased efficacy per dose and minimizes adverse events during treatment, including by minimizing the ratio of Cmax to Cmin, resulting in a reduction in initial drug peak after administration.

Description

[0001] Cross-reference to related applications

[0002] This application claims the benefits of U.S. Provisional Application No. 63 / 460,201, filed April 18, 2023; U.S. Provisional Application No. 63 / 470,621, filed June 2, 2023; International Application No. PCT / US2023 / 025791, filed June 20, 2023; U.S. Provisional Application No. 63 / 540,884, filed September 27, 2023; and U.S. Provisional Application No. 63 / 612,840, filed December 20, 2023. The entire contents of these applications are incorporated herein by reference for all purposes. Technical Field

[0003] This invention provides dosage and regimens based on the discovery of unexpectedly high and sustained exposure to INX-315 after administration to individuals in need. The surprisingly high and sustained exposure to INX-315 was unpredictable prior to administration to humans. This surprising pharmacokinetic behavior results in increased efficacy per dose and minimizes adverse events during treatment, including minimizing the initial peak at administration time (C0). max With C min The ratio. Background Technology

[0004] Cell division is regulated by the cell cycle, which consists of four phases: G1 phase (cell growth and machinery synthesis), S phase (DNA replication to produce two identical sets of chromosomes), G2 phase (cell growth and supplementary machinery synthesis), and M phase (a single cell divides into two identical daughter cells). The progression between cell cycle phases is primarily controlled by cyclins and cyclin-dependent kinases (CDKs) (Asghar et al., Nat Rev Drug Discov. 14(2):130-46(2015)), which are activated or inhibited in response to complex cellular signaling networks that interpret extracellular signals.

[0005] Cyclin-dependent kinase 2 (CDK2) is activated upon binding to cyclin E and is essential for entering the S phase of the cell cycle (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)). The CDK2 / cyclin E protein complex and the CDK4 / 6 / cyclin D protein complex phosphorylate retinoblastoma (Rb) and release G1 transcription factor E2F to promote S phase completion (Sherr, CJ Mammalian G1 cyclins. Cell. 73(6):1059-65 (1993 Jun 18); Asghar et al. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 14(2):130-146 (2015)). In addition to regulating the G1 / S phase transition, the CDK2 / cyclin E protein complex also mediates histone biosynthesis and centrosome replication (Matsumoto, YK et al. CDK2 is required for centrosome duplication in mammalian cells. Curr Biol. 9:429-432(1999); 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(2002Nov)).

[0006] CDK2-mediated hyperphosphorylation leads to complete inactivation of the Rb protein, which is essential for the completion of S phase. Therefore, retinoblastoma is considered a key protein in the cell cycle system, which includes the CDK2 / cyclin E protein complex. Evidence suggests that CDK2 fundamentally regulates cell proliferation and CDK4 / 6 inhibitor resistance mechanisms, highlighting the potential of targeting CDK2 in cancer (Tadesse, S. et al. Cyclin-Dependent Kinase 2 Inhibitors in Cancer Therapy: An Update. J Med Chem. 62(9):4233-4251(2019 May 9)).

[0007] Several CDK2 inhibitors are currently undergoing human clinical trials for the treatment of cancer (including, for example, BLU-222, Blueprint Medicines Corporation; PF-07104091, Pfizer; INX-315, IncyclixBio; INCB123667, Incyte Medical; and AVZO-021, Avenzo Therapeutics).

[0008] Administration of BLU-222 or PF-07104091 to humans has demonstrated peak plasma concentrations that may lead to side effects. For example, in an open-label, first-in-human, phase 1 / 2 clinical trial (NCT05252416) evaluating the CDK2 inhibitor BLU-222 in advanced solid tumors, several ocular adverse events (AEs) affecting vision were observed in 5 patients (19%). These ocular AEs included transient, reversible light sensitivity, blurred vision, photophobia, and changes in visual acuity. Most ocular AEs were mild, except for one patient who received 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 clinical pause on patient enrollment in February 2023 (Blueprint Medicines announced a partial clinical pause in the phase 1 / 2 VELA trial of BLU-222. Press release (February 10, 2023)), which was lifted following a remission program.

[0009] BLU-222 has the following structure:

[0010] .

[0011] Pfizer's CDK2 inhibitor PF-07104091 is currently being evaluated in a phase 1 study in advanced or metastatic solid tumors (NCT04553133; 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)).

[0012] PF-07104091 has the following structure:

[0013] .

[0014] It was noted that the most common treatment-related adverse events (AEs) of 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).

[0015] Another CDK2 inhibitor that has just entered Phase I clinical trials is INX-315, which was originally disclosed in WO2021 / 236650 by G1 Therapeutics, Inc. and exclusively licensed to IncyclixBio (see also WO2023 / 249974 submitted by Incyclix Bio).

[0016] .

[0017] There remains a need for improved treatment and dosing regimens that can be used to treat patients with cancer (including CDK4 / 6 resistant tumors) while minimizing off-target toxicity. Summary of the Invention

[0018] This invention provides dosage and regimens based on the groundbreaking discovery of the first administration in humans of a CDK2 inhibitor having the following structure:

[0019] (INX-315)

[0020] This compound exhibits unique and highly unexpected pharmacokinetic characteristics, which are significantly inconsistent with mathematical pharmacokinetic models extrapolated from other mammalian species (dogs, rats, and mice).

[0021] In one aspect of the invention, advantageous pharmaceutical compositions of INX-315 or pharmaceutically acceptable salts thereof are provided, which, upon administration to humans, result in i) a decrease or minimum of the peak plasma concentration of INX-315 over time, and ii) sustained release of INX-315 into the plasma, allowing for an extended drug half-life. While not wishing to limit itself to a single theory, it is proposed that INX-315 binds to human blood cells in vivo to a much greater degree than observed in other tested mammals or predicted prior to administration to humans. This increases the amount of drug available in the human bloodstream and creates a reservoir effect that prolongs drug availability due to the release of the drug from red blood cells into the plasma and then to the site of treatment over time.

[0022] In another aspect of the invention, a solid dosage form pharmaceutical formulation of INX-315 or a pharmaceutically acceptable salt thereof is provided, which enhances the bioavailability and release characteristics 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 acting as a precipitation inhibitor. INX-315 is highly insoluble and readily crystallizes. This compound tends to self-aggregate and crystallize in solid form. This can occur during production, storage, and even after human administration. As a result of studies on the formulation, it has been found that the efficacy of the drug is enhanced when a pharmaceutically acceptable precipitation inhibitor is included in the amorphous spray-dried dispersion. Certain suitable precipitation inhibitors include, but are not limited to, polyvinylpyrrolidone, polymethyl methacrylate, pharmaceutically acceptable cellulose derivatives (e.g., hydroxypropyl methylcellulose succinate (HPMCAS)), etc., which adequately prevent precipitation of INX-315, as further described in the “Detailed Description”. The ASD can be granulated together with a suitable excipient. In some embodiments, the pharmaceutical composition is a tablet comprising a mixture of INX-315 ASD granules containing a sufficient amount of a precipitation enhancer and one or more excipients (i.e., excipients added after granulation but before compression or tableting). This pharmaceutical composition is well tolerated in human patients and has been successfully administered in exemplary solid dosage forms, such as 100, 200, and 300 mg strength tablets.

[0023] Surprisingly, INX-315 has also been found to be effective in treating Rb-independent (Rb-negative) cancers in humans, based on human data. As noted in the background section of this invention, INX-315 is a CDK2 inhibitor that is activated upon binding to its binding partner, cyclin E. When cyclin E amplifies, the cell enters the S phase of the cell cycle, leading to uncontrolled replication in cancer cases. CDK2-mediated hyperphosphorylation inactivates Rb proteins, which are essential for the completion of the S phase. However, it has now been found that INX-315 can also inhibit uncontrolled replication in certain cancers that do not involve the cyclin E / retinoblastoma mechanism. INX-315 may also inhibit cyclin A-mediated replication, which occurs downstream of the retinoblastoma pathway. Using this alternative pathway, INX-315 can be used in doses effective in treating Rb-independent cancers (including, but not limited to, small cell lung cancer (SCLC)) (see, for example...). Figure 15C-15D Other cancers include Rb-independent cancers selected from the following: 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.

[0024] This discovery represents an advancement in cancer therapy by providing a CDK2 inhibitor that can be used to treat both Rb-dependent and Rb-independent tumors (which may include heterogeneous tumors of both). Furthermore, INX-315 can be used in combination with CDK4 / 6 inhibitors, including but not limited to ribociclib (Novartis), abecilib (Eli Lilly), palbociclib (Pfizer Inc.), or lerociclib (G1 Therapeutics, Inc.). In some embodiments, INX-315 is administered daily, and the CDK4 / 6 inhibitor is typically administered for 21 days during a 28-day cycle with a 7-day drug holiday.

[0025] Highly unexpectedly, administration of INX-315 did not result in a peak drug concentration at the initial administration, as is often seen with other drugs such as BLU-222 and PF-07104091. The peak effect is caused by a large initial concentration at the start of administration. max With C min The ratio indicator gradually decreases after application (see [link to relevant documentation]). Figure 2 and Figure 3 Conversely, when C max With C minA lower ratio indicates the absence of a peak. As a non-limiting example, in the first two individuals who received INX-315 at 100 mg once daily, the C0.05 of INX-315 was... max With C min The ratio was measured to be approximately 2.2, while the estimated C was based on published human results for BLU-222 (400 mg twice daily). max With C min The ratio was 9.3, and the estimated C of BLU-222 (600 mg twice daily) was... max With C min The ratio is 22. Similarly, based on publicly available human data, the estimated C of PF-07104091 max With C min The ratio is 16-64 (see Table 5 and...). Figure 2 and Figure 3 The presence of a post-dose peak (a short-term excess of the drug in the blood) can cause side effects and is generally undesirable. Based on this human finding, methods for treating CDK2-mediated cancers have been proposed, which include administering C at the time of administration. max With C min Apply an effective amount of INX-315 at a ratio not exceeding 6, 5, 4, or even 3.

[0026] INX-315 exhibits a very high AUC on day 1 of administration (extending to day 15), significantly higher than predicted based on characteristics observed in non-human mammalian models. As described more fully in specific embodiments of the invention, it is unpredictable beforehand that human pharmacokinetic parameters in humans will be superior to those in other tested mammals. The non-limiting range of AUC in humans administered INX-315 once daily (range 100-300 mg) is 1,000-40,000 ng x hr / ml (in plasma). AUC naturally increases with increasing dose and varies from person to person depending on individual metabolic patterns and individuality.

[0027] It was found that INX-315 binds to red blood cells at higher levels than in plasma, and the ratio of red blood cells to plasma (K0.05) in humans is also higher. RBC / P The ratio of INX-315 in whole blood to plasma may vary between approximately 12-30, 15-30, or approximately 12.0-20.0, which is higher than the ratios in other mammals tested (see Example 2, Table 7). Furthermore, the whole blood to plasma ratio (KL) of INX-315 in humans... WB / P The ratios are approximately 4-10, 5-10, or 6-10, which are also higher than the ratios of other mammals (Table 7).

[0028] For example, as described in Example 10, based on a mammalian model, the predicted AUC of INX-315 administered once daily at 100 mg is approximately 740 (ng). The AUC was measured at hr / mL, however, on day 1 it was 2020 (mean of 5 human patients), and on day 15 it was 3290. These results exceeded predictions by more than 2.7 times and 4.4 times, respectively. Similarly, the predicted C for a 100 mg once-daily dose was... max The concentration (ng / mL) was 39.3, while the concentration measured on day 1 was C. max The value was 148, and C was measured on day 15. max The result was 211. These results exceeded predictions by more than 3.7 times and 5.3 times, respectively. Furthermore, the predicted C for the same dose... min The value was 19.1 (ng / mL), while the actual C on day 1 was... min The value is 103, and the actual C value on day 15 is... min The value is 177. The calculated C at this dose... min 游离 The concentration (ng / mL) was 0.997, while the C observed on day 1 was... min 游离 It was 5.4, and on day 15, C min 游离 The value is 9.2 (see Typical Example 2, Table 2).

[0029] As another example, as described in Example 10, based on a mammalian model, the predicted AUC of INX-315 administered once daily at 200 mg was 1380 (ng). The AUC was 8940 (mean of 5 human patients) measured on day 1 and 12200 on day 15. These results exceeded predictions by more than 6.4 and 8.8 times, respectively. Similarly, the predicted C for a 200 mg once-daily dose was... max The concentration (ng / mL) was 72.3, while the concentration C measured on day 1 was... max The value was 590, and C was measured on day 15. max The result was 922. These results exceeded the predictions by more than 8.1 times and 12.7 times, respectively.

[0030] Furthermore, INX-315 in the range of 0.03 µM to 10 µM exhibited a blood-to-plasma partition ratio (K0.03) of 25–29. RBC / P ), and the whole blood to plasma ratio is 10-16 (K). WB / P Both of these values ​​were significantly higher than those of the mammals tested (Table 8).

[0031] In whole blood, based on a mammalian model, the predicted AUC was 5560 (ng). The actual AUC in humans was a surprising 50,550 on day 1 and 116,350 on day 15 (Table 9). This exceeds the model by 9 times on day 1 and by more than 20 times on day 15 (Table 9).

[0032] As reported in this article, AUC, C max C min and C min 游离 The curves in plasma were approximately 2-3 times higher than predicted based on studies using three non-human animal models, and approximately 9 times higher than in whole blood. This appears to be because the drug binds disproportionately to human erythrocytes compared to those of non-human mammals.

[0033] The invention described herein also includes 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 with a precipitation inhibitor (e.g., a polymer precipitation inhibitor) in a solvent to form a favorable amorphous spray-dried dispersion (ASD) formulation. The precipitation inhibitor minimizes crystallization of INX-315 in the ASD formulation. In a non-limiting embodiment, the mixed solvent can be, for example, a mixture of THF and water, and as a non-limiting embodiment, 90% THF and 10% water. In some embodiments, the mixed solvent is a mixture of THF and water, such as 92% THF and 8% water. In some embodiments, THF is stabilized with butylated hydroxytoluene (BHT). As a non-limiting example in Example 3, the INX-315 ASD formulation disperses INX-315 across a polymer matrix (e.g., a precipitation inhibitor, such as HPMCAS), preventing INX-315 from crystallizing in the ASD formulation, such as high THF. g and low T m / T g The ratio is shown ( Figures 9A-9B ).

[0034] This invention comprises an amorphous spray-dried dispersion of INX-315 or a pharmaceutically acceptable salt thereof, having a significant amount of an anti-precipitant, for example, 20% to 60% INX-315 by weight of ASD. In some embodiments, the contained amorphous INX-315 ranges from, for example, about 25% to about 60% by weight of ASD, or, for example, about 35% to 45% by weight of ASD, or even 40% by weight (Tables 17 and 20). In some embodiments, INX-315 is spray-dried together with a precipitation inhibitor, such as, but not limited to, hydroxypropyl methylcellulose succinate-highly substituted (HPMCAS-HG), or other precipitation inhibitors as further described herein. The precipitation inhibitor may, for example, be contained in the range of about 50% to about 70% by weight of ASD, or, for example, between about 55% to about 65% by weight of ASD, or even, for example, about 60% by weight of ASD (Tables 17 and 20).

[0035] In another aspect, this document describes advantageous pharmaceutical compositions comprising an ASD formulation added together with one or more other pharmaceutically acceptable excipients. As a non-limiting illustration in Example 4, the INX-315 ASD formulation was dry-granulated, dry-mixed, and then tableted together with one or more other pharmaceutically acceptable excipients (e.g., including but not limited to microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silica, and sodium stearoyl fumarate (Tables 21 and 23)) to form a pharmaceutical composition to be administered to a subject in need.

[0036] In some embodiments, the amorphous INX-315 included ranges from about 10% to about 30% by weight of the pharmaceutical composition, or from about 15% to about 35% by weight of the pharmaceutical composition, or, for example, about 20% by weight of the pharmaceutical composition (Tables 17 and 20). The precipitation inhibitor may be included, for example, in the range of about 20% to about 50% by weight of the pharmaceutical composition, or, for example, from about 25% to about 45% by weight of the pharmaceutical composition, or, for example, about 30% by weight of the pharmaceutical composition (Tables 17 and 20).

[0037] Pharmaceutical compositions containing the INX-315 ASD formulation described herein exhibit favorable total drug and dissolved drug concentrations over extended periods. Figures 8A-8C This means that most INX-315 is found in micelles, small colloids, small self-assembled drug aggregates, or free molecular drugs. Figure 7 , Figure 10A-13BWhile not wishing to be bound by a single theory, sustained absorption of INX-315 is facilitated by drug shuttle crossing the intestinal mucosal boundary layer, which is rapidly replaced by free drug upon absorption, and continuously replaced by intermittently dissolved INX-315 drug / polymer colloids. The formation of multiple INX-315 drug / polymer and micellar structures in vivo leads to sustained INX-315 dissolution and absorption, resulting in a "reservoir effect" where drug levels rise and persist for a longer period than predicted based on previous preclinical animal studies. In the case of INX-315, the compound advantageously and rapidly reaches its C60-64 ... max There is no "peak effect" in the human body, and C remains constant for many hours. max and C min Small differences between them (i.e., low C) max With C min (Ratio), as shown, for example, in Figure 1.

[0038] INX-315 is currently used to treat individuals with tumors containing intact, functional retinoblastoma proteins. Examples of cancers containing intact, functional retinoblastoma proteins 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).

[0039] Surprisingly, it was also found that INX-315 is effective in treating Rb-independent cancers through an Rb-independent mechanism (see, for example...). Figure 15C-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.

[0040] In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof in the ASD formulation described herein provides an additive or synergistic effect with the anticancer or antiproliferative activity of additional therapeutic agents. In some embodiments, the additional therapeutic agents are selected from CDK4 / 6 inhibitors, endocrine therapies, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example...). Figure 15C-15D and Figure 16B This improvement represents a significant advancement in existing technologies for 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, abeciclib, trilaciclib, leroxiclib, 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 abeciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is leroxiclib (G1 Therapeutics, Inc.).

[0041] INX-315 can be advantageously administered, for example, to patients with CDK4 / 6 resistant tumors or cyclin E overexpressing tumors, such as... Figure 16B As shown in the diagram. INX-315 can also be administered in combination with a selective CDK4 inhibitor. In some 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, abeciclib, triasidib, lerosiclib, or dalcidib. 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 abeciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is lerosiclib (G1 Therapeutics, Inc.).

[0042] Surprisingly, it has been found that administration of INX-315 at certain dosing regimens achieved improved pharmacokinetic parameters compared to predictions generated using preclinical mammalian models. These dosing regimens are sufficient to treat human patients in need, such as those with cancers sensitive to CDK2 inhibitors.

[0043] Non-limiting examples of aspects of the present invention include:

[0044] 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 a precipitation inhibitor.

[0045] 2. The pharmaceutical composition of embodiment 1, wherein INX-315 is about 20% to about 60% by weight of ASD.

[0046] 3. The pharmaceutical composition of embodiment 1, wherein INX-315 is about 30% to about 50% by weight of ASD.

[0047] 4. The pharmaceutical composition of embodiment 1, wherein INX-315 is about 40% by weight of ASD.

[0048] 5. The pharmaceutical composition of any one of embodiments 1-4, wherein the pharmaceutical composition comprises INX-315 at a concentration of about 100 mg to about 500 mg.

[0049] 6. The pharmaceutical composition of any one of embodiments 1-4, wherein the precipitation inhibitor is selected from cellulose derivatives, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethyl methacrylate, hydroxypropyl methylcellulose, HPMC 2910, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose 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 carboxymethyl cellulose (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 VA37.

[0050] 7. The pharmaceutical composition of embodiment 6, wherein the precipitation inhibitor is HPMCAS-HG.

[0051] 8. The pharmaceutical composition of any one of embodiments 1-7, wherein the precipitation inhibitor in the ASD is about 40% to about 80% by weight of the ASD.

[0052] 9. The pharmaceutical composition of any one of embodiments 1-7, wherein the precipitation inhibitor in the ASD is about 60% by weight of the ASD.

[0053] 10. A pharmaceutical composition according to any one of embodiments 1-9, wherein the ASD is about 40% to about 60% by weight of the pharmaceutical composition.

[0054] 11. A pharmaceutical composition according to any one of embodiments 1-9, wherein the ASD is about 50% by weight of the pharmaceutical composition.

[0055] 12. A pharmaceutical composition according to any one of embodiments 1-11, wherein the pharmaceutical composition comprises an insoluble diluent.

[0056] 13. The pharmaceutical composition of embodiment 12, wherein the insoluble diluent is microcrystalline cellulose.

[0057] 14. The pharmaceutical composition of claim 12 or 13, wherein the insoluble diluent is about 15% to about 25% by weight of the pharmaceutical composition.

[0058] 15. A pharmaceutical composition according to any one of embodiments 1-14, wherein the pharmaceutical composition comprises a soluble diluent.

[0059] 16. The pharmaceutical composition of embodiment 15, wherein the soluble diluent is mannitol.

[0060] 17. The pharmaceutical composition of claim 15 or 16, wherein the soluble diluent is about 15% to about 25% by weight of the pharmaceutical composition.

[0061] 18. A pharmaceutical composition according to any one of embodiments 1-17, wherein the pharmaceutical composition comprises a disintegrant.

[0062] 19. The pharmaceutical composition of embodiment 18, wherein the disintegrant is croscarmellose sodium.

[0063] 20. The pharmaceutical composition of embodiment 18 or 19, wherein the disintegrant is about 1% to about 10% by weight of the pharmaceutical composition.

[0064] 21. A pharmaceutical composition according to any one of embodiments 1-20, wherein the pharmaceutical composition comprises a gliding agent.

[0065] 22. The pharmaceutical composition of embodiment 21, wherein the gliding agent is colloidal silica.

[0066] 23. The pharmaceutical composition of embodiment 21 or 22, wherein the gliding agent is about 0.1% to about 5% by weight of the pharmaceutical composition.

[0067] 24. A pharmaceutical composition according to any one of embodiments 1-20, wherein the pharmaceutical composition comprises a lubricant.

[0068] 25. The pharmaceutical composition of embodiment 24, wherein the lubricant is sodium stearoyl fumarate.

[0069] 26. The pharmaceutical composition of embodiment 24 or 25, wherein the lubricant is about 0.1% to about 5% by weight of the pharmaceutical composition.

[0070] 27. A method for treating individuals with heterogeneous CDK2-mediated cancers, comprising administering to a person in need an effective amount of INX-315 or a pharmaceutically acceptable salt thereof.

[0071] The heterogeneous CDK2-mediated cancers mentioned above include a mixture of retinoblastoma (Rb)-dependent cells and Rb-independent cells.

[0072] 28. The method of embodiment 27, wherein 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 between about 100 mg and about 500 mg of INX-315; and

[0073] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0074] 29. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in the mean plasma area under the curve (AUC) measured on day 1 of administration (ng). (hr / mL) is between about 1,250 and about 50,000;

[0075] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0076] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0077] 30. The method of any one of embodiments 27-29, wherein the mean plasma AUC measured on day 1 of administration is between 6,000 and 50,000.

[0078] 31. The method of any one of embodiments 27-29, wherein the mean plasma AUC measured on day 1 of administration is between 9,000 and 50,000.

[0079] 32. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum plasma concentration (C) measured on day 1 of administration. max (ng / mL) is between about 75 and about 2,400;

[0080] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0081] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0082] 33. The method of any one of embodiments 27-32, wherein the mean plasma C measured on day 1 of administration max Between 350 and 2,400.

[0083] 34. The method of any one of embodiments 27-32, wherein the mean plasma C measured on day 1 of administration max Between 525 and 2,400.

[0084] 35. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean minimum plasma concentration (C0.05) measured on day 1 of administration. min) (ng / mL) is between about 20 and about 1,000;

[0085] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0086] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0087] 36. The method of any one of embodiments 27-35, wherein the mean plasma C measured on day 1 of administration min Between 120 and 1,000.

[0088] 37. The method of any one of embodiments 27-35, wherein the mean plasma C measured on day 1 of administration min Between 180 and 1,000.

[0089] 38. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean free minimum plasma concentration (Cmax) measured on day 1 of administration. min 游离 (ng / mL) is between about 4.0 and about 48.0;

[0090] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0091] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0092] 39. The method of any one of implementation schemes 27-38, wherein the average C measured on day 1 of administration min 游离 Between 10 and 48.

[0093] 40. The method of any one of embodiments 27-38, wherein the average C measured on day 1 of administration min 游离 Between 15 and 48.

[0094] 41. A method of treating a person with CDK2-mediated cancer, comprising administering to a human patient in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean plasma area under the curve (AUC) measured on day 15 of administration (ng). (hr / mL) is between about 1,250 and about 56,000;

[0095] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0096] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0097] 42. The method of any one of embodiments 27-41, wherein the mean plasma AUC measured on day 15 of administration is between 11,000 and 56,000.

[0098] 43. The method of any one of embodiments 27-41, wherein the mean plasma AUC measured on day 15 of administration is between 16,500 and 56,000.

[0099] 44. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum plasma concentration (C) measured on day 15 of administration. max (ng / mL) is between approximately 90 and approximately 4,000;

[0100] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0101] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0102] 45. The method of any one of embodiments 27-44, wherein the mean plasma C measured on day 15 of administration max Between 700 and 4,000.

[0103] 46. ​​The method of any one of embodiments 27-44, wherein the mean plasma C measured on day 15 of administration max Between 1,050 and 4,000.

[0104] 47. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean minimum plasma concentration (C0.05) measured on day 15 of administration. min (ng / mL) is between about 100 and about 2,000;

[0105] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0106] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0107] 48. The method of any one of embodiments 27-47, wherein the mean plasma C measured on day 15 of administration min Between 250 and 2,000.

[0108] 49. The method of any one of embodiments 27-47, wherein the mean plasma C measured on day 15 of administration min Between 375 and 2,000.

[0109] 50. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean free minimum plasma concentration (Cmax) measured on day 15 of administration. min 游离 (ng / mL) is between about 6.0 and about 80.0;

[0110] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0111] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0112] 51. The method of any one of embodiments 27-50, wherein the average C measured on day 15 of administration min 游离 Between 14 and 80.

[0113] 52. The method of any one of implementation schemes 27-50, wherein the average C measured on day 15 of administration min 游离 Between 21 and 80.

[0114] 53. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in the mean area under the curve (AUC) of whole blood measured on day 1 of administration (ng). (hr / mL) is between approximately 25,000 and approximately 480,000;

[0115] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0116] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0117] 54. The method of any one of Implementation Schemes 27-53, wherein the mean whole blood AUC measured on day 1 of administration is between 80,000 and 480,000.

[0118] 55. The method of any one of Implementation Schemes 27-53, wherein the mean whole blood AUC measured on day 1 of administration is between 120,000 and 480,000.

[0119] 56. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum whole blood concentration (C0.05) measured on day 1 of administration. max (ng / mL) is between about 2,000 and about 28,000;

[0120] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0121] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0122] 57. The method of any one of implementation schemes 27-56, wherein the mean whole blood C measured on day 1 of administration max Between 4,500 and 28,000.

[0123] 58. The method of any one of implementation schemes 27-56, wherein the mean whole blood C measured on day 1 of administration max Between 6,750 and 28,000.

[0124] 59. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean minimum whole blood concentration (C0.05) measured on day 1 of administration. min (ng / mL) is between about 500 and about 14,400;

[0125] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0126] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0127] 60. The method of any one of implementation schemes 27-59, wherein the mean whole blood C measured on day 1 of administration min Between 1,800 and 14,400.

[0128] 61. The method of any one of implementation schemes 27-59, wherein the mean whole blood C measured on day 1 of administration min Between 2,700 and 14,400.

[0129] 62. A method of administering to a person in need a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in the mean area under the curve (AUC) of whole blood measured on day 15 of administration (ng). (hr / mL) is between approximately 25,000 and approximately 800,000;

[0130] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0131] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0132] 63. The method of any one of Implementation Schemes 27-62, wherein the mean whole blood AUC measured on day 15 of administration is between 120,000 and 800,000.

[0133] 64. The method of any one of Implementation Schemes 27-62, wherein the mean whole blood AUC measured on day 15 of administration is between 180,000 and 800,000.

[0134] 65. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum whole blood concentration (C0.05) measured on day 15 of administration. max (ng / mL) is between about 3,000 and about 56,000;

[0135] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0136] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0137] 66. The method of any one of implementation schemes 27-65, wherein the mean whole blood C measured on day 15 of administration. max Between 7,000 and 56,000.

[0138] 67. The method of any one of implementation schemes 27-65, wherein the mean whole blood C measured on day 15 of administration. max Between 10,500 and 56,000.

[0139] 68. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean minimum whole blood concentration (C0.05) measured on day 15 of administration. min (ng / mL) is between about 1,000 and about 24,000;

[0140] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0141] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0142] 69. The method of any one of embodiments 27-68, wherein the average whole blood C min Between 2,600 and 24,000.

[0143] 70. The method of any one of embodiments 27-68, wherein the average whole blood C min Between 3,900 and 24,000.

[0144] 71. The method of any one of implementation schemes 27-70, which further results in a) average plasma C max With plasma C min The ratio is between 1.25 and 5 and / or b) the average whole blood C max With whole blood C min The ratio is between 1.25 and 5.

[0145] 72. The method of any one of embodiments 27-70, which further leads to average plasma C max With plasma C min The ratio is between 3 and 5.

[0146] 73. The method of any one of implementation schemes 27-70, which further leads to an average whole blood C max With whole blood C min The ratio is between 3 and 5.

[0147] 74. A method of treating a person with CDK2-mediated cancer, comprising administering to a person in need an effective amount of a pharmaceutical composition containing INX-315 or a pharmaceutically acceptable salt thereof, which results in a mean plasma C max With C min The ratio is less than about 5 but greater than about 1.25;

[0148] The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing INX-315 at a concentration of about 100 mg to about 500 mg; and

[0149] The amount of INX-315 in the ASD is between 20% and 60% by weight.

[0150] 75. The method of implementing scheme 74, wherein C max With C min The ratio is less than 3.

[0151] 76. The method of implementing Implementation 74, wherein C max With C min The ratio is less than 2.25.

[0152] 77. The method of any one of implementation schemes 74-76, wherein C max With C min The ratio is measured in plasma.

[0153] 78. The method of any one of implementation schemes 74-76, wherein C max With C min The ratio was measured in whole blood.

[0154] 79. The method of any one of implementation schemes 27-78, which results in t between about 5 hours and about 32 hours 1 / 2 .

[0155] 80. The method of any one of embodiments 27-78, which results in t between about 8 hours and about 28 hours 1 / 2 .

[0156] 81. The method of any one of embodiments 27-78, which results in t between about 12 hours and about 18 hours 1 / 2 .

[0157] 82. The method of any one of implementation schemes 79-81, wherein t 1 / 2 It takes about 14 hours.

[0158] 83. The method of any one of implementation schemes 79-81, wherein t 1 / 2 It takes about 15 hours.

[0159] 84. The method of any one of implementation schemes 79-81, wherein t 1 / 2 It takes about 16 hours.

[0160] 85. The method of any one of implementation schemes 27-84, wherein INX-315 is applied once daily.

[0161] 86. The method of any one of Implementation Schemes 27-85, wherein INX-315 is administered orally.

[0162] 87. The method of any one of embodiments 28-86, wherein the amount of INX-315 in the ASD is about 40%.

[0163] 88. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 100 mg.

[0164] 89. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 125 mg.

[0165] 90. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 150 mg.

[0166] 91. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 175 mg.

[0167] 92. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 200 mg.

[0168] 93. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 225 mg.

[0169] 94. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 250 mg.

[0170] 95. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 275 mg.

[0171] 96. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 300 mg.

[0172] 97. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 325 mg.

[0173] 98. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 350 mg.

[0174] 99. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 375 mg.

[0175] 100. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 400 mg.

[0176] 101. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 425 mg.

[0177] 102. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 450 mg.

[0178] 103. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 475 mg.

[0179] 104. The method of any one of embodiments 28-87, wherein the total amount of INX-315 in the pharmaceutical composition is about 500 mg.

[0180] 105. The method of any one of embodiments 28-104, wherein the pharmaceutical composition further comprises a precipitation inhibitor.

[0181] 106. The method of embodiment 105, wherein the amount of precipitation inhibitor in the ASD is between 40% by weight and 70% by weight.

[0182] 107. The method of embodiment 105 or 106, wherein the amount of the precipitation inhibitor in the ASD is about 60% by weight.

[0183] 108. The method of any one of embodiments 105-107, wherein the precipitation inhibitor is selected from cellulose derivatives, polyvinylpyrrolidone (PVP), PVP / VA (vinyl acetate), polymethyl methacrylate, hydroxypropyl methylcellulose, HPMC 2910, hydroxyethyl cellulose (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 carboxymethyl cellulose (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 VA37.

[0184] 109. The method of embodiment 108, wherein the precipitation inhibitor is HPMCAS.

[0185] 110. The method of any one of embodiments 28-109, wherein the pharmaceutical composition further comprises one or more other pharmaceutically acceptable excipients.

[0186] 111. The method of any one of embodiments 27-110, wherein the human patient has a tumor.

[0187] 112. The method of any one of embodiments 29-110, 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.

[0188] 113. The method of implementation scheme 112, wherein the CDK2-mediated cancer is lung cancer.

[0189] 114. The method of implementation scheme 113, wherein the lung cancer is small cell lung cancer (SCLC).

[0190] 115. The method of implementation scheme 112, wherein the CDK2-mediated cancer is breast cancer.

[0191] 116. The method of implementation scheme 115, wherein the breast cancer is hormone receptor positive (HR+).

[0192] 117. The method of implementation scheme 115 or 116, wherein the breast cancer is estrogen receptor positive (ER+).

[0193] 118. The method of any one of embodiments 115-117, wherein the breast cancer is progesterone receptor positive (PR+).

[0194] 119. The method of any one of embodiments 115-118, wherein the breast cancer is HER2 negative (HER2-).

[0195] 120. The method of implementation scheme 115, wherein the breast cancer is triple-negative breast cancer.

[0196] 121. The method of implementation scheme 112, wherein the CDK2-mediated cancer is bladder cancer.

[0197] 122. The method of implementation scheme 112, wherein the CDK2-mediated cancer is ovarian cancer.

[0198] 123. The method of implementation scheme 112, wherein the CDK2-mediated cancer is prostate cancer.

[0199] 124. The method of implementation scheme 112, wherein the CDK2-mediated cancer is a sarcoma.

[0200] 125. The method of implementation scheme 112, wherein the CDK2-mediated cancer is uterine cancer.

[0201] 126. The method of any one of embodiments 29-125, wherein the CDK2-mediated cancer is advanced unresectable and / or metastatic cancer.

[0202] 127. The method of any one of embodiments 29-126, wherein the CDK2-mediated cancer is cyclin E amplification or overexpression.

[0203] 128. The method of implementation 127, wherein next-generation sequencing (NGS) panel assays are used to confirm cyclin E overexpression or amplification status.

[0204] 129. The method of any one of embodiments 29-128, wherein the CDK2-mediated cancer is an Rb-positive cancer.

[0205] 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.

[0206] 131. The method of implementation 130, wherein the Rb-positive cancer is HR+ / HER2- breast cancer.

[0207] 132. The method of implementation 130, wherein the Rb-positive cancer is ER+ / HER2- breast cancer.

[0208] 133. The method of implementation scheme 130, wherein the Rb-positive cancer is high-grade serous ovarian cancer (HGSOC).

[0209] 134. The method of implementation 130, wherein the Rb-positive cancer is non-small cell lung cancer (NSCLC).

[0210] 135. The method of any one of embodiments 29-128, wherein the CDK2-mediated cancer is an Rb-independent cancer.

[0211] 136. The method of implementation 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.

[0212] 137. The method of implementation 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.

[0213] 138. The method of implementation 137, wherein the Rb-independent cancer is SCLC.

[0214] 139. The method of implementation scheme 137, wherein the Rb-independent cancer is TNBC.

[0215] 140. The method of any one of embodiments 27-139, wherein the person has previously received at least one previous line of chemotherapy.

[0216] 141. The method of any one of embodiments 27-140, wherein the person has previously received at least two previous lines of chemotherapy.

[0217] 142. The method of any one of embodiments 27-141, wherein the person has previously received at least one prior line of CDK4 / 6 inhibitor therapy.

[0218] 143. The method of any one of embodiments 27-142, wherein the person has previously received at least one prior line of endocrine therapy.

[0219] 144. The method of any one of embodiments 27-143, wherein the CDK2-mediated cancer is recurrent.

[0220] 145. The method of any one of embodiments 27-144, wherein the CDK2-mediated cancer is CDK4 / 6 inhibitor resistant.

[0221] 146. The method of any one of embodiments 27-145, wherein the CDK2-mediated cancer progresses following a prior regimen including endocrine therapy.

[0222] 147. The method of any one of embodiments 27-146, wherein the CDK2-mediated cancer is endocrine therapy resistant.

[0223] 148. The method of any one of embodiments 27-147, wherein the treatment results in fewer treatment-related adverse events compared to the predicted number of treatment-related adverse events in subjects receiving CDK2 treatment other than INX-315.

[0224] 149. The method of any one of embodiments 27-148, wherein the treatment results in a reduction in the number of laboratory abnormality events compared to the predicted number of events in subjects receiving CDK2 treatment other than INX-315.

[0225] 150. The method of any one of embodiments 27-149, 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.

[0226] 151. The method of any one of embodiments 27-150, 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.

[0227] 152. The method of any one of embodiments 27-151, 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.

[0228] 153. The method of any one of embodiments 27-152, wherein the treatment results in improved progression-free survival (PFS) compared with the predicted progression-free survival (PFS) in subjects receiving CDK2 treatment other than INX-315.

[0229] 154. The method of any one of embodiments 27-153, 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.

[0230] 155. The method of any one of embodiments 27-154, wherein the treatment results in a prolonged time to progression (TTP) compared to the predicted time to progression (TTP) in subjects receiving CDK2 treatment other than INX-315.

[0231] 156. The method of any one of embodiments 148-155, wherein CDK2 treatment other than INX-315 comprises administration of a CDK2 inhibitor selected from BLU-222 or PF-07104091.

[0232] 157. The method of implementation scheme 156, wherein the CDK2 inhibitor is BLU-222.

[0233] 158. The method of implementation scheme 156, wherein the CDK2 inhibitor is PF-07104091.

[0234] 159. The method of any one of embodiments 148-158, wherein a CDK2 inhibitor other than INX-315 is administered at the same dose and frequency as INX-315.

[0235] 160. A method for manufacturing a pharmaceutical composition according to any one of embodiments 1-26, comprising:

[0236] (i) Spray drying of a solution containing INX-315 or a pharmaceutically acceptable salt thereof and a precipitation inhibitor to produce an amorphous spray-dried dispersion (ASD);

[0237] (ii) Granulate ASD together with one or more pharmaceutically acceptable excipients to provide granules;

[0238] (iii) The particles are dry-mixed with one or more other pharmaceutically acceptable excipients; and

[0239] (iv) Compress the dry-mixed granules into tablets.

[0240] 161. The method of embodiment 160, wherein the pharmaceutical composition has a nominal tablet strength between about 100 mg and about 500 mg.

[0241] 162. The method of embodiment 160, wherein the pharmaceutical composition has a nominal tablet strength of about 100 mg.

[0242] 163. The method of embodiment 160, wherein the pharmaceutical composition has a nominal tablet strength of about 200 mg.

[0243] 164. The method of embodiment 160, wherein the pharmaceutical composition has a nominal tablet strength of about 300 mg.

[0244] 165. The method of embodiment 160, wherein the pharmaceutical composition has a nominal tablet strength of about 400 mg. Attached Figure Description

[0245] Figure 1A This is a graph showing the plasma concentrations of INX-315 obtained from oral administration of 100 mg once daily (QD) on day 1 (circle) and day 15 (square). The x-axis is the time after administration (measured in hours), and the y-axis is the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)).

[0246] Figure 1B This is a graph showing the free concentration of INX-315 in unbound plasma proteins obtained from oral administration of 100 mg once daily (QD) of INX-315, measured on day 1 (circle) and day 15 (square). The x-axis is the time after administration start (measured in hours), and the y-axis is the free concentration of INX-315 in plasma (measured in nanograms per milliliter (ng / mL)).

[0247] Figure 2 This is a graph showing the plasma concentration of INX-315 (circles) administered at 100 mg once daily (QD) relative to the concentration of the commercially available CDK2 inhibitor BLU-222 (triangles) administered at 50 mg, 100 mg, 200 mg, 400 mg, or 600 mg twice daily (BID). The x-axis represents the time since 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)).

[0248] Figure 3 This is a graph showing the plasma concentration of INX-315 (circles) after continuous dosing on day 15, administered at 100 mg once daily (QD), relative to the concentration of the commercially available CDK2 inhibitor PF-07104091 (triangles) after dosing at 75 mg, 150 mg, 225 mg, 300 mg, or 500 mg twice daily (BID). 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)).

[0249] Figure 4 This is a graph showing the concentration of INX-315 in whole blood obtained by oral administration of 100 mg once daily (QD) on day 1 (d1) and day 15 (d15). The x-axis is the time after administration start (measured in hours), and the y-axis is the concentration of INX-315 in whole blood (measured in nanograms per milliliter (ng / mL)).

[0250] Figure 5A –5C is a SEM image of the INX-315 free base as described in Example 3.

[0251] Figure 6A –6C is a SEM image of the INX-315 HCl salt as described in Example 3.

[0252] Figure 7 This represents the micelle distribution of the free INX-315 drug as described in Example 3. The volume fraction of micelles (Vm) is expressed on the x-axis, while the Dt / Df ratio is expressed on the y-axis.

[0253] Figure 8A This indicates the setup of the non-drain dissolution method as described in Example 3.

[0254] Figure 8B This represents a non-sinking dissolution method in which samples of free INX-315 and spray-dried INX-315 amorphous solid dispersion are microcentrifuged for different durations, as shown on the x-axis, and the total INX-315 drug concentration is measured, as shown on the y-axis, as described in Example 3.

[0255] Figure 8C This indicates a non-sinking dissolution method in which samples of free INX-315 and spray-dried INX-315 amorphous solid dispersion are ultracentrifuged for different durations, as shown on the x-axis, and the concentration of dissolved INX-315 drug, as shown on the y-axis, is measured, as described in Example 3.

[0256] Figure 9A The differential scanning calorimetry (DSC) thermal analysis plot of INX-315 during the first scan (before quenching) shows the temperature on the x-axis and the normalized heat flux (W / g) on ​​the y-axis. The DSC thermal analysis plot was obtained as described in Example 3.

[0257] Figure 9BThe differential scanning calorimetry (DSC) thermal analysis plot of INX-315 during the second scan (after quenching) shows the normalized reversible heat flux and the normalized irreversible heat flux. Temperature is represented on the x-axis, and normalized heat flux (W / g) is represented on the y-axis. The DSC thermal analysis plot was obtained as described in Example 3.

[0258] Figure 10A –10B is a SEM image of a 25% INX-315:HPMCAS-H spray-dried amorphous solid dispersion formulation as described in Example 3.

[0259] Figure 11A –11B is a SEM image of a 40% INX-315:HPMCAS-H spray-dried amorphous solid dispersion formulation as described in Example 3.

[0260] Figure 12A –12B is a SEM image of a 25% INX-315:HPMCAS-M spray-dried amorphous solid dispersion formulation as described in Example 3.

[0261] Figure 13A –13B is a SEM image of a 40% INX-315:HPMC-E3 spray-dried amorphous solid dispersion formulation as described in Example 3.

[0262] Figure 14 These are powder X-ray diffraction (PXRD) patterns of various spray-dried INX-315 amorphous solid dispersion formulations as described in Example 3.

[0263] Figure 15A This is a graph showing the weight measurements of the six treatment groups in Group 1 as described in Example 5. The y-axis is the weight (± standard error of the mean) as a function of time (measured in study days) on the x-axis, measured in grams (g). The term "mpk" refers to milligrams per kilogram (mg / kg).

[0264] Figure 15B This is a graph showing the weight measurements of the six treatment groups in group 2 as described in Example 5. The y-axis is the weight (± standard error of the mean) as a function of time (measured in study days) on the x-axis, measured in grams (g). The term "mpk" refers to milligrams per kilogram (mg / kg).

[0265] Figure 15C This is a graph showing the tumor volume measurements in the six treatment groups of Group 1 as described in Example 5. The y-axis is the mean tumor volume (± standard error of the sample) as a function of time (measured in study days) on the x-axis, expressed in cubic millimeters (mm). 3Measurement. The term "mpk" refers to milligrams per kilogram (mg / kg).

[0266] Figure 15D This is a graph showing the tumor volume measurements in the six treatment groups of Group 2 as described in Example 5. The y-axis represents the mean tumor volume (± standard error of the sample) as a function of time (measured in study days) on the x-axis, expressed in cubic millimeters (mm). 3 Measurement. The term "mpk" refers to milligrams per kilogram (mg / kg).

[0267] Figure 16A This is a graph showing the weight measurement results of the different treatment groups as described in Example 6. The y-axis is the weight (± standard deviation) as a function of time (measured in study days) on the x-axis, measured in grams (g).

[0268] Figure 16B This is a graph showing the tumor volume measurements of different treatment groups as described in Example 6. The y-axis represents the mean tumor volume (± standard error of the mean) as a function of time (measured in study days) on the x-axis, expressed in cubic millimeters (mm). 3 )Measurement.

[0269] Figure 17A This is a graph showing the whole blood concentration of INX-315 obtained from oral administration of 100 mg once daily (QD) in 6 individual subjects in Group 1, as described in Example 7, as measured on Day 1. The x-axis is the time after administration start (measured in hours), and the y-axis is the concentration of INX-315 in whole blood (measured in nanograms per milliliter (ng / mL)).

[0270] Figure 17B This is a graph showing the whole blood concentration of INX-315 obtained from oral administration of 100 mg once daily (QD) in 6 individual subjects in Group 1, as described in Example 7, as measured on day 15. The x-axis is the time after administration start (measured in hours), and the y-axis is the concentration of INX-315 in whole blood (measured in nanograms per milliliter (ng / mL)).

[0271] Figure 17C This is a graph showing the plasma concentration of INX-315 obtained from oral administration of 100 mg once daily (QD) to 6 individual subjects in Group 1, as described in Example 7, as measured on Day 1. The x-axis is the time after administration (measured in hours), and the y-axis is the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)).

[0272] Figure 17DThis is a graph showing the plasma INX-315 concentration obtained from oral administration of 100 mg once daily (QD) to 6 individual subjects in Group 1, as described in Example 7, as measured on day 15. The x-axis is the time after administration start (measured in hours), and the y-axis is the plasma INX-315 concentration (measured in nanograms per milliliter (ng / mL)).

[0273] Figure 17E This is a graph showing the concentrations of INX-315 in whole blood and plasma obtained from oral administration of 100 mg once daily (QD) on days 1 and 15 in group 1 for six individual subjects as described in Example 7. The x-axis is the time after administration (measured in hours), and the y-axis is the concentration of INX-315 in whole blood or plasma (measured in nanograms per milliliter (ng / mL)).

[0274] Figure 18A This is a graph showing the plasma concentration of INX-315 administered as described in Example 8 at a dose of 100 mg once daily (QD) (grey) versus 200 mg QD (black). The x-axis is the time after administration (measured in hours), and the y-axis is the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)).

[0275] Figure 18B This is a graph showing the plasma concentrations of INX-315 administered as described in Example 8 at 100 mg once daily (QD) (grey) versus 200 mg QD (black). The x-axis represents time points expressed in cycles (C#) and days (D#), starting from C1D1, and the y-axis is the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)).

[0276] Figure 18C This is a graph showing the plasma free concentration of INX-315 administered at 100 mg once daily (QD) (grey) versus 200 mg QD (black) as described in Example 8. The x-axis represents days 1 and 7, and the y-axis is the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)).

[0277] Figure 19AThis is a graph illustrating the preliminary plasma INX-315 concentration-time curves for Group 1 (100 mg QD) as described in Example 10. The x-axis represents time measured in hours (h) after dose administration on Day 1 (black line) and Day 15 (grey line). The y-axis is linear and represents the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)). The dose is shown in the top header row; the subject ID is shown in the second header row.

[0278] Figure 19B This is a graph illustrating the preliminary plasma INX-315 concentration-time curves for Group 1 (100 mg QD) as described in Example 10. The x-axis represents the time following dose administration on Day 1 (black line) and Day 15 (grey line), measured in hours (h). The y-axis is logarithmic and represents the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)). The dose is shown in the top header row; the subject ID is shown in the second header row.

[0279] Figure 19C This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for Group 1 (100 mg QD) on day 1 after administration as described in Example 10. The gray line represents the individual concentration-time curve, and the black solid line represents the mean concentration-time curve for the entire group.

[0280] Figure 19D This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for Group 1 (100 mg QD) on day 15 after administration as described in Example 10. The gray line represents the individual concentration-time curve, and the black solid line represents the mean ± SD concentration-time curve for the entire group.

[0281] Figure 20A This is a graph illustrating the preliminary plasma INX-315 concentration-time curves for group 2 (200 mg QD) as described in Example 10. The x-axis represents time measured in hours (h) after dose administration on day 1 (black line) and day 15 (grey line). The y-axis is linear and represents the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)). The dose is shown in the top header row; the subject ID is shown in the second header row.

[0282] Figure 20BThis is a graph illustrating the preliminary plasma INX-315 concentration-time curves for group 2 (200 mg QD) as described in Example 10. The x-axis represents time measured in hours (h) after dose administration on day 1 (black line) and day 15 (grey line). The y-axis is logarithmic and represents the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)). The dose is shown in the top header row; the subject ID is shown in the second header row.

[0283] Figure 20C This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for Group 2 (200 mg QD) on day 1 after administration as described in Example 10. The gray line represents the individual concentration-time curve, and the black solid line represents the mean concentration-time curve for the entire group.

[0284] Figure 20D This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for Group 2 (200 mg QD) on day 15 after administration as described in Example 10. The gray line represents the individual concentration-time curve, and the black solid line represents the mean concentration-time curve for the entire group.

[0285] Figure 21A This is a graph illustrating the preliminary plasma INX-315 concentration-time curves for group 3 (300 mg QD) as described in Example 10. The x-axis represents the time (measured in hours (h) after dose administration on day 1 (black line) and day 15 (grey line). The y-axis is linear and represents the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)). The dose is shown in the top header row; the subject ID is shown in the second header row.

[0286] Figure 21B This is a graph illustrating the preliminary plasma INX-315 concentration-time curves for group 3 (300 mg QD) as described in Example 10. The x-axis represents time measured in hours (h) after dose administration on day 1 (black line) and day 15 (grey line). The y-axis is logarithmic and represents the plasma concentration of INX-315 (measured in nanograms per milliliter (ng / mL)). The dose is shown in the top header row; the subject ID is shown in the second header row.

[0287] Figure 21C This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for group 3 (300 mg QD) on day 1 after administration as described in Example 10. The gray line represents the individual concentration-time curve, and the black solid line represents the mean concentration-time curve for the entire group.

[0288] Figure 21D This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for Group 3 (300 mg QD) on day 15 after administration as described in Example 10. The gray line represents the individual concentration-time curve, and the black solid line represents the mean concentration-time curve for the entire group.

[0289] Figure 22A This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for all groups on day 1 after administration, as described in Example 10. The dashed lines represent individual concentration-time curves. The solid lines represent the mean ± SD concentration-time curves for groups 1 (black line), 2 (dark gray line), and 3 (light gray line).

[0290] Figure 22B This is a graph illustrating the individual and mean (SD) plasma INX-315 concentration-time curves for all groups on day 15 after administration, as described in Example 10. The dashed lines represent individual concentration-time curves. The solid lines represent the mean ± SD concentration-time curves for groups 1 (black line) and 2 (dark gray line), excluding group 3 (light gray line), where group 3 (light gray line) represents the median concentration-time curve.

[0291] Figure 23 The chemical structure of INX-315 is provided. Detailed Implementation

[0292] As the first human administration of INX-315, the compound unexpectedly exhibited unique and highly unpredictable pharmacokinetic characteristics, which were significantly inconsistent with the predicted mathematical pharmacokinetic models extrapolated from other mammalian species (dogs, rats, and mice). While not wishing to be confined to a single theory, it is proposed that INX-315 binds to human blood cells in vivo to a much greater extent than observed in other tested mammals and from these other mammalian models. This increases the amount of drug available in the blood and produces a reservoir effect that prolongs drug availability as the drug is released from red blood cells into the plasma and then to the treatment site over time.

[0293] Surprisingly, INX-315 was also found to be effective in treating Rb-independent (i.e., Rb-negative) cancers. This article shows that the CDK2 inhibitor INX-315 can be used at doses that are effective in treating Rb-independent cancers, including but not limited to Rb-independent small cell lung cancer (SCLC) (see, for example...). Figure 15C-15D Other Rb-independent cancers include Rb-independent 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.

[0294] This discovery represents an advancement in the field of cancer therapy by providing a CDK2 inhibitor that can be used to treat both Rb-dependent and Rb-independent tumors (which may include heterogeneous tumors of both). In some embodiments, INX-315 is administered in combination with a CDK4 / 6 inhibitor, including but not limited to ribociclib (Novartis), abecilibi (Eli Lilly), palbociclib (Pfizer Inc.), or leroximate (G1 Therapeutics, Inc.). In some embodiments, INX-315 is administered daily, and the CDK4 / 6 inhibitor is typically administered for 21 days during a 28-day cycle with a 7-day drug holiday. In some embodiments, INX-315 is administered daily, and the CDK4 / 6 inhibitor is administered continuously.

[0295] According to the present invention, INX-315 can be used to treat tumors with intact, 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, the INX-315 described herein, or a pharmaceutically acceptable salt or ASD formulation thereof, provides an additive or synergistic effect with additional therapeutic agents for treating Rb-positive cancers in terms of anticancer or antiproliferative activity. In some embodiments, the additional therapeutic agent is selected from CDK4 / 6 inhibitors, endocrine therapy, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example...). Figure 15C-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, abeciclib, triamcinolone, leroxiclib, or dalciribé. 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 abeciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is leroxiclib (G1 Therapeutics, Inc.).

[0296] Surprisingly, INX-315 was also found to be effective in treating Rb-independent cancers (see example...). Figure 15C-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. In some embodiments, the INX-315 described herein, or a pharmaceutically acceptable salt or ASD formulation thereof, provides an additive or synergistic effect with the anticancer or antiproliferative activity of additional therapeutic agents for treating Rb-independent cancers. In some embodiments, the additional therapeutic agents are selected from CDK4 / 6 inhibitors, endocrine therapies, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example...). Figure 15C-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, abeciclib, triamcinolone, leroxiclib, or dalciribé. 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 abeciclib (Eli Lilly). In some embodiments, the CDK4 / 6 inhibitor is leroxiclib (G1 Therapeutics, Inc.).

[0297] Highly unexpectedly, administration of INX-315 did not result in the initial peak drug concentration, as is often seen with other drugs such as BLU-222 and PF-07104091. The peak effect is caused by a large initial concentration at the beginning. max With C min The ratio indicator gradually decreases after application (see [link to relevant documentation]). Figure 2 and Figure 3 Conversely, when C max With C min A lower ratio indicates no peak. In the first two individuals administered 100 mg once daily, the C of INX-315 was... max With C min The ratio was measured to be 2.2, while the estimated C was based on published human results for BLU-222 (400 mg twice daily). max With C minThe ratio was 9.3, and the estimated C of BLU-222 (600 mg twice daily) was... max With C min The ratio is 22. Similarly, based on publicly available human data, the estimated C of PF-07104091 max With C min The ratio is 16-64 (see Table 5 and...). Figure 2 and Figure 3 The presence of a peak after administration (which is a short-term overdose of the drug in the blood) can cause side effects and is generally undesirable.

[0298] Surprisingly and unexpectedly, administration of INX-315 or a pharmaceutically acceptable salt thereof provided particularly improved plasma and whole blood pharmacokinetic parameters compared to values ​​predicted based on non-human preclinical model studies. In some embodiments, cancers with amplified or overexpressed cyclin E develop acquired or intrinsic resistance (e.g., SCLC) (see example...). Figure 15C-15D ) resistant to CDK4 / 6 inhibitors (see, for example) Figure 16B Rb-positive and / or resistant to endocrine therapy (e.g., estrogen receptor degraders). The dosing regimens described herein comprising administration of INX-315 or a pharmaceutically acceptable salt thereof may be used to treat Rb-positive and Rb-independent cancers, such as SCLC (see example). Figure 15C-15D The improved administration regimens described herein can be used to treat refractory cancers with cyclin E amplification, including unresectable solid tumors with CCNE1 amplification and platinum-resistant or platinum-refractory cancers with CCNE1 amplification. Non-limiting examples of the beneficial properties exhibited by the dosage regimens containing INX-315 administration described herein include an enhanced area under the curve (AUC) (ng) compared to predictions based on preclinical models in non-human mammals. hr / mL value, average maximum concentration (C max (ng / mL) value, enhanced minimum average concentration (C min (ng / mL) value, enhanced mean free minimum plasma concentration (C min 游离 (ng / mL) value and enhanced C max With C min Ratio. Compared to clinically developed CDK2 inhibitors, these improved PK profiles provide prolonged duration of concentration above the therapeutic threshold, superior exposure profiles, and prolonged half-life (t). 1 / 2And reduced off-target activity. Sustained homeostatic levels of INX-315 in plasma result in sustained on-target drug activity and a tumor microenvironment conducive to resensitizing tumors to other therapeutic agents, including but not limited to CDK4 / 6 inhibitors, endocrine therapies such as SERDs, chemotherapeutic agents, immune checkpoint inhibitors, or combinations thereof (see, for example...). Figure 15C-15D and Figure 16B This improvement represents a significant advancement in existing technologies for cancer treatment.

[0299] As described in this article, 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 polymer precipitation inhibitors in solvents to produce advantageous amorphous spray-dried dispersion (ASD) formulations. The precipitation inhibitors minimize crystallization of INX-315 in the ASD formulation. In non-limiting embodiments, the solvent is a mixture of THF and water, such as 90% THF and 10% water (see, for example, Table 20). In some embodiments, the solvent is a mixture of THF and water, such as 92% THF and 8% water (see, for example, Table 33). In some embodiments, THF is stabilized with butylated hydroxytoluene (BHT). As a non-limiting illustration in Example 3, the INX-315 ASD formulation disperses INX-315 across a polymer matrix (e.g., a precipitation inhibitor such as HPMCAS), preventing crystallization of INX-315 in the ASD formulation, such as high-T... g and low T m / T g The ratio is shown ( Figures 9A-9B ).

[0300] In some embodiments, the amorphous INX-315 included ranges from about 20 wt% to about 50 wt% of ASD, for example from about 25 wt% to about 45 wt% of ASD, or for example about 40 wt% of ASD (Tables 17 and 20). In some embodiments, INX-315 is spray-dried together with a precipitation inhibitor, such as, but not limited to, hydroxypropyl methylcellulose succinate-highly substituted (HPMCAS-HG), or other precipitation inhibitors as further described herein. The precipitation inhibitor may, for example, be included in the range of about 50 wt% to about 70 wt% of ASD, or for example from about 55 wt% to about 65 wt% of ASD, or for example about 60 wt% of ASD (Tables 17 and 20).

[0301] In another aspect, this document describes advantageous pharmaceutical compositions comprising an ASD formulation added together with one or more other pharmaceutically acceptable excipients. As a non-limiting illustration in Example 4, the INX-315 ASD formulation was dry-granulated, dry-mixed, and then tableted together with one or more other pharmaceutically acceptable excipients (e.g., including but not limited to microcrystalline cellulose, mannitol, croscarmellose sodium, colloidal silica, and sodium stearoyl fumarate) (Tables 21 and 23) to form a pharmaceutical composition to be administered to a subject in need.

[0302] In some embodiments, the amorphous INX-315 included ranges from about 10% to about 30% by weight of the pharmaceutical composition, or from about 15% to about 35% by weight of the pharmaceutical composition, or, for example, about 20% by weight of the pharmaceutical composition (Tables 17 and 20). The precipitation inhibitor may be included, for example, in the range of about 20% to about 50% by weight of the pharmaceutical composition, or, for example, from about 25% to about 45% by weight of the pharmaceutical composition, or, for example, about 30% by weight of the pharmaceutical composition (Tables 17 and 20).

[0303] the term

[0304] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although the invention may be practiced with similar or equivalent methods and materials to those described herein, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In case of any conflict, this specification (including definitions) shall prevail. Furthermore, materials, methods, and examples are for illustrative purposes only and are not intended to be limiting.

[0305] The terms “a” and “an” do not indicate a limitation of quantity, but rather that at least one of the referenced items exists. The term “or” means “and / or”. Unless otherwise stated herein, the description of numerical ranges is intended only to serve as a shorthand for individually referencing each individual value falling within the range, and each individual value is incorporated into the specification as if it were described separately herein. The endpoints of all ranges are included within the range and can be combined independently. Unless otherwise stated herein or where the context clearly contradicts, all methods described herein can be performed in a suitable order. The use of examples or exemplary language (e.g., “for example”) is intended only to better illustrate the invention and, unless otherwise stated, does not constitute a limitation on the scope of the invention. Unless otherwise defined, the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0306] In some implementations, the term "about" means ±10%.

[0307] Unless otherwise stated, the “patient” or “subject” or “participant” being treated is typically a human patient. In alternative embodiments, the methods described herein can be used to treat or test other animals that respond similarly, such as mammals, including animals used for preclinical testing, including but not limited to mice, rats, monkeys, dogs, pigs, and rabbits; as well as domestic pigs (pigs and hogs), ruminants, horses, poultry, felines, cattle, rats, canines, etc.

[0308] As used in this article, "effective amount" refers to the amount that provides therapeutic benefit.

[0309] As used herein, the term "mean" is synonymous with the average, such as the central value point in a set of values. In some implementations, for PK parameters (e.g., C) with an assumed skewed distribution... max The average value (AUC) refers to the geometric mean, used to illustrate the composite effect.

[0310] As used herein, the term “adverse event occurring during treatment” refers to an adverse event that occurs or worsens after the first administration or during treatment.

[0311] As used herein, the term “overall survival (OS)” refers to the time from the first dose until death from any cause.

[0312] As used herein, the term “overall response rate (ORR)” refers to the occurrence of the best overall response of a confirmed CR or PR, as determined by the RECIST v1.1 criteria.

[0313] As used herein, the term “Disease Control Rate (DCR)” refers to the occurrence of a confirmed CR, PR, or SD as the best overall response, as determined by RECIST v1.1 criteria.

[0314] As used herein, the term “progression-free survival (PFS)” refers to the period from the first dose until the first recorded disease progression or death from any cause (whichever occurs first).

[0315] As used herein, the term “duration of response (DOR)” refers to the time from the first recorded confirmed optimal overall response (CR) or PR to the first recorded disease progression or death from any cause (whichever occurs first).

[0316] As used herein, the term “time to progression (TTP)” refers to the time from the first dose to the first recorded disease progression.

[0317] As used herein, the term “MTD” refers to the maximum tolerated dose of a compound (e.g., INX-315).

[0318] As used herein, the term “AUC” refers to the area under the concentration-time curve of a compound in whole blood or plasma.

[0319] As used in this article, the term "AUC" 0-t "or AUC" last "AUC" refers to the time when the concentration of a compound (e.g., INX-315) was last measurable.

[0320] As used in this article, the term "AUC" 0-∞ "" refers to the AUC of a compound (e.g., INX-315) over infinite time.

[0321] As used herein, the term "Cl" refers to the clearance rate of a compound (e.g., INX-315).

[0322] As used in this article, the term "C" max "" refers to the maximum concentration of a compound (e.g., INX-315) in whole blood or plasma.

[0323] As used in this article, the term "C" last "" refers to the final quantifiable concentration of a compound (e.g., INX-315) in whole blood or plasma.

[0324] As used herein, the term "IC" 50 "IC" refers to the half-maximal inhibitory concentration (IC5) of a compound (e.g., INX-315). 50 It is a measure of drug efficacy, indicating the concentration of the target compound that inhibits a selected biological process by half compared to a control compound.

[0325] As used in this article, the term "t" 1 / 2 "" refers to the half-life of a compound (e.g., INX-315).

[0326] As used in this article, the term "t" max "This refers to the concentration of a compound (e.g., INX-315) in whole blood or plasma reaching a certain level." max The time.

[0327] As used in this article, the term "t" last "" refers to the time when a compound (e.g., INX-315) reaches its final measurable concentration.

[0328] 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 prevent the crystallization of INX-315 in the ASD formulation. Non-limiting examples of precipitation inhibitors include, but are not limited to, hydroxypropyl methylcellulose, such as HPMCAS, or other agents as further described herein.

[0329] As used herein, “intrinsic resistance,” also known as primary resistance, refers to a condition in which cancer does not respond or responds insufficiently to the inhibitory effects of initial anticancer therapy, including, but not limited to, CDK4 / 6 inhibitor therapy or endocrine therapy. In some embodiments of the treatments described herein, the cancer to be treated is intrinsically resistant to CDK4 / 6 inhibitors. Mutations and conditions associated with, for example, intrinsic resistance to CDK4 / 6 inhibitors include, but are not limited to: increased cyclin-dependent kinase 1 (CDK1) activity; increased cyclin-dependent kinase 2 (CDK2) activity; loss, deficiency, or absence (Rb deficiency) 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 with intrinsic resistance to CDK4 / 6 inhibitors are characterized by decreased expression of retinoblastoma tumor suppressor protein or one or more retinoblastoma family member proteins (e.g., but not limited to p107 and p130). In some embodiments, tumors or cancers inhibited by intrinsically resistant selective CDK4 / 6 inhibitors are those whose cell population as a whole does not undergo significant G1 cell cycle arrest when exposed to the selective CDK4 / 6 inhibitor. In some embodiments, tumors or cancers inhibited by intrinsically resistant CDK4 / 6 inhibitors are those in which less than 25%, 20%, 15%, 10%, or 5% of the cells in the cell population undergo G1 cell cycle arrest when exposed to the selective CDK4 / 6 inhibitor. In some alternative embodiments of the treatment methods described herein, the cancer to be treated is intrinsically resistant to endocrine therapies, such as estrogen inhibitor therapies, such as SERD. In some alternative embodiments of the treatment methods described herein, the cancer being treated is intrinsically resistant to therapeutic agents or other anticancer therapies.

[0330] As used herein, “acquired resistance” refers to a condition in which a cancer initially sensitive to the inhibitory effect of an anticancer therapy becomes unresponsive or less responsive over time to the administration of that therapy. In some embodiments of the methods described herein, the cancer to be treated exhibits acquired resistance to a selective CDK4 / 6 inhibitor. Without wishing to be bound by any single theory, it is assumed that acquired resistance to a CDK4 / 6 inhibitor occurs due to 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, a non-limiting exemplary cause of acquired resistance to a CDK4 / 6 inhibitor might be the presence of one or more genetic aberrations associated with “intrinsic resistance.” In addition, other non-limiting exemplary causes of acquired resistance to CDK4 / 6 inhibitors may include increased expression of cyclin E; CCNE1 / 2 amplification; E2F amplification; CDK2 amplification; CDK6 amplification; CDK4 amplification; p16 amplification; WEE1 overexpression; MDM2 overexpression; CDK7 overexpression; FZR1 deletion; HDAC activation; FGFR pathway activation; PI3K / AKT / mTOR pathway activation; loss of ER or PR expression; higher transcriptional activity of AP-1; epithelial-mesenchymal transition; Smad 3 inhibition; autophagy activation; Rb1 deletion or inactivation of RB1 mutations; or combinations thereof. A general review of CDK4 / 6 resistance mechanisms can be found, for example, 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, selective CDK4 / 6 inhibitor inhibition of acquired resistance tumors or cancers is defined as tumors or cancers in which the cell population (as a whole) no longer undergoes significant G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, leading to disease progression. In some embodiments, selective CDK4 / 6 inhibitor inhibition of acquired resistance tumors or cancers is defined as tumors or cancers in which less than 50%, 40%, 30%, 20%, 15%, 10%, or 5% of the cells in the cell population undergo G1 cell cycle arrest upon exposure to the selective CDK4 / 6 inhibitor, leading to disease progression. In some embodiments, the cancer progresses following a prior treatment regimen that includes administration of a CDK4 / 6 inhibitor. In some alternative embodiments of the treatment methods described herein, the treated cancer is acquired resistance, such as resistance to estrogen inhibitor therapies (e.g., SERD) (e.g., but not limited to fulvestrant or ellastrant).In some alternative implementations of the treatment methods described herein, the cancer being treated has acquired resistance to other anticancer therapies.

[0331] The retinoblastoma susceptibility gene (RB1) is the first molecularly defined tumor suppressor gene. Retinoblastoma (Rb) (encoded by the protein RB1) is frequently mutated or deleted in retinoblastoma and osteosarcoma, and indeterminately mutated or deleted in certain other tumor 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.

[0332] 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).

[0333] The terms “Rb-plus,” “Rb+,” “Rb-proficient,” “Rb-dependent,” or “Rb-positive” refer to various 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.

[0334] The presence or normal function (Rb-positive) of retinoblastoma (Rb) tumor suppressor proteins can be determined by any standard assay 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 will depend on the tissue, cell line, or substitute tissue sample used. For example, Western blotting and ELISA can be used for any or all types of tissue, cell line, or substitute tissue, while IHC is more suitable where the tissue used in the methods described herein is a tumor biopsy. FAC analysis is best suited for samples that are single-cell suspensions, such as cell lines and isolated peripheral blood mononuclear cells. See, for example, US 20070212736, “Functional Immunohistochemical Cell Cycle Analysis as a Prognostic Indicator for Cancer.” Alternatively, molecular genetic testing can be used to determine the genetic status of retinoblastoma. Molecular genetic testing for retinoblastoma includes the following, as 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).

[0335] The terms “Rb-independent,” “Rb-negative,” “Rb-deficient,” “Rb-minus,” “Rb-null,” or “Rb-” refer to several 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 absent or there is no detectable amount 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 Rb-deficient cells, tumors, or cancers. In some embodiments, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers characterized by a loss-of-function mutation in the RBI, which may include missense mutations (i.e., encoding incorrect amino acids) or nonsense mutations (i.e., encoding stop codons). In some implementations, Rb-independent cells, tumors, or cancers include cells, tumors, or cancers characterized by the complete or partial deletion of the RBI gene.

[0336] INX-315 Dosing Regimen

[0337] The invention described herein provides a treatment for human patients in need, such as those with CDK2-mediated cancers (including, but not limited to, hormone receptor-positive (HR+), HER2-positive, and HER2-positive cancers). - A method for administering INX-315 to human patients with negative breast cancer, ovarian cancer, or small cell lung cancer (SCLC), the method comprising administering INX-315 or a pharmaceutically acceptable salt thereof, which provides plasma and whole blood profiles of INX-315 in humans. In another embodiment, the invention comprises administering INX-315 to human patients with CDK2-mediated cancer sensitive to CDK2 inhibitors. In yet another embodiment, the invention comprises administering INX-315 to human patients with CDK2-mediated cancer overexpressing cyclin E.

[0338] In one aspect, this article provides a method for treating a person with CDK2-mediated cancer, comprising administering to the person in need an effective amount of a pharmaceutical composition comprising a compound having an INX-315 structure or a pharmaceutically acceptable salt thereof, resulting in the mean plasma area under the curve (AUC) measured on day 1 of administration (ng). The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) of at least about 1,250 to about 50,000 hr / mL, the ASD containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average AUC is at least about 6,000. In some embodiments, the average AUC is at least about 9,000.

[0339] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising a compound having the INX-315 structure or a pharmaceutically acceptable salt thereof, resulting in a mean maximum plasma concentration (C0.05) measured on day 1 of administration. max The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C max It is at least approximately 350. In some implementations, the average C max It is at least approximately 525.

[0340] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the INX-315 structure or a pharmaceutically acceptable salt thereof, resulting in a mean minimum plasma concentration (C0.05) measured on day 1 of administration. min The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C min It is at least approximately 120. In some implementations, the average C min It is at least approximately 180.

[0341] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising a compound having the INX-315 structure or a pharmaceutically acceptable salt thereof, resulting in a mean free minimum plasma concentration (C0.05) measured on day 1 of administration. min 游离The concentration (ng / mL) is at least about 4.0 to about 48.0, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C min 游离 It is at least about 10.0. In some implementations, the average C min 游离 It is at least approximately 15.0.

[0342] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising a compound having an INX-315 structure or a pharmaceutically acceptable salt thereof, resulting in the mean plasma area under the curve (AUC) measured on day 15 of administration (ng). The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average AUC is at least about 11,000. In some embodiments, the average AUC is at least about 16,500.

[0343] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum plasma concentration (C0.05) measured on day 15 of administration. max The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C max It is at least approximately 700. In some implementations, the average C max It is at least approximately 1,050.

[0344] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition comprising a compound having the INX-315 structure or a pharmaceutically acceptable salt thereof, resulting in a mean minimum plasma concentration (C0.05) measured on day 15 of administration.min The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C min It is at least approximately 250. In some implementations, the average C min It is at least approximately 375.

[0345] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean free minimum plasma concentration (Cmax) measured on day 15 of administration. min 游离 The concentration (ng / mL) is at least about 6.0 to about 80.0, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C min 游离 It is at least approximately 14.0. In some implementations, the average C... min 游离 It is at least approximately 21.0.

[0346] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in the mean area under the curve (AUC) of whole blood measured on day 1 of administration (ng). The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) of at least about 25,000 to about 480,000 hr / mL, the ASD containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average AUC is at least about 80,000. In some embodiments, the average AUC is at least about 120,000.

[0347] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum whole blood concentration (C0.05) measured on day 1 of administration. max The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C max It is at least approximately 4,500. In some implementations, the average C max It is at least approximately 6,750.

[0348] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to the recipient an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean minimum whole blood concentration (C0.05) measured on day 1 of administration. min The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C min It is at least approximately 1,800. In some implementations, the average C min It is at least approximately 2,700.

[0349] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in the mean whole blood area under the curve (AUC) measured on day 15 of administration (ng). The pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) of at least about 25,000 to about 800,000 hr / mL, the ASD containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average AUC is at least about 120,000. In some embodiments, the average AUC is at least about 180,000.

[0350] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean maximum whole blood concentration (C0.05) measured on day 15 of administration. max The concentration (ng / mL) is at least about 3,000 to about 56,000, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C max It is at least approximately 7,000. In some implementations, the average C max It is at least approximately 10,500.

[0351] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to the recipient an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, resulting in a mean minimum whole blood concentration (C0.05) measured on day 15 of administration. min The concentration (ng / mL) is at least about 1,000 to about 24,000, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, the average C min It is at least approximately 2,600. In some implementations, the average C min It is at least approximately 3,900.

[0352] In another aspect, this article provides a method for treating individuals with CDK2-mediated cancers, comprising administering to a person in need an effective amount of a pharmaceutical composition containing a compound having the structure INX-315 or a pharmaceutically acceptable salt thereof, which results in a mean plasma C max With C min The ratio is less than about 5 but greater than about 1.25, wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) containing between about 100 mg and about 500 mg of INX-315, and wherein the amount of INX-315 in the ASD is between 20% by weight and 50% by weight. In some embodiments, C max With C min The ratio is less than 3. In some implementations, C max With C minThe ratio is less than 2.25. In some implementations, where C max With C min The ratio is measured in plasma. In some implementations, C... max With C min The ratio was measured in whole blood.

[0353] In some implementation schemes, t 1 / 2 Between approximately 5 hours and approximately 32 hours. In some implementations, t 1 / 2 Between approximately 8 hours and approximately 28 hours. In some implementations, t 1 / 2 Between approximately 12 and approximately 18 hours. In some implementations, t 1 / 2 It takes approximately 14 hours. In some implementations, t 1 / 2 It takes approximately 15 hours. In some implementations, t 1 / 2The duration 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 the 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 approximately 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.

[0354] In some embodiments, the pharmaceutical composition further comprises a precipitation inhibitor. In some embodiments, the amount of the precipitation inhibitor in the ASD is between 40% by weight and 70% by weight. In some embodiments, the amount of the precipitation inhibitor in the ASD is about 60% by weight. In some embodiments, the precipitation inhibitor comprises hydroxypropyl methylcellulose succinate (HPMCAS) selected from the following: 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 other pharmaceutically acceptable excipients.

[0355] In some embodiments, INX-315 is administered at doses of about 100, about 125, about 150, or about 175 mg. In some embodiments, INX-315 is administered at doses of about 200 mg, about 225 mg, about 250 mg, or about 275 mg. In other embodiments, INX-315 is administered at doses of about 300 mg, about 325 mg, about 350 mg, or about 375 mg. In some embodiments, INX-315 is administered at doses of about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0356] In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in an average C max With C min The ratio is less than about 5 but greater than about 1.25. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in an average C max With C min The ratio is less than about 4.75 but greater than about 1.5. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in an average C max With C min The ratio is less than about 4.5 but greater than about 1.75. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in an average C max With C minThe ratio is less than about 4.25 but greater than about 2. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in an average C max With C min The ratio is approximately 2.2. In some embodiments, INX-315 is administered once daily. In some embodiments, INX-315 is administered in doses between approximately 100 mg and 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 a spray-dried dispersion. In some embodiments, C... max With C min The ratio is measured in plasma. In some implementations, C max With C min The ratio was measured in whole blood.

[0357] In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 hours and approximately 24 hours. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 and approximately 18 hours. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12.5 hours and approximately 17.5 hours. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 13 and 17 hours. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 13.5 hours and approximately 16.5 hours. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 14 and 16 hours. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2For approximately 14 hours. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 15 hours. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 The duration is approximately 16 hours. In some implementations, the t-value of INX-315 in plasma is measured. 1 / 2 In some implementations, the t-value of INX-315 is measured for whole blood INX-315. 1 / 2 .

[0358] In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 8 hours and approximately 28 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 10 hours and approximately 26 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 hours and approximately 26 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 13 and approximately 25 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 14 and approximately 24 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 15 and approximately 23 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 14 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 15 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 16 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 17 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2For approximately 18 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 19 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 20 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 For approximately 21 hours. In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 The duration is approximately 22 hours. In some implementations, the t-value of INX-315 in plasma is measured. 1 / 2 In some implementations, the t-value of INX-315 is measured for whole blood INX-315. 1 / 2 .

[0359] In different implementation schemes, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 5 hours and approximately 32 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 8 hours and approximately 28 hours. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 hours and approximately 24 hours. In some implementations, the t of INX-315 in plasma is measured. 1 / 2 In some implementations, the t-value of INX-315 is measured for whole blood INX-315. 1 / 2 .

[0360] In some implementations, the treatment method provides a red blood cell to plasma ratio (K0.05). RBC / P (Greater than approximately 12 but less than approximately 50.) In some implementations, K RBC / P Between approximately 15 and approximately 45. In some implementations, K RBC / P Between approximately 20 and approximately 40. In some embodiments, the treatment method provides K RBC / P Greater than approximately 12 but less than 40. In some embodiments, the treatment method provides K... RBC / P Greater than approximately 15 but less than 40. In some embodiments, the treatment method provides K... RBC / P Greater than approximately 20 but less than 40. In some embodiments, the treatment method provides K... RBC / P Greater than approximately 25 but less than 40.

[0361] In some implementations, the treatment method provides a whole blood to plasma ratio (K0.05). WB / P K is greater than approximately 4 and less than approximately 20. In some implementations, K WB / P Between approximately 6 and approximately 18. In some implementations, K WB / P Between approximately 10 and approximately 14. In some embodiments, the treatment method provides K WB / P Greater than approximately 4 but less than 14. In some embodiments, the treatment method provides K... WB / P Greater than approximately 6 but less than 14. In some embodiments, the treatment method provides K... WB / P Greater than approximately 8 but less than 14. In some embodiments, the treatment method provides K... WB / P Greater than approximately 10 but less than 14.

[0362] Importantly, these PK / PD parameters indicate that sufficiently effective levels of INX-315 can be achieved with daily oral administration to treat CDK2 inhibitor-sensitive cancers without significant drug spikes when administered to humans, minimizing adverse and / or off-target events seen with other CDK2 inhibitors currently in development. Under the supervision of the U.S. Food and Drug Administration (FDA), the INX-315 dosing regimen has been established in a Phase I human clinical trial in the United States for the treatment of individuals with recurrent advanced / metastatic cancers, including hormone receptor-positive (HR+) / human epidermal growth factor receptor 2-negative (HER2-) breast cancer that has progressed with prior cyclin-dependent kinase 4 / 6 inhibitor (CDK4 / 6i) regimens, and solid tumors (with and without CCNE1 amplification) that have progressed with standard of care. INX-315 may also be used to treat other cancers that are treatable with CDK2 inhibitors, and particularly those showing cyclin E overexpression or otherwise resistance to CDK4 / 6 inhibitors (see, for example...). Figure 16B ).

[0363] The results described in this article are surprising because two other selective CDK2 inhibitors currently in clinical development, BLU-222 and PF-07104091, have significantly higher maximum drug plasma concentrations (C0.05). maxThe pharmacokinetic parameters of INX-315 described herein could not be achieved, and this was most significant during the once-daily dosing regimen. This approach provides a surprising treatment for cancer while significantly reducing therapy-limiting off-target side effects, such as diarrhea and vomiting, associated with other CDK2 inhibitors. These dosing regimens used in humans are particularly useful for long-term treatment regimens such as those for HR+ / HER2- breast cancer, ovarian cancer, and solid tumors (with and without CCNE1 amplification) that have progressed in CDK4 / 6i regimens and / or prior standard of care. The long half-life (t0.05) of INX-315 relative to other CDK2 inhibitors without significant accumulation was observed. 1 / 2 (Due to the erythrocyte reservoir effect) this facilitates these improved dosing regimens, thereby allowing for a prolonged period of continuous administration of INX-315, while also benefiting from low C max With C min ratio.

[0364] Due to low C max With C min In some embodiments, INX-315 can be administered for extended periods, such as 2, 3, 4, 5, 6 months or more, or even indefinitely as authorized by a healthcare provider, until the cancer or other impairment is successfully treated or other therapies are used. In some embodiments, INX-315 can be administered daily for extended periods as prescribed by a healthcare practitioner, such as once daily, which improves patient adherence. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered orally once daily (QD) at doses of, for example, from about 100 mg to 400 or 500 mg (e.g., 100, 125, 150, 175, 200, 250, 300, or 400 mg / day) to enhance patient adherence to the dosing regimens described herein.

[0365] In one respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 1 of administration (ng). (hr / mL) at approximately 2750 ng hr / mL to approximately 28000ng Between hr / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 1 of administration (ng). (hr / mL) at approximately 1250 ng hr / mL to approximately 20000 ng Between hr / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 1 of administration (ng). (hr / mL) at approximately 5000 ng hr / mL to approximately 50,000 ng Between hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 2750 ng. hr / mL, approximately or greater than 3000 ng hr / mL, or approximately or greater than 3250 ng hr / mL but less than about 7000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 2750 ng. hr / mL but less than about 7000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 3000 ng. hr / mL but less than about 7000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 3250 ng. hr / mL but less than about 7000 ng hr / mL. In different implementation methods, the mean plasma AUC was approximately or greater than 1250 ng. hr / mL, approximately or greater than 1500 ng hr / mL, or approximately or greater than 1750 ng hr / mL but less than about 5000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 1250 ng. hr / mL but less than about 5000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 1500 ng. hr / mL but less than about 5000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 1750 ng. hr / mL but less than about 5000 ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 5000 ng. hr / mL, approximately or greater than 6000 ng hr / mL, or approximately or greater than 7000 ng hr / mL but less than about 12500 ng hr / mL. In different implementations, the average AUC is approximately or greater than 5000 ng. hr / mL but less than about 12500 ng hr / mL. In different implementation methods, the average AUC is approximately or greater than 6000 ng. hr / mL but less than about 12500 ng hr / mL. In different implementations, the average AUC was approximately or greater than 7000 ng. hr / mL but less than about 12500 ng hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 5500 ng. hr / mL, approximately or greater than 6000 ng hr / mL, or approximately or greater than 6500 ng hr / mL but less than about 14000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 5500 ng. hr / mL but less than about 14000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 6000 ng. hr / mL but less than about 14000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 6500 ng. hr / mL but less than about 14000ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 2500 ng. hr / mL, approximately or greater than 3000 ng hr / mL, or approximately or greater than 3500 ng hr / mL but less than about 10,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 2500 ng. hr / mL but less than about 10,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 3000 ng. hr / mL but less than about 10,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 3500 ng. hr / mL but less than about 10,000 ng hr / mL. In different implementations, the mean plasma AUC is approximately or greater than 10,000 ng. hr / mL, approximately or greater than 12000 ng hr / mL, or approximately or greater than 14000 ng hr / mL but less than about 25000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 10,000 ng. hr / mL but less than about 25000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 12000 ng. hr / mL but less than about 25000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 14000 ng. hr / mL but less than about 25000 ng hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 8250 ng. hr / mL, approximately or greater than 9000 ng hr / mL, or approximately or greater than 9750 ng hr / mL but less than about 21000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 8250 ng. hr / mL but less than about 21000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 9000 ng. hr / mL but less than about 21000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 9750 ng. hr / mL but less than about 21000 ng hr / mL. In different implementation methods, the mean plasma AUC was approximately or greater than 3750 ng. hr / mL, approximately or greater than 4500 ng hr / mL, or approximately or greater than 5250 ng hr / mL but less than about 15000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 3750 ng. hr / mL but less than about 15000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 4500 ng. hr / mL but less than about 15000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 5250 ng. hr / mL but less than about 15000 ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 15000 ng. hr / mL, approximately or greater than 18000 ng hr / mL, or approximately or greater than 21000 ng hr / mL but less than approximately 37,500 ng hr / mL. In different implementations, the average AUC was approximately or greater than 15000 ng. hr / mL but less than approximately 37,500 ng hr / mL. In different implementations, the average AUC is approximately or greater than 18000 ng. hr / mL but less than approximately 37,500 ng hr / mL. In different implementations, the average AUC was approximately or greater than 21000 ng. hr / mL but less than approximately 37,500 ng hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 11,000 ng. hr / mL, approximately or greater than 12000 ng hr / mL, or approximately or greater than 13000 ng hr / mL but less than about 28000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 11,000 ng. hr / mL but less than about 28000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 12000 ng. hr / mL but less than about 28000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 13,000 ng. hr / mL but less than about 28000 ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 5000 ng. hr / mL, approximately or greater than 5750 ng hr / mL, or approximately or greater than 6500 ng hr / mL but less than about 20,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 5000 ng. hr / mL but less than about 20,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 5750 ng. hr / mL but less than about 20,000 ng hr / mL. In different implementation methods, the average AUC is approximately or greater than 6500 ng. hr / mL but less than about 20,000 ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 20,000 ng. hr / mL, approximately or greater than 24000 ng hr / mL, or approximately or greater than 28000 ng hr / mL but less than about 50,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 20,000 ng. hr / mL but less than about 50,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 24,000 ng. hr / mL but less than about 50,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 28,000 ng. hr / mL but less than about 50,000 ng hr / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma Ch. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0366] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum plasma concentration (C0.05) measured on day 1 of administration in humans. max(ng / mL) ranges from about 150 ng / mL to about 2000 ng / mL. In different respects, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum plasma concentration (C) in humans measured on day 1 of administration. max (ng / mL) is between about 100 ng / mL and about 1600 ng / mL. In different respects, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum plasma concentration (C) in humans measured on day 1 of administration. max (ng / mL) is between about 75 ng / mL and about 2400 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 150 ng / mL, approximately or greater than 175 ng / mL, or approximately or greater than 200 ng / mL but less than approximately 500 ng / mL. In some embodiments, C max It is approximately or greater than 150 ng / mL but less than approximately 500 ng / mL. In some embodiments, C max It is approximately or greater than 175 ng / mL but less than approximately 500 ng / mL. In some embodiments, C max It is approximately or greater than 200 ng / mL but less than approximately 500 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 100 ng / mL, approximately or greater than 125 ng / mL, or approximately or greater than 150 ng / mL but less than approximately 400 ng / mL. In different embodiments, C... max It is approximately or greater than 100 ng / mL but less than approximately 400 ng / mL. In different implementations, C max It is approximately or greater than 125 ng / mL but less than approximately 400 ng / mL. In different implementations, C max It is approximately or greater than 150 ng / mL but less than approximately 400 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 75 ng / mL, approximately or greater than 180 ng / mL, or approximately or greater than 210 ng / mL but less than approximately 600 ng / mL. In different embodiments, C... max It is approximately or greater than 75 ng / mL but less than approximately 600 ng / mL. In different implementations, C max It is approximately or greater than 180 ng / mL but less than approximately 600 ng / mL. In different implementations, C max The concentration is approximately or greater than 210 ng / mL but less than approximately 600 ng / mL. In some embodiments, the average C maxThe concentration is approximately or greater than 300 ng / mL, approximately or greater than 350 ng / mL, or approximately or greater than 400 ng / mL but less than approximately 1000 ng / mL. In some embodiments, C max It is approximately or greater than 300 ng / mL but less than approximately 1000 ng / mL. In some embodiments, C max The concentration is approximately or greater than 350 ng / mL but less than approximately 1000 ng / mL. In some embodiments, C max It is approximately or greater than 400 ng / mL but less than approximately 1000 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 200 ng / mL, approximately or greater than 250 ng / mL, or approximately or greater than 300 ng / mL but less than approximately 800 ng / mL. In different implementations, C... max It is approximately or greater than 200 ng / mL but less than approximately 800 ng / mL. In different implementations, C max It is approximately or greater than 250 ng / mL but less than approximately 800 ng / mL. In different implementations, C max It is approximately or greater than 300 ng / mL but less than approximately 800 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 150 ng / mL, approximately or greater than 360 ng / mL, or approximately or greater than 420 ng / mL but less than approximately 1200 ng / mL. In different embodiments, C... max It is approximately or greater than 150 ng / mL but less than approximately 1200 ng / mL. In different implementations, C max It is approximately or greater than 360 ng / mL but less than approximately 1200 ng / mL. In different implementations, C max The concentration is approximately or greater than 420 ng / mL but less than approximately 1200 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 450 ng / mL, approximately or greater than 525 ng / mL, or approximately or greater than 600 ng / mL but less than approximately 1500 ng / mL. In some embodiments, C max The concentration is approximately or greater than 450 ng / mL but less than approximately 1500 ng / mL. In some embodiments, C max It is approximately or greater than 525 ng / mL but less than approximately 1500 ng / mL. In some embodiments, C max It is approximately or greater than 600 ng / mL but less than approximately 1500 ng / mL. In different implementations, the average C... maxThe concentration is approximately or greater than 300 ng / mL, approximately or greater than 375 ng / mL, or approximately or greater than 450 ng / mL but less than approximately 1200 ng / mL. In different embodiments, C... max It is approximately or greater than 300 ng / mL but less than approximately 1200 ng / mL. In different implementations, C max It is approximately or greater than 375 ng / mL but less than approximately 1200 ng / mL. In different implementations, C max It is approximately or greater than 450 ng / mL but less than approximately 1200 ng / mL. In different implementations, the average C... max The concentrations are approximately or greater than 225 ng / mL, approximately or greater than 540 ng / mL, or approximately or greater than 630 ng / mL but less than approximately 1800 ng / mL. In different implementations, C... max It is approximately or greater than 225 ng / mL but less than approximately 1800 ng / mL. In different implementations, C max It is approximately or greater than 540 ng / mL but less than approximately 1800 ng / mL. In different implementations, C max The concentration is approximately or greater than 630 ng / mL but less than approximately 1800 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 600 ng / mL, approximately or greater than 700 ng / mL, or approximately or greater than 800 ng / mL but less than approximately 2000 ng / mL. In some embodiments, C max The concentration is approximately or greater than 600 ng / mL but less than approximately 2000 ng / mL. In some embodiments, C max It is approximately or greater than 700 ng / mL but less than approximately 2000 ng / mL. In some embodiments, C max It is approximately or greater than 800 ng / mL but less than approximately 2000 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 400 ng / mL, approximately or greater than 500 ng / mL, or approximately or greater than 600 ng / mL but less than approximately 1600 ng / mL. In different implementations, C... max It is approximately or greater than 400 ng / mL but less than approximately 1600 ng / mL. In different implementations, C max It is approximately or greater than 500 ng / mL but less than approximately 1600 ng / mL. In different implementations, C max It is approximately or greater than 600 ng / mL but less than approximately 1600 ng / mL. In different implementations, the average C... maxThe concentration is approximately or greater than 300 ng / mL, approximately or greater than 720 ng / mL, or approximately or greater than 840 ng / mL but less than approximately 2400 ng / mL. In different implementations, C... max It is approximately or greater than 300 ng / mL but less than approximately 2400 ng / mL. In different implementations, C max It is approximately or greater than 720 ng / mL but less than approximately 2400 ng / mL. In different implementations, C max The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0367] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean plasma concentration (C) measured on day 1 of administration. min (ng / mL) is between about 50 ng / mL and about 1000 ng / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the lowest mean plasma concentration (C) measured on day 1 of administration. min (ng / mL) is between about 20 ng / mL and about 600 ng / mL. In some embodiments, the average plasma C min The concentration is approximately or greater than 50 ng / mL, approximately or greater than 60 ng / mL, or approximately or greater than 75 ng / mL but less than approximately 250 ng / mL. In some embodiments, C min The concentration is approximately or greater than 50 ng / mL but less than approximately 250 ng / mL. In some embodiments, C min The concentration is approximately or greater than 60 ng / mL but less than approximately 250 ng / mL. In some embodiments, C min The concentration is approximately or greater than 75 ng / mL but less than approximately 250 ng / mL. In different implementation methods, the average plasma C... minThe concentration is approximately or greater than 20 ng / mL, approximately or greater than 40 ng / mL, or approximately or greater than 60 ng / mL but less than approximately 150 ng / mL. In different implementations, C... min It is approximately or greater than 20 ng / mL but less than approximately 150 ng / mL. In different implementations, C min The concentration is approximately or greater than 40 ng / mL but less than approximately 150 ng / mL. In different implementations, C... min The concentration is approximately or greater than 60 ng / mL but less than approximately 150 ng / mL. In some embodiments, the average plasma C... min The concentration is approximately or greater than 100 ng / mL, approximately or greater than 120 ng / mL, or approximately or greater than 150 ng / mL but less than approximately 500 ng / mL. In some embodiments, C min It is approximately or greater than 100 ng / mL but less than approximately 500 ng / mL. In some embodiments, C min It is approximately or greater than 120 ng / mL but less than approximately 500 ng / mL. In some embodiments, C min The concentration is approximately or greater than 150 ng / mL but less than approximately 500 ng / mL. In different implementation methods, the average plasma C... min The concentration is approximately or greater than 40 ng / mL, approximately or greater than 80 ng / mL, or approximately or greater than 120 ng / mL but less than approximately 300 ng / mL. In different embodiments, C... min It is approximately or greater than 40 ng / mL but less than approximately 300 ng / mL. In different implementations, C min It is approximately or greater than 80 ng / mL but less than approximately 300 ng / mL. In different implementations, C min The concentration is approximately or greater than 120 ng / mL but less than approximately 300 ng / mL. In some embodiments, the average plasma C min The concentration is approximately or greater than 150 ng / mL, approximately or greater than 180 ng / mL, or approximately or greater than 225 ng / mL but less than approximately 750 ng / mL. In some embodiments, C min It is approximately or greater than 150 ng / mL but less than approximately 750 ng / mL. In some embodiments, C min It is approximately or greater than 180 ng / mL but less than approximately 750 ng / mL. In some embodiments, C min The concentration is approximately or greater than 225 ng / mL but less than approximately 750 ng / mL. In different implementation methods, the average plasma C... minThe concentration is approximately or greater than 60 ng / mL, approximately or greater than 120 ng / mL, or approximately or greater than 180 ng / mL but less than approximately 450 ng / mL. In different embodiments, C... min It is approximately or greater than 60 ng / mL but less than approximately 450 ng / mL. In different implementations, C min It is approximately or greater than 120 ng / mL but less than approximately 450 ng / mL. In different implementations, C min The concentration is approximately or greater than 180 ng / mL but less than approximately 450 ng / mL. In some embodiments, the average plasma C min The concentration is approximately or greater than 200 ng / mL, approximately or greater than 240 ng / mL, or approximately or greater than 300 ng / mL but less than approximately 1000 ng / mL. In some embodiments, C min The concentration is approximately or greater than 200 ng / mL but less than approximately 1000 ng / mL. In some embodiments, C min It is approximately or greater than 240 ng / mL but less than approximately 1000 ng / mL. In some embodiments, C min The concentration is approximately or greater than 300 ng / mL but less than approximately 1000 ng / mL. In different implementation methods, the average plasma C... min The concentration is approximately or greater than 80 ng / mL, approximately or greater than 160 ng / mL, or approximately or greater than 240 ng / mL but less than approximately 600 ng / mL. In different implementations, C... min It is approximately or greater than 80 ng / mL but less than approximately 600 ng / mL. In different implementations, C min It is approximately or greater than 160 ng / mL but less than approximately 600 ng / mL. In different implementations, C min The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0368] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean lowest free plasma concentration (C) measured on day 1 of administration. min 游离 (ng / mL) is between about 4.0 ng / mL and about 48.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 4.0 ng / mL, approximately or greater than 5.0 ng / mL, or approximately or greater than 6.0 ng / mL but less than approximately 12.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 4.0 ng / mL but less than approximately 12.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 5.0 ng / mL but less than approximately 12.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 6.0 ng / mL but less than approximately 12.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 8.0 ng / mL, approximately or greater than 10.0 ng / mL, or approximately or greater than 12.0 ng / mL but less than approximately 24.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 8.0 ng / mL but less than approximately 24.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 10.0 ng / mL but less than approximately 24.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 12.0 ng / mL but less than approximately 24.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 12.0 ng / mL, approximately or greater than 15.0 ng / mL, or approximately or greater than 18.0 ng / mL but less than approximately 36.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 12.0 ng / mL but less than approximately 36.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 15.0 ng / mL but less than approximately 36.0 ng / mL. In some embodiments, the average C min 游离The concentration is approximately or greater than 18.0 ng / mL but less than approximately 36.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 16.0 ng / mL, approximately or greater than 20.0 ng / mL, or approximately or greater than 24.0 ng / mL but less than approximately 48.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 16.0 ng / mL but less than approximately 48.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 20.0 ng / mL but less than approximately 48.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0369] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 15 of administration (ng). (hr / mL) at approximately 5000 ng hr / mL to approximately 56000 ng Between hr / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 15 of administration (ng). (hr / mL) at approximately 1250 ng hr / mL to approximately 28000 ng Between hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 5000 ng. hr / mL, approximately or greater than 5500 ng hr / mL, or approximately or greater than 6000 ng hr / mL but less than about 14000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 5000 ng. hr / mL but less than about 14000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 5500 ng. hr / mL but less than about 14000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 6000 ng. hr / mL but less than about 14000 ng hr / mL. In different implementation methods, the mean plasma AUC was approximately or greater than 1250 ng. hr / mL, approximately or greater than 2100 ng hr / mL, or approximately or greater than 2450 ng hr / mL but less than about 7000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 1250 ng. hr / mL but less than about 7000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 2100 ng. hr / mL but less than about 7000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 2450 ng. hr / mL but less than about 7000 ng hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 10,000 ng. hr / mL, approximately or greater than 11000 ng hr / mL, or approximately or greater than 12000 ng hr / mL but less than about 28000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 10,000 ng. hr / mL but less than about 28000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 11,000 ng. hr / mL but less than about 28000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 12000 ng. hr / mL but less than about 28000 ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 2500 ng. hr / mL, approximately or greater than 4200 ng hr / mL, or approximately or greater than 4900 ng hr / mL but less than about 14000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 2500 ng. hr / mL but less than about 14000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 4200 ng. hr / mL but less than about 14000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 4900 ng. hr / mL but less than about 14000 ng hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 15,000 ng. hr / mL, approximately or greater than 16500 ng hr / mL, or approximately or greater than 18000 ng hr / mL but less than approximately 42,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 15,000 ng. hr / mL but less than approximately 42,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 16500 ng. hr / mL but less than approximately 42,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 18,000 ng. hr / mL but less than approximately 42,000 ng hr / mL. In different implementation methods, the average plasma AUC was about or greater than 3750 ng. hr / mL, approximately or greater than 6300 ng hr / mL, or approximately or greater than 7350 ng hr / mL but less than about 21000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 3750 ng. hr / mL but less than about 21000 ng hr / mL. In different implementation methods, the average AUC was approximately or greater than 6300 ng. hr / mL but less than about 21000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 7350 ng. hr / mL but less than about 21000 ng hr / mL. In some implementations, the mean plasma AUC is approximately or greater than 20,000 ng. hr / mL, approximately or greater than 22000 ng hr / mL, or approximately or greater than 24000 ng hr / mL but less than about 56000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 20,000 ng. hr / mL but less than about 56000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 22,000 ng. hr / mL but less than about 56000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 24,000 ng. hr / mL but less than approximately 56,000 ng hr / mL. In different implementation methods, the mean plasma AUC is approximately or greater than 5000 ng. hr / mL, approximately or greater than 8400 ng hr / mL, or approximately or greater than 9800 ng hr / mL but less than about 28000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 5000 ng. hr / mL but less than about 28000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 8400 ng. hr / mL but less than about 28000 ng hr / mL. In different implementation methods, the average AUC was approximately or greater than 9800 ng. hr / mL but less than about 28000 ng hr / mL. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma Ch. maxWith C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0370] In an alternative context, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum plasma concentration (C0.05) in humans measured on day 15 of administration. max (ng / mL) ranges from about 300 ng / mL to about 4000 ng / mL. In different respects, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum plasma concentration (C) in humans, measured on day 15 of administration. max (ng / mL) is between about 90 ng / mL and about 2800 ng / mL. In some embodiments, the average plasma C max The concentration is approximately or greater than 300 ng / mL, approximately or greater than 300 ng / mL, or approximately or greater than 350 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 300 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 350 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 400 ng / mL but less than approximately 1000 ng / mL. In different implementation methods, the average plasma C... max The concentrations are approximately or greater than 90 ng / mL, approximately or greater than 210 ng / mL, or approximately or greater than 245 ng / mL but less than approximately 700 ng / mL. In different implementations, the average C... max It is approximately or greater than 90 ng / mL but less than approximately 700 ng / mL. In different implementations, the average C... max It is approximately or greater than 210 ng / mL but less than approximately 700 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 245 ng / mL but less than approximately 700 ng / mL. In some embodiments, the average plasma C... max The concentration is approximately or greater than 600 ng / mL, approximately or greater than 700 ng / mL, or approximately or greater than 800 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C maxThe concentration is approximately or greater than 600 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 700 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 800 ng / mL but less than approximately 2000 ng / mL. In different implementation methods, the average plasma C... max The values ​​are approximately or greater than 180 ng / mL, approximately or greater than 420 ng / mL, or approximately or greater than 490 ng / mL but less than approximately 1400 ng / mL. In different implementations, the average C... max It is approximately or greater than 180 ng / mL but less than approximately 1400 ng / mL. In different implementations, the average C... max It is approximately or greater than 420 ng / mL but less than approximately 1400 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 490 ng / mL but less than approximately 1400 ng / mL. In some embodiments, the average plasma C... max The concentrations are approximately or greater than 900 ng / mL, approximately or greater than 1050 ng / mL, or approximately or greater than 1200 ng / mL but less than approximately 3000 ng / mL. In some embodiments, the average C... max The concentration is approximately or greater than 900 ng / mL but less than approximately 3000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 1050 ng / mL but less than approximately 3000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 1200 ng / mL but less than approximately 3000 ng / mL. In different implementation methods, the average plasma C... max The values ​​are approximately or greater than 270 ng / mL, approximately or greater than 630 ng / mL, or approximately or greater than 735 ng / mL but less than approximately 2100 ng / mL. In different implementations, the average C... max It is approximately or greater than 270 ng / mL but less than approximately 2100 ng / mL. In different implementations, the average C... max It is approximately or greater than 630 ng / mL but less than approximately 2100 ng / mL. In different implementations, the average C... max The concentration is approximately or greater than 735 ng / mL but less than approximately 2100 ng / mL. In some embodiments, the average plasma C max The concentration is approximately or greater than 1200 ng / mL, approximately or greater than 1400 ng / mL, or approximately or greater than 1600 ng / mL but less than approximately 4000 ng / mL. In some embodiments, the average Cmax The concentration is approximately or greater than 1200 ng / mL but less than approximately 4000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 1400 ng / mL but less than approximately 4000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 1600 ng / mL but less than approximately 4000 ng / mL. In different implementation methods, the average plasma C... max The values ​​are approximately or greater than 360 ng / mL, approximately or greater than 840 ng / mL, or approximately or greater than 980 ng / mL but less than approximately 2800 ng / mL. In different implementations, the average C... max It is approximately or greater than 360 ng / mL but less than approximately 2800 ng / mL. In different implementations, the average C... max It is approximately or greater than 840 ng / mL but less than approximately 2800 ng / mL. In different implementations, the average C... max The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0371] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean plasma concentration (C) measured on day 15 of administration. min (ng / mL) is between about 100 ng / mL and about 2000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 100 ng / mL, approximately or greater than 125 ng / mL, or approximately or greater than 150 ng / mL but less than approximately 500 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 100 ng / mL but less than approximately 500 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 125 ng / mL but less than approximately 500 ng / mL. In some embodiments, the average C minThe concentration is approximately or greater than 150 ng / mL but less than approximately 500 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 200 ng / mL, approximately or greater than 250 ng / mL, or approximately or greater than 300 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 200 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 250 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 300 ng / mL but less than approximately 1000 ng / mL. In some embodiments, the average C min The concentrations are approximately or greater than 300 ng / mL, approximately or greater than 375 ng / mL, or approximately or greater than 450 ng / mL but less than approximately 1500 ng / mL. In some embodiments, the average C... min The concentration is approximately or greater than 300 ng / mL but less than approximately 1500 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 375 ng / mL but less than approximately 1500 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 450 ng / mL but less than approximately 1500 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 400 ng / mL, approximately or greater than 500 ng / mL, or approximately or greater than 600 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 400 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 500 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C min The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0372] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean lowest free plasma concentration (C) measured on day 15 of administration. min 游离 (ng / mL) is between about 6.0 ng / mL and about 80.0 ng / mL. In some embodiments, the average C min 游离 The concentrations are approximately or greater than 6.0 ng / mL, approximately or greater than 7.0 ng / mL, and approximately or greater than 8.0 ng / mL but less than approximately 20.0 ng / mL. In some embodiments, the average C... min 游离 The concentration is approximately or greater than 6.0 ng / mL but less than approximately 20.0 ng / mL. In some embodiments, the average C min 游离 It is approximately or greater than 7.0 ng / mL but less than approximately 20.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 8.0 ng / mL but less than approximately 20.0 ng / mL. In some embodiments, the average C min 游离 The concentrations are approximately or greater than 12.0 ng / mL, approximately or greater than 14.0 ng / mL, and approximately or greater than 16.0 ng / mL but less than approximately 40.0 ng / mL. In some embodiments, the average C... min 游离 The concentration is approximately or greater than 12.0 ng / mL but less than approximately 40.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 14.0 ng / mL but less than approximately 40.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 16.0 ng / mL but less than approximately 40.0 ng / mL. In some embodiments, the average C min 游离 The concentrations are approximately or greater than 18.0 ng / mL, approximately or greater than 21.0 ng / mL, and approximately or greater than 24.0 ng / mL but less than approximately 60.0 ng / mL. In some embodiments, the average C... min 游离 The concentration is approximately or greater than 18.0 ng / mL but less than approximately 60.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 21.0 ng / mL but less than approximately 60.0 ng / mL. In some embodiments, the average C min游离 The concentration is approximately or greater than 24.0 ng / mL but less than approximately 60.0 ng / mL. In some embodiments, the average C min 游离 The concentrations are approximately or greater than 24.0 ng / mL, approximately or greater than 28.0 ng / mL, and approximately or greater than 32.0 ng / mL but less than approximately 80.0 ng / mL. In some embodiments, the average C... min 游离 The concentration is approximately or greater than 24.0 ng / mL but less than approximately 80.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately or greater than 28.0 ng / mL but less than approximately 80.0 ng / mL. In some embodiments, the average C min 游离 The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0373] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the curve (AUC) of whole blood measured on day 1 of administration (ng). (hr / mL) at approximately 30,000 ng hr / mL to approximately 480,000 ng Between hr / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the mean area under the curve (AUC) of whole blood measured on day 1 of administration (ng). (hr / mL) at approximately 25000 ng hr / mL to approximately 400,000 ng Between hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 30,000 ng. hr / mL, approximately or greater than 40,000 ng hr / mL, or approximately or greater than 50,000 ng hr / mL but less than approximately 120,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 30,000 ng. hr / mL but less than approximately 120,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 40,000 ng. hr / mL but less than approximately 120,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 50,000 ng. hr / mL but less than approximately 120,000 ng hr / mL. In different implementation methods, the mean whole blood AUC is approximately or greater than 25,000 ng. hr / mL, approximately or greater than 27500 ng hr / mL, or approximately or greater than 30,000 ng hr / mL but less than approximately 100,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 25000 ng. hr / mL but less than approximately 100,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 27,500 ng. hr / mL but less than approximately 100,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 30,000 ng. hr / mL but less than approximately 100,000 ng hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 60,000 ng. hr / mL, approximately or greater than 80,000 ng hr / mL, or approximately or greater than 100,000 ng hr / mL but less than approximately 240,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 60,000 ng. hr / mL but less than approximately 240,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 80,000 ng. hr / mL but less than approximately 240,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 100,000 ng. hr / mL but less than approximately 240,000 ng hr / mL. In different implementation methods, the mean whole blood AUC is approximately or greater than 50,000 ng. hr / mL, approximately or greater than 55000 ng hr / mL, or approximately or greater than 60,000 ng hr / mL but less than approximately 200,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 50,000 ng. hr / mL but less than approximately 200,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 55,000 ng. hr / mL but less than approximately 200,000 ng hr / mL. In different implementation methods, the average AUC is approximately or greater than 60,000 ng. hr / mL but less than approximately 200,000 ng hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 90,000 ng. hr / mL, approximately or greater than 120,000 ng hr / mL, or approximately or greater than 150,000 ng hr / mL but less than approximately 360,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 90,000 ng. hr / mL but less than approximately 360,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 120,000 ng. hr / mL but less than approximately 360,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 150,000 ng. hr / mL but less than approximately 360,000 ng hr / mL. In different implementation methods, the mean whole blood AUC was approximately or greater than 75,000 ng. hr / mL, approximately or greater than 82500 ng hr / mL, or approximately or greater than 90,000 ng hr / mL but less than approximately 300,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 75,000 ng. hr / mL but less than approximately 300,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 82,500 ng. hr / mL but less than approximately 300,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 90,000 ng. hr / mL but less than approximately 300,000 ng hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 120,000 ng. hr / mL, approximately or greater than 160,000 ng hr / mL, or approximately or greater than 200,000 ng hr / mL but less than approximately 480,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 120,000 ng. hr / mL but less than approximately 480,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 160,000 ng. hr / mL but less than approximately 480,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 200,000 ng. hr / mL but less than approximately 480,000 ng hr / mL. In different implementation methods, the mean whole blood AUC is approximately or greater than 100,000 ng. hr / mL, approximately or greater than 110,000 ng hr / mL, or approximately or greater than 120,000 ng hr / mL but less than approximately 400,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 100,000 ng. hr / mL but less than approximately 400,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 110,000 ng. hr / mL but less than approximately 400,000 ng hr / mL. In different implementations, the average AUC is approximately 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 a dose between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma Ch. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0374] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum whole blood concentration (C0.05) measured on day 1 of administration in humans. max (ng / mL) is between approximately 2000 ng / mL and approximately 28000 ng / mL. In some embodiments, the average whole blood C max The concentration is approximately or greater than 2000 ng / mL, approximately or greater than 2250 ng / mL, or approximately or greater than 2500 ng / mL but less than approximately 7000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 2000 ng / mL but less than approximately 7000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 2250 ng / mL but less than approximately 7000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 2500 ng / mL but less than approximately 7000 ng / mL. In some embodiments, the average whole blood C... max The concentrations are approximately or greater than 4000 ng / mL, approximately or greater than 4500 ng / mL, or approximately or greater than 5000 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average C... max The concentration is approximately or greater than 4000 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 4500 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 5000 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average whole blood C... max The concentrations are approximately or greater than 6000 ng / mL, approximately or greater than 6750 ng / mL, or approximately or greater than 7500 ng / mL but less than approximately 21000 ng / mL. In some embodiments, the average C... maxThe concentration is approximately or greater than 6000 ng / mL but less than approximately 21000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 6750 ng / mL but less than approximately 21000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 7500 ng / mL but less than approximately 21000 ng / mL. In some embodiments, the average whole blood C... max The concentration is approximately or greater than 8000 ng / mL, approximately or greater than 9000 ng / mL, or approximately or greater than 10000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 8000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 9000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average C max The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0375] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean whole blood concentration (C0.05) measured on day 1 of administration. min (ng / mL) ranges from about 800 ng / mL to about 14400 ng / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the mean lowest whole blood concentration (C) measured on day 1 of administration. min (ng / mL) is between about 500 ng / mL and about 8000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 800 ng / mL, approximately or greater than 900 ng / mL, or approximately or greater than 1000 ng / mL but less than approximately 3600 ng / mL. In some embodiments, the average C minIt is approximately or greater than 800 ng / mL but less than approximately 3600 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 900 ng / mL but less than approximately 3600 ng / mL. In some embodiments, the average C min It is approximately or greater than 1000 ng / mL but less than approximately 3600 ng / mL. In different implementations, the average C... min The concentrations are approximately or greater than 500 ng / mL, approximately or greater than 575 ng / mL, or approximately or greater than 650 ng / mL but less than approximately 2000 ng / mL. In different implementations, the average C... min It is approximately or greater than 500 ng / mL but less than approximately 2000 ng / mL. In different implementations, the average C... min It is approximately or greater than 575 ng / mL but less than approximately 2000 ng / mL. In different implementations, the average C... min The concentration is approximately or greater than 650 ng / mL but less than approximately 2000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 1600 ng / mL, approximately or greater than 1800 ng / mL, or approximately or greater than 2000 ng / mL but less than approximately 7200 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 1600 ng / mL but less than approximately 7200 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 1800 ng / mL but less than approximately 7200 ng / mL. In some embodiments, the average C min It is approximately or greater than 2000 ng / mL but less than approximately 7200 ng / mL. In different implementations, the average C... min The values ​​are approximately or greater than 1000 ng / mL, approximately or greater than 1150 ng / mL, or approximately or greater than 1300 ng / mL but less than approximately 4000 ng / mL. In different implementation schemes, the average C... min It is approximately or greater than 1000 ng / mL but less than approximately 4000 ng / mL. In different implementations, the average C... min It is approximately or greater than 1150 ng / mL but less than approximately 4000 ng / mL. In different implementations, the average C... min The concentration is approximately or greater than 1300 ng / mL but less than approximately 4000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 2400 ng / mL, approximately or greater than 2700 ng / mL, or approximately or greater than 3000 ng / mL but less than approximately 10800 ng / mL. In some embodiments, the average Cmin The concentration is approximately or greater than 2400 ng / mL but less than approximately 10800 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 2700 ng / mL but less than approximately 10800 ng / mL. In some embodiments, the average C min It is approximately or greater than 3000 ng / mL but less than approximately 10800 ng / mL. In different implementations, the average C... min The values ​​are approximately or greater than 1500 ng / mL, approximately or greater than 1725 ng / mL, or approximately or greater than 1950 ng / mL but less than approximately 6000 ng / mL. In different implementation schemes, the average C... min It is approximately or greater than 1500 ng / mL but less than approximately 6000 ng / mL. In different implementations, the average C... min It is approximately or greater than 1725 ng / mL but less than approximately 6000 ng / mL. In different implementations, the average C... min The concentration is approximately or greater than 1950 ng / mL but less than approximately 6000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 3200 ng / mL, approximately or greater than 3600 ng / mL, or approximately or greater than 4000 ng / mL but less than approximately 14400 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 3200 ng / mL but less than approximately 14400 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 3600 ng / mL but less than approximately 14400 ng / mL. In some embodiments, the average C min It is approximately or greater than 4000 ng / mL but less than approximately 14400 ng / mL. In different implementations, the average C... min The values ​​are approximately or greater than 2000 ng / mL, approximately or greater than 2300 ng / mL, or approximately or greater than 2600 ng / mL but less than approximately 8000 ng / mL. In different implementation schemes, the average C... min It is approximately or greater than 2000 ng / mL but less than approximately 8000 ng / mL. In different implementations, the average C... min It is approximately or greater than 2300 ng / mL but less than approximately 8000 ng / mL. In different implementations, the average C... minThe concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0376] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the curve (AUC) of whole blood measured on day 15 of administration. (hr / mL) at approximately 50,000 ng hr / mL to approximately 800,000 ng Between hr / mL. In different respects, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in the mean area under the curve (AUC) of whole blood measured on day 15 of administration (ng). (hr / mL) at approximately 25000 ng hr / mL to approximately 600,000 ng Between hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 50,000 ng. hr / mL, approximately or greater than 60,000 ng hr / mL, or approximately or greater than 70,000 ng hr / mL, but less than approximately 200,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 50,000 ng. hr / mL but less than approximately 200,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 60,000 ng. hr / mL but less than approximately 200,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 70,000 ng. hr / mL but less than approximately 200,000 ng hr / mL. In different implementation methods, the mean whole blood AUC is approximately or greater than 25,000 ng. hr / mL, approximately or greater than 45000 ng hr / mL, or approximately or greater than 52,500 ng hr / mL, but less than approximately 150,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 25000 ng. hr / mL but less than approximately 150,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 45,000 ng. hr / mL but less than approximately 150,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 52,500 ng. hr / mL but less than approximately 150,000 ng hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 100,000 ng. hr / mL, approximately or greater than 120,000 ng hr / mL, or approximately or greater than 140,000 ng hr / mL, but less than approximately 400,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 100,000 ng. hr / mL but less than approximately 400,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 120,000 ng. hr / mL but less than approximately 400,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 140,000 ng. hr / mL but less than approximately 400,000 ng hr / mL. In different implementation methods, the mean whole blood AUC is approximately or greater than 50,000 ng. hr / mL, approximately or greater than 90,000 ng hr / mL, or approximately or greater than 105,000 ng hr / mL, but less than approximately 300,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 50,000 ng. hr / mL but less than approximately 300,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 90,000 ng. hr / mL but less than approximately 300,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 105,000 ng. hr / mL but less than approximately 300,000 ng hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 150,000 ng. hr / mL, approximately or greater than 120,000 ng hr / mL, or approximately or greater than 140,000 ng hr / mL, but less than approximately 600,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 150,000 ng. hr / mL but less than approximately 600,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 180,000 ng. hr / mL but less than approximately 600,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 210,000 ng. hr / mL but less than approximately 600,000 ng hr / mL. In different implementation methods, the mean whole blood AUC was approximately or greater than 75,000 ng. hr / mL, approximately or greater than 135,000 ng hr / mL, or approximately or greater than 157,500 ng hr / mL, but less than approximately 450,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 75,000 ng. hr / mL but less than approximately 450,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 135,000 ng. hr / mL but less than approximately 450,000 ng hr / mL. In different implementations, the average AUC was approximately or greater than 157,500 ng. hr / mL but less than approximately 450,000 ng hr / mL. In some implementations, the mean whole blood AUC is approximately or greater than 200,000 ng. hr / mL, approximately or greater than 240,000 ng hr / mL, or approximately or greater than 280,000 ng hr / mL, but less than approximately 800,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 200,000 ng. hr / mL but less than approximately 800,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 240,000 ng. hr / mL but less than approximately 800,000 ng hr / mL. In some implementations, the average AUC is approximately or greater than 280,000 ng. hr / mL but less than approximately 800,000 ng hr / mL. In different implementation methods, the mean whole blood AUC is approximately or greater than 100,000 ng. hr / mL, approximately or greater than 180,000 ng hr / mL, or approximately or greater than 210,000 ng hr / mL, but less than approximately 600,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 100,000 ng. hr / mL but less than approximately 600,000 ng hr / mL. In different implementations, the average AUC is approximately or greater than 180,000 ng. hr / mL but less than approximately 600,000 ng hr / mL. In different implementations, the average AUC is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma Ch. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0377] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean maximum whole blood concentration (C0.05) measured on day 15 of administration in humans. max(ng / mL) is between approximately 3000 ng / mL and approximately 56000 ng / mL. In some embodiments, the average whole blood C max The concentration is approximately or greater than 3000 ng / mL, approximately or greater than 3500 ng / mL, or approximately or greater than 4000 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 3000 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 3500 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 4000 ng / mL but less than approximately 14000 ng / mL. In some embodiments, the average whole blood C... max The concentrations are approximately or greater than 6000 ng / mL, approximately or greater than 7000 ng / mL, or approximately or greater than 8000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average C... max The concentration is approximately or greater than 6000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 7000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 8000 ng / mL but less than approximately 28000 ng / mL. In some embodiments, the average whole blood C... max The concentrations are approximately or greater than 9000 ng / mL, approximately or greater than 10500 ng / mL, or approximately or greater than 12000 ng / mL but less than approximately 42000 ng / mL. In some embodiments, the average C... max The concentration is approximately or greater than 9000 ng / mL but less than approximately 42000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 10,500 ng / mL but less than approximately 42,000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 12,000 ng / mL but less than approximately 42,000 ng / mL. In some embodiments, the average whole blood C... max The values ​​are approximately or greater than 12,000 ng / mL, approximately or greater than 14,000 ng / mL, or approximately or greater than 16,000 ng / mL but less than approximately 56,000 ng / mL. In some embodiments, the average C max The concentration is approximately or greater than 12,000 ng / mL but less than approximately 56,000 ng / mL. In some embodiments, the average C maxThe concentration is approximately or greater than 14,000 ng / mL but less than approximately 56,000 ng / mL. In some embodiments, the average C max The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0378] In another respect, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean whole blood concentration (C0.05) measured on day 15 of administration. min (ng / mL) is between approximately 1000 ng / mL and approximately 24000 ng / mL. In some embodiments, the average whole blood C min The concentrations are approximately or greater than 1000 ng / mL, approximately or greater than 1300 ng / mL, or approximately or greater than 1600 ng / mL but less than approximately 6000 ng / mL. In some embodiments, the average C... min The concentration is approximately or greater than 1000 ng / mL but less than approximately 6000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 1300 ng / mL but less than approximately 6000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 1600 ng / mL but less than approximately 6000 ng / mL. In some embodiments, the average whole blood C... min The concentration is approximately or greater than 2000 ng / mL, approximately or greater than 2600 ng / mL, or approximately or greater than 3200 ng / mL but less than approximately 12000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 2000 ng / mL but less than approximately 12000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 2600 ng / mL but less than approximately 12000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 3200 ng / mL but less than approximately 12000 ng / mL. In some embodiments, the average whole blood C... minThe concentrations are approximately or greater than 3000 ng / mL, approximately or greater than 3900 ng / mL, or approximately or greater than 4800 ng / mL but less than approximately 18000 ng / mL. In some embodiments, the average C... min The concentration is approximately or greater than 3000 ng / mL but less than approximately 18000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 3900 ng / mL but less than approximately 18000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 4800 ng / mL but less than approximately 18000 ng / mL. In some embodiments, the average whole blood C... min The concentrations are approximately or greater than 4000 ng / mL, approximately or greater than 5200 ng / mL, or approximately or greater than 6400 ng / mL but less than approximately 24000 ng / mL. In some embodiments, the average C... min The concentration is approximately or greater than 4000 ng / mL but less than approximately 24000 ng / mL. In some embodiments, the average C min The concentration is approximately or greater than 5200 ng / mL but less than approximately 24000 ng / mL. In some embodiments, the average C min The concentration is approximately 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 between 100 mg and 500 mg. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a mean plasma C0.05. max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, C max With C min The ratio is less than 3. In some implementations, C max With C min The ratio is less than 2.25.

[0379] In one respect, administration of INX-315 or its pharmaceutically acceptable salts to human patients in need resulted in an average C max With C min The ratio is less than 5, less than 4, less than 3, or less than 2.25 but greater than about 1.25. In some implementations, the average C max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, the average C max With C min The ratio is less than 4 but greater than about 1.25. In some implementations, the average C max With C minThe ratio is less than 3 but greater than about 1.25. In some implementations, the average C max With C min The ratio is less than 2.25 but greater than about 1.25. In some implementations, C max With C min The ratio is approximately 2.2. In some implementations, C max With C min The ratio is measured in plasma. In some implementations, C max With 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 between 100 mg and 500 mg.

[0380] In one aspect, treating a person with CDK2-mediated cancer involves administering an effective amount of INX-315 or a pharmaceutically acceptable salt thereof to the person in need, resulting in an area under the curve (AUC) ratio of whole blood to plasma measured on day 1 of administration of at least about 6 to about 22. In some embodiments, the AUC ratio of whole blood to plasma measured on day 1 of administration of at least about 12 to about 20.

[0381] In another aspect, treating individuals with CDK2-mediated cancers involves administering an effective amount of INX-315 or a pharmaceutically acceptable salt thereof to the recipient, resulting in an area under the curve (AUC) ratio of whole blood to plasma measured on day 15 of administration of at least about 6 to about 40. In some embodiments, the AUC ratio of whole blood to plasma measured on day 15 of administration of at least about 8 to about 18.

[0382] In another aspect, treating people with CDK2-mediated cancers involves administering an effective amount of INX-315 or a pharmaceutically acceptable salt thereof to those in need, which results in a higher ratio of RBCs to plasma (K... RBC / P The ratio of RBCs to plasma is at least about 10.0 to about 20.0. In different embodiments, the ratio of RBCs to plasma (K...) is... RBC / P () is at least about 20.0 to about 50.0.

[0383] In different respects, treatment for people with CDK2-mediated cancers includes administering an effective amount of INX-315 or a pharmaceutically acceptable salt thereof to those in need, resulting in a whole blood to plasma ratio (K... WB / P The ratio of whole blood to plasma is at least about 4.0 to about 10.0. In different embodiments, the ratio of whole blood to plasma (K...) is... WB / P () is at least about 8.0 to about 20.0.

[0384] In another aspect, the treatment method provides the t of INX-315 in humans 1 / 2Between approximately 12 hours and approximately 24 hours. In some implementations, t 1 / 2 Greater than approximately 12 hours but less than approximately 18 hours. In some implementations, t 1 / 2 For approximately or greater than approximately 12 hours, approximately or greater than approximately 13 hours, approximately or greater than approximately 14 hours, approximately or greater than approximately 15 hours, approximately or greater than approximately 16 hours, approximately or greater than approximately 17 hours, or approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 14 hours, greater than approximately 16 hours, greater than approximately 16.5 hours, greater than approximately 17 hours, greater than approximately 17.5 hours, or greater than approximately 18 hours. In some implementations, t 1 / 2 For approximately or more than approximately 14 hours. In some implementations, t 1 / 2 For approximately or more than approximately 15 hours. In some implementations, t 1 / 2 For approximately or more than approximately 16 hours. In some implementations, the t of INX-315 1 / 2 This is for measuring INX-315 in plasma. In some implementations, the t of INX-315 is... 1 / 2 This is a measurement of INX-315 in whole blood. In some embodiments, INX-315 or an acceptable salt thereof is administered once daily at a dose between 100 mg and 500 mg.

[0385] In another aspect, the treatment method provides the t of INX-315 in humans 1 / 2 Between approximately 8 hours and approximately 28 hours. In different implementations, t 1 / 2 Greater than approximately 10 hours but less than approximately 26 hours. In different implementations, t 1 / 2 The duration is approximately or greater than approximately 8 hours, approximately or greater than approximately 10 hours, approximately or greater than approximately 12 hours, approximately or greater than approximately 14 hours, approximately or greater than approximately 15 hours, approximately or greater than approximately 16 hours, approximately or greater than approximately 18 hours, or approximately 20 hours. In different implementation schemes, t 1 / 2 The duration is approximately or greater than approximately 12 hours, greater than approximately 14 hours, greater than approximately 16 hours, greater than approximately 18 hours, greater than approximately 20 hours, or greater than approximately 20 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 9 hours. In some implementations, t 1 / 2 For approximately or more than approximately 10 hours. In different implementations, t 1 / 2 For approximately or more than approximately 11 hours. In different implementations, t 1 / 2 For approximately or more than approximately 12 hours. In different implementations, t 1 / 2 For approximately or more than approximately 13 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 14 hours. In different implementations, t 1 / 2For approximately or more than approximately 15 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 16 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 17 hours. In different implementations, t 1 / 2 For approximately or more than approximately 18 hours. In different implementations, t 1 / 2 For approximately or more than approximately 19 hours. In different implementations, t 1 / 2 For approximately or more than approximately 20 hours. In different implementations, t 1 / 2 For approximately or more than approximately 21 hours. In different implementations, t 1 / 2 For approximately or more than approximately 22 hours. In different implementations, t 1 / 2 It is approximately or greater than approximately 23 hours. In different implementations, t 1 / 2 The duration is approximately or greater than approximately 24 hours. In different implementations, the t of INX-315... 1 / 2 This is for plasma INX-315 measurements. In different implementations, the t of INX-315... 1 / 2 This is a measurement of INX-315 in whole blood. In different implementations, INX-315 or an acceptable salt thereof is administered once daily at a dose between 100 mg and 500 mg.

[0386] In another aspect, the treatment method provides the t of INX-315 in humans 1 / 2 Between approximately 5 hours and approximately 32 hours. In different implementations, t 1 / 2 Greater than approximately 8 hours but less than approximately 28 hours. In different implementations, t 1 / 2 The duration is approximately or greater than approximately 5 hours, approximately or greater than approximately 8 hours, approximately or greater than approximately 10 hours, approximately or greater than approximately 12 hours, approximately or greater than approximately 14 hours, approximately or greater than approximately 15 hours, approximately or greater than approximately 16 hours, approximately or greater than approximately 18 hours, or approximately 20 hours. In different implementation schemes, t 1 / 2 For approximately or greater than approximately 8 hours, approximately or greater than approximately 12 hours, greater than approximately 14 hours, greater than approximately 16 hours, greater than approximately 18 hours, greater than approximately 20 hours, or greater than approximately 20 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 5 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 6 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 7 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 8 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 9 hours. In some implementations, t 1 / 2For approximately or more than approximately 10 hours. In different implementations, t 1 / 2 For approximately or more than approximately 11 hours. In different implementations, t 1 / 2 For approximately or more than approximately 12 hours. In different implementations, t 1 / 2 For approximately or more than approximately 13 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 14 hours. In different implementations, t 1 / 2 For approximately or more than approximately 15 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 16 hours. In different implementation schemes, t 1 / 2 For approximately or more than approximately 17 hours. In different implementations, t 1 / 2 For approximately or more than approximately 18 hours. In different implementations, t 1 / 2 For approximately or more than approximately 19 hours. In different implementations, t 1 / 2 For approximately or more than approximately 20 hours. In different implementations, t 1 / 2 For approximately or more than approximately 21 hours. In different implementations, t 1 / 2 For approximately or more than approximately 22 hours. In different implementations, t 1 / 2 It is approximately or greater than approximately 23 hours. In different implementations, t 1 / 2 The duration is approximately or greater than approximately 24 hours. In different implementations, the t of INX-315... 1 / 2 This is for plasma INX-315 measurements. In different implementations, the t of INX-315... 1 / 2 This is a measurement of INX-315 in whole blood. In different implementations, INX-315 or an acceptable salt thereof is administered once daily at a dose between 100 mg and 500 mg.

[0387] Treatment

[0388] As considered in this article, or for the treatment of patients (including humans) in need, including administration of an effective amount of INX-315 or a pharmaceutically acceptable salt thereof, which provides substantially improved blood pharmacokinetic (PK) or pharmacodynamic (PD) characteristics, resulting in higher and longer-than-expected blood and plasma levels without significant peak immediately after administration.

[0389] In one aspect, 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, TNBC is Rb-independent. In some embodiments, the breast cancer has amplification or overexpression of cyclin E. In some embodiments, the breast cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the breast cancer has progressed with a previous 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 in need results in an average C max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 and approximately 18 hours. In some implementations, t 1 / 2 For approximately or more than approximately 14 hours. In some implementations, t 1 / 2 For approximately or more than approximately 15 hours. In some implementations, t 1 / 2 The duration is approximately 16 hours or longer. In some embodiments, INX-315 is administered in doses between approximately 100 mg and 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).

[0390] In some embodiments, the cancer is ovarian cancer. In some embodiments, the ovarian cancer has amplification or overexpression of cyclin E. 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, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in an average C... max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients with lung cancer results in t 1 / 2 Between approximately 12 hours and approximately 24 hours. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 and approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 14 hours but less than approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 15 hours but less than approximately 18 hours. In some implementations, t 1 / 2 The duration of administration is approximately 16 hours or more but less than approximately 18 hours. In some embodiments, INX-315 is administered in doses between approximately 100 mg and 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).

[0391] 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, the SCLC has amplification or overexpression of cyclin E. In some embodiments, the SCLC is Rb-independent. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to a human patient with lung cancer results in an average C... max With C minThe ratio is less than 5 but greater than about 1.25. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients with lung cancer results in t 1 / 2 Between approximately 12 hours and approximately 24 hours. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients with lung cancer resulted in t 1 / 2 Between approximately 12 and approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 14 hours but less than approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 15 hours but less than approximately 18 hours. In some implementations, t 1 / 2 The duration of administration is approximately 16 hours or more but less than approximately 18 hours. In some embodiments, INX-315 is administered in doses between approximately 100 mg and 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).

[0392] In some implementations, the cancer is prostate cancer.

[0393] In some implementations, the cancer is bladder cancer.

[0394] In some implementations, the cancer is a sarcoma.

[0395] In some embodiments, the cancer is uterine cancer. In some embodiments, the uterine cancer is endometrial cancer.

[0396] In some embodiments, the treatment methods described herein are used to treat solid tumors. In some embodiments, the solid tumor has amplification or overexpression of cyclin E. In some embodiments, the solid tumor has progressed with standard care.

[0397] In some aspects, the cancer treated using the methods described 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, the cancer is esophageal cancer. In some embodiments, the esophageal cancer includes esophageal adenocarcinoma. In some embodiments, the ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is advanced, unresectable, and / or metastatic cancer. In some embodiments, the cancer is cyclin E amplification or overexpression. In some embodiments, a next-generation sequencing (NGS) panel test is used to confirm cyclin E overexpression or amplification. In some embodiments, the person has previously received at least one previous line of chemotherapy. In some embodiments, the person has previously received at least two previous lines of chemotherapy. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one previous line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after previous standard of care therapy. In some embodiments, the cancer progressed after previous systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard or care therapy. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after a previous regimen including a platinum analogue. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the cancer progressed after a previous regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy resistant.

[0398] In one aspect, the cancer treated using the methods described herein is Rb-positive cancer. In some implementations, Rb-positive cancer is selected from Rb-positive lung cancer, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, melanoma of the skin or eye, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, gastric cancer, colon cancer, breast cancer, uterine cancer, fallopian tube cancer, endometrial cancer, cervical cancer, vaginal cancer, vulvar cancer, esophageal cancer, small bowel cancer, endocrine system cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, urethral cancer, penile cancer, prostate cancer, bladder cancer, kidney or ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system (CNS) tumors, primary CNS lymphoma, spinal axis tumors, brainstem gliomas, or pituitary adenomas. 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).

[0399] In some embodiments, the INX-315 described herein, or a pharmaceutically acceptable salt or ASD formulation thereof, provides an additive or synergistic effect with the action of a CDK4 / 6 inhibitor used to treat Rb-positive 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, abeciclib, triasilib, leroximate, or dalcirib. 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 leroximate. In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, piroxicillin (birociclib, 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, the CDK4 / 6 inhibitor is administered at a standard dose and administration 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 combinations 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, the SERD is selected from fulvestrant or elacestrant. In some embodiments, the person has previously received at least one previous line of standard care therapy. In some embodiments, the person has previously received at least two previous lines of standard care therapy. 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 is recurrent. In some embodiments, the cancer progressed after prior standard of care therapy. In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard or care therapy. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after prior regimens including platinum analogs. In some embodiments, the cancer is platinum refractory or platinum resistant. In some embodiments, the cancer progressed after prior regimens including CDK4 / 6 inhibitors. In some embodiments, the cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the cancer progressed after prior regimens including endocrine therapy. In some embodiments, the cancer is endocrine therapy resistant.

[0400] In various aspects, the cancers treated using the methods described herein are Rb-independent cancers. In some embodiments, 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. 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 neuroendocrine prostate 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.

[0401] In some embodiments, the INX-315 described herein, or a pharmaceutically acceptable salt or ASD formulation thereof, provides an additive or synergistic effect with the action of a CDK4 / 6 inhibitor used to treat 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, abeciclib, trilaciclib, leroxiclib, or dalcilibiclib. 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 leroxiclib. In some embodiments, the CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, piroxicillin (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, the CDK4 / 6 inhibitor is administered at a standard dose and administration 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 combinations 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, the SERD is selected from fulvestrant or ellastrant. In some embodiments, the person has previously received at least one previous line of standard care therapy. In some embodiments, the person has previously received at least two previous lines of standard care therapy. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some implementations, the person has previously received at least one prior line of endocrine therapy.In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after previous standard of care therapy. In some embodiments, the cancer progressed after previous systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard or care therapy. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after previous regimens including platinum analogs. In some embodiments, the cancer is platinum refractory or platinum resistant. In some embodiments, the cancer progressed after previous regimens including CDK4 / 6 inhibitors. In some embodiments, the cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the cancer progressed after previous regimens including endocrine therapy. In some embodiments, the cancer is endocrine therapy resistant.

[0402] In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD formulation thereof, as described herein, is combined with palbociclib for the treatment of a subject with cancer. In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD formulation thereof, is combined with palbociclib administered for 21 days during a 28-day cycle with a 7-day drug holiday. 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, the cancer is endometrial cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer includes esophageal adenocarcinoma. In some embodiments, the ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is advanced unresectable and / or metastatic cancer. In some embodiments, the cancer includes Rb-independent cancer. In some embodiments, the Rb-independent cancer is SCLC. In some embodiments, the 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 combinations 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, the SERD is selected from fulvestrant or elastin. In some embodiments, the person has previously received at least one previous line of standard of care. In some embodiments, the person has previously received at least two previous lines of standard of care. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one previous line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after previous standard of care therapy.In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard or adequate care. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after prior regimens including platinum analogs. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after prior regimens including CDK4 / 6 inhibitors. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after prior regimens including endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0403] In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD formulation thereof, as described herein, is combined with ribociclib for the treatment of a subject with cancer. In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD formulation thereof, is combined with ribociclib administered for 21 days during a 28-day cycle with a 7-day drug holiday. 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, the cancer is endometrial cancer. In some embodiments, the cancer is esophageal cancer. In some embodiments, the esophageal cancer includes esophageal adenocarcinoma. In some embodiments, the ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is advanced unresectable and / or metastatic cancer. In some embodiments, the cancer includes Rb-independent cancer. In some embodiments, the Rb-independent cancer is SCLC. In some embodiments, the 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 combinations 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, the SERD is selected from fulvestrant or elastin. In some embodiments, the person has previously received at least one previous line of standard of care. In some embodiments, the person has previously received at least two previous lines of standard of care. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one previous line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after previous standard of care therapy.In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard or adequate care. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after prior regimens including platinum analogs. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after prior regimens including CDK4 / 6 inhibitors. In some embodiments, the cancer is CDK4 / 6 inhibitor-resistant. In some embodiments, the cancer progressed after prior regimens including endocrine therapy. In some embodiments, the cancer is endocrine therapy-resistant.

[0404] In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD preparation thereof, as described herein, is combined with abexicillin for the treatment of a subject with cancer. In some embodiments, the cancer is breast cancer. In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD preparation thereof, is administered in combination with continuously administered abexicillin. 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, the esophageal cancer includes esophageal adenocarcinoma. In some embodiments, the ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is advanced unresectable and / or metastatic cancer. In some embodiments, the cancer includes Rb-independent cancer. In some embodiments, the Rb-independent cancer is SCLC. In some embodiments, the 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 combinations 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, the SERD is selected from fulvestrant or elastin. In some embodiments, the person has previously received at least one previous line of standard of care. In some embodiments, the person has previously received at least two previous lines of standard of care. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one previous line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after previous standard of care therapy. In some embodiments, the cancer progressed after previous systemic therapy.In some embodiments, the cancer is intolerant to or unsuitable for standard or care therapy. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after a previous regimen including a platinum analog. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the cancer progressed after a previous regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy resistant.

[0405] In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD preparation thereof, as described herein, is combined with leroximate for the treatment of a subject with cancer. In some embodiments, the cancer is breast cancer. In some embodiments, INX-315, or a pharmaceutically acceptable salt or ASD preparation thereof, is administered in combination with serially administered leroximate. 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, the esophageal cancer includes esophageal adenocarcinoma. In some embodiments, the ovarian cancer includes high-grade serous ovarian cancer (HGSOC). In some embodiments, the cancer is prostate cancer. In some embodiments, the cancer is sarcoma. In some embodiments, the cancer is uterine cancer. In some embodiments, the cancer is gastric cancer. In some embodiments, the cancer is advanced unresectable and / or metastatic cancer. In some embodiments, the cancer includes Rb-independent cancer. In some embodiments, the Rb-independent cancer is SCLC. In some embodiments, the 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 combinations 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, the SERD is selected from fulvestrant or elastin. In some embodiments, the person has previously received at least one previous line of standard of care. In some embodiments, the person has previously received at least two previous lines of standard of care. In some embodiments, the person has previously received at least one previous line of CDK4 / 6 inhibitor therapy. In some embodiments, the person has previously received at least one previous line of endocrine therapy. In some embodiments, the cancer is recurrent. In some embodiments, the cancer progressed after previous standard of care therapy. In some embodiments, the cancer progressed after previous systemic therapy.In some embodiments, the cancer is intolerant to or unsuitable for standard or care therapy. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after a previous regimen including a platinum analog. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the cancer progressed after a previous regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy resistant.

[0406] In some embodiments, the INX-315 described herein, or a pharmaceutically acceptable salt or ASD formulation thereof, provides additive or synergistic anticancer or antiproliferative activity with chemotherapeutic agents used to treat Rb-independent cancers. In some embodiments, the chemotherapeutic agent is selected from 5-fluorouracil (5-FU), capecitabine, carboplatin, cisplatin, docetaxel, etoposide, gemcitabine, irinotecan, mitomycin, paclitaxel, vincristine, or combinations thereof. 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 is recurrent. In some embodiments, the cancer progressed after prior standard of care therapy. In some embodiments, the cancer progressed after prior systemic therapy. In some embodiments, the cancer is intolerant to or unsuitable for standard or care therapy. In some embodiments, the cancer is refractory. In some embodiments, the cancer progressed after a previous regimen including a platinum analogue. In some embodiments, the cancer is platinum-refractory or platinum-resistant. In some embodiments, the cancer progressed after a previous regimen including a CDK4 / 6 inhibitor. In some embodiments, the cancer is CDK4 / 6 inhibitor resistant. In some embodiments, the cancer progressed after a previous regimen including endocrine therapy. In some embodiments, the cancer is endocrine therapy resistant.

[0407] In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean plasma area under the curve (AUC) measured on day 1 of administration (ng). (hr / mL) is approximately or greater than 2750 ng hr / mL but less than about 28000 ng hr / mL. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 1 of administration (ng). (hr / mL) is approximately or greater than 1250 ng hr / mL but less than about 20,000 ng hr / mL. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the plasma curve (AUC) measured on day 1 of administration (ng). (hr / mL) is approximately or greater than 5000 ng hr / mL but less than about 50,000 ng hr / mL. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum plasma concentration (C2) in humans measured on day 1 of administration. max (ng / mL) is about or greater than 150 ng / mL but less than about 2000 ng / mL. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum plasma concentration (C) in humans measured on day 1 of administration. max (ng / mL) is about or greater than 100 ng / mL but less than about 1600 ng / mL. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum plasma concentration (C) in humans measured on day 1 of administration. max (ng / mL) is about or greater than 75 ng / mL but less than about 2400 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the lowest mean plasma concentration (C) measured on day 1 of administration. min (ng / mL) is about or greater than 50 ng / mL but less than about 1000 ng / mL. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean plasma concentration (C) measured on day 1 of administration. min (ng / mL) is about or greater than 20 ng / mL but less than about 600 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean minimum free plasma concentration (C) measured on day 1 of administration. min 游离(ng / mL) is about or greater than 4.0 ng / mL but less than about 48.0 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean plasma area under the curve (AUC) measured on day 15 of administration (ng / mL). (hr / mL) is approximately or greater than 5000 ng hr / mL but less than approximately 56,000 ng hr / mL. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean plasma area under the curve (AUC) measured on day 15 of administration (ng). (hr / mL) is approximately or greater than 1250 ng hr / mL but less than about 28000 ng hr / mL. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum plasma concentration (C2) in humans measured on day 15 of administration. max (ng / mL) is about or greater than 300 ng / mL but less than about 4000 ng / mL. In different embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum plasma concentration (C) in humans measured on day 15 of administration. max (ng / mL) is about or greater than 90 ng / mL but less than about 2800 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean plasma concentration (C) measured on day 15 of administration. min (ng / mL) is about or greater than 100 ng / mL but less than about 2000 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean minimum free plasma concentration (C) measured on day 15 of administration. min 游离 (ng / mL) is about or greater than 6.0 ng / mL but less than about 80.0 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean area under the curve (AUC) of whole blood measured on day 1 of administration (ng / mL). (hr / mL) is approximately or greater than 30,000 ng hr / mL but less than approximately 480,000 ng hr / mL. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the curve (AUC) of whole blood measured on day 1 of administration (ng). (hr / mL) is approximately or greater than 25000 ng hr / mL but less than approximately 400,000 ng hr / mL. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum whole blood concentration (C2) measured in humans on day 1 of administration. max (ng / mL) is about or greater than 2000 ng / mL but less than about 28000 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean lowest whole blood concentration (C) measured on day 1 of administration. min (ng / mL) is about or greater than 800 ng / mL but less than about 14400 ng / mL. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the lowest mean whole blood concentration (C) measured on day 1 of administration. min (ng / mL) is about or greater than 500 ng / mL but less than about 8000 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean area under the curve (AUC) of whole blood measured on day 15 of administration (ng / mL). (hr / mL) is approximately or greater than 50,000 ng hr / mL but less than approximately 800,000 ng hr / mL. In different implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need resulted in the mean area under the curve (AUC) of whole blood measured on day 15 of administration (ng). (hr / mL) is approximately or greater than 25000 ng hr / mL but less than approximately 600,000 ng hr / mL. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the mean maximum whole blood concentration (C2) measured in humans on day 15 of administration. max (ng / mL) is about or greater than 3000 ng / mL but less than about 56000 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in the lowest mean whole blood concentration (C) measured on day 15 of administration. minThe concentration (ng / mL) is about or greater than 1000 ng / mL but less than about 24000 ng / mL. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in a whole blood to plasma area under the curve (AUC) ratio of about 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 in need results in a whole blood to plasma area under the curve (AUC) ratio of about 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 in need results in a mean C max With C min The ratio is less than 5 but greater than about 1.25. In some implementations, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients with lung cancer results in t 1 / 2 Between approximately 12 hours and approximately 24 hours. In some embodiments, administration of INX-315 or a pharmaceutically acceptable salt thereof to human patients in need results in t 1 / 2 Between approximately 12 and approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 14 hours but less than approximately 18 hours. In some implementations, t 1 / 2 The duration is approximately or greater than approximately 15 hours but less than approximately 18 hours. In some implementations, t 1 / 2 The duration of administration is approximately 16 hours or more but less than approximately 18 hours. In some embodiments, INX-315 is administered in doses between approximately 100 mg and 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).

[0408] In some aspects, this document discloses methods for treating a person with cancer, said 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 includes cancers with cyclin E amplification or overexpression. In some embodiments, the sample of the subject to be treated has at least 1.5-fold, at least 2.0-fold, at least 2.5-fold, at least 3.0-fold, at least 3.5-fold, at least 4.0-fold, at least 4.5-fold, at least 5.0-fold, or greater than 5.0-fold overexpression and / or activation of cyclin E1 (CCNE1) and / or cyclin E2 (CCNE2) compared to a control sample. In some embodiments, said method further includes 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, abecilib, trilaciclib, lerocilib, or dalcilib. In some embodiments, the additional CDK4 / 6 inhibitor is selected from BPI-16350, narazaciclib (ON-123300), FLX-925 (AMG-925), UCT-03-008, GLR2007, piroxicamib (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 assay is used to confirm CCNE1 or CCNE2 overexpression or amplification status. In some implementations, the NGS panel test confirming CCNE1 or CCNE2 overexpression or amplification 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 implementations, the patient sample is selected from tumor tissue, formalin-fixed paraffin-embedded (FFPE) tumor tissue, blood, or plasma.

[0409] In some embodiments, INX-315 is administered in doses of about 100 mg to about 500 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses of about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses of about 100 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses of about 200 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered in doses of about 300 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered at a dose of about 400 mg. In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof is administered at a dose of about 500 mg. In some embodiments, INX-315 is administered orally. In some embodiments, INX-315 is formulated as an amorphous spray-dried dispersion (ASD).

[0410] Pharmaceutical Compositions and Dosage Forms

[0411] INX-315 or a pharmaceutically acceptable salt thereof may be administered to the host in an effective amount according to the methods described herein to treat any of the disorders described herein using any suitable method to achieve the desired therapeutic outcome. The amount and timing of INX-315 administration are, of course, dependent on the host receiving treatment, the instructions of the supervising medical professional, the duration of exposure, the route of administration, pharmacokinetic properties, and the judgment of the prescribing physician. Therefore, due to the variability between hosts, the dosages given below are guidelines, and physicians may titrate the dosage of the compound to achieve treatment that the physician deems appropriate for the host. In considering the required level of treatment, physicians may balance various factors such as the host's age and weight, the presence of pre-existing conditions, and the presence of other illnesses.

[0412] Amorphous solid dispersions spray-dried formulations

[0413] In some embodiments, INX-315 is co-spray-dried with a precipitation inhibitor in a solvent to form an amorphous spray-dried dispersion (ASD) to achieve the desired function of the ASD for use in the final pharmaceutical composition.

[0414] Spray drying is the process of converting a feed from a fluid state into a dry particulate form by spraying the feed into a hot drying medium. Spray drying methods for manufacturing ASD typically include the following steps: (i) feed atomization, wherein the feed is atomized into a fine spray; (ii) drying the atomized feed droplets with a hot drying gas to form solid particles; and (iii) separating the dried particles from the gas.

[0415] In some embodiments, the spray-dried solution contains 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 hydroxypropyl methylcellulose, such as HPMC 2910, hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose acetate succinate (HPMCAS), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate phthalate (CAP), sodium carboxymethyl cellulose (Na-CMC), polyacrylic acid, polyethylene glycol such as PEG 4000, PEG 6000, PEG 8000, and PEG 20000, and polyvinylpyrrolidone such as PVP K 30, PVP K 25, PVP VA64, and PVP VA37. In some embodiments, the 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, the HPMCAS is HPMCAS-H. In some embodiments, the HPMCAS is HPMCAS-HF. In some embodiments, the HPMCAS is HPMCAS-HG. In some embodiments, the precipitation inhibitor is selected from erythritol, maltodextrin, mannitol, copovidone, colloidal silica, polysorbate 80, lactose, PVP, PVP-VA, chitosan hydrochloride, meglumine, copovidone, HPMC, sodium alginate, or sodium carboxymethyl cellulose.

[0416] In some embodiments, INX-315 comprises about 20% to about 50% by weight of ASD. In some embodiments, INX-315 comprises about 25% to about 45% by weight of ASD. In some embodiments, INX-315 comprises about 40% by weight of ASD. In some embodiments, the precipitation inhibitor in ASD comprises about 40% to about 70% by weight of ASD. In some embodiments, the precipitation inhibitor in ASD comprises about 45% to about 65% by weight of ASD. In some embodiments, the precipitation inhibitor in ASD comprises about 60% by weight of ASD.

[0417] The liquid feed used in spray drying can be a suspension, solution, or emulsion. The liquid solution, suspension, or emulsion can be pumped from the feed container into the drying chamber through an atomizing nozzle. In some embodiments, water is used as the solvent in the liquid feed. In some embodiments, the liquid feed is prepared using a suitable non-toxic organic solvent and / or co-solvent or aqueous suspension suitable for pharmaceutical formulations. In some embodiments, the solvent is selected from water, ethanol, isopropanol, dioxane, chloroform, THF, THF stabilized with butylated hydroxytoluene (BHT), methanol, EtOAc, 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, diethyl ether, ethyl formate, formic acid, heptane, isobutyl acetate, isooctane, isopropyl ether, methyl acetate, methyl isopropyl ketone, methyltetrahydrofuran, 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 comprises methanol and water or is composed of methanol and water. In some embodiments, the solvent comprises THF and water or is composed of THF and water. In some embodiments, the solvent comprises 80% THF and 20% water or is composed of 80% THF and 20% water. In some embodiments, the solvent comprises 90% THF and 10% water, or is composed of 90% THF and 10% water. In some embodiments, the solvent comprises 92% THF and 8% water, or is composed of 92% THF and 8% water. Atomization is typically accomplished using a pressurized nozzle or a rotary disc atomizer. In alternative embodiments, an ultrasonic nozzle or a two-fluid nozzle may be used.

[0418] Once the liquid feed is atomized, the fine spray comes into contact with the hot drying gas. In some embodiments, the hot drying gas is nitrogen. The flow of the feed and gas can be countercurrent, cocurrent, or mixed. During the drying step, the liquid evaporates almost instantaneously, producing solid particles. In spray drying, the feed dries extremely quickly because it can be atomized into a fine spray or mist with a large surface area that facilitates solvent evaporation. The solid particles produced by spray drying can be granules, powders, or agglomerates.

[0419] The final step in the spray drying process is to separate the dried particles from the gas. This can be done, for example, using a filter or a cyclone separator.

[0420] In some embodiments, the pharmaceutical composition is manufactured 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 a precipitation inhibitor, wherein the ASD formulation is dry-granulated, dry-mixed, and then tableted with one or more pharmaceutically acceptable excipients. In some embodiments, using 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.

[0421] In one aspect, this document provides a pharmaceutical composition comprising an amorphous spray-dried dispersion (ASD) of a compound having the INX-315 structure or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, wherein the ASD further comprises a precipitation inhibitor. In some embodiments, INX-315 is about 20% to about 60% by weight of the ASD. In some embodiments, INX-315 is about 30% to about 50% by weight of the ASD. In some embodiments, INX-315 is about 40% by weight of the ASD. In some embodiments, the pharmaceutical composition comprises INX-315 between about 100 mg and about 500 mg. In some embodiments, the precipitation inhibitor is hydroxypropyl methylcellulose succinate (HPMCAS). In some embodiments, the precipitation inhibitor is HPMCAS-HG. In some embodiments, the precipitation inhibitor 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, ASD is about 40% to about 60% by weight of the pharmaceutical composition. In some embodiments, ASD is about 50% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises 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 comprises 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 comprises 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 comprises a flow aid. In some embodiments, the flow aid is colloidal silica. In some embodiments, the flow aid is about 0.1% to about 5% by weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a lubricant. In some embodiments, the lubricant is sodium stearoyl fumarate. In some embodiments, the lubricant is about 0.1% to about 5% by weight of the pharmaceutical composition.

[0422] Pharmaceutical compositions can be formulated into any pharmaceutically useful form, such as liquid oral dosage forms, solid oral dosage forms, semi-solid oral dosage forms, as aerosols, creams, gels, pills, injectable or infusion solutions, capsules, tablets, syrups, transdermal patches, subcutaneous patches, dry powders, inhalation formulations, medical devices, suppositories, buccal or sublingual formulations, parenteral formulations, or ophthalmic solutions. Some dosage forms, such as tablets and capsules, are subdivided into appropriately sized unit doses containing an appropriate amount of the active ingredient, such as an effective amount to achieve the desired purpose.

[0423] INX-315 or its pharmaceutically acceptable salts as described herein can be administered orally, topically, parenterally, by inhalation or spray, sublingually, via implants (including ocular implants), transdermally, buccally, rectally, as an ophthalmic solution, by injection (including ocular injection), intramuscularly, by inhalation, intra-aortic, intracranial, subdermal, intraperitoneal, subcutaneous, nasal, sublingual, or rectal, or by other means, in dosage units containing conventional pharmaceutically acceptable carriers. For ocular delivery, compounds can be administered as needed, such as via intravitreal, intrastromal, anterior chamber, sub-tenon, subretinal, retrobulbar, peribulbar, suprachorodial, conjunctival, subconjunctival, suprascleral, periocular, transscleral, retrobulbar, posterior juxtacleral, pericardial, or lacrimal duct injection, or via mucus, mucin, or mucosal barrier, either immediately or in a controlled manner, or through ocular devices.

[0424] In some embodiments, the pharmaceutical composition comprising amorphous INX-315 of ASD or a pharmaceutically acceptable salt thereof is administered orally. For example, in some embodiments, the pharmaceutical composition comprising amorphous INX-315 of ASD or a pharmaceutically acceptable salt thereof and a precipitation inhibitor is administered orally.

[0425] The therapeutically effective dose of INX-315 or its pharmaceutically acceptable salt may be determined by a healthcare practitioner based on the patient's condition, body size and age, and route of delivery. In some non-limiting embodiments, doses of about 0.1 to about 200 mg / kg are therapeutically effective, all weights being based on the weight of INX-315, including when salt is used. In some embodiments, the dose is about or greater than 0.1, 0.5, 1, 5, 10, or 25 mg / kg.

[0426] In some embodiments, the pharmaceutical composition is in a dosage form containing about 50 to 500 mg, for example 100 to 400 or 500 mg, or further, for example 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, or 500 mg of INX-315. In some embodiments, the pharmaceutical composition is in 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 in a dosage form containing about 200 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is in a dosage form containing about 300 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is in the form of a dosage form containing about 400 mg of INX-315 or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition is in the form of a dosage form containing about 500 mg of INX-315 or a pharmaceutically acceptable salt thereof. The pharmaceutical composition may also contain a molar ratio of INX-315 or a pharmaceutically acceptable salt thereof to an additional active agent (e.g., a selective CDK4 inhibitor) to achieve the desired results.

[0427] 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 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 one year, or longer, including indefinitely, or until a healthcare provider determines that the drug is no longer necessary.

[0428] According to the currently disclosed methods, oral administration can be in any desired form, such as solid, gel, or liquid, including solutions, suspensions, or emulsions. In some embodiments, INX-315 or its salts are administered as liposome suspensions via inhalation or intramuscular injection. When administered by inhalation, INX-315 or its salts can be in the form of multiple solid particles or droplets having any desired particle size, such as about 0.01, 0.1, or 0.5 to about 5, 10, 20, or more micrometers, and optionally about 1 to about 2 micrometers.

[0429] The pharmaceutical formulation may be contained in INX-315 or a pharmaceutically acceptable salt thereof in any pharmaceutically acceptable carrier. Water may sometimes be the preferred carrier for water-soluble compounds or salts, if the solution is desired. For water-soluble compounds or salts, organic media, such as glycerol, propylene glycol, polyethylene glycol, or mixtures thereof, may be suitable. In the latter case, the organic media may contain a significant amount of water. The solution in either case may then be sterilized in a manner known to those skilled in the art, and, for example, filtered through a 0.22-micron filter.

[0430] The carrier comprises excipients and diluents and must possess sufficiently high purity and low toxicity to be suitable for administration to patients receiving treatment. The carrier may be inert, or it may have its own pharmaceutical benefits. The amount of carrier used with INX-315 is sufficient to provide an amount of actual material for each unit dose of INX-315 administration.

[0431] Carriers include, but are not limited to, binders, buffers, colorants, diluents, disintegrants, emulsifiers, flavoring agents, glidants, lubricants, preservatives, stabilizers, surfactants, tableting agents, and wetting agents. Some carriers may be listed in multiple categories; for example, vegetable oils may be used as lubricants in some formulations and as diluents in others. Exemplary pharmaceutically acceptable carriers include sugars, starches, celluloses, tragacanth gum, malt, gelatin, talc, and vegetable oils. Optional active agents may be included in the pharmaceutical composition that do not substantially interfere with the activity of INX-315.

[0432] In addition, auxiliary substances, such as wetting agents or emulsifiers, biological buffers, and surfactants, can be present in such media. Biological buffers can be any pharmacologically acceptable solution that provides the formulation with the desired pH, i.e., a pH within a physiologically acceptable range. Examples of buffer solutions include saline, phosphate-buffered saline, Tris-buffered saline, Hank's buffered saline, etc.

[0433] Depending on the intended method of administration, the pharmaceutical composition may be in the form of a solid, semi-solid, or liquid dosage form, such as tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions, etc., preferably in a unit dosage form suitable for a precise single-dose administration. The composition will comprise an effective amount of INX-315 combined with a pharmaceutically acceptable carrier, and may also include other pharmaceutical agents, adjuvants, diluents, buffers, etc.

[0434] In certain independent embodiments of the invention, a pharmaceutical composition comprising: i) an ASD formulation of the invention comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof, spray-dried together with a precipitation inhibitor; and ii) optionally additionally comprising one or more pharmaceutically acceptable excipients, wherein the ASD formulation is dry-granulated, dry-mixed, and then tableted together with one or more optional pharmaceutically acceptable excipients. In some embodiments, the precipitation inhibitor in the ASD comprises hydroxypropyl methylcellulose 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, INX-315 is present in the form of 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 the form of about 20% by weight of the pharmaceutical composition. In some embodiments, the precipitation inhibitor in the ASD is about 20% to about 50% by weight of the pharmaceutical composition. In some embodiments, the precipitation inhibitor in the ASD is about 25% to about 45% by weight of the pharmaceutical composition. In some embodiments, the precipitation inhibitor in the ASD is about 30% by weight of the pharmaceutical composition.

[0435] In some embodiments, the weight / weight percentage range of amorphous INX-315 or its pharmaceutically acceptable salts and precipitation inhibitors in the ASD formulations and pharmaceutical compositions described herein is as follows:

[0436]

[0437] In some embodiments, the pharmaceutical composition comprises amorphous INX-315 or its pharmaceutically acceptable salt and precipitation inhibitor, spray-dried together with the ASD formulation, and thereafter, one or more pharmaceutically acceptable excipients selected from insoluble diluents, soluble diluents, disintegrants, glidants 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-tocopherol polyethylene glycol succinate), mannitol, cellulose (e.g., microcrystalline cellulose), croscarmellose sodium, silica (e.g., untreated fumed colloidal), and sodium stearoyl fumarate. In some embodiments, the pharmaceutical composition according to the invention is formulated in dosage unit form, such as oral dosage unit form. In some embodiments, the pharmaceutical composition according to the invention is formulated in tablet dosage form.

[0438] In some embodiments, pharmaceutical compositions comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof comprise one or more of the following pharmaceutically acceptable excipients:

[0439]

[0440] In some embodiments, a method for preparing a pharmaceutical composition comprising INX-315 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient includes: (i) spray-drying a solution comprising INX-315 or a pharmaceutically acceptable salt thereof and a precipitation inhibitor 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 with one or more pharmaceutically acceptable excipients; and (iv) compressing the dry-mixed granules into tablets to provide a pharmaceutical composition comprising amorphous INX-315 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient in the form of an oral dose unit. In some embodiments, the nominal tablet strength of the oral dose unit form is between about 100 mg and about 500 mg. In some embodiments, the nominal tablet strength of the oral dose unit form is between about 100 mg and about 300 mg. In some embodiments, the nominal tablet strength of the oral dose unit form is about 100 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is about 150 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is between about 200 mg and about 400 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is about 200 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is about 250 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is about 300 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is about 350 mg. In some embodiments, the nominal tablet strength in the oral dose unit form is about 400 mg.

[0441] Therefore, the compositions disclosed herein can be administered as pharmaceutical preparations, including those suitable for oral (including oral and sublingual), rectal, nasal, topical, pulmonary, vaginal, or parenteral (including intramuscular, intrathecal, and subcutaneous) administration, or in the form of inhalation or insufflation. A preferred mode of administration is oral, with convenient daily dosage regimens that can be adjusted according to the degree of discomfort.

[0442] For solid compositions, conventional non-toxic solid carriers include, for example, pharmaceutical-grade mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, etc. Pharmaceutically applicable liquid compositions can be prepared, for example, by dissolving, dispersing, etc., INX-315 or its pharmaceutically acceptable salts, along with optional pharmaceutical adjuvants, in excipients (e.g., water, saline, glucose aqueous solution, glycerol, ethanol, etc.), thereby forming a solution or suspension. If desired, the pharmaceutical composition to be applied may also contain small amounts of non-toxic excipients, such as wetting agents or emulsifiers, pH buffers, etc., for example, sodium acetate, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate, etc. The actual methods for preparing such dosage forms are known or obvious to those skilled in the art; see, for example, 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).

[0443] In yet another embodiment, a penetration enhancer excipient is used, including polymers such as: polycationic (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanionic (N-carboxymethyl chitosan, polyacrylic acid); and thiolized polymers (carboxymethyl cellulose-cysteine, polycarbofil-cysteine, chitosan-thiobutylamidine, chitosan-thioglycolic acid, chitosan-glutathione conjugate).

[0444] For oral administration, the compositions are typically in the form of tablets, capsules, soft gel capsules, or may be aqueous or non-aqueous solutions, suspensions, or syrups. Tablets and capsules are preferred forms for oral administration. Tablets and capsules for oral use may include one or more commonly used carriers, such as lactose and corn starch. Lubricants, such as magnesium stearate, are often added. Typically, the compositions of this disclosure can be combined with oral, non-toxic, pharmaceutically acceptable inert carriers (e.g., lactose, starch, sucrose, glucose, methylcellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol, etc.). In addition, suitable binders, lubricants, disintegrants, and colorants may be incorporated into the mixture when needed or necessary. Suitable binders include starch, gelatin, natural sugars (e.g., glucose or β-lactose), corn sweeteners, natural and synthetic gums (e.g., gum arabic, tragacanth, or sodium alginate), carboxymethyl cellulose, polyethylene glycol, waxes, etc. The lubricants used in these formulations include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, and sodium chloride. Disintegrants include, but are not limited to, starch, methylcellulose, agar, bentonite, and xanthan gum.

[0445] When used as a liquid suspension, INX-315 can be combined with any orally administered, non-toxic, pharmaceutically acceptable inert carrier (e.g., ethanol, glycerin, water, etc.) and with emulsifiers and suspending agents. Flavoring agents, coloring agents, and / or sweeteners may also be added if desired. Other optional ingredients used in this document for incorporation into oral formulations include, but are not limited to, preservatives, suspending agents, thickeners, etc.

[0446] Parenteral preparations can be prepared in conventional forms (as a liquid solution or suspension, a solid form suitable for dissolving or suspending in a liquid prior to injection, or as an emulsion). Preferably, sterile injectable suspensions are formulated using suitable carriers, dispersants or wetting agents, and suspending agents according to techniques known in the art. Sterile injectable preparations can also be sterile injectable solutions or suspensions in non-toxic, parenteral diluents or solvents. Among acceptable media and solvents, water, Ringer's solution, and isotonic sodium chloride solution can be used. In addition, sterile, fixed oils, fatty esters, or polyols are commonly used as solvents or suspension media. Furthermore, parenteral administration can involve the use of sustained-release or continuous-release systems to maintain a constant dose level. Parenteral administration includes intra-articular, intramuscular, intradermal, intraperitoneal, and subcutaneous routes. Administration via certain parenteral routes may involve introducing the preparations of this disclosure into the patient via a needle or catheter propelled by a sterile syringe or certain other mechanical device (e.g., a continuous infusion system). The formulations provided in this disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.

[0447] In addition to INX-315 or its pharmaceutically acceptable salts, pharmaceutical formulations may contain other additives, such as pH-adjusting additives. Specifically, useful pH adjusters include acids, such as hydrochloric acid, bases, or buffers, such as sodium lactate, sodium acetate, sodium phosphate, sodium citrate, sodium borate, or sodium gluconate. Furthermore, formulations may contain antimicrobial preservatives. Useful antimicrobial preservatives include methylparaben, propylparaben, and benzyl alcohol. Antimicrobial preservatives are typically used when formulations are placed in vials designed for multiple-dose administration. The pharmaceutical formulations described herein can be lyophilized using techniques well known in the art.

[0448] In some embodiments, INX-315 or a pharmaceutically acceptable salt thereof may be provided in the form of a lyophilized product capable of being reconstituted with a suitable pharmaceutically acceptable carrier to form a liquid formulation suitable for injection into a host. When INX-315 or a pharmaceutically acceptable salt thereof is substantially insoluble in water, a sufficient amount of a physiologically acceptable emulsifier may be used to emulsify INX-315 or a pharmaceutically acceptable salt thereof in an aqueous carrier. Particularly useful emulsifiers include phosphatidylcholine and lecithin.

[0449] Pharmaceutical formulations are also provided that provide controlled release of INX-315 as described herein or a pharmaceutically acceptable salt thereof, including through the use of biodegradable polymers known in the art.

[0450] As used herein, the term “pharmaceutically acceptable salt” means, within reasonable medical judgment, a salt suitable for use in contact with a host (e.g., a human host) without excessive toxicity, irritation, allergic reactions, etc., commensurate with a reasonable benefit / risk ratio, and effective for its intended use, and, where possible, the zwitterionic form of INX-315 described herein.

[0451] Therefore, the term "salt" refers to the relatively non-toxic inorganic and organic acid addition salts of INX-315. These salts can be prepared during the final separation and purification of the compound, or by reacting the purified free base form of INX-315 with a suitable organic or inorganic acid and then separating the resulting salt. Basic compounds are capable of forming a wide variety of salts with a variety of inorganic and organic acids. Acid addition salts of basic compounds are prepared by contacting the free base form with a sufficient amount of the desired acid in a conventional manner to produce the salt. The free base form can be regenerated by contacting the salt form with a base and separating the free base in a conventional manner. The free base form may differ from its respective salt form in certain physical properties, such as solubility in polar solvents.

[0452] Salts that can be prepared from inorganic acids include hydrochlorides, sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, and iodides. Inorganic acids include hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, and phosphorus. Representative salts include hydrobromide, hydrochloride, sulfates, hemisulfates, bisulfates, nitrates, acetates, oxalates, valerates, oleates, palmitates, stearates, laurates, borates, benzoates, lactates, phosphates, toluenesulfonates, citrates, maleates, fumarates, succinates, tartrates, naphthalates, methanesulfonates, gluconates, lacturonic acids, dodecyl sulfonates, and hydroxyethyl sulfonates, etc. Salts can also be prepared from organic acids, such as aliphatic monocarboxylic acids and dicarboxylic acids, phenyl-substituted alkanes, hydroxyalka...

Claims

1. A pharmaceutical composition comprising an amorphous spray-dried dispersion (ASD) of INX-315 and a pharmaceutically acceptable excipient; wherein INX-315 is a compound of the following structure: or a pharmaceutically acceptable salt thereof; and wherein the ASD further comprises a precipitation preventing agent.

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

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

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

5. The pharmaceutical composition of any one of claims 1-4, wherein the pharmaceutical composition comprises between about 100 mg to about 500 mg of INX-315.

6. The pharmaceutical composition of any one of claims 1-4, wherein the precipitation preventing agent is selected from 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 VA37.

7. The pharmaceutical composition of claim 6, wherein the precipitation preventing agent is HPMCAS-HG.

8. The pharmaceutical composition of any one of claims 1-7, wherein the precipitation preventing agent in the ASD is about 40% to about 80% by weight of the ASD.

9. The pharmaceutical composition of any one of claims 1-7, wherein the precipitation preventing agent in the ASD is about 60% by weight of the ASD.

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

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

12. The pharmaceutical composition of any one of claims 1-11, wherein the pharmaceutical composition comprises an insoluble diluent.

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

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

15. The pharmaceutical composition of any one of claims 1-14, wherein the pharmaceutical composition comprises a soluble diluent.

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

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

18. The pharmaceutical composition of any one of claims 1-17, wherein the pharmaceutical composition comprises a disintegrant.

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

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

21. The pharmaceutical composition of any one of claims 1-20, wherein the pharmaceutical composition comprises a glidant.

22. The pharmaceutical composition of claim 21, wherein the glidant is colloidal silicon dioxide.

23. The pharmaceutical composition of claim 21 or 22, wherein the glidant is about 0.1% to about 5% by weight of the pharmaceutical composition.

24. The pharmaceutical composition of any one of claims 1-20, wherein the pharmaceutical composition comprises a lubricant.

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

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

27. A method of treating a human having a heterogeneous CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a compound of the following structure: or a pharmaceutically acceptable salt thereof, (INX-315), wherein the heterogeneous CDK2-mediated cancer comprises a mixture of retinoblastoma (Rb)-dependent cells and Rb-independent cells.

28. The method of claim 27, wherein 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) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

29. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure or a pharmaceutically acceptable salt thereof: wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and (INX-315), which results in a mean plasma area under the curve (AUC) (ng hr / mL) measured on day 1 of dosing of between about 1,250 to about 50,000; wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. ​ 30. The method of any one of claims 27-29, wherein the mean plasma AUC measured on Day 1 of dosing is between 6,000 and 50,000.

31. The method of any one of claims 27-29, wherein the mean plasma AUC measured on Day 1 of dosing is between 9,000 and 50,000.

32. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean maximum plasma concentration (Cmax) max )(ng / mL) between about 75 and about 2,400 measured on Day 1 of dosing; or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

33. The method of any one of claims 27-32, wherein the mean blood plasma C max between 350 and 2,400.

34. The method of any one of claims 27-32, wherein the mean blood plasma C max between 525 and 2,400.

35. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean minimum plasma concentration (C min )(ng / mL) measured on day 1 of dosing between about 20 and about 1,000; or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

36. The method of any one of claims 27-35, wherein the mean blood plasma C min between 120 and 1,000.

37. The method of any one of claims 27-35, wherein the mean blood plasma C min between 180 and 1,000.

38. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean free minimum plasma concentration (C min 游离 ) between about 4.0 and about 48.0; or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

39. The method of any one of claims 27-38, wherein the mean C min 游离 Between 10 and 48.

40. The method of any one of claims 27-38, wherein the mean C min 游离 Between 15 and 48.

41. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which resulted in a mean plasma area under the curve (AUC) (ng hr / mL) between about 1,250 to about 56,000 measured at day 15 of dosing; or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

42. The method of any one of claims 27-41, wherein the mean plasma AUC measured on Day 15 of dosing is between 11,000 and 56,000.

43. The method of any one of claims 27-41, wherein the mean plasma AUC measured on Day 15 of dosing is between 16,500 and 56,000.

44. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: or a pharmaceutically acceptable salt thereof; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. (INX-315), which results in a mean maximum plasma concentration (Cmax) max )(ng / mL) between about 90 and about 4,000 measured at day 15 of dosing; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

45. The method of any one of claims 27-44, wherein the mean plasma C max between 700 and 4,000.

46. The method of any one of claims 27-44, wherein the mean blood plasma C max between 1,050 and 4,000.

47. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean minimum plasma concentration (C min )(ng / mL) between about 100 and about 2,000 measured at day 15 of dosing; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

48. The method of any one of claims 27-47, wherein the mean blood plasma C min between 250 and 2,000.

49. The method of any one of claims 27-47, wherein the mean blood plasma C min between 375 and 2,000.

50. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean free minimum plasma concentration (C min 游离 ) between about 6.0 and about 80.0; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

51. The method of any one of claims 27-50, wherein the mean C min 游离 between 14 and 80.

52. The method of any one of claims 27-50, wherein the mean C min 游离 Between 21 and 80.

53. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean whole blood area under the curve (AUC) (ng hr / mL) between about 25,000 to about 480,000 measured on day 1 of dosing. wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

54. The method of any one of claims 27-53, wherein the mean whole blood AUC measured on Day 1 of dosing is between 80,000 to 480,000.

55. The method of any one of claims 27-53, wherein the mean whole blood AUC measured on Day 1 of dosing is between 120,000 to 480,000.

56. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean maximum whole blood concentration (Cmax) max )(ng / mL) between about 2,000 to about 28,000 measured on Day 1 of dosing; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

57. The method of any one of claims 27-56, wherein the mean whole blood C max between 4,500 and 28,000.

58. The method of any one of claims 27-56, wherein the mean whole blood C max Between 6,750 and 28,000.

59. A method of treating a human having a CDK2-mediated cancer, comprising administering to the human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean minimum whole blood concentration (C min )(ng / mL) between about 500 and about 14,400 measured on Day 1 of dosing; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight. wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

60. The method of any one of claims 27-59, wherein the mean whole blood C min between 1,800 and 14,400.

61. The method of any one of claims 27-59, wherein the mean whole blood C min between 2,700 and 14,400.

62. A method of administering to a human in need thereof a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean whole blood area under the curve (AUC) (ng hr / mL) between about 25,000 to about 800,000 measured at day 15 of dosing. wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

63. The method of any one of claims 27-62, wherein the mean whole blood AUC is between 120,000 to 800,000 measured on day 15 of dosing.

64. The method of any one of claims 27-62, wherein the mean whole blood AUC is between 180,000 to 800,000 measured on day 15 of dosing.

65. A method of treating a human having a CDK2-mediated cancer comprising administering to a human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean maximum whole blood concentration (Cmax) max )(ng / mL) between about 3,000 to about 56,000 measured at day 15 of dosing; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

66. The method of any one of claims 27-65, wherein the mean whole blood C max between 7,000 and 56,000.

67. The method of any one of claims 27-65, wherein the mean whole blood C max between 10,500 and 56,000.

68. A method of treating a human having a CDK2-mediated cancer comprising administering to a human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean minimum whole blood concentration (C min )(ng / mL) between about 1,000 and about 24,000 measured at day 15 of dosing; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

69. The method of any one of claims 27-68, wherein the mean whole blood C min between 2,600 and 24,000.

70. The method of any one of claims 27-68, wherein the mean whole blood C min between 3,900 and 24,000.

71. The method of any one of claims 27-70, further resulting in a) mean plasma C max With plasma C min The ratio is between 1.25 and 5 and / or b) the average whole blood C max With whole blood C min The ratio is between 1.25 and 5.

72. The method of any one of claims 27-70, further resulting in average plasma C max With plasma C min The ratio is between 3 and 5.

73. The method of any one of claims 27-70, further resulting in a ratio of mean whole blood C max to whole blood C min of between 3 and 5.

74. A method of treating a human having a CDK2-mediated cancer comprising administering to a human in need thereof an effective amount of a pharmaceutical composition comprising a compound of the following structure: (INX-315), which results in a mean plasma C max a ratio of C min less than about 5 but greater than about 1.25; wherein the pharmaceutical composition comprises an amorphous spray-dried dispersion (ASD) comprising between about 100 mg to about 500 mg of INX-315; and wherein the amount of INX-315 in the ASD is between 20% to 60% by weight.

75. The method of claim 74, wherein C max With C min The ratio is less than 3.

76. The method of claim 74, wherein C max with a ratio of C min less than 2.

25.

77. The method of any one of claims 74-76, wherein C max with a ratio of C min measured in plasma.

78. The method of any one of claims 74-76, wherein C max with a ratio of C min measured in whole blood.

79. The method of any one of claims 27-78, which results in a t 1 / 2 .

80. The method of any one of claims 27-78, which results in a t 1 / 2 .

81. The method of any one of claims 27-78, which results in a t 1 / 2 .

82. The method of any one of claims 79-81, wherein t 1 / 2 is about 14 hours.

83. The method of any one of claims 79-81, wherein t 1 / 2 is about 15 hours.

84. The method of any one of claims 79-81, wherein t 1 / 2 is about 16 hours.

85. The method of any one of claims 27-84, wherein INX-315 is administered once a day.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

105. The method of any one of claims 28-104, wherein the pharmaceutical composition further comprises a precipitation preventing agent.

106. The method of claim 105, wherein the amount of the precipitation preventing agent in the ASD is 40-70% by weight.

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

108. The method of any one of claims 105-107, wherein the precipitation preventing agent is selected from 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 VA37.

109. The method of claim 108, wherein the precipitation preventing agent is HPMCAS.

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

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

112. The method of any one of claims 29-110, 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, stomach cancer, uterine cancer.

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

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

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

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

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

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

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

120. The method of claim 115, wherein the breast cancer is triple negative breast cancer.

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

122. The method of claim 112, wherein the CDK2-mediated cancer is an ovarian cancer.

123. The method of claim 112, wherein the CDK2-mediated cancer is a prostate cancer.

124. The method of claim 112, wherein the CDK2-mediated cancer is a sarcoma.

125. The method of claim 112, wherein the CDK2-mediated cancer is a uterine cancer.

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

127. The method of any one of claims 111-126, wherein the CDK2-mediated cancer is cyclin E amplified or overexpressed.

128. The method of claim 127, wherein cyclin E overexpression or amplification status is confirmed using a next generation sequencing (NGS) panel test.

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

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

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

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

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

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

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

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

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

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

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

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

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

142. The method of any one of claims 27-141, wherein the human has previously received at least one prior line of CDK4 / 6 inhibitor therapy.

143. The method of any one of claims 27-142, wherein the human has previously received at least one prior line of endocrine therapy.

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

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

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

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

148. The method of any one of claims 27-147, wherein the treatment results in a decrease in the number of events of treatment- induced adverse events compared to the number of events of treatment-induced adverse events predicted in a subject receiving a CDK2 therapy other than INX-315.

149. The method of any one of claims 27-148, wherein the treatment results in a decrease in the number of events of laboratory abnormalities compared to the number of events of laboratory abnormalities predicted in a subject receiving a CDK2 therapy other than INX-315.

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

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

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

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

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

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

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

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

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

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

160. A method of making the pharmaceutical composition of any one of claims 1-26, comprising: v) spray drying a solution comprising INX-315 or a pharmaceutically acceptable salt thereof and a precipitation preventing agent to produce an amorphous spray-dried dispersion (ASD); vi) granulating the ASD with one or more pharmaceutically acceptable excipients to provide granules; vii) dry mixing the granules with one or more additional pharmaceutically acceptable excipients; and viii) compressing the dry mixed granules into tablets.

161. The method of claim 160, wherein the pharmaceutical composition has a nominal tablet strength of between about 100 mg to about 500 mg.

162. The method of claim 160, wherein the pharmaceutical composition has a nominal tablet strength of about 100 mg.

163. The method of claim 160, wherein the pharmaceutical composition has a nominal tablet strength of about 200 mg.

164. The method of claim 160, wherein the pharmaceutical composition has a nominal tablet strength of about 300 mg.

165. The method of claim 160, wherein the pharmaceutical composition has a nominal tablet strength of about 400 mg.

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