Cancer treatment with TLR agonists

Abstract

Providing cancer treatment with TLR agonists. [Solution] This specification provides a method for monotherapy for cancer using imidazoquinolineamine drugs. Further methods provide coordination with immune checkpoint inhibitor therapy for cancer. This specification discloses dosages and patient populations in which imidazoquinolineamine drugs, 1-[4-amino-2-(ethoxymethyl)imidazo[4,5-c]quinoline-1-yl]-2-methylpropan-2-ol, or pharmaceutically acceptable salts thereof, compound A (unless otherwise indicated in the context) may be administered systemically as monotherapy for the treatment of cancer, having therapeutic utility and acceptable toxicity.

Description

Technical Field

[0001] Cross - Reference to Related Applications This application claims the benefit of U.S. Provisional Patent Application No. 63 / 070,376, filed Aug. 26, 2020, the content of which is incorporated herein by reference in its entirety.

Background Art

[0002] Background The therapeutic potential of imidazoquinoline amines, such as imiquimod and Compound A, has long been recognized. It has been found difficult to realize that potential. Imidazoquinoline amines are generally agonists of Toll - like receptor (TLR) 7 and / or TLR8 and have both antiviral and anticancer activities in vitro. Imiquimod has been developed and successfully used as a topical treatment for actinic keratosis and genital and perianal warts. However, imidazoquinoline amines have not yet been successfully developed as systemic drugs due to dose - limiting toxicity (DLT).

Summary of the Invention

Means for Solving the Problems

[0003] Summary This specification discloses imidazoquinolineamine drugs, 1-[4-amino-2-(ethoxymethyl)imidazo[4,5-c]quinoline-1-yl]-2-methylpropan-2-ol, or pharmaceutically acceptable salts thereof, compound A (unless otherwise indicated in context) may be administered systemically as monotherapy for the treatment of cancer, possessing therapeutic utility and acceptable toxicity, dosages, and patient populations. In some embodiments, compound A is administered in the form of a free base or conjugate base. In some embodiments, compound A is administered in the form of a pharmaceutically acceptable salt. Further embodiments include formulations thereof. Dosages described herein are based on the free base, even when salts such as sulfates are administered (unless otherwise specified). In some embodiments, dosages are adjusted based on the molecular weight of the particular species being administered.

[0004] Some embodiments use compound A at a concentration of 0.10 to 1.2 mg / m². 2 A method for treating cancer in patients requiring treatment, comprising administering a dose of [a specific substance]. In some embodiments, the dose is at least 0.10, 0.15, 0.30, 0.45, or 0.6 mg / m². 2 In some embodiments, compound A is administered at concentrations of 0.75, 0.9, 1.0, 1.1, or 1.2 mg / m². 2 This includes administering a dose not exceeding a certain threshold. In some embodiments, the dose of compound A administered is within a range limited by any of these values. In some embodiments, the patient is human.

[0005] In some embodiments, compound A is used as monotherapy. That is, treatment with compound A is not initiated until after the last dose of previous cancer treatment, and other anticancer drugs are not administered within the same timeframe as compound A. In some embodiments, treatment with compound A is not initiated until the concentration of previous anticancer drugs in the patient's body has substantially decreased or been eliminated. In some embodiments, treatment with compound A is not initiated until at least two weeks or at least four weeks after the last dose of previous anticancer drugs. In some embodiments, treatment with compound A is initiated within three or six months after the last dose of previous anticancer drugs. In some embodiments, treatment with compound A is not initiated until after the point in time when the next dose of previous treatment would have been administered if such treatment had not been discontinued.

[0006] In some embodiments, compound A is more effective after another cancer treatment (even if the patient's cancer has progressed with other treatments). In some embodiments, the prior treatment was chemotherapy, such as cytotoxic therapy or targeted therapy. In some embodiments, the prior treatment was immune checkpoint inhibitor therapy, such as PD-1 blockade.

[0007] Some embodiments describe a method for treating cancer in a patient requiring treatment, comprising administering compound A after a series of immune checkpoint inhibitor treatments, which include at least one, two, three, four, five, or six doses (or any range of doses limited by these values) of an immune checkpoint inhibitor. In some embodiments, the administration of the immune checkpoint inhibitor is discontinued around the time or before the treatment with compound A is initiated. That is, compound A is administered after the last dose of the immune checkpoint inhibitor, but within three months thereafter. In some embodiments, the treatment with compound A is initiated after the first dose of the immune checkpoint inhibitor is administered, but the immune checkpoint inhibitor treatment is not discontinued. In some embodiments, the patient's cancer progresses during the initial immune checkpoint inhibitor treatment, and the treatment with compound A is initiated after the progression is observed. The immune checkpoint inhibitor treatment is PD-1 blockade.

[0008] In some embodiments, PD-1 blockade includes the administration of an anti-PD-1 antibody. In other embodiments, PD-1 blockade includes the administration of an anti-PD-L1 antibody.

[0009] Some embodiments involve administering a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, to a patient. a. Maximum plasma concentration of compound A free base (C) of at least 8 ng / mL max );or b. Area under the curve (AUC) of free base of compound A at least 3 ng / mL*day; or c. Both A method for treating cancer, comprising obtaining a plasma concentration profile in the patient including, This increases the potential for clinical benefit compared to treatment with compound A, which does not reach the plasma concentration profile.

[0010] Some embodiments involve administering a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody to a patient. a. Maximum plasma concentration of free base of compound A (Cmax ) is at least 7 ng / mL; or b. The area under the curve (AUC) of the free base of compound A is at least 2 ng / mL*day; or c. Both A method for treating cancer, comprising obtaining a plasma concentration profile in the patient including, This increases the potential for clinical benefit compared to treatment with compound A, which does not reach the plasma concentration profile.

[0011] Some embodiments involve administering a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody to a patient. a. Maximum plasma concentration of compound A free base (C) of at least 10 ng / mL max );or b. Area under the curve (AUC) of free base of compound A at least 2 ng / mL*day; or c. Both A method for treating cancer, comprising obtaining a plasma concentration profile in the patient including, This increases the potential for clinical benefit compared to treatment with compound A, which does not reach the plasma concentration profile.

[0012] In some embodiments, compound A is administered parenterally. In some embodiments, parenteral administration includes intravenous injection or infusion. In some embodiments, compound A is infused over a period of 15 to 90 minutes, or over a period of 30 to 60 minutes.

[0013] Some embodiments further include measuring the change in plasma or whole blood concentration of interferon-inducible protein 10 (IP-10) before and after administration of compound A. Some embodiments further include determining the change in IP-10 transcript in plasma or whole blood before and after administration of compound A. In some embodiments, the concentration or transcription level of IP-10 after administration of compound A is determined after three or six administrations of compound A. In various aspects of these embodiments, IP-10 increases by more than twofold, threefold, fourfold, or fivefold. In some embodiments, the dose of compound A is increased if the IP-10 concentration in plasma or whole blood has not increased beyond a threshold level, e.g., twofold, threefold, fourfold, or fivefold.

[0014] In some embodiments, compound A is administered in a dose sufficient to produce a Cmax of free base of compound A in plasma of at least 9.4 ng / ml in the patient. In some embodiments, compound A is administered in a dose sufficient to produce an AUC of free base of compound A in plasma of at least 2.09 ng / mL*day in the patient. If either of these thresholds is not met, the dose of compound A may be increased. In some embodiments, Tmax is 15 to 90 minutes after administration. In some embodiments, Tmax is within 60 minutes after administration. In some embodiments, "after administration" refers to the time after the start of infusion.

[0015] In some embodiments, when increasing the dose of compound A, the dose may be 0.15, 0.1, or 0.05 mg / m². 2 Increase it by one increment.

[0016] Compound A can be administered 1 to 6 times over 3 to 6 weeks by intravenous infusion over 20 to 90 minutes, and administration should not be more frequent than once a week. In certain embodiments, Compound A is administered weekly in a 3-week cycle, i.e., on days 1, 8, and 15 of a 21-day cycle. In another particular embodiment, Compound A is administered once in a 3-week cycle, i.e., on day 1 of a 21-day cycle. In yet another particular embodiment, Compound A is administered once in a 6-week cycle, i.e., on day 1 of a 42-day cycle. Further specific embodiments matching the patterns described above are also conceivable. These embodiments can be freely combined with other variable aspects of the treatment methods disclosed herein, including dosage, dose adjustments, and patient population, such as depending on the type of cancer or prior treatment. [Brief explanation of the drawing]

[0017] [Figure 1] Figure 1 shows the pharmacokinetics of the salt form of compound A at escalating doses, measured over time by the concentration of the free base form of compound A in plasma on day 1 of cycle 1 after the initial infusion. Each cycle shows the mean plasma concentration of the free base of compound A detected by mass spectrometry. Quantification of compound A in plasma samples was analyzed for subjects at dose levels 1 (0.30 mg / m2; n=8), 2 (0.45 mg / m2; n=8), 3 (0.60 mg / m2; n=7), and 4 (0.75 mg / m2; n=11).

[0018] [Figure 2A]Figures 2A and 2B present an analysis of interferon-inducible protein 10 (IP-10) production in response to various doses of compound A. Figure 2A shows the induction from baseline IP-10 production in response to four dose levels of compound A (1-0.30 mg / m2; 2-0.45 mg / m2; 3-0.60 mg / m2; 4-0.75 mg / m2) on a logarithmic scale. The number in parentheses after the dose level indicates the number of subjects. The interquartile range is indicated by the horizontal line outside each plot connected by a vertical line. Rectangle: Interquartile range; Brace: Minimum / Maximum; Horizontal line: 1 (unity) (no change from baseline. The internal horizontal line shows the median (lower line) and geometric mean (upper line). * means p < 0.05 (Wilcoxon rank-sum test in the logarithmic region)). Figure 2B shows a comparison of the baseline induction rate of IP-10 production for various dose levels of compound A (D1-D4, corresponding to 1-4 in Figure 1). Calculations were performed in the logarithmic domain (Wilcoxon rank-sum test). Each horizontal line represents a 95% confidence interval. Black circles are estimates of the multiplicative change in IP-10 production. P-values ​​are shown to the right of each horizontal line. Vertical dashed lines represent null values. [Figure 2B]Figures 2A and 2B present an analysis of interferon-inducible protein 10 (IP-10) production in response to various doses of compound A. Figure 2A shows the induction from baseline IP-10 production in response to four dose levels of compound A (1-0.30 mg / m2; 2-0.45 mg / m2; 3-0.60 mg / m2; 4-0.75 mg / m2) on a logarithmic scale. The number in parentheses after the dose level indicates the number of subjects. The interquartile range is indicated by the horizontal line outside each plot connected by a vertical line. Rectangle: Interquartile range; Brace: Minimum / Maximum; Horizontal line: 1 (unity) (no change from baseline. The internal horizontal line shows the median (lower line) and geometric mean (upper line). * means p < 0.05 (Wilcoxon rank-sum test in the logarithmic region)). Figure 2B shows a comparison of the baseline induction rate of IP-10 production for various dose levels of compound A (D1-D4, corresponding to 1-4 in Figure 1). Calculations were performed in the logarithmic domain (Wilcoxon rank-sum test). Each horizontal line represents a 95% confidence interval. Black circles are estimates of the multiplicative change in IP-10 production. P-values ​​are shown to the right of each horizontal line. Vertical dashed lines represent null values.

[0019] [Figure 3]Figures 3A and 3B show the pharmacodynamic-pharmacokinetic (PD-PK) analysis of the change in IP-10 relative to plasma concentration of compound A. Figure 3A shows the percentage of baseline IP-10 induction for compound A's PK at days 1 and 8 of cycle 1 (white circles connected by lines for each subject) by Cmax (left panel) and AUEC quartiles (right panel). The numbers in parentheses above represent the number of subjects at days 1 and 8 of cycle 1 in each quartile. The median (thick black line) and geometric mean (square) are shown within the interquartile range (gray braces). A gray horizontal line represents 1 (unity) (no change in IP-10 induction from baseline), and a black circle indicates that the multiple of induction is less than 1. Figure 3B shows the percentage of baseline induction IP-10 from baseline AUEC, compared between the quartiles for Cmax (left panel) and AUC (right panel). Each horizontal line represents a 95% confidence interval. Black circles are estimates. The p-values ​​are displayed to the right of each horizontal line. The vertical dashed lines represent null values. The calculations were performed in the logarithmic domain (Wilcoxon rank-sum test).

[0020] [Figure 4] Figure 4 shows the analysis of IP-10 cytokine induction levels in 32 patients after infusion in Cycle 1. IP-10 induction levels are presented as induction multipliers from baseline and then divided into two groups according to the pharmacokinetic parameter AUC of compound A: a low AUC group (AUC below 2.09 ng / mL*day) with 16 patients and a high AUC group (AUC above 2.09) with 16 patients. The IP-10 induction levels for these two groups were calculated as mean + / - SEM, and statistical differences between the two groups were analyzed by Student's t-test. The mean induction levels of IP-10 from baseline were 3.68-fold and 27.2-fold for the low AUC group and the high AUC group, respectively.

[0021] [Figure 5]Figure 5 shows the analysis of IP-10 cytokine induction levels in 32 patients after infusion in Cycle 1. IP-10 induction levels were expressed as induction multipliers from baseline and divided into two groups according to the pharmacokinetic parameter Cmax of compound A: a low Cmax group (Cmax below 9.4 ng / mL) and a high Cmax group (Cmax above 9.4 ng / mL), with 16 patients in each group. The IP-10 induction levels for these two groups were calculated as mean + / - SEM, and statistical differences between the two groups were analyzed by Student's t-test. The mean induction levels were 5.09-fold and 31.9-fold for the low Cmax group and the high Cmax group, respectively.

[0022] [Figure 6A] Figures 6A-C show the percentage of patients who achieved partial response or long-term stable disease with plasma free base AUC and Cmax above and below thresholds for compound A after treatment with compound A monotherapy (Figure 6A), compound A in combination with an anti-PD-1 mAb (Figure 6B), and compound A in combination with an anti-PD-L1 mAb (Figure 6C). [Figure 6B] Figures 6A-C show the percentage of patients who achieved partial response or long-term stable disease with plasma free base AUC and Cmax above and below thresholds for compound A after treatment with compound A monotherapy (Figure 6A), compound A in combination with an anti-PD-1 mAb (Figure 6B), and compound A in combination with an anti-PD-L1 mAb (Figure 6C). [Figure 6C] Figures 6A-C show the percentage of patients who achieved partial response or long-term stable disease with plasma free base AUC and Cmax above and below thresholds for compound A after treatment with compound A monotherapy (Figure 6A), compound A in combination with an anti-PD-1 mAb (Figure 6B), and compound A in combination with an anti-PD-L1 mAb (Figure 6C). [Modes for carrying out the invention]

[0023] Detailed explanation In this specification, 1-[4-amino-2-(ethoxymethyl)imidazo[4,5-c]quinoline-1-yl]-2-methylpropane-2-ol, [ka] Disclosed are methods for treating cancer using compound A, or a pharmaceutically acceptable salt thereof, collectively (unless otherwise indicated in the context). In some embodiments, compound A is administered as monotherapy. In some embodiments, the patient has been previously treated with an immune checkpoint inhibitor, e.g., a PD-1 / L1 axis immune checkpoint inhibitor. In some embodiments, immune checkpoint inhibitor therapy is continued in conjunction with treatment with compound A. In other embodiments, immune checkpoint inhibitor therapy is discontinued before initiating treatment with compound A.

[0024] Much interest and research has been conducted on the use of compound A in cancer treatment, but this has not been successful in clinical practice. It is widely recognized that compound A has no therapeutic concentration range when used systemically, especially when administered intravenously, meaning that its toxic effects outweigh its therapeutic benefits. These problems are most serious with compound A monotherapy. Nevertheless, this specification discloses dosages and administration schedules for intravenous administration of compound A, particularly pharmaceutically acceptable salts, as well as preferred patient populations, that can provide therapeutic benefits without causing unacceptable levels of toxicity with compound A monotherapy. In the absence of drug interactions, this therapeutic benefit should persist even when used in combination with other treatments.

[0025] In some embodiments, the patient has been treated with several other cancer treatments prior to initiating treatment with compound A. In various embodiments, the other treatments may be chemotherapeutic agents such as immune checkpoint inhibitors, cytotoxic or targeted therapies, or therapeutic monoclonal antibodies. In various embodiments, the therapeutic monoclonal antibody may be an antagonist or agonist immune checkpoint inhibitor, an anti-cancer antigen antibody, a don't-eat-me signal blocker, or an anti-M2 macrophage depletion-mediated antibody. It may be a body. In some embodiments, as described above, other treatments are discontinued before initiating treatment with compound A. In other embodiments, other treatments are continued in conjunction with treatment with compound A. In yet another embodiment, treatment with compound A is suspended, the previous other treatment is repeated and discontinued again, and treatment with compound A is resumed. Some embodiments specifically include one or more treatment modes. Some embodiments specifically exclude one or more treatment modes.

[0026] In this specification, monotherapy refers to a cancer treatment regimen that utilizes a single anticancer drug. This does not exclude previous (or subsequent) treatments with other drugs, but merely indicates that the administration of the monotherapy agent is not temporally coordinated with or coordinated with the administration of another anticancer treatment. At a minimum, the initiation of monotherapy is not started until after the last dose of the previous drug has been administered. In some embodiments, treatment with compound A is not started until after the point in time when the next dose of the previous anticancer treatment would have been administered if such treatment had not been discontinued. In some embodiments, the initiation of monotherapy is not started until the presence of the previous anticancer drug in the body has substantially decreased or been removed. In some embodiments, monotherapy relates to another anticancer drug, i.e., a composition administered to the patient's body. In such embodiments, monotherapy may temporally overlap with or coordinate with surgical procedures or radiation therapy.

[0027] In this specification, chemotherapy refers to the use of small molecule drugs for the treatment of cancer. Historically, chemotherapeutic drugs were drugs that damaged DNA or disrupted the mechanisms of cell division and were generally cytotoxic to dividing cells. Such drugs are sometimes called cytotoxic or DNA-damaging chemotherapeutic drugs. More recently, so-called targeted therapies have been developed. These also include the use of small molecule drugs. However, these drugs act on specific proteins, often kinases, that are involved in regulating cell division. These drug-targeted proteins are usually expressed only in some cells of the body and may even be overexpressed in cancer cells. As a result, the effects of the drugs are more specific than those of conventional cytotoxic chemotherapeutic drugs. Some embodiments relate to patients who have undergone chemotherapy pretreatment. In some of those embodiments, the chemotherapy was cytotoxic or DNA-damaging chemotherapy. In other embodiments, the chemotherapy was finely targeted chemotherapy. Other embodiments specifically exclude pretreatment with any or all of these forms of chemotherapy.

[0028] Immune checkpoint inhibitor therapy refers to the use of drugs, usually biologics, that act on regulatory pathways in T cell differentiation and activation to facilitate the passage of the T cell development program through these checkpoints, thereby achieving antitumor (or other therapeutic) activity. Drugs that provide immune checkpoint therapy are generally called immune checkpoint inhibitors, and it is important to understand that what is inhibited is the checkpoint related to T cell development. Therefore, while many immune checkpoint inhibitors also inhibit receptor-ligand pair interactions (e.g., the interaction between programmed cell death 1 (PD-1) and programmed cell death ligand 1 (PD-L1)), other checkpoint inhibitors (e.g., anti-OX40, anti-GITR, anti-CD137, anti-CD122, anti-CD40, and anti-ICOS) act as agonists of targets that deactivate or inhibit the checkpoints of T cell development, ultimately promoting effector function and / or inhibiting regulatory function. While inhibition of some checkpoints has proven sufficient in some cases to mediate clinical improvement, inhibition of other checkpoints is most effective when used in combination. Most commonly, an antibody against one member of a receptor-ligand pair is used. In alternative embodiments, the antibody is replaced by another protein that also binds to the immune checkpoint target molecule. In some cases, these non-antibody molecules contain the extracellular portion of the ligand or binding partner of the immune checkpoint target molecule; that is, at least the extracellular portion is required to mediate binding to the immune checkpoint target molecule. In some embodiments, this extracellular binding portion of the ligand is bound to a further polypeptide within the fusion protein. In some embodiments, this further polypeptide contains the Fc or constant region of the antibody.

[0029] Programmed cell death protein 1 (PD-1) is a checkpoint protein on T cells. Antibodies against both PD-1 and its binding partner, programmed cell death ligand 1 (PD-L1), are clinically used as immune checkpoint inhibitors (PD-1 blockade). Non-limiting examples of monoclonal antibodies (mAbs) targeting PD-1 / PD-L1 include anti-PD-1 mAb nivolumab (OPDIVO®, Bristol-Myers Squibb), pembrolizumab (KEYTRUDA®, Merck & Co.), cemiplimab-rwlc (LIBTAYO®, Regeneron Pharmaceuticals), and anti-PD-L1 mAbs durvalumab (MEDI4736, IMFINZI™, Medimmune), atezolizumab (MPDL3280A; TECENTRIQ®, Hoffmann-La Roche), avelumab (BAVENCIO®, EMD Serono), and BMS-936559 (Bristol-Myers Squibb). These may be referred to as means for PD-1 blockade, means for inhibiting PD-1 / PD-L1 binding, or means for immune checkpoint inhibition.

[0030] CTLA-4 is an immune checkpoint molecule expressed on the surface of CD4 and CD8 T cells and on CD25+, FOXP3+ T regulatory (Treg) cells. Non-limiting examples of monoclonal antibodies targeting CTLA-4 include ipilimumab (YERVOY®; Bristol-Myers Squibb) and tremelimumab (Medimmune). These may be referred to as means for inhibiting CTLA-4 or means for immune checkpoint inhibition.

[0031] TIM-3 (T cell immunoglobulin and mucin domain-containing-3) is an IFN-γ-producing CD4 + T helper 1 (Th1) and CD8 +It is a molecule selectively expressed in T-cytotoxic 1 (Tc1) T cells. Exemplary antibodies against TIM-3, not limited to those listed above, are disclosed in U.S. Patent Application Publication No. 20160075783, which, with respect to all its content relating to anti-TIM-3 antibodies, is incorporated herein by reference. Other anti-TIM-3 antibodies include TSR-022 (Tesaro). These are sometimes referred to as means for inhibiting TIM-3, or means for immune checkpoint inhibition.

[0032] LAG-3 (lymphocyte activation gene 3; CD223) negatively regulates T cell proliferation, activation, and homeostasis in a similar manner to CTLA-4 and PD-1, and plays a role in Treg suppression. Exemplary antibodies against LAG-3, not limited to these, include GSK2831781 (GlaxoSmithKline), relatlimab (BMS-986016, Bristol-Myers Squibb), and the antibody disclosed in U.S. Patent Application Publication No. 2011 / 0150892, which is incorporated herein by reference in its entirety with respect to anti-LAG-3 antibodies. These are sometimes referred to as means for inhibiting LAG-3, or means for immune checkpoint inhibition.

[0033] TIGIT (T-cell immune receptor with Ig and ITIM domains) is an immune receptor inhibitory checkpoint involved in tumor immune surveillance. It competes with the immune-activating receptor CD226 (DNAM-1) for the same set of ligands: CD155 (PVR or poliovirus receptor) and CD112 (nectin-2 or PVRL2). Anti-TIGIT antibodies have shown synergistic effects with anti-PD-1 / PD-L1 antibodies in preclinical models. Tiragolumab (Roche), etigilimab (OncoMed), vivostolimab (MK-7684; Merck), and EOS-448 (iTeos Therapeutics) are not limited examples of anti-TIGIT antibodies. These are sometimes referred to as means of inhibiting TIGIT, or means of immune checkpoint inhibition.

[0034] GITR (glucocorticoid-induced TNFR-related protein) promotes effector T cell function and inhibits the suppression of the immune response by regulatory T cells. Similar to OX-40 mentioned earlier, checkpoint inhibitors are agonists of the target, in this case GITR. The agonist antibody TRX518 is currently undergoing human clinical trials in cancer. While it may not be sufficient on its own to mediate substantial clinical improvement in advanced cancer, its combination with other checkpoint inhibitors such as PD-1 blockade has shown promise.

[0035] Other targets for immune checkpoint inhibitors include, but are not limited to, B and T cell attenuators (BTLA), CD40, CD122, inducible T cell costimulator (ICOS), OX40 (tumor necrosis factor receptor superfamily, member 4), Siglec-15, B7H3, and CD137 (4-1BB; checkpoint inhibition is achieved with an agonist, similar to CD40 and OX40), which are potentially useful in the methods of this disclosure. Several anti-OX40 agonist monoclonal antibodies have entered early-stage cancer clinical trials, including, but are not limited to, MEDI0562 and MEDI6469 (Medimmune), MOXR0916 (Genetech), and PF-04518600 (Pfizer); as well as the anti-ICOS agonist antibody, JTX-2011 (Jounce Therapeutics). Anti-CD40 agonist antibodies currently in clinical study include dasetuzumab, CP-870, 893 (celicrelumab), and Chi Lob 7 / 4. Anti-siglec-15 antibodies are also known (see, e.g., U.S. Patent No. 8,575,531). Anti-CD137 agonist antibodies include, but are not limited to, urelumab and utomirumab. Furthermore, CD122 has been targeted in cancer clinical trials using benpegaldesleukin (NKTR-214, pegylated IL-2 used as a CD122 bias agonist). B7H3 is targeted by enobrituzumab, 131 I-Omblutamab,177 Lu-DTPA-Omblutamab, 131 I-8H9, 124 Reagents such as I-8H9, MCG018, and DS-7300a are used to target both immune checkpoints and tumor antigens. These are sometimes referred to as means for immune checkpoint inhibition, or means for inhibiting (or activating, if necessary) their respective targets.

[0036] Treatment with compound A may be followed by treatment with other types of therapeutic monoclonal antibodies. In some embodiments, the therapeutic monoclonal antibodies block the so-called "Don't Eat Me" signal; these include antibodies that recognize ILT2 (e.g., BND-22), ILT4 (e.g., MK-4830), CD47 (e.g., Hu5F9-G4), and SIRPα (e.g., KWAR23). The "Don't Eat Me" signal can also be blocked with products such as TTI-621, which is a fusion protein of the SIRP protein and the antibody Fc region, acting similarly to an anti-CD47 antibody by blocking the binding of SIRPα to CD47.

[0037] In some embodiments, the therapeutic monoclonal antibody is a cancer antigen, for example, but not limited to, Her2, CD133 / prominin, TROP2, claudin 18.2 (e.g., claudiximab (IMAB362) or zo The antibodies recognize rubetuximab, CD73 / NT5E (e.g., MEDI9447, BMS986179, SRF373 / NZV930, CPI-006 / CPX-006, IPH5301, or TJ004309; CD73 / NT5E is also considered an immune checkpoint), crypto-1, or CEACAM5. In some embodiments, the anti-cancer antigen antibody is conjugated to a cytotoxic agent. Examples that are not limited to these include antibody-drug conjugates (ADCs) such as SAR408701, which combines a humanized antibody targeting CEACAM5 with the potent cytotoxic maytansinoid derivative DM4; PF-06664178, which targets Trop-2 and delivers the auristatin microtubule inhibitor Aur0101; sacituzumab govitecan (IMMU-132), which targets Trop-2 and delivers SN-38; DS-1062a, which targets Trop-2 and delivers DXd, a topoisomerase I inhibitor and derivative of exatecan; and AC133-vcMMAF, a mouse anti-human CD133 antibody (AC133) conjugated to the potent cytotoxic drug monomethyl auristatin.

[0038] In some embodiments, therapeutic monoclonal antibodies, such as anti-CD206 antibodies, can be used to deplete M2 macrophages. In some embodiments, anti-CD206 antibodies are conjugated to toxins such as diphtheria toxin.

[0039] Pharmaceutically acceptable salts include hydrochlorides, sulfates, acetates, phosphates, diphosphates, chlorides, maleates, citrates, mesylates, nitrates, tartrates, and glucons. Various embodiments of salts of compound A are the genus containing these salts, any subset thereof, or any individual species. In some embodiments, this individual salt of compound A is a chloride, hydrochloride, sulfate, acetate, or phosphate. Dosage

[0040] The dosage of the salt form of compound A is generally expressed in mg / kg, mainly for convenience. However, this is actually a rather inaccurate method for estimating drug exposure. Therapeutic coefficient (in the case of humans, TD) 50 / ED 50 When the ratio of the tolerated dose to the effective dose for 50% of the population is large, variability in drug exposure may not be significant. When the dose is small, more precise dosing is required to achieve efficacy while avoiding unacceptable toxicity. Since drug exposure is more closely proportional to the subject's body surface area (BSA) than to their body weight, mg / m 2 Drug dosages expressed in units of can provide this higher precision. To achieve this higher precision in exposure to compound A, the dosage of compound A is expressed herein as mg / m 2 It is expressed in units of . In the following example, the Mostler formula was used for BSA (BSA(m 2 ) = √height (cm) × weight (kg) / 3600). However, other formulas, for example, Dubois & Dubois formula (BSA(m 2 )=0.20247×Height (m) 0.725 ×Weight (kg) 0.425 The following equations exist. The differences are not significant because these equations yield sufficiently similar results.

[0041] In various embodiments, the dosage of compound A is 0.10 mg / m². 2 ~1.2 mg / m² 2 , or 0.15 mg / m² 2 ~1.0 mg / m² 2 (0.2-1.3 mg / m³ by mass of sulfate) 2 ) is administered weekly by intravenous infusion. In some embodiments, the dose is 0.75, 0.80, 0.90, or 1.0 mg / m². 2 It shall not exceed 0.15, 0.30, 0.45, or 0.60 mg / m². In some embodiments, the dose is at least 0.15, 0.30, 0.45, or 0.60 mg / m². 2In some embodiments, the dosage is within the range enclosed by any pair of these values. In other embodiments, compound A is administered weekly, bi-weekly, every three weeks, or at intervals of any integer number of days between weekly and every three weeks.

[0042] In some embodiments, when used in combination with PD-1 blockade, the efficacy is 0.5 to 0.9 mg / m². 2 (or 0.66-1.2 mg / m³ by mass of sulfate) 2 This can be achieved with the dosage of compound A.

[0043] Estimates of average BSA vary depending on the population surveyed. According to one editorial, the average BSA for men aged 20-79 in the United States is 2.060 m 2 The average BSA for American women of the same age is 1.830m. 2 The figures for adult cancer patients in the UK were 1.91m for men and 1.91m for women, respectively. 2 and 1.71m 2 This was approximately 7% less. Table 1 shows exemplary dose ranges based on BSA estimates. [Table 1]

[0044] In some embodiments, compound A, or a pharmaceutically acceptable salt thereof, is administered by intravenous infusion, for example, in 100 mL of normal saline. To obtain the required dose, an appropriate amount of a more concentrated solution is added to the intravenous solution to obtain the dose required for each individual patient. Therefore, the prepared dosage form may be a solution of compound A or a pharmaceutically acceptable salt thereof at concentrations of, for example, 0.5, 1.0, 1.5, 2.0, 2.5 mg / ml, or within the range enclosed by any pair of these values. In some embodiments, this solution is contained in a vial (or similar container) filled with 1-2 mL of the solution.

[0045] In some embodiments, the dosage form contains compound A sulfate. In some embodiments, the concentration of compound A sulfate in the dosage form solution is 1.0 to 2.5 mg / mL. In some embodiments, the concentration of compound A sulfate in the dosage form solution is 1.31 mg / mL (equivalent to 1 mg / mL of compound A free base). In some embodiments, the dosage form comprises a 2 mL injection vial containing 1.5 mL of the dosage form solution. In some embodiments, the dosage form solution further comprises 9.1 mg / mL of sodium chloride, 0.71 mg / mL of sodium citrate dehydrate, citrate dehydrate or citric acid sufficient to adjust the pH to 4.0 to 5.0 (including both ends), and water for injection for volume adjustment.

[0046] When establishing an administration schedule, it is common to attempt to achieve steady-state concentrations in the bloodstream or other parts of the body, or to maintain concentrations of the free base form of compound A above a certain minimum level. In embodiments, compound A is administered weekly, despite the fact that even at the maximum dose, compound A is substantially eliminated from the body within 24 hours. This has been found to be sufficient to obtain the desired immunotherapeutic effect and, furthermore, to avoid driving patients to high levels of toxicity due to cytokine release syndrome or other adverse events.

[0047] In some embodiments, the dose of compound A is adjusted during treatment based on the IP-10 induction level. In some embodiments, the dose of compound A is increased if the IP-10 induction factor is less than 2x, 5x, 10x, 20x, 30x, or 40x. In some embodiments, the dose adjustment of compound A is 0.15 mg / m². 2 In some embodiments, the dosage of compound A is adjusted to 0.10 mg / m². 2 Or 0.05 mg / m² 2 In some embodiments involving more than one dose adjustment, the first dose adjustment(s) may be 0.15 mg / m². 2However, as we approach the desired induction factor of IP-10, the magnitude of the dose adjustment becomes, for example, 0.10 mg / m². 2 Or 0.05 mg / m² 2 It decreases to [a certain value]. Toxicity and adverse events

[0048] The relationship between the efficacy and toxicity of a drug is generally expressed in terms of the therapeutic concentration range and the therapeutic coefficient. The therapeutic concentration range ranges from the lowest dose that shows a detectable therapeutic effect to the maximum tolerated dose (MTD), which is the highest dose that produces the desired therapeutic effect without causing unacceptable toxicity. This is the dose range up to that which will have the desired therapeutic effect. The typical therapeutic coefficient is LD if based on animal studies. 50 :ED 50 It is calculated as a ratio, and if based on human studies, TD 50 :ED 50 It is calculated as a ratio (however, this calculation can also be derived from animal studies and is sometimes called a protection factor). Here, LD 50 , TD 50 , and ED 50 These are the lethal, toxic, and effective doses, respectively, in 50% of the test population.

[0049] In some embodiments, the dosage of compound A avoids or reduces the severity or incidence of toxicity and associated adverse events. In various aspects of these embodiments, toxicity can be observable toxicity, substantial toxicity, serious toxicity, tolerable toxicity, or dose-limiting toxicity (e.g., MTD, but not limited to these). Observable toxicity means that the effect is negligible or mild while the change is observed. Substantial toxicity means that there is an adverse effect on the patient's overall health or quality of life. In some cases, substantial toxicity may be mitigated or eliminated by other ongoing medical interventions. Serious toxicity means that the effect requires acute medical intervention and / or dose reduction or temporary discontinuation of treatment. The tolerability of toxicity is influenced by the specific disease being treated, its severity, and whether the medical intervention can be mitigated.

[0050] Toxicity and adverse events may be graded on a 5-point scale. Grade 1 or mild toxicity may be asymptomatic or cause only mild symptoms and may be characterized only by clinical or diagnostic observation, with no intervention prescribed. Grade 2 or moderate toxicity may interfere with activities of daily living (e.g., preparing meals, shopping, managing money, using the telephone), but only minimal, local, or non-invasive interventions are prescribed. Grade 3 toxicity is medically significant but not immediately life-threatening, and hospitalization or extended hospitalization may be prescribed, potentially impairing self-care activities of daily living (bathing, dressing, eating independently, using the toilet, taking medication, and not being bedridden). Grade 4 toxicity is life-threatening and requires emergency intervention. Grade 5 toxicity results in death related to the adverse event. Accordingly, in various embodiments, the use of compound A in the regimens disclosed herein or in specific doses reduces the grade of toxicity associated with the treatment by at least one level compared to the use of the drug in a different regimen. In other embodiments, the use of compound A in a specific regimen or in specific doses limits toxicity to grade 2 or less, grade 1 or less, or no toxicity is observed.

[0051] In some embodiments, if unacceptable levels of toxicity are observed, the dose of compound A is reduced. In some embodiments, the dose of compound A is 0.15 mg / m². 2 To reduce. In some embodiments, the dose of compound A is 0.10 mg / m². 2 Or 0.05 mg / m² 2 To reduce. In some embodiments, the injection time is extended to mitigate adverse reactions. Cytokine induction

[0052] Monotherapy with compound A as described herein induces the expression of several cytokines, notably the inflammatory cytokines IFN-γ and IP-10. In this specification, induction refers to a twofold or greater increase in expression from the baseline level prior to the initiation of compound A monotherapy. In alternative embodiments, induction refers to a fivefold or greater increase in expression from the baseline level prior to the initiation of compound A monotherapy. In some embodiments, the induction factor is based on the AUC of IP-10. In some embodiments, IP-10 induction is based on Cmax.

[0053] Observations have shown that higher levels of IP-10 induction were associated with prior immune checkpoint inhibition, particularly PD-1 blockade therapy (either anti-PD-1 or anti-PD-L1). Greater IP-10 induction was also associated with prior chemotherapy, particularly DNA damage chemotherapy. Greater IP-10 induction was also associated with prior targeted therapy. Furthermore, higher baseline levels of IP-10 may indicate a greater likelihood of further IP-10 induction response to monotherapy with compound A.

[0054] In some embodiments, cytokine induction is monitored during monotherapy with compound A. Monitoring may include assaying plasma or serum levels of cytokines such as IFN-γ and IP-10, or IFN-γ-inducible gene products such as CXCL10 (IP-10) or CXCL11. Monitoring may include quantification of whole blood RNA transcripts encoding these proteins. Baseline readings are established before the first infusion of compound A monotherapy, and samples may be taken at specific points in time thereafter. (Preferably, samples for baseline readings are taken 1–6 hours before initiating infusion, but anytime within 24 hours prior to infusion is acceptable.) Cytokine induction may be assessed after the first infusion of compound A, after the second infusion of compound A, after 6 weeks of treatment, at the time of the first efficacy assessment scan, at the time of disease progression, at the time of clinical response, at the time of adverse events, or on a regular schedule, for example, every 3 or 6 weeks counting from the initiation of treatment or the first measurement after the initiation of treatment. Depending on changes in cytokine levels, such as IP-10 levels, the dosage of compound A may be adjusted for subsequent infusions to increase the likelihood of a response and / or reduce the risk of serious adverse events. The importance of IP-10 induction for immune response and methods for correlating IP-10 induction with cancer response.

[0055] IP-10 is a single-tube, CD4 + Th1 T cell, effector CD8 + It is known to exert antitumor immunity by binding to CXCR3 expressed on immune cells such as T cells, NK cells, and dendritic cells. IP-10 is induced by both IFN-γ and type I interferon, and CD4 + It is produced by T cells, NK / NKT cells, monocytes, dendritic cells, fibroblasts, endothelial cells, and epithelial cells. IP-10 induction causes Th1 polarization via CXCR3, promoting the maturation and activation of cytotoxic T lymphocytes, NK and macrophages, as well as their migration to the tumor microenvironment. IP-10 induction is mediated by CXCR3 + CD4 + / CD8 + It can also activate T cells to enhance anti-tumor immunity.

[0056] In contrast, IP-10 bound to CXCR3 expressed in cancer cells can promote survival and metastasis through autocrine signaling. While enhanced IP-10-CXCR3 signaling in the tumor microenvironment is considered a negative predictor of the response, the IP-10-CXCR3 paracrine signaling axis in immune cells triggers an antitumor immune response. Therefore, induction of IP-10 in the blood may be a predictor of paracrine signaling for antitumor immunity. However, to fully correlate IP-10 induction with the antitumor response, it is necessary to evaluate the migration of activated immune cells and CXCR3 expression in the tumor microenvironment.

[0057] IFN-γ-mediated gene signatures, including IP-10, are well-studied predictive biomarkers for cancer patient responses. IFN-γ / IP-10 induction has been associated with increased antitumor immunity and has led to clinical responses in various solid tumors. Interestingly, these studies involved immunomodulatory agents such as anti-PD-(L)1 mAbs, anti-CTLA-4 mAbs, IFN-α, poly-I:C, and DNA vaccines inducing antitumor immunity via IFN-γ / IP-10 induction. Furthermore, PD-1 and CTLA-4 blockade induced macrophage-derived IP-10 that correlated with antitumor immune responses. In other instances where IP-10 was induced in stromal cells or after chemoradiotherapy, Treg recruitment was preferred to suppress immune activity. Therefore, the role of IFN-γ / IP-10 induction as immune activation versus suppression may depend on the tumor and treatment type (e.g., immunotherapy versus chemotherapy) which can alter the balance between Treg-mediated and Th1-mediated immune cells. Treatment method

[0058] This specification provides a method for treating cancer in mammals, such as humans, comprising administering compound A by intravenous infusion as monotherapy. The dosage is set to mg / m² to more precisely control the patient's exposure to compound A. 2It is specified in units of . As mentioned above, the dosage is 0.10 mg / m². 2 ~1.2 mg / m² 2 This may be within a certain range. This amount of drug is typically infused over 20–90 minutes, e.g., 30 minutes, or 60 minutes, or any range enclosed by a pair of these values. Compound A is administered by infusion 1–6 times over 3–6 weeks, with administration no more frequent than once a week. It may be convenient to call such a unit of treatment a “cycle,” but there is no required event that marks the end of one cycle or the start of the next. In fact, treatment can and often will continue without interruption according to the cycle schedule until 1) the disease (cancer) progresses and the drug is stopped because it cannot achieve its desired effect, 2) the treatment is toxic to the patient and needs to be discontinued, 3) the patient and / or the treating physician determine that another treatment would be better for the patient, or 4) all disease (cancer) has disappeared and the patient and / or the treating physician decide to stop treatment. In some cases, instead of discontinuing treatment as described above, it may be more appropriate to adjust the dosage according to ineffectiveness or toxicity.

[0059] Monotherapy with compound A following prior treatment can be initiated at any time after the last dose of the prior treatment and after a decision has been made to adopt a new treatment. In some embodiments, compound A treatment is initiated after a rest period to substantially reduce or eliminate the amount of the prior treatment in the body, to recover from surgery, or to resolve any adverse events caused by the prior treatment. In various embodiments, the interval between the last dose of the prior treatment and the initiation of compound A monotherapy is at least two, three, or four weeks, or one month. In some embodiments, compound A monotherapy is not initiated until the toxicity from the prior treatment has decreased to grade 1 or less or to baseline. In some embodiments, the prior treatment has caused permanent organ damage, and compound A monotherapy is not initiated until palliative treatment for the dysfunction or loss of function of the damaged organ has been established. For example, the thyroid or pituitary gland may be damaged, and hormone replacement therapy may be administered. In one aspect of these embodiments, the prior treatment was immunotherapy, e.g., immune checkpoint inhibitor therapy. In another aspect of these embodiments, the prior treatment was chemotherapy, e.g., cytotoxic or DNA-damaging chemotherapy.

[0060] Observations have shown that prior treatment may bias the response to compound A monotherapy. For example, prior PD-1 blocking immune checkpoint inhibitors were associated with greater IP-10 induction and a better clinical response. Therefore, in some embodiments, compound A monotherapy is used to treat patients who have been deviated from immune checkpoint inhibitor therapy (e.g., due to progressive disease or unacceptable toxicity). In one aspect of these embodiments, the patient has also received prior treatment with chemotherapy, e.g., cytotoxic chemotherapy or DNA damage chemotherapy. In some of these embodiments, compound A monotherapy is initiated within 12 weeks or 24 weeks (or within 3 months or 6 months) of the last dose of prior treatment, or within 12 weeks or 24 weeks (or within 3 months or 6 months) of the last dose of prior immune checkpoint inhibitor therapy. In some embodiments, the prior immune checkpoint inhibitor therapy was anti-PD-1 therapy, anti-PD-L1 therapy, or either of the above. In some embodiments, the prior immune checkpoint inhibitor therapy was anti-CTLA-4 therapy. In further embodiments, the previous immune checkpoint inhibitor therapy was anti-LAG-3, anti-Siglec-15, anti-TIGIT, or anti-TIM-3. In further embodiments, the previous immune checkpoint inhibitor therapy may be anti-B7H3, anti-CD137, anti-OX40, anti-CD40, anti-CD122, anti-ICOS, or anti-CD73 / NT5E.

[0061] In other embodiments, immune checkpoint inhibitor therapy and treatment with compound A are performed as sequential treatments in which at least 1 to 3 doses of the immune checkpoint inhibitor are administered before the treatment with compound A is initiated. In some embodiments, immune checkpoint inhibitor therapy is discontinued before the treatment with compound A is initiated. In other embodiments, administration of the immune checkpoint inhibitor is continued in conjunction with the treatment with compound A. In these embodiments, the immune checkpoint inhibitor is administered according to its usual schedule.

[0062] In various embodiments, the window in which monotherapy or sequential therapy with compound A is initiated is defined by any of the above teachings regarding the earliest possible administration and the timeframe in which it should be initiated.

[0063] The effectiveness of the procedure can be monitored during the procedure. Monitoring can be achieved, for example, by imaging one or more tumors with simple X-rays, CAT or CT scans, PET scans, or MRI. In some embodiments, these scanning techniques can be called means for imaging, and performing such scans can be called steps for imaging.

[0064] The effectiveness of cancer treatment is usually measured in terms of "response." Techniques for monitoring response may be similar to those used to diagnose cancers, but are not limited to: • Some lumps or tumors, including those containing lymph nodes, can be palpated and measured externally through physical examination. Some internal cancerous tumors appear on X-rays, CT scans, PET scans, CT / PET scans, or MRI, and can be measured with a ruler. • Blood tests, including those measuring organ function, can be performed. Tumor marker tests can be performed for certain types of cancer.

[0065] Regardless of the test used—whether a blood test, cell count test, or tumor marker test—the test is repeated at specific intervals so that the results can be compared with previous tests of the same type.

[0066] The response to cancer treatment can be defined in several ways: • Complete response – all cancer or tumors disappear; no evidence of disease. Tumor marker levels (if applicable) may be within the normal range. • Partial response – The tumor has shrunk by a certain percentage, but the disease remains. Tumor marker levels (if applicable) may have decreased (or increased, based on tumor markers as an indicator of tumor volume reduction), but evidence of disease remains. • Stable disease - The cancer is neither growing nor shrinking. The amount of disease remains unchanged. Tumor markers (if applicable) have not changed significantly. • Disease progression - the cancer is growing. The disease is now more advanced than before treatment. Tumor marker tests (if applicable) show elevated tumor marker levels.

[0067] Other measures of the effectiveness of cancer treatment include overall survival (time from diagnosis or initiation of treatment under evaluation to death from any cause), cancer-free survival (time after complete response when cancer is not detected), and progression-free survival (time after disease stabilization, partial response, or complete response when no resumption of tumor growth is detected).

[0068] There are two standard methods, the WHO criteria and the RECIST criteria, for evaluating the treatment response of solid tumors in terms of tumor size (tumor volume). These methods measure solid tumors to compare current tumors to past measurements, compare changes to future measurements, and modify treatment regimen plans. The WHO method measures the long and short axes of a solid tumor and then calculates the product of these two measurements. If there are multiple solid tumors, the sum of all products is calculated. The RECIST method measures only the long axis. If there are multiple solid tumors, the sum of all long axis measurements is calculated. However, if lymph nodes are present, the short axis is measured instead of the long axis.

[0069] Based on the concentration of free base in plasma, a beneficial association has been observed between the clinical benefit of compound A and a specific pharmacokinetic profile. A plasma Cmax of free base of compound A of 8.3 ng / mL and / or an area under the curve (AUC) of free base of compound A of 3.4 ng / mL*day is associated with a high probability of clinical benefit from monotherapy with compound A. Therefore, some embodiments are methods for treating cancer, comprising administering a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, to a patient to obtain a plasma concentration profile in the patient that includes a maximum plasma concentration (Cmax) of free base of compound A of >8.3 ng / mL, an AUC of free base of compound A of >3.4 ng / mL*day, or both. In some embodiments, and in further embodiments, the potential for clinical benefit is increased compared to treatment with compound A that does not achieve the plasma concentration profile. In other embodiments, the achieved Cmax profiles are >5, >6, >7, >8, >9, >10, >11, or >12 ng / mL. In other embodiments, the AUC profile achieved is >1, >2, >3, >4, or >5 ng / mL*day.

[0070] Free base of compound A in plasma C maxThe fact that the Cmax is 7.6 ng / mL and / or the AUC of the free base of compound A in plasma is 2.2 ng / mL*day is associated with the potential for clinical benefit from combination therapy with compound A and an anti-PD1 antibody. Therefore, some embodiments are methods for treating cancer, comprising administering a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody to a patient to obtain a plasma concentration profile in the patient in which the maximum plasma concentration (Cmax) of the free base of compound A is 7.6 ng / mL, the area under the curve (AUC) of the free base of compound A is 2.2 ng / mL*day, or both. In further embodiments, the potential for clinical benefit is increased compared to treatment with compound A that does not achieve the plasma concentration profile. In other embodiments, the Cmax profile achieved is >5, >6, >7, >8, >9, or >10 ng / mL. In other embodiments, the AUC profile achieved is >1, >2, >3, >4, or >5 ng / mL*day.

[0071] Free base of compound A in plasma C max The fact that the free base of compound A is 10.5 ng / mL and / or the plasma AUC of free base of compound A is 2.1 ng / mL*day is related to the high potential for clinical benefit from combination therapy with compound A and an anti-PD-L1 antibody. Therefore, some embodiments administer a therapeutically effective amount of compound A, or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody to the patient to achieve the maximum plasma concentration of free base of compound A (C max A method for treating cancer, comprising obtaining a plasma concentration profile in the patient, comprising a Cmax of 10.5 ng / mL and an area under the curve (AUC) of free base of compound A of 2.1 ng / mL*day, or both. In further embodiments, the potential clinical benefit is increased compared to treatment with compound A that does not achieve the plasma concentration profile. In other embodiments, the achieved Cmax profile is >5, >6, >7, >8, >9, >10, >11, or >12 ng / mL. In other embodiments, the achieved AUC profile is >1, >2, >3, >4, or >5 ng / mL*day.

[0072] In certain embodiments, “clinical benefit” means complete response, partial response, or stable disease for more than 18 weeks, as defined by RECIST version 1.1.

[0073] The term “treatment” or “treatment” broadly includes any treatment activity of any kind, including the diagnosis, mitigation, or prevention of a disease or manifestation thereof in humans or other animals, or any activity that otherwise affects the structure or any function of the body of a human or other animal. Treatment activities include administering the drugs, dosage forms, and pharmaceutical compositions described herein to a patient, in particular in accordance with the various treatment methods disclosed herein, whether by a medical professional, the patient themselves, or any other person. Treatment activities include the direction, guidance, and advice of a medical professional, such as a physician, physician's assistant, or nurse practitioner, which is performed by other people, including other medical professionals or the patient themselves. In some embodiments, the direction, guidance, and advice of a treatment activity may also include encouraging, inducing, or ordering that a particular drug or combination of drugs be selected for the treatment of a condition, such as by approving insurance coverage for a drug, not allowing the use of alternative drugs, including or excluding a drug prescription from a drug prescription, or offering a reward for using a drug, which may be done by an insurance company or drug benefit management company, and the drug is actually used. In some embodiments, the treatment activity may also include encouraging, inducing, or ordering the selection of a particular medicine for the treatment of a condition by a policy or standard of practice that may be established by a hospital, clinic, health maintenance organization, medical practice, or medical team, and that medicine is actually used. All such instructions, guidance, and advice are considered to be conditional on receiving the benefits of the treatment by following the instructions. In some cases, the patient may receive a financial benefit by complying with such instructions, guidance, and advice. In some cases, the healthcare professional may receive a financial benefit by complying with such instructions, guidance, and advice.

[0074] Examples of cancers that can be treated by the disclosed methods include, but are not limited to, acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-associated lymphoma, AIDS-associated malignancies, anal cancer, cholangiocarcinoma, bladder cancer, bone cancer, brainstem glioma, brain tumors (e.g., astrocytoma, cerebellar astrocytoma; cerebral astrocytoma / malignant glioma, ependymomatous brain tumor, supratentorial primitive brain tumor, neuroectodermal tumor, glioma of the visual pathway and hypothalamus, etc.), breast cancer, bronchial adenoma / carcinoid, carcinoid tumor, cancer ( Adrenocortical carcinoma, gastrointestinal cancer, islet cell carcinoma, skin cancer, cancer of unknown primary origin, etc.; cervical cancer, childhood cancer, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myeloproliferative disorder, clear cell sarcoma of the tendon sheath, colon cancer, colorectal cancer, cutaneous T-cell lymphoma, endometrial cancer, ependymoma, epithelial cancer, esophageal cancer, Ewing family tumors, extracranial germ cell tumors, extragonadal germ cell tumors, extrahepatic bile duct cancer, eye cancer, intraocular melanoma, gallbladder cancer, stomach cancer, gastrointestinal carcinoid tumors, ovarian germ cell tumors, gestational trophoblastic tumors, hairy cell leukemia, head and neck cancer, hepatocellular carcinoma, Hodgkin lymphoma, Hypopharyngeal cancer, islet cell carcinoma (pancreatic endocrine part), Kaposi's sarcoma, kidney cancer, laryngeal cancer, lip and oral cancer, primary liver cancer, lung cancer, non-small cell lung cancer, small cell lung cancer, primary central nervous system lymphoma, non-Hodgkin lymphoma, Waldenström macroglobulinemia, malignant mesothelioma, malignant thymoma, medulloblastoma, melanoma, Merkel cell carcinoma, primary metastatic squamous cell carcinoma of the neck, multiple endocrine neoplasia syndrome, multiple myeloma / plasmacytic neoplasm, mycosis fungoides, myelodysplastic syndrome, multiple myeloma, nasal cavity and paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, oral cancer, Examples of cancers that can be treated include pharyngeal cancer, ovarian epithelial cancer, low-grade ovarian tumors, pancreatic cancer, parathyroid cancer, pheochromocytoma, penile cancer, pineal and supratentorial primitive neuroectodermal tumors, pituitary tumors, pleuroblastoma, prostate cancer, rectal cancer, kidney cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcomas (e.g., Ewing family tumors, Kaposi's sarcoma, osteosarcoma / bone, malignant fibrous histiocytoma of soft tissue, etc.), Sézary syndrome, skin cancer, small intestine cancer, testicular cancer, thymoma, thyroid cancer, trophoblastic tumor, vaginal cancer, vulvar cancer, or Wilms' tumor. Some embodiments are methods for treating solid tumors. Some embodiments are methods for treating carcinoma, or sarcoma, or hematological malignancies.

[0075] Each of the treatment methods disclosed herein may be described as the corresponding composition for use in the treatment of cancer, the use of the composition in the treatment of cancer, or the use of the composition in the manufacture of a pharmaceutical product for the treatment of cancer. formulation

[0076] A pharmaceutical composition containing compound A may optionally contain other pharmaceutically acceptable components (or pharmaceutical components), which may include, but are not limited to, buffers, preservatives, tonicity modifiers, salts, antioxidants, osmolality modifiers, physiological substances, pharmacological substances, bulking agents, emulsifiers, wetting agents, sweeteners, or flavoring agents. The pharmaceutical compositions disclosed herein may be prepared using various buffers and means for adjusting pH, provided that the resulting preparations are pharmaceutically acceptable. Such buffers may include, but are not limited to, acetate buffer, borate buffer, citrate buffer, phosphate buffer, neutral buffered saline, and phosphate buffered saline. It is understood that acids or bases may be used to adjust the pH of the composition as needed. Pharmaceutically acceptable antioxidants may include, but are not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole, and butylated hydroxytoluene. Useful preservatives include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercury acetate, phenylmercury nitrate, stabilized oxychloro compositions such as sodium chlorite, and chelating agents such as DTPA or DTPA-bisamide, DTPA calcium, and CaNaDTPA-bisamide. Useful tonic modifiers for pharmaceutical compositions include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol, or glycerin, and other pharmaceutically acceptable tonic modifiers.

[0077] Liquid formulations suitable for injection may include physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injection solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents, or vehicles include, but are not limited to, water, ethanol, polyols (such as propylene glycol, polyethylene glycol (PEG), and glycerol), suitable mixtures thereof, vegetable oils (such as olive oil), polymers, liposomes, nanoparticles, nanomicelle formulations, pegylated materials, aluminum gels, related proteins or polypeptides such as albumin, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coatings such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0078] The pharmaceutical composition of compound A may optionally include a pharmaceutically acceptable carrier that facilitates the processing of the active compound into a pharmaceutically acceptable composition. Such carriers are generally permitted to be mixed with the active compound or to dilute or encapsulate the active compound. A variety of pharmaceutically acceptable carriers may be used, but are not limited to, aqueous media such as water, saline, glycine, and hyaluronic acid; solvents; dispersion media; polymers, liposomes, nanoparticles, nanomicelle formulations, pegylated materials, and aluminum gels; related proteins or polypeptides such as albumin; antimicrobial and antifungal agents; isotonic and absorption retardants; or any other inert components.

[0079] In some embodiments, an appropriate dose of compound A based on the patient's BSA is diluted in 100 ml of saline solution for infusion.

[0080] In some embodiments, the compound A injection solution is a sterile, preservative-free, colorless solution for intravenous use, containing compound A and an inert component, sodium chloride, and sodium citrate. The primary packaging consists of a 2 mL glass vial containing 1.5 mL of the compound A injection solution. The concentration of free base of compound A may be 1.0 mg / mL (however, this solution may be prepared by dissolving a pharmaceutically acceptable salt such as sulfate), and the volume of the drug solution in the vial to be added to 100 mL of physiological saline is calculated based on the patient's mass or body size (BSA) and the vial's concentration of 1.0 mg / mL. Instructions for use, including the preparation and administration requirements of the administration solution, may be described in the pharmacy manual or prescribing information (package insert).

[0081] In some embodiments, the vials of compound A injection solution are for single use only and can be supplied in 2 ml clear vials. The vials are capped with a 13 mm rubber stopper and sealed with a 13 mm plastic-aluminum seal. An aluminum seal with a plastic flip-off cap can be used to secure the closure in place. The vials can be shipped in small cardboard boxes containing multiple vials, for example, six vials each. The vials are stored at room temperature (15-25°C) and protected from light in a safe, temperature-controlled, and restricted area. The final compound A sulfate concentration may be approximately 1.3 mg / mL, which corresponds to approximately 1.0 mg / mL of free base. [Examples]

[0082] The following examples, which are not limited to this specification, are provided for illustrative purposes only to facilitate a more complete understanding of the representative embodiments currently being considered. These examples should not be construed as limiting any of the embodiments described herein. Example 1 Pharmacokinetics and safety of compound A

[0083] A multicenter, open-label, dose-escalation / dose-expansion phase 1 trial of compound A sulfate as a monotherapy is ongoing in subjects with histologically confirmed, unresectable or metastatic solid tumors that are relapsed or refractory to standard treatment, or in subjects with no approved treatment options. Subjects will receive compound A sulfate in 100 ml of saline intravenously. The treatment cycle is 21 days, with three weekly infusions on days 1, 8, and 15.

[0084] The ongoing Phase 1 dose-escalation trial has so far enrolled 36 subjects who have been treated with at least one dose of compound A salt as monotherapy. A summary of the subject population (Table 2) shows the demographics recorded at screening and previous treatment lines. (A single treatment line consists of one or more complete cycles of monotherapy, a regimen of several drug combinations, or planned sequential treatment of various regimens.) There were 15 types of solid tumors among the enrolled subjects, the most common being NSCLC, endometrial carcinoma / sarcoma, and ovarian cancer. [Table 2]

[0085] The dosage of compound A was initially specified in mg / kg, but this proved problematic. Considering inter-subject variability in body weight and drug exposure, a body surface area (BSA)-based dosage (mg / m²) was developed. 2 The dosage was based on the Mostler formula: BSA = √height (cm) × weight (kg) / 3600. Five escalating doses (0.30 mg / m²) were used. 2 , 0.45 mg / m² 2 , 0.60 mg / m² 2 , 0.75 mg / m² 2 , and 0.90 mg / m² 2When compound A was administered intravenously, a dose-dependent increase in free base exposure to compound A was observed, with an approximate half-life of 4 hours (Figure 1). Compound A was effectively eliminated from the bloodstream within approximately 24 hours post-infusion for all doses, and no signs of drug accumulation were observed from day 1 to day 8 of cycle 1.

[0086] In this trial, there was no apparent dose-dependent increase in toxicity. Monotherapy with compound A was generally well-tolerated, with no grade 4 or 5 adverse events (AEs), and 11 out of 36 subjects (31%) experienced no drug-related AEs. The most common drug-related AEs were associated with immune activation.

[0087] Patient IP-10 induction multipliers did not show a correlation with the safety profile. This is because the overall safety profile was similar between subjects with substantial IP-10 induction and those with minimal IP-10 induction (Table 3). However, IP-10 induction has been shown to correlate with clinical benefit in patients receiving compound A monotherapy. [Table 3]

[0088] IP-10 induction (>5-fold increase) was more likely in subjects previously treated with anti-PD-(L)1 mAb and / or chemotherapy (Table 3). However, such immune activation was more favorable to the clinical response in subjects previously treated with anti-PD-(L)1 mAb. Example 2 Cytokine biomarker assay

[0089] For each subject treated with at least one dose of compound A salt monotherapy, blood samples were collected before administration and at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours post-infusion on day 1 of cycle 1, day 8 of cycle 1, and day 1 of cycle 3 (only before administration and at 1 and 4 hours post-infusion on day 1 of cycle 3). Pharmacodynamic analysis of compound A included cytokine quantification and whole blood RNA transcription profiling.

[0090] The collected plasma samples were quantified for cytokine biomarkers involved in inflammatory responses, immune system modulation, and other biological processes. Assays for cytokine quantification were performed by Frontage Laboratories, Inc. using Meso Scale Discovery (MSD) V-PLEX and U-PLEX plates pre-coated with capture antibodies against IL-5, IL-17A, IFN-γ, IL-2, IL-6, IL-8, IL-10, IL-12p70, TNF-α, IFN-α, IFN-β, and IP-10. Plasma samples were added directly to the plates to conjugate the analytes in the samples to the capture antibodies. Electrochemiluminescence-labeled (MSD SOLFO-TAG®)-conjugated detection antibodies were then added, and the plates were visualized using an MSD plate reader. The amount of captured analyte (or cytokine level) in each sample was quantified by measuring the luminescence intensity.

[0091] RNA extracted from whole blood samples is used in a pre-designed Human Pan Cancer Gene expression was analyzed using the NanoString nCounter platform, a highplex assay designed to quantify gene expression using genes from an Immune Profiling panel. Within-patient comparisons were also performed at various time points. Relative transcription levels of selected genes were analyzed based on data from cytokine quantification.

[0092] The handling of subject samples and laboratory analysis were carried out in accordance with Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) standards for conducting clinical trials of pharmaceuticals.

[0093] Cytokine quantification data analysis revealed that monotherapy with compound A significantly increased serum IP-10 levels (Figure 2A) and IFN-γ (data not shown). The most potent cytokine induction was observed at the highest dose level of compound A tested, 0.75 mg / m². 2 Observed in response to dose level 4, the increased levels of IFN-γ and IP-10 strongly suggest that compound A upregulates interferon-inducible gene signatures, which are well-known markers of antitumor immunity. The expression of IP-10 and IFN-γ induced by compound A, as well as the increase in interferon-inducible gene transcripts, correlated with clinical response (see Example 4). Example 3 Pharmacokinetics of cytokines in response to administration of compound A salt

[0094] To evaluate the effect of intravenous administration of compound A salt on cytokine production, commercially available MSD The plasma levels of IFN-α, IFN-β, IFN-γ, IL-2, IL-5, IL-6, IL-8, IL-10, IL-12, IL-17, interferon-inducible protein 10 (IP-10), and TNF-α were quantified using the V-plex assay (Meso Scale Discoveries) according to the manufacturer's instructions. Plasma samples were collected in cycles 1, 3, and 6. Of the quantified cytokines, IP-10, IFN-γ, IL-6, IL-8, IL-10, and TNF-α were detected. Peak cytokine levels were normalized for each subject to baseline on day 1 of cycle 1 and compared based on the dose level of compound A (Table 4). The higher peak cytokine level on either day 1 or day 8 of cycle 1 was selected for analysis to include all subjects. Dose-dependent increases were observed for IP-10 and IFN-γ, indicating immunoactivation by compound A. Table 4 shows the median and range of peak cytokine levels / baseline from each dose level. Cytokine induction also correlated with the peak plasma concentration of compound A (Figure 3). [Table 4]

[0095] IP-10 and IFN-γ induction were found to be most potent at higher compound A salt doses (Table 4), and such IP-10 and IFN-γ inductions were statistically significant (p=0.002 and p=0.013, respectively). Dose-dependent increases in IP-10 transcripts were also observed in whole blood RNA (data not shown). Furthermore, dose-dependent increases in IP-10 induction were observed even when the change in IP-10 from baseline was shown at AUEC levels (Figure 2A). The dose-dependent increase in IP-10 by compound A was observed at 0.75 mg / m², as shown in Figure 2B. 2 The largest finding was observed at D4 (dose level 4), which was statistically significant.

[0096] The median IP-10 / IFN-γ change was higher in subjects with partial response and long-term stable disease (SD) (data not shown), indicating that IP-10 and IFN-γ induction correlated with the clinical response to compound A. This was confirmed by RNA transcription profiling using nanostring analysis, which showed increased IFN-inducible gene transcription levels of CXCL10, CXCL11, and indoleamine 2,3-dioxygenase (IDO1) in responders (partial response and stable disease >18 weeks) (data not shown). The window of immune activation required for response can be defined by a 5- to 40-fold increase in IP-10 induction, observed in PR (2 out of 2 subjects) and long-term SD subjects (6 out of 7 subjects). Outside the window of IP-10 induction exceeding a 100-fold increase may necessitate dose reduction to minimize the risk of toxicity such as cytokine release syndrome. Example 4 Efficacy of monotherapy with compound A salt

[0097] According to irRECIST, a disease control rate of 63% was achieved (2 partial responses [PR] + 18 stable disease [SD]). Seven subjects (22%) achieved long-term disease control (study period > 18 weeks), one of whom had the longest study period at 68 weeks with monotherapy of compound A salt. The response was best among 12 subjects with progressive disease (PD, 38%). Both subjects with partial response received a dose of 0.75 mg / m². 2 A high dose of compound A salt was administered. Example 5 Pharmacokinetics, pharmacodynamics, IP-10 induction markers, and correlations with clinical efficacy of compound A salt.

[0098] We conducted analyses to investigate the pharmacokinetic parameters of compound A in its free base form, its relationship to plasma IP-10 induction levels from baseline, and its correlation with clinical response. Response was defined as the best overall response – immune-related partial response (irPR), immune-related stable disease (irSD) with a study duration greater than or less than 18 weeks, and unconfirmed immune-related progressive disease (uirPD). Clinical benefit was defined as a partial response (irPR) or an irSD greater than 18 weeks. IP-10 cytokine induction levels were analyzed for the cycle 1 dose in 32 patients for whom efficacy was evaluable. Due to inter-patient variability in ADME (absorption, distribution, metabolism, and excretion) of individual patients, the AUC or Cmax values ​​of compound A (measured as free base) can vary considerably even in patients receiving the same dose, which in turn can lead to very different downstream pharmacodynamic effects, such as IP-10 induction. For example, patient A, administered at a slower dose level 2, may have a higher AUC and / or Cmax than patient B, administered at dose level 3, resulting in patient A having a higher IP-10 induction level than baseline. Ultimately, it may be appropriate to adjust the dosage of compound A based on pharmacokinetic (AUC or Cmax) or pharmacodynamic (e.g., IP-10 induction) factors.

[0099] As shown in Figure 4, the IP-10 induction levels, as indicated by induction from baseline, were divided into two groups according to the AUC of compound A: 16 patients in the low AUC group (AUC below 2.09 ng / mL* days) and 16 patients in the high AUC group (AUC above 2.09 ng / mL* days). The mean IP-10 induction level was 3.68 times higher in the low AUC group and 27.2 times higher in the high AUC group, indicating that a minimum AUC of 2.09 ng / ng / mL* days is required to induce IP-10 and subsequently provide clinical benefit to the patient. This difference is statistically significant (p<0.05). In fact, based on the best response, only 2 patients in the low AUC group (irSD > 18 weeks) achieved clinical benefit, compared to 7 patients in the high AUC group (2 irPRs, 5 irSDs > 18 weeks) who achieved therapeutic benefit. This clearly demonstrated that patients in the high AUC group were significantly more likely to experience clinical benefits.

[0100] As shown in Figure 5, IP-10 induction levels are shown as induction from baseline, and patients were divided into two groups according to their Cmax for compound A: 16 patients in the low Cmax group (Cmax below 9.4 ng / mL* days) and 16 patients in the high AUC group (Cmax above 9.4 ng / mL* days). The mean IP-10 induction level was 5.09 times higher in the low Cmax group and 31.9 times higher in the high Cmax group, indicating that a minimum Cmax of 9.4 ng / mL is required to induce sufficient IP-10 and subsequently provide clinical benefit to the patient. This difference is statistically significant (p<0.05). In fact, based on the best response, only 2 patients in the low Cmax group (irSD > 18 weeks) achieved clinical benefit, compared to 7 patients in the high Cmax group (2 irPRs, 5 irSDs > 18 weeks) who achieved therapeutic benefit. This clearly demonstrated that patients in the high AUC group were significantly more likely to experience clinical benefits.

[0101] A correlation was found between higher IP-10 induction and efficacy, and this correlation was higher than that between IP-10 induction and IFN-γ induction. The median IP-10 induction (peak concentration between C1D1 and C1D8) was 13.5 times above baseline for subjects with clinical benefit (irPR + irSD > 18 weeks), compared to 4.0 times and 3.4 times for subjects with irSD < 18 weeks and uirPD, respectively. Similarly, the median IFN-γ induction was 7.5 times above baseline for subjects with clinical benefit (irPR + irSD > 18 weeks), compared to 3.0 times and 2.5 times for subjects with irSD < 18 weeks and uirPD, respectively. It is clear that higher dose levels lead to greater IP-10 or IFN-γ induction, which in turn correlates with better clinical efficacy. Example 6 Sulfate solution of compound A for injection

[0102] The dosage form was prepared to obtain 1.5 mL of a solution of compound A sulfate at a concentration of 1.31 mg / mL (1 mg of free base per mL) in a 2 mL injection vial. The master formula for preparing this solution (per mL) was as follows: Compound A sulfate 1.31 mg Sodium chloride 9.1 mg • Sodium citrate dihydrate 0.71 mg • Citrate dehydrate or citric acid to adjust the pH to 4.0-5.0 • Water for injection to adjust the volume to 1 mL

[0103] Compound A sulfate is C 17 H 22 It is N4O2·H2SO4, with a molecular weight of 412.46. The crystalline form was confirmed during the manufacturing process (crystalline form A, as specified in International Publication No. 2018232725, incorporated herein by reference).

[0104] To administer the drug, withdraw an appropriate volume from the injection vial, pour it into an intravenous solution container (e.g., 100 mL of saline solution), and inject it intravenously into the patient. For example, 0.75 mg / m² to a patient with a BSA of 1.80. 2 To administer the free base of compound A, i.e., a dose of 1.35 mg, 1.35 mL of compound A sulfate solution would be withdrawn from the injection vial and injected into a container for intravenous solution. Example 7 Correlation between compound A and clinical efficacy in monotherapy or in combination therapy with anti-PD-1 or anti-PD-L1 therapy.

[0105] Compound A was administered as monotherapy to subjects with progressive solid tumors, and also as an anti-PD-1 agent. The effects were evaluated in combination therapy with an mAb (pembrolizumab) or an anti-PD-L1 mAb (atezolizumab). The analysis was performed to investigate the correlation between the clinical benefit and pharmacokinetic parameters of the free base form of compound A administered as monotherapy or in combination with an anti-PD-1 mAb or anti-PD-L1 mAb. Clinical benefit was defined as complete response, partial response, or stable disease for more than 18 weeks on radiography, based on the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1.

[0106] As shown in Figure 6A, compound A was evaluated as monotherapy in 32 patients with advanced solid tumors. Patients were divided into two groups according to the AUC of compound A: 18 patients in the low AUC group (AUC below 3.42 ng / mL* days) and 14 patients in the high AUC group (AUC above 3.42 ng / mL* days). Clinical benefit from treatment was observed in 11% of patients in the low AUC group, compared to 50% of patients in the high AUC group, indicating that an AUC of at least 3.42 ng / mL* days is likely to provide clinical benefit in patients. Cmax was also evaluated in the same patients, dividing them into two groups according to the Cmax of compound A: 17 patients in the low Cmax group (Cmax below 8.38 ng / mL) and 15 patients in the high Cmax group (Cmax above 8.38 ng / mL). Clinical benefit from the treatment was observed in 12% of patients in the low Cmax group compared to 47% in the high Cmax group, indicating that a Cmax of at least 8.38 ng / mL is likely to provide clinical benefit in patients.

[0107] As shown in Figure 6B, compound A was evaluated in combination with pembrolizumab in 26 patients with advanced solid tumors. Patients were divided into two groups according to the AUC of compound A: 11 patients in the low AUC group (AUC less than 2.19 ng / mL* days) and 15 patients in the high AUC group (AUC greater than 2.19 ng / mL* days). Clinical benefit from the treatment was observed in 27% of patients in the low AUC group, compared to 47% in the high AUC group, indicating that an AUC of at least 2.19 ng / mL* days is likely to provide clinical benefit to patients. Cmax was also evaluated in the same patients, dividing them into two groups according to the Cmax of compound A: 10 patients in the low Cmax group (Cmax less than 7.65 ng / mL) and 16 patients in the high Cmax group (Cmax greater than 7.65 ng / mL). Clinical benefit from the treatment was observed in 30% of patients in the low Cmax group compared to 44% in the high Cmax group, indicating that a Cmax of at least 7.65 ng / mL is likely to provide clinical benefit in patients.

[0108] As shown in Figure 6C, compound A was evaluated in combination with atezolizumab in 25 patients with advanced solid tumors. Patients were divided into two groups according to the AUC of compound A: 15 patients in the low AUC group (AUC less than 2.14 ng / mL* days) and 10 patients in the high AUC group (AUC greater than 2.14 ng / mL* days). Clinical benefit from the treatment was observed in 20% of patients in the low AUC group, compared to 50% of patients in the high AUC group, indicating that an AUC of at least 2.14 ng / mL* days is likely to provide clinical benefit to patients. Cmax was also evaluated in the same patients, dividing them into two groups according to the Cmax of compound A: 15 patients in the low Cmax group (Cmax less than 10.5 ng / mL) and 10 patients in the high Cmax group (Cmax greater than 10.5 ng / mL). Clinical benefit from the treatment was observed in 27% of patients in the low Cmax group compared to 40% in the high Cmax group, indicating that a Cmax of at least 10.5 ng / mL is likely to provide clinical benefit in patients.

[0109] Finally, while aspects of this specification are emphasized by reference to specific embodiments, it should be understood that those skilled in the art will readily grasp that these disclosed embodiments are merely illustrative of the principles of the subject matter disclosed herein. Therefore, it will be understood that the disclosed subject matter is by no means limited to the specific methodologies, protocols, and / or reagents, etc., described herein. Accordingly, various modifications, alterations, or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of this specification. Finally, the terminology used herein is intended solely to describe specific embodiments and is not intended to limit the scope of the invention as defined solely by the claims. Therefore, the invention is not limited to what is precisely shown and described.

[0110] Specific embodiments of the Invention, including the best mode known to the inventors for carrying out the Invention, are described herein. Of course, variations of these described embodiments will be apparent to those skilled in the art by reading the preceding description. The inventors expect that those skilled in the art will adopt such variations as needed, and the inventors intend that the Invention may be carried out in ways other than those specifically described herein. Accordingly, the Invention includes all modifications and equivalents of the subject matter described in the claims appended herein, as permitted by applicable law. Furthermore, any combination of the above embodiments in all possible variations thereof is incorporated herein unless otherwise indicated herein or unless it is clearly inconsistent with the context.

[0111] The grouping of alternative embodiments, elements, or steps of the present invention shall not be construed as limitation. Each group member may be referenced and claimed individually or in any combination with other group members disclosed herein. For convenience and / or patentability reasons, it is anticipated that one or more members of a group may be included in or removed from a group. If such inclusion or removal occurs, this specification shall be deemed to include that group as modified and thus satisfy all descriptions of Markush groups used in the appended claims.

[0112] Unless otherwise indicated, all figures representing features, items, quantities, parameters, characteristics, terms, etc., used herein and in the claims are understood to be modified in any case by the term “approximately.” In this specification, the term “approximately” means that the thus limited feature, item, quantity, parameter, characteristic, or term encompasses a range of plus or minus 10 percent above or below the value of the described feature, item, quantity, parameter, characteristic, or term. Therefore, unless otherwise indicated, the numerical parameters described in the specification and the appended claims are variable approximations. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the claims, each numerical representation should be interpreted by applying ordinary rounding techniques, taking into account the number of significant figures reported. Although the numerical ranges and values ​​representing the broad scope of the invention are approximations, the numerical ranges and values ​​shown in specific examples are reported as accurately as possible. However, any numerical range and value inherently contains certain errors that inevitably arise from the standard deviation found in each test measurement. The description of a numerical range of values ​​is intended solely as a shorthand notation for individually referring to each numerical value that falls within that range. Unless otherwise indicated herein, each individual value within a numerical range is incorporated herein as if it were individually listed herein.

[0113] In the context describing the present invention (particularly in the context of the following claims), the terms “a,” “an,” “the,” and similar reference subjects are to be interpreted as covering both singular and plural forms unless otherwise indicated herein or unless clearly contradicted by the context. All methods described herein may be performed in any suitable order unless otherwise indicated herein or unless clearly contradicted by the context. Any examples or illustrative language provided herein (e.g., “etc.”) are intended merely to better illustrate the present invention and do not limit the scope of the present invention to any other claims. No language herein should be interpreted as indicating an unclaimed element essential to the practice of the present invention.

[0114] Certain embodiments disclosed herein may be further limited in the claims using the language of consisting of or essentially consisting of. Where used in the claims, whether at the time of filing or added with each amendment, the transitional term "consisting of" excludes any element, step, or component not specified in the claims. The transitional term "essentially consisting of" limits the claims to the specified material or step and one or more basic and novel features without substantially affecting them. Embodiments of the invention as thus claimed are essentially or expressly described and enabled herein.

[0115] All patents, patent publications, and other publications referenced and identified herein are incorporated herein by reference, individually and expressly, in their entirety, for the purpose of describing and disclosing, for example, compositions and methodologies described in such publications that may be used in connection with the present invention. These publications are provided only for those disclosed prior to the filing date of this application. In this regard, the inventors should not be construed as acknowledging that they do not have prior rights to such disclosures for prior invention or other reasons. All statements regarding dates or expressions regarding the contents of these documents are based on information available to the applicant and do not constitute any endorsement of the accuracy of the dates or contents of these documents. In certain embodiments, for example, the following items are provided: (Item 1) A method for treating cancer in patients who require treatment for cancer, [ka] Alternatively, a pharmaceutically acceptable salt thereof (compound A) may be administered as monotherapy at a dose of 0.10 mg / m³ of the free base. 2 From 1.2 mg / m² 2 A method that includes administering the drug in the specified dosage. (Item 2) The aforementioned dosage of compound A is 0.30 mg / m². 2 From 0.75 mg / m² 2 The method described in item 1. (Item 3) The aforementioned dosage of compound A is approximately 0.75 mg / m². 2 The method described in item 1. (Item 4) The method described in any one of items 1 to 3, wherein the patient has previously been treated with immune checkpoint inhibitor therapy. (Item 5) The method according to item 4, wherein the cancer of the patient progressed during the previous treatment. (Item 6) The method according to item 4 or 5, wherein monotherapy with compound A is initiated between two weeks and six months after the last dose of the prior treatment. (Item 7) The method according to item 6, wherein monotherapy with compound A is initiated within 12 weeks after the last dose of the prior treatment. (Item 8) The method described in any one of items 4 to 7, wherein the aforementioned prior treatment further includes chemotherapy. (Item 9) The method described in item 8, wherein the chemotherapy was cytotoxic therapy. (Item 10) The method described in item 8, wherein the chemotherapy was targeted therapy. (Item 11) The method according to any one of items 4 to 10, wherein the immune checkpoint inhibitor treatment was PD-1 / PD-L1 blockade. (Item 12) The method according to item 11, wherein PD-1 / PD-L1 blockade included administration of an anti-PD-1 antibody. (Item 13) The method according to item 11, wherein PD-1 / PD-L1 blockade included administration of an anti-PD-L1 antibody. (Item 14) The method according to any one of items 1 to 13, further comprising the quantification of interferon-inducible protein 10 (IP-10) concentration or transcription level in plasma or whole blood before the first dose of compound A to establish a baseline level, and after six doses of compound A to determine the response level. (Item 15) If the plasma or whole blood concentration of IP-10 after six administrations of compound A is at least twice the baseline level of IP-10, then the initial dose of compound A is 0.90 mg / m². 2 The method according to item 14, wherein if the dose is less than the amount, the dose of compound A is increased. (Item 16) A method for treating cancer in a patient requiring treatment for cancer, comprising administering a therapeutically effective amount of compound A to the patient, a. Maximum plasma concentration of free base of compound A exceeding 8 ng / mL (C max ); and / or b. Area under the curve (AUC) of free base of compound A exceeding 3 ng / mL*day A method comprising obtaining a plasma concentration profile in the patient, including the patient. (Item 17) A method for treating cancer in a patient requiring treatment for cancer, comprising administering a therapeutically effective amount of compound A and an anti-PD-1 antibody to the patient, a. Maximum plasma concentration of free base of compound A exceeding 7 ng / mL (C max ); and / or b. 2 ng / mL * Area under the curve (AUC) of the free base of compound A over a certain period of time. A method comprising obtaining a plasma concentration profile in the patient, including the patient. (Item 18) A method for treating cancer in a patient requiring treatment for cancer, comprising administering a therapeutically effective amount of compound A and an anti-PD-L1 antibody to the patient, a. Maximum plasma concentration of free base of compound A exceeding 10 ng / mL (C max ); and / or b. 2 ng / mL * Area under the curve (AUC) of the free base of compound A over a certain period of time. A method comprising obtaining a plasma concentration profile in the patient, including the patient. (Item 19) C max Average time until (T max The method according to any one of items 16 to 18, wherein the time is 15 to 90 minutes after administration. (Item 20) The method according to any one of items 16 to 18, wherein compound A is included in a dosage form for systemic administration. (Item 21) The method according to item 20, wherein the dosage form is administered via parenteral injection routes, including intravenous, intraperitoneal, intramuscular, subcutaneous, or intradermal. (Item 22) The method according to item 21, wherein the intravenous route includes an intravenous bolus or intravenous infusion. (Item 23) Administer at least 1-3 doses of an immune checkpoint inhibitor, and then [ka] or a pharmaceutically acceptable salt thereof (compound A), 0.10 mg / m² 2 From 1.2 mg / m² 2 A method for treating cancer in patients requiring treatment, including administering a certain dose. (Item 24) The method according to item 23, wherein no further doses of the immune checkpoint inhibitor are administered after the initial dose of compound A. (Item 25) The method according to item 23, wherein treatment with the aforementioned immune checkpoint inhibitor is continued in conjunction with treatment with compound A.

Claims

[Claim 1] The invention described in the specification.

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