Methods of stimulating Anti-tumor response using selective glucocorticoid receptor modulator

Abstract

To provide a drug for use in methods of decreasing regulatory T-cells in a cancer patient having a solid tumor.SOLUTION: The drug for use in methods of decreasing regulatory T-cells in a cancer patient having a solid tumor comprises relacorilant, which is a nonsteroidal selective glucocorticoid receptor antagonist (SGRA). The methods comprise administering, to the cancer patient, an effective amount of cancer treatment and an effective amount of the nonsteroidal SGRA, thereby decreasing regulatory T-cells in the patient.SELECTED DRAWING: Figure 13

Description

[Technical field]

[0001] Cortisol, the endogenous glucocorticoid receptor (GR) agonist, has widespread effects on many body systems, including the immune system. Excess cortisol is associated with and causes many disorders, including Cushing's syndrome, hyperglycemia, hypertension, hormonal disorders, psychological disorders, and other diseases and disorders. However, cortisol activity is evident even under normal physiological conditions. The normal range of morning serum cortisol, 10-20 ug / dL or 276-552 nM, is related to its biochemical K for the GR ligand binding domain. D High morning cortisol levels prepare the body for the night-to-day transition, increase alertness, and ensure a blunted immune response to external agents. Cortisol action is initiated by binding to GR. Cortisol-bound GR results in receptor agonism, transcriptional repression of cytoplasmic NFκB signaling, nuclear transport, and transcriptional enhancement of a broad range of immunosuppressive transcriptional programs. [Background technology]

[0002] Glucocorticoid receptor (GR)-mediated signaling pathways have dynamic biological effects that involve different components of the immune system, and their in vivo effects are unpredictable. For example, glucocorticoids have been reported to have both immunosuppressive effects, such as suppressing proinflammatory cytokines, promoting anti-inflammatory cytokines, inhibiting dendritic cells, suppressing natural killer cells, promoting T regulatory cells, and inducing T cell apoptosis, as well as immune enhancing effects. See Hinrichs J.Immunother.2005:28(6):517-524. The effects of GR-mediated signaling pathways on cancer cells are similarly elusive. Activation of GR signaling pathways has been suggested to induce apoptosis in certain types of cancer cells, such as malignant lymphomas. See Schlossmacher, J.Endocrino.(2011). However, other and opposite effects have also been reported (see, for example, U.S. Pat. No. 9,149,485).

[0003] In recent years, immunotherapy targeting immune checkpoint signaling pathways has been shown to be effective in treating cancer. These pathways are important in suppressing immune responses and maintaining self-tolerance, regulating the duration and amplitude of physiological immune responses in peripheral tissues, and minimizing collateral tissue damage. It has been suggested that tumor cells can activate immune checkpoint signaling pathways to reduce the effectiveness of immune responses against tumor tissue. Many of these immune checkpoint signaling pathways are initiated by the interaction between checkpoint proteins and their ligands present on the surface of cells involved in the immune response, such as T cells, and therefore can be easily blocked by drugs or regulated by recombinant forms of checkpoint proteins or ligands or receptors. Agents that block immune suppressive pathways induced by checkpoint proteins are generally referred to as checkpoint inhibitors, and several are commercially available. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4, or CTLA-4) antibodies, which block immune suppressive pathways via the checkpoint protein CTLA4, were the first of this class of immunotherapeutic agents to receive U.S. Food and Drug Administration (FDA) approval. Clinical findings with blockade of additional immune checkpoint proteins, such as programmed cell death protein 1 (PD-1), represent broad and diverse opportunities to improve anti-tumor immunity with the potential to generate durable clinical responses.

[0004] GR is expressed in most human cells, and is particularly abundant in immune cells.The effect and extent of endogenous cortisol on immune system, and its possible consequences on immune response, including antitumor immune response, are not fully understood.Therefore, there is a need for improved methods and treatments for disorders related to cortisol excess, for the effect of cortisol on immune system, and for improving immune-related treatments. Summary of the Invention

[0005] Applicants disclose herein a method of improving immune function in a cancer patient with a solid tumor, comprising administering to the cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal glucocorticoid receptor (GR) modulating agent (GRM), preferably a selective glucocorticoid receptor modulator (SGRM), thereby improving immune function in the patient. In some embodiments, this improved immune function is effective to produce an anti-cancer effect in the patient with the solid tumor, thereby slowing tumor growth, halting tumor growth, reducing tumor load, or a combination thereof. In some embodiments, the improved immune function includes increased CD8+ T cell activation compared to CD8+ T cell activation before administration of the nonsteroidal SGRM; the improved immune function includes increased proinflammatory cytokine secretion compared to proinflammatory cytokine secretion before administration of the nonsteroidal SGRM; the improved immune function includes increased tumor necrosis factor alpha (TNFα) secretion compared to TNFα secretion before administration of the nonsteroidal SGRM; the improved immune function includes increased interferon gamma IFNγ secretion compared to IFNγ secretion before administration of the nonsteroidal SGRM; and combinations thereof. In some embodiments, the immune function is improved after 2-3 to several days of administration of the nonsteroidal GRM or SGRM (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, or more days of administration).

[0006] In some cases, the GRM (e.g., SGRM) is a non-steroidal compound comprising a fused azadecalin structure, wherein the fused azadecalin structure is as described and disclosed in U.S. Patent No. 7,928,237 and U.S. Patent No. 8,461,172. In some cases, the GRM (e.g., SGRM) is a non-steroidal compound comprising a heteroaryl ketone fused azadecalin structure, wherein the heteroaryl ketone fused azadecalin structure is as described and disclosed in U.S. Patent No. 8,859,774. In some cases, the GRM (e.g., SGRM) is a non-steroidal compound comprising an octahydro fused azadecalin structure, wherein the octahydro fused azadecalin structure is as described and disclosed in U.S. Patent No. 10,047,082.

[0007] In some cases, the GRM (eg, an SGRM, eg, a non-steroidal SGRM) is administered orally.

[0008] In some embodiments, the GRM is administered by a cancer treatment. In some embodiments, the cancer treatment includes one or more of cancer radiation therapy, administration of a growth factor inhibitor, and administration of an anti-angiogenic factor. In some embodiments, the cancer treatment includes administration of a chemotherapeutic agent or an antibody checkpoint inhibitor. In some embodiments, the GRM is administered by at least one chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is an agent selected from a taxane, an alkylating agent, a topoisomerase inhibitor, an endoplasmic reticulum stress inducer, an antimetabolite, a mitotic inhibitor, and combinations thereof. For example, in some embodiments, the chemotherapeutic agent is a taxane, such as nab-paclitaxel. In some embodiments, the antibody checkpoint inhibitor is directed to a protein target selected from PD-1, PD-L1, PD-L2, CTLA-4, LAG3, B7-H3, B7-H4, OX-40, CD137, and TIM3.

[0009] To better understand the role of endogenous cortisol in immunosuppression, we applied selective GR antagonist Trela ​​Corylant to in vitro, in vivo, and ex vivo systems that recapitulate the physiological effects of normal GC activity.These data show that antagonizing GR can promote the benefits of ICI therapy.Other improvements and advantages are discussed herein. [Brief description of the drawings]

[0010] [Figure 1] Figure 1 shows that glucocorticoid receptor (GR) expression levels ("GR H-score") correlate with tumor and immune infiltration. CD3+ T cell infiltration correlated with GR expression in melanoma and TNBC tumors.

[0011] [Diagram 2] FIG. 2 shows that GR expression correlates with PD-L1 expression.

[0012] [Figure 3A] FIG. 3A shows that GR expression positively correlates with CD8+ T cells and regulatory T cells (Tregs).

[0013] [Figure 3B] FIG. 3B shows that GR expression is negatively correlated with TH1 T cells and positively correlated with TH2 T cells.

[0014] [Figure 4] 4 shows that in the presence of physiological levels of cortisol, Relacorilant restores T cell activation. Expression of CD137 (aka 41-BB) in CD8+ cells was reduced by cortisol and restored by Relacorilant.

[0015] [Diagram 5] FIG. 5 shows the suppression of CD3+ cell surface receptors by cortisol and restoration of CD3+ cell surface receptors by relacorilant following stimulation with phytohemagglutinin (PHA).

[0016] [Figure 6A] Figure 6A shows the suppression of cytokines and chemokines by cortisol and the restoration of cytokine / chemokine levels by Relacorilant after stimulation with phytohemagglutinin (PHA). Physiological levels of cortisol suppressed cytokines and chemokines, and this suppression was reversed by Relacorilant.

[0017] [Figure 6B] Figure 6B shows the suppression of cytokines and chemokines by cortisol and restoration of cytokine / chemokine levels by Relacorilant after stimulation with αCD3+IL-12. Physiological levels of cortisol suppressed cytokines and chemokines, and this suppression was reversed by Relacorilant.

[0018] [Figure 7] Figure 7 shows that Relacorilant enhances the response to an anti-PD1 antagonist antibody (RPM1-14) in the EG7 mouse model. The combination of RMP1-14 and Relacorilant was evaluated in the EG7 tumor model. Relacorilant significantly increased the efficacy of the anti-PD1 antibody in this model.

[0019] [Figure 8] FIG. 8 provides further data demonstrating that Relacorilant enhances the effect of anti-PD1 antibodies in the EG7 model.

[0020] [Figure 9] FIG. 9 shows the effect of Relacorilant alone (Group 3) compared to control (Group 1) on serum IL-10 in the EG7 mouse model.

[0021] [Figure 10]Figure 10 shows that treatment with the combination of relaxorilant and nab-paclitaxel suppressed gene expression in patients with solid tumors. Genes suppressed included IL8 (CXCL8), IDO1, and EP4 (PTGER4) (n=46).

[0022] [Figure 11] Figure 11 shows a summary of the effects on selected biomarkers in a patient in complete remission (CR) on treatment with relacorilant + nab-paclitaxel. The patient showed a decrease in neutrophil to lymphocyte ratio (NLR), as well as changes in CD4+ cells, CD8+ cells, CD3+ T cells, ptgs2 and dusp1m expression, and other changes. (C1D1 indicates day 1 of cycle 1 of treatment; C1D15 indicates day 15 of cycle 1 of treatment; C4D1 indicates day 1 of cycle 4 of treatment, and EOT indicates end of treatment.)

[0023] [Figure 12] Figure 12 provides a table summarizing the characteristics and prior treatments of human cancer patients who responded well to treatment with the combination of Relacorilant + nab-paclitaxel. (PR indicates partial response; CR indicates complete response; SD indicates stable disease (no tumor progression).)

[0024] [Figure 13] FIG. 13 further shows the effects on NLR, GR-regulated gene transcription, immunomodulatory cytokines, and immune cells in human cancer patients who responded highly to treatment with the combination of relacorilant + nab-paclitaxel.

[0025] [Figure 14] Figure 14 shows the effect of short-term Relacorilant treatment on T cell function. The results of the short-term pharmacodynamic study (performed to evaluate the effect of Relacorilant on T cell function prior to any observable effect on tumor volume) show that mean body weight and tumor volume were not affected by any of the treatments evaluated during this time frame.

[0026] [Figure 15] Figure 15 shows the short-term effects of GR antagonism in combination with αPD1 in the EG7 syngeneic model. In a 7-day pharmacodynamic study, Relacorilant + αPD1 increased antigen-specific T cells in the spleen (left) and tumor (right).

[0027] [Figure 16] Figure 16 shows the effect of Relacorilant and αPD1 on splenocytes assessed after the 7-day EG7 study. PD1 expression (top left) and CD69 expression (top right) on splenic CD8+ T cells are shown as a percentage of CD8+ T cells. CD3+CD8+ T cells are shown as a percentage of splenic CD45.1+ cells (bottom left). P values ​​from unpaired non-parametric T-tests are shown.

[0028] [Figure 17] FIG. 17 shows the effects of Relacorilant and αPD1, serum TNFα and IL-6 levels assessed after the 7-day EG7 study. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0029] A. (Introduction) GR expression was observed in human tumors and immune cells, and its abundance correlated positively with PDL1 expression and tumor infiltration of Th2 and Treg cells, whereas it correlated negatively with Th1 cell infiltration. Cortisol inhibited, and leracorilant restored, T cell activation and proinflammatory cytokine secretion in in vitro stimulated human PBMCs. In the EG7 mouse model, leracorilant significantly increased the efficacy of anti-PD1 antibodies. In a phase I nab-paclitaxel combination study in patients with advanced solid tumors, leracorilant systemically suppressed expression IL-8, EP4, and IDO1 and normalized the neutrophil-to-lymphocyte ratio (NLR). In a subset of patients with durable responses, leracorilant increased CD3+ cells and IFNγ, decreased Treg and IL-10, and suppressed the transcription of known GR-regulated genes. Together, these data characterize the broad immunosuppressive effects of cortisol that can be reversed by relacorilant.

[0030] Applicant discloses herein the effects of selective glucocorticoid receptor modulators (SGRMs). Many SGRMs are GR antagonists. For example, lelacorilant is a potent and selective GR antagonist. Half-maximal GR binding was observed at 0.15 nM, but progesterone receptor (PR) binding was not observed at concentrations above 1000 nM. In human stimulated PBMCs, TNF-α was suppressed by GR agonists, and lelacorilant restored TNF-α production, with half-maximal effects observed at 9 nM. Orally administered lelacorilant at doses that achieved systemic exposure similar to that seen in Phase I studies normalized glucose and insulin in a rat model of corticosterone-induced insulin resistance. Phase I healthy volunteer studies demonstrated tolerability and the ability to reverse the pharmacodynamic effects of a single dose of prednisone. The pharmacodynamic effects of GR agonists included induction of FKBP5 mRNA, a canonical GR-regulated gene, and suppression of eosinophil abundance in whole blood, both of which were reversed by relacorilant. Unlike mifepristone, steroid analogs, and hormone receptor modulators, GR inverse agonism was not observed with relacorilant. In a Phase II study in patients with Cushing's disease, relacorilant demonstrated the ability to reverse the effects of excess cortisol on hypertension and insulin resistance.

[0031] Applicant herein discloses a method of improving immune function in a cancer patient with a solid tumor, comprising administering to the cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM), thereby improving the immune function of the patient. Such improved immune function can include an improvement in the patient's immune system to produce an anti-cancer effect. In some embodiments, the improved immune function is effective to produce an anti-cancer effect in the patient with a solid tumor, thereby slowing tumor growth, halting tumor growth, reducing tumor burden, or a combination thereof. In some embodiments, improved immune function includes increased CD8+ T cell activation compared to CD8+ T cell activation before administration of the nonsteroidal SGRM; improved immune function includes increased proinflammatory cytokine secretion compared to proinflammatory cytokine secretion before administration of the nonsteroidal SGRM; improved immune function includes increased TNFα secretion compared to TNFα secretion before administration of the nonsteroidal SGRM; improved immune function includes increased IFNγ secretion compared to IFNγ secretion before administration of the nonsteroidal SGRM; and combinations thereof. In some embodiments, immune function is improved after 2-3 to several days of administration of the nonsteroidal GRM or SGRM (e.g., 1, 2, 3, 4, 5, 6, 7, 10, 14, or more days of administration).

[0032] In some embodiments of the methods disclosed herein, the non-steroidal SGRM is a compound comprising a heteroaryl ketone-fused azadecalin structure having the following formula:

[0033] [ka]

[0034] During the ceremony R 1is a heteroaryl ring having 5 to 6 ring members and having 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, each heteroaryl ring being independently R 1a may be substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, N-oxide, C 3-8 Cycloalkyl and C 3-8 heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein said heterocycloalkyl ring and heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of 1 to 4 R 2c may be substituted with a group; Or, two R attached to the same carbon 2 groups combine to form an oxo group (=O); Or, two R2 groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2d may be substituted with a group; R 2a and R 2b are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 2c are each independently hydrogen, halogen, hydroxy, or C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, and NR 2a R 2b selected from the group consisting of; R 2d are each independently hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Each has 1 to 4 R 3a phenyl and pyridyl, each optionally substituted with a group; R 3a are each independently hydrogen, halogen, or C 1-6 haloalkyl; The subscript n is an integer from 0 to 3.

[0035] In some embodiments of the method wherein the non-steroidal SGRM is a heteroaryl-ketone fused azadecalin, the non-steroidal SGRM is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, referred to as a relacorilant, having the following structure:

[0036] [ka]

[0037] In some embodiments of the methods wherein the nonsteroidal selective GRA is a heteroaryl-ketone fused azadecalin, the nonsteroidal SGRM is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, designated CORT122928, having the following structure:

[0038] [ka]

[0039] In some embodiments of the methods wherein the non-steroidal SGRM comprises a heteroaryl-ketone fused azadecalin, the non-steroidal SGRM is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, designated CORT113176, having the following structure:

[0040] [ka]

[0041] In some embodiments of the methods disclosed herein, the non-steroidal SGRM is an octahydro-fused azadecalin structure compound having the following formula:

[0042] [ka]

[0043] During the ceremony R1 is a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O, and S, each heteroaryl ring being independently selected from R 1a may be substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of aryl and heteroaryl rings having 5-6 ring members and 1-4 heteroatoms, each independently selected from the group consisting of N, O, and S; R 2 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 groups are combined to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, said heterocycloalkyl ring being comprised of 1-3 R 2cmay be substituted with a group; R 2a , R 2b , and R 2c are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 3a are each independently a halogen; The subscript n is an integer from 0 to 3.

[0044] In some embodiments of the methods disclosed herein, the non-steroidal SGRM is an octahydro-fused azadecalin structure compound having the following formula:

[0045] [ka]

[0046] During the ceremony, R 1 are each independently R 1a is selected from the group consisting of pyridine and thiazole, optionally substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; R 2 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 selected from the group consisting of haloalkyl, and -CN; R 3a is F; The subscript n is an integer from 0 to 3.

[0047] In some embodiments where the nonsteroidal SGRM comprises an octahydro-fused azadecalin structure, the nonsteroidal SGRM is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, referred to as an exicholant, having the following structure:

[0048] [ka]

[0049] In some embodiments, the non-steroidal SGRM has the chemical name ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, designated “CORT125329,” and is an octahydro-fused azadecalin compound having the following structure:

[0050] [ka]

[0051] In some cases, the effective amount of the GRM (e.g., an SGRM, e.g., a nonsteroidal SGRM) is a daily dose of 1-100 mg / kg / day, or about 1-20 mg / kg / day. In some embodiments, the daily dose of the GRM is 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg / day. In some cases, the GRM is administered for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weeks. In some embodiments, the GRM is an SGRM. In some preferred embodiments, the GRM is a GR antagonist (GRA), which may be a selective GRA.

[0052] In some embodiments, the GRM is administered in conjunction with a cancer treatment. In some embodiments of the methods disclosed herein, the cancer treatment comprises administration of a chemotherapeutic agent. In some embodiments, the chemotherapeutic agent is selected from the group consisting of taxanes, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, antimetabolites, mitotic inhibitors, and combinations thereof. In some embodiments, the chemotherapeutic agent is a taxane, which may be, for example, nab-paclitaxel.

[0053] In some embodiments of the methods disclosed herein, the cancer treatment comprises administration of an immunotherapeutic agent. For example, in some embodiments of the methods disclosed herein, the cancer treatment comprises administration of an antibody checkpoint inhibitor. Thus, in some embodiments, the methods disclosed herein comprise administration of an antibody checkpoint inhibitor (an antibody against a protein target) directed to a target selected from PD-1, PD-L1, PD-L2, CTLA-4, LAG3, B7-H3, B7-H4, OX-40, CD137, and TIM3. In some embodiments, the cancer treatment comprises one or more of cancer radiation therapy, administration of a growth factor inhibitor, and administration of an anti-angiogenic factor.

[0054] In some embodiments of the methods disclosed herein, the cancer treatment comprises a method of treating a subject suffering from a solid tumor, comprising identifying a patient suffering from a solid tumor and having excess cortisol; administering a combination treatment comprising: 1) a selective glucocorticoid receptor modulator (SGRM); and 2) a cancer chemotherapeutic agent; thereby restoring CD8+ T cell activation, restoring pro-inflammatory cytokine secretion, or both. In some embodiments, the method comprises one or more of increasing T cell numbers, increasing plasma interferon gamma (IFNγ), decreasing Treg cells, decreasing interleukin-10 (IL-10), and combinations thereof.

[0055] (definition) As used herein, the genes cxcl8, ido1, and ptger4, as well as others, are referred to as follows:

[0056] [Table 1]

[0057] As used herein, the terms "tumor" and "cancer" are used interchangeably and both refer to abnormal tissue growth resulting from excessive cell division. Tumors that can invade surrounding tissues and / or metastasize are referred to as "malignant." Tumors that do not metastasize are referred to as "benign."

[0058] As used herein, the term "patient" refers to a human who is receiving, will be receiving, or has received medical treatment for a disease or condition.

[0059] As used herein, the terms "administer," "administering," "administered," or "administration" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. For example, the compound or composition may be orally administered to the patient.

[0060] As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of a pharmacological agent effective to treat, eliminate, or alleviate at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" can refer to an amount of a functional agent or pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective amount can be an amount that is effective to cause an anti-tumor response. For purposes of this disclosure, an effective amount of an SGRM or an effective amount of a chemotherapeutic agent is an amount that, when combined with a chemotherapeutic agent or an SGRM, respectively, can reduce tumor burden or cause other desired beneficial clinical outcomes related to cancer amelioration.

[0061] As used herein, the terms "administer," "administering," "administered," or "administration" refer to providing a compound or composition (e.g., those described herein) to a subject or patient. Administration may be by oral administration (i.e., the subject receives the compound or composition via the mouth as a pill, capsule, liquid, or other form suitable for administration via the mouth. Oral administration may be buccal (the compound or composition is held in the mouth, e.g., under the tongue, where it is absorbed). Administration may be by injection, i.e., by delivering the compound or composition via a needle, microneedle, pressure syringe, or any means that pierces the skin or forces the compound or composition through the subject's skin. Injection may be intravenous (i.e., into a vein); intraarterial (i.e., into an artery); intraperitoneal (i.e., into the peritoneum); intramuscular (i.e., into a muscle); or other injection route. Routes of administration may also include rectal, intravaginal, transdermal, via the lungs (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition), or by other routes.

[0062] As used herein, the term "combination therapy" refers to administering at least two agents to a subject to treat a disease. The two agents may be administered simultaneously or sequentially in any order over the entire or partial treatment period. The at least two agents may be administered according to the same or different dosing regimens. In some cases, one agent is administered according to a planned regimen, while the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, the one agent, e.g., an SGRM, is administered daily, and the other agent, e.g., a chemotherapeutic agent, is administered every 2, 3, or 4 days.

[0063] As used herein, the term "compound" is used to refer to a molecular moiety of a unique, identifiable chemical structure. The molecular moiety ("compound") may exist in the form of a free species not associated with other molecules. The compound may also exist as part of a larger aggregate not associated with other molecule(s) but nevertheless retaining its chemical identity. A solvate, in which a molecular moiety of a given chemical structure ("compound") is associated with a molecule(s) of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The description "compound" refers to the molecular moiety itself (of the described structure), whether it exists in free or associated form.

[0064] As used herein, the term "pharmaceutical acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with such active compound, their use in the above compositions is contemplated. Additional active compounds may be incorporated into the above compositions.

[0065] As used herein, the term "adrenocorticotropic hormone" (ACTH) refers to a peptide hormone produced and secreted by the anterior pituitary gland that stimulates the adrenal cortex to secrete glucocorticoid hormones that help cells synthesize glucose, catabolize proteins, mobilize free fatty acids, and inhibit inflammation in allergic reactions. One such glucocorticoid hormone is cortisol, which regulates carbohydrate, fat, and protein metabolism. In healthy mammals, ACTH secretion is tightly regulated. ACTH secretion is positively regulated by corticotropin-releasing hormone (CRH) released by the hypothalamus. ACTH secretion is negatively regulated by cortisol and other glucocorticoids.

[0066] The terms "adrenal hormones", "adrenal prehormones", and "adrenal hormones or prehormones" refer to steroid molecules that are hormones or precursors to hormones produced by the adrenal glands. As used herein, without limitation, "adrenal hormones or prehormones" may be one or more of 17α-hydroxypregnenolone, 17α-hydroxyprogesterone, 11-deoxycortisol, pregnenolone, progesterone, 11-deoxycorticosterone, corticosterone, 18-hydroxycorticosterone, aldosterone, dehydroepiandrosterone (androstenolone, DHEA), dehydroepiandrosterone sulfate (DHEA-S), and androstenedione. As used herein, the terms "adrenal hormones", "adrenal prehormones", and "adrenal hormones or prehormones" refer to hormones and prehormones other than cortisol, unless expressly stated that cortisol is also intended to be included.

[0067] In the context of ACTH, cortisol, adrenal hormones, adrenal prehormones, or other hormones or steroids, the term "measuring the level" refers to determining, detecting, or quantifying the amount, level, or concentration of cortisol, ACTH, or other steroid in a sample obtained, for example, from a subject. The sample can be, for example, a blood sample, a saliva sample, a urine sample, or other sample obtained from a patient. The level can be measured from a fraction of the sample. For example, the level (e.g., ACTH or cortisol) can be measured in the plasma fraction of a blood sample; in the serum fraction of a blood sample; or, in some embodiments, in whole blood.

[0068] The term "immune response" refers to the actions of, for example, lymphocytes, antigen-presenting cells, phagocytes, granulocytes, and soluble macromolecules produced by such cells or the liver, including antibodies, cytokines, and complement, that result in the selective damage to, destruction of, or elimination from the human body of invading pathogens, pathogen-infected cells or tissues, cancerous cells, or, in the case of autoimmune or pathological inflammation, normal human cells or tissues.

[0069] Cells of the immune system are identified herein according to terminology commonly used and generally accepted in the art. For example, the terms "Treg" and "T reg " are used interchangeably herein to refer to regulatory T cells. "IFN" refers to interferon, so that, for example, IFNγ will refer to interferon gamma. "IL" refers to interleukin, so that, for example, IL-10 will refer to interleukin 10. "TNF" refers to tumor necrosis factor, so that, for example, TNFα will refer to tumor necrosis factor alpha. Other terms and acronyms are known and used by those of skill in the art.

[0070] As used herein, the term "checkpoint inhibitor-sensitive cancer" refers to a cancer that is responsive to a checkpoint inhibitor. Administration of one or more checkpoint inhibitors to a patient with such a tumor can result in a reduction in tumor burden or other desired beneficial clinical outcomes related to cancer amelioration.

[0071] As used herein, the phrase "amount effective to enhance" refers to an amount of a pharmacological agent effective to improve the activity of another therapeutic agent in treating, eliminating, or alleviating at least one symptom of the disease being treated. The agent used to enhance the activity of another may or may not be effective in treating, eliminating, or alleviating the symptoms of the disease itself. In some cases, such an enhancer is ineffective, and the effect of enhancement may be indicated by an increased degree of alleviation of the symptoms resulting from treatment with a combination of these two agents compared to treatment with such therapeutic agent alone. In some cases, the enhancer itself is effective in treating the symptoms, and the enhancement effect may be indicated by a synergistic effect between the enhancer and the therapeutic agent. For example, an SGRM may act as an enhancer to enhance the activity of a checkpoint inhibitor in treating cancer, regardless of whether the SGRM may be effective in treating the cancer when administered alone. In some embodiments, an enhancement effect of 10% to 1000% may be achieved. In some embodiments, the SGRM is administered in an amount that sensitizes the tumor to the checkpoint inhibitor, i.e., shows a reduction in tumor burden or other relevant clinical benefit that is not otherwise evident when treated with the checkpoint inhibitor in the absence of the SGRM.

[0072] As used herein, the term "checkpoint protein" refers to a protein present on the surface of certain types of cells, such as T cells and certain tumor cells, that can trigger checkpoint signaling pathways and result in suppression of immune responses. Commonly known checkpoint proteins include CTLA4, PD-1, PD-L1, PD-L2, LAG3, B7-H3, B7-H4, TIM3, CD160, CD244, VISTA, TIGIT, and BTLA. (Pardoll, 2012, Nature Reviews Cancer 12:252-264; Baksh, 2015, Semin Oncol. 2015 Jun;42(3):363-77). For example, CTLA4, PD-1, and PD-L1 have been well studied, and therapies targeting these proteins are commonly used clinical treatments.

[0073] In some cases, the checkpoint inhibitor is a small molecule, non-proteinaceous compound that inhibits at least one checkpoint protein, hi some embodiments, the checkpoint inhibitor is a small molecule, non-proteinaceous compound that inhibits a checkpoint protein selected from the group consisting of CTLA-4, PD-1, PD-L1, PD-L2, LAG3, B7-H3, B7-H4, TIM3, CD160, CD244, VISTA, TIGIT, and BTLA.

[0074] In some cases, the checkpoint inhibitor is an antibody against at least one checkpoint protein, such as PD-1, CTLA-4, PD-L1, PD-L2, CTLA-4, LAG3, B7-H3, B7-H4, TIM3, CD160, CD244, VISTA, TIGIT, and BTLA. In some cases, the checkpoint inhibitor is an antibody that is effective against two or more of the checkpoint proteins selected from the group of PD-1, CTLA-4, PD-L1, PD-L2, AG3, B7-H3, B7-H4, TIM3, CD160, CD244, VISTA, TIGIT, and BTLA.

[0075] In some cases, the checkpoint inhibitor is an antibody against a checkpoint protein or against more than one checkpoint protein. Such antibody checkpoint inhibitors may be referred to as "α" and may be identified by the Greek letter "α" preceding the name of the target protein. Thus, for example, an antibody checkpoint inhibitor against PD1 may be referred to as "αPD1", an antibody checkpoint inhibitor against CD3 may be referred to as "αCD3". Treatments involving administration of such antibody checkpoint inhibitors may also be similarly identified, such that a treatment using an anti-PD1 antibody may be referred to as "αPD1" or "αPD1 treatment", a treatment using an anti-CD3 antibody may be referred to as "αCD3" or "αCD3 treatment", etc.

[0076] As used herein, the term "PD-1" refers to programmed cell death protein 1 (also known as CD279), a cell surface membrane protein of the immunoglobulin superfamily. PD-1 is expressed by B cells, T cells, and NK cells. The primary role of PD-1 is to limit the activity of T cells in peripheral tissues during inflammation in response to infection, as well as to limit autoimmunity. PD-1 expression is induced in activated T cells, and binding of PD-1 to one of its endogenous ligands acts to inhibit T cell activation by inhibiting stimulatory kinases. PD-1 also acts to inhibit the TCR "stop signal." PD-1 is highly expressed in Treg cells (regulatory T cells) and can increase their proliferation in the presence of ligand (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0077] As used herein, the term "PD-L1" refers to programmed cell death ligand 1 (also known as CD274 and B7-H1), a ligand for PD-1. PD-L1 is found on activated T cells, B cells, myeloid cells, macrophages, and tumor cells. Although there are two endogenous ligands for PD-1, PD-L1 and PD-L2, anti-tumor therapy has focused on anti-PD-L1. The complex of PD-1 and PD-L1 inhibits the proliferation of CD8+ T cells and reduces the immune response (Topalian et al., 2012, N. Engl J. Med. 366:2443-54; Brahmer et al., 2012, N. Engl J. Med. 366:2455-65).

[0078] As used herein, the term "PD-L2" refers to programmed cell death ligand 2. PD-L2 competes with PD-L1 for binding to PD-1.

[0079] As used herein, the terms "CTLA4" and "CTLA-4" refer to cytotoxic T-lymphocyte antigen 4 (also known as CD152), a member of the immunoglobulin superfamily that is exclusively expressed in T cells. CTLA4 acts to inhibit T cell activation and has been reported to inhibit helper T cell activity and enhance regulatory T cell immunosuppressive activity. The exact mechanism of action of CTL4-A is still under investigation, but it has been suggested to inhibit T cell activation by outcompeting CD28 in binding to CD80 and CD86 on antigen-presenting cells and actively delivering inhibitor signals to T cells (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0080] As used herein, the term "LAG3" refers to lymphocyte activation gene-3 (also known as CD223).

[0081] As used herein, the term "B7-H3" refers to an immune checkpoint protein also known as CD276; B7-H3 is often overexpressed in cancer cells (e.g., some solid tumors).

[0082] As used herein, the term "B7-H4" refers to an immune checkpoint protein, also known as V-set domain-containing T-cell activation inhibitor 1, which may be present on the surface of antigen-presenting cells.

[0083] As used herein, the term "TIM3" refers to a protein also known as T-cell immunoglobulin and mucin domain-containing protein 3.

[0084] As used herein, the term "CD160" refers to a 27 kilodalton glycoprotein that in humans is encoded by the CD160 gene. Expression of CD160 is closely associated with peripheral blood NK cells and CD8 T lymphocytes that possess cytolytic effector activity.

[0085] As used herein, the term "CD244" refers to a protein also known as "cluster of differentiation 244." It is a member of the immunomodulatory receptor signaling lymphocyte activation molecule (SLAM) family.

[0086] As used herein, the term "VISTA" refers to an immune checkpoint protein, also known as V-domain Ig suppressor of T-cell activation, which is encoded by the C10orf54 gene.

[0087] As used herein, the term "TIGIT" (T cell immunoreceptor with Ig and ITIM domains) refers to an immunoreceptor protein also called WUCAM and Vstm3.

[0088] As used herein, the term "BTLA" (B- and T-lymphocyte attenuator) refers to a checkpoint protein encoded in humans by the BTLA gene, which is also called CD272 (cluster of differentiation 272).

[0089] As used herein, the term "checkpoint inhibitor" refers to any molecule, including antibodies and small molecules, that blocks the immunosuppressive pathways triggered by one or more checkpoint proteins.

[0090] The term "antibody" as used herein includes full-length antibodies as well as "antigen-binding proteins" of antibodies. The term "antigen-binding proteins" as used herein refers to one or more fragments of an antibody (e.g., PD-1) that retain the ability to specifically bind to an antigen. Examples of binding fragments encompassed within the term "antigen-binding proteins" of an antibody include (i) a Fab fragment, which is a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; (ii) a F(ab')2 fragment, which is a bivalent fragment containing two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single arm of an antibody; (v) a dAb fragment consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined using recombinant methods by a synthetic linker that allows them to be made into a single protein chain in which the VL and VH regions pair to form a monovalent molecule (known as single-chain Fv (scFv); see, e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883; and Osbourn et al. 1998, Nature Biotechnology 16:778). Such single-chain antibodies are also intended to be encompassed within the term antibody "antigen-binding protein". Any VH and VL sequence of a specific scFv can be linked to human immunoglobulin constant region cDNA or genomic sequences to generate expression vectors encoding complete IgG molecules or other isotypes. The VH and VI may also be used in the generation of Fab, Fv or other fragments of immunoglobulins, using either protein chemistry or recombinant DNA techniques. Other forms of single chain antibodies, such as diabodies, are also encompassed.Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but are forced to pair with the complementary domains of another chain to create two antigen-binding sites by using a linker that is too short to allow pairing between the two domains on the same chain (see, e.g., Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA 90:6444-6448; Poljak, RJ, et al. (1994) Structure 2:1121-1123).

[0091] The antibodies may be polyclonal or monoclonal; xenogeneic, allogeneic, or syngeneic; or modified forms thereof, such as humanized, chimeric, etc. The antibodies of the present invention specifically or substantially specifically bind to one or more checkpoint proteins. The term "monoclonal antibody" refers to a population of antibody molecules that contain only one species of antigen-binding site capable of immunoreacting with a particular epitope of an antigen, while the terms "polyclonal antibody" and "polyclonal antibody composition" refer to a population of antibody molecules that contain multiple species of antigen-binding sites capable of interacting with a particular antigen. A monoclonal antibody composition typically exhibits a single binding affinity to the particular antigen with which it immunoreacts.

[0092] As used herein, the term "antibody effective against a checkpoint protein" refers to an antibody that can bind to a checkpoint protein and antagonize the function of the checkpoint protein in suppressing an immune response. For example, an antibody against PD-1 refers to an antibody that can bind to PD-1 and block the inhibitory function of PD-1 in an immune response, for example, through blocking the interaction between PD-1 and PD-L1. In some cases, an antibody can be against two checkpoint proteins, i.e., capable of binding to two checkpoint proteins and inhibiting their function.

[0093] The term "cortisol" refers to the natural glucocorticoid hormone (also known as hydrocortisone) produced by the zona fasciculata of the adrenal gland. Cortisol has the following structure:

[0094] [ka]

[0095] The term "total cortisol" refers to cortisol bound to cortisol binding globulin (CBG or transcortin) and free cortisol (cortisol not bound to CBG). The term "free cortisol" refers to cortisol not bound to cortisol binding globulin (CBG or transcortin). As used herein, the term "cortisol" refers to total cortisol, free cortisol, and / or cortisol bound to CBG.

[0096] The term "glucocorticosteroids" ("GC") or "glucocorticoids" refers to steroid hormones that bind to the glucocorticoid receptor. Glucocorticosteroids are typically characterized as having 21 carbon atoms, an α,β-unsaturated ketone in ring A, and an α-ketol group attached to ring D. They vary in the degree of oxygenation or hydroxylation at C-11, C-17, and C-19; Rawn, "Biosynthesis and Transport of Membrane Lipids and See, Formation of Cholesterol Derivatives,” in Biochemistry, Daisy et al. (eds.), 1989, pg. 567.

[0097] As used herein, the phrase "not otherwise indicated for treatment with a glucocorticoid receptor modulator" refers to a patient who is not suffering from any condition recognized by the medical community as being effectively treatable with a glucocorticoid receptor antagonist, except for hepatic steatosis. Conditions known in the art and accepted by the medical community as being effectively treatable with a glucocorticoid receptor antagonist include psychosis associated with interferon-α treatment, psychotic major depression, dementia, stress disorder, autoimmune disease, neurological damage, and Cushing's syndrome.

[0098] The mineralocorticoid receptor (MR), also known as the type I glucocorticoid receptor (GR I), is activated by aldosterone in humans.

[0099] As used herein, the term "glucocorticoid receptor" ("GR") refers to type II GR, a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs, such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292). The glucocorticoid receptor is also referred to as the cortisol receptor. The term also includes isoforms of GR, recombinant GR, and mutant GR.

[0100] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates GC binding to GR or modulates any biological response associated with GR binding to agonist. For example, GRM acting as agonist, such as dexamethasone, increases the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRM acting as antagonist, such as mifepristone, decreases the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the article by A. Ali et al., J.Med.Chem., 2004, 47, 2441-2452.

[0101] As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to any composition or compound that modulates GC binding to GR or modulates any biological response associated with GR binding to an agonist. By "selective," the drug preferentially binds to GR rather than other nuclear receptors, such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). Such selective glucocorticoid receptor modulators have a 10-fold greater affinity (K) for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d In some more preferred embodiments, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 100-fold greater (K) than its affinity to MR, AR, or PR; both MR and PR; both MR and AR; both AR and PR; or MR, AR, and PR. d In some further embodiments, the selective glucocorticoid receptor modulator binds to GR with an affinity that is 1000-fold greater (K) than its affinity to MR, AR, or PR; both MR and PR; both MR and AR; both AR and PR; or MR, AR, and PR.d Relacorilant binds to GR with an affinity (1 / 1000th of the value of the receptor).

[0102] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits GC binding to GR or inhibits any biological response associated with the binding of GR to an agonist. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the effect of dexamethasone. TAT activity can be measured as outlined in the article by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRAs have an IC of less than 10 micromolar. 50 (half-maximal inhibitory concentration). See Example 1 of U.S. Patent No. 8,859,774, the entire contents of which are incorporated herein by reference in their entirety.

[0103] As used herein, the term "selective glucocorticoid receptor antagonist" (SGRA) refers to any composition or compound that inhibits GC binding to GR or modulates any biological response associated with GR binding to an agonist (inhibition being determined with respect to said response in the absence of said compound). By "selective" it is meant that the drug preferentially binds to GR rather than other nuclear receptors such as the progesterone receptor (PR), mineralocorticoid receptor (MR) or androgen receptor (AR). The selective glucocorticoid receptor antagonist has a 10-fold greater affinity (K) for MR, AR, or PR; both MR and PR; both MR and AR; both AR and PR; or MR, AR, and PR. d In some more preferred embodiments, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 100-fold greater (K) than its affinity for MR, AR, or PR; both MR and PR; both MR and AR; both AR and PR; or MR, AR, and PR. dIn some further embodiments, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 1000-fold greater (K) than its affinity for MR, AR, or PR; both MR and PR; both MR and AR; both AR and PR; or MR, AR, and PR. d It binds to GR with an affinity (1 / 1000th of the value of that of the receptor).

[0104] Non-steroidal GRA, SGRA, GRM, and SGRM compounds include compounds containing a fused azadecalin structure (sometimes referred to as a fused azadecalin backbone), compounds containing a heteroaryl-ketone fused azadecalin structure (sometimes referred to as a heteroaryl-ketone fused azadecalin backbone), and compounds containing an octahydro fused azadecalin structure (sometimes referred to as an octahydro fused azadecalin backbone).

[0105] Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds containing fused azadecalin structures include those described in U.S. Patent Nos. 7,928,237 and 8,461,172. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds containing heteroaryl-ketone fused azadecalin structures include those described in U.S. Patent No. 8,859,774. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds containing octahydro fused azadecalin structures include those described in U.S. Patent No. 10,047,082. All patents, patent publications, and patent applications disclosed herein are incorporated herein by reference in their entirety.

[0106] Exemplary glucocorticoid receptor antagonists that include a fused azadecalin structure include those described in U.S. Patent No. 7,928,237; and U.S. Patent No. 8,461,172. In some embodiments, the fused azadecalin GRA is the compound (R)-4-a-ethoxymethyl-1-(4-fluoro-phenyl)-6-(4-trifluoromethyl-benzenesulfonyl)-4,4a,5,6,7,8-hexahydro-1H,1,2,6-triaza-cyclopenta[b]naphthalene ("CORT108297"), which has the following structure:

[0107] [ka]

[0108] Exemplary heteroaryl-ketone fused azadecalin compounds are described in U.S. Patent No. 8,859,774; U.S. Patent No. 9,273,047; U.S. Patent No. 9,707,223; and U.S. Patent No. 9,956,216, all of which are incorporated herein by reference in their entirety. In some embodiments, the heteroaryl-ketone fused azadecalin GRA is the compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Example 18 of U.S. Patent No. 8,859,774), also known as "Relacorilant" and "CORT125134", and has the following structure:

[0109] [ka]

[0110] In some embodiments, the heteroaryl-ketone fused azadecalin GRA is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone (referred to as "CORT122928"), having the following structure:

[0111] [ka]

[0112] In some embodiments, the heteroaryl-ketone fused azadecalin GRA is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone (referred to as "CORT113176"), having the following structure:

[0113] [ka]

[0114] Exemplary glucocorticoid receptor antagonists comprising an octohydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082. In some embodiments, the octahydro-fused azadecalin compound is the compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (also called exicholant, or CORT125281), which has the following structure:

[0115] [ka]

[0116] In some cases, the non-steroidal SGRM is CORT125329, i.e., ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, having the following structure:

[0117] [ka]

[0118] As used herein, the term "composition" is intended to encompass products that include specific components, such as the above compounds, their tautomeric forms, their derivatives, their analogs, their stereoisomers, their polymorphs, their deuterated species, their pharma- ceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharma- ceutical acceptable solvates, and pharma- ceutical acceptable compositions, in specific amounts, as well as any products that are obtained directly or indirectly from the combination of the specific components in specific amounts. Such terms relating to pharmaceutical compositions are intended to encompass products that include active ingredient(s) and inactive ingredient(s) that constitute the carrier, as well as any products that result, directly or indirectly, in the combination, conjugation, or aggregation of any two or more of the components, or that result from the dissociation of one or more of the components, or from any other type of reaction or interaction of one or more of the components. Thus, the pharmaceutical compositions of the present invention are intended to encompass any compositions made by combining the compounds of the present invention and their pharma- ceutical acceptable carriers.

[0119] In some embodiments, the term "consisting essentially of" refers to a composition in a formulation in which the active ingredient is the only active ingredient indicated, but other compounds may be included for stabilization, preservation, etc. of the formulation, but are not directly involved in the therapeutic effect of the indicated active ingredient. In some embodiments, the term "consisting essentially of" can refer to a composition containing the active ingredient and a component that facilitates the release of the active ingredient. For example, the composition may contain one or more components that provide a sustained release of the active ingredient to a subject over time. In some embodiments, the term "consisting of" refers to a composition containing the active ingredient and a pharma- ceutically acceptable carrier or excipient.

[0120] As used herein, the term "nonsteroidal" and phrase "nonsteroidal backbone" in the context of GRMs and SGRMs means that the GRMs and SGRMs do not share structural homology with, or are not modifications of, cortisol, which has a steroid backbone containing 17 carbon atoms attached in four fused rings. Such compounds include synthetic mimetics and analogs of proteins, including partial peptidic, pseudopeptidic and nonpeptidic molecular entities.

[0121] Non-steroidal GRA, SGRA, GRM, and SGRM compounds include compounds that contain fused azadecalin structures (sometimes referred to as fused azadecalin backbones), compounds that contain heteroaryl ketone fused azadecalin structures (sometimes referred to as heteroaryl ketone fused azadecalin backbones), and compounds that contain octahydro fused azadecalin structures (sometimes referred to as octahydro fused azadecalin backbones). Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds that contain fused azadecalin structures include those described in U.S. Patent Nos. 7,928,237 and 8,461,172. Exemplary non-steroidal GRA, SGRA, GRM, and SGRM compounds that contain heteroaryl ketone fused azadecalin structures include those described in U.S. Patent No. 8,859,774. Exemplary nonsteroidal GRA, SGRA, GRM, and SGRM compounds containing an octahydro-fused azadecalin structure include those described in U.S. Patent No. 10,047,082. All patents, patent publications, and patent applications disclosed herein are hereby incorporated by reference in their entirety.

[0122] Substituents, when specified by these conventional chemical formulas written from left to right, equally encompass the chemically identical substituents that would result from writing the structures from right to left, e.g., -CH2O- is equivalent to -OCH2-.

[0123] "Alkyl" refers to a straight or branched chain saturated aliphatic radical having the number of carbon atoms indicated. 1-2 , C 1-3 , C 1-4 , C 1-5 , C 1-6 , C 1-7 , C 1-8 , C 1-9 , C 1-10 , C 2-3 , C 2-4 , C 2-5 , C 2-6 , C 3-4 , C 3-5 , C 3-6 , C 4-5, C 4-6 , and C 5-6 For example, C 1-6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, and hexyl.

[0124] "Alkoxy" refers to an alkyl group having an oxygen atom connecting the alkyl group to the point of attachment: alkyl-O-. With respect to said alkyl group, an alkoxy group is one having a C 1-6 Alkoxy groups can have any suitable number of carbon atoms, such as, for example, methoxy, ethoxy, propoxy, iso-propoxy, butoxy, 2-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy, hexoxy, and the like.

[0125] "Halogen" refers to fluorine, chlorine, bromine and iodine.

[0126] "Haloalkyl" refers to an alkyl as defined above in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to the alkyl group, the haloalkyl group includes C 1 -C 2 -C 3 -C 4 -C 5 -C 6 -C 7 -C 8 -C 9 -C 10 -C 11 -C 12 -C 13 -C 14 -C 15 -C 16 -C 17 -C 18 -C 19 -C 20 -C 21 -C 22 -C 23 -C 24 -C 25 -C 36 -C 17 -C 26 -C 37 -C 18 -C 27 -C 38 -C 39 -C 40 -C 50 -C 28 -C 39 -C 41 -C 51 -C 29 -C 39 -C 42 -C 52 -C 39 -C 53 1-6 The group may have any suitable number of carbon atoms, such as

[0127] The term "perfluoro" can be used to define a compound or radical in which all hydrogens have been replaced by fluorines. For example, perfluoromethane includes 1,1,1-trifluoromethyl.

[0128] "Haloalkoxy" refers to an alkoxy group in which some or all of the hydrogen atoms are replaced by halogen atoms. With respect to the alkyl groups described above, the haloalkoxy group is 1-6The alkoxy group may have any suitable number of carbon atoms, such as 1, 2, 3, or more than 1. The alkoxy group may be substituted by one, two, three, or more halogens. When all hydrogens are replaced by halogens, such as fluorine, the compound is persubstituted, such as perfluorinated. Haloalkoxy includes, but is not limited to, trifluoromethoxy, 2,2,2,-trifluoroethoxy, and perfluoroethoxy.

[0129] "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic, fused bicyclic, or bridged polycyclic ring assembly containing 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl is any of the groups represented by C 3-6 , C 4-6 , C 5-6 , C 3-8 , C 4-8 , C 5-8 , C 6-8 , C 3-9 , C 3-10 , C 3-11 , and C 3-12 Cycloalkyl groups may have any number of carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Saturated bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, [2.2.2]bicyclooctane, decahydronaphthalene, and adamantane. Cycloalkyl groups may be partially unsaturated, with one or more double or triple bonds in the ring. Representative cycloalkyl groups that are partially unsaturated include, but are not limited to, cyclobutene, cyclopentene, cyclohexene, cyclohexadiene (1,3- and 1,4-isomers), cycloheptene, cycloheptadiene, cyclooctene, cyclooctadiene (1,3-, 1,4-, and 1,5-isomers), norbornene, and norbornadiene. Cycloalkyl groups may be saturated monocyclic C 3-8 When cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. 3-6When it is cycloalkyl, exemplary groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0130] "Heterocycloalkyl" refers to a saturated ring system having 3-12 ring members and 1-4 heteroatoms of N, O, and S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may also be oxidized, such as, but not limited to, -S(O)- and -S(O)2-. Heterocycloalkyl groups may contain any number of ring atoms, such as 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. The heterocycloalkyl groups may contain any suitable number of heteroatoms, such as 1, 2, 3, or 4, or 1-2, 1-3, 1-4, 2-3, 2-4, or 3-4. The heterocycloalkyl groups may include groups such as aziridine, azetidine, pyrrolidine, piperazine, azepane, azocane, quinuclidine, pyrazoline, imidazolidine, piperazine (1,2-, 1,3- and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The heterocycloalkyl groups may also be fused with aromatic or non-aromatic ring systems to form members including, but not limited to, indoline.

[0131] When the heterocycloalkyl contains 3 to 8 ring members and 1 to 3 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperazine, tetrahydrofuran, oxane, tetrahydrothiophene, thiane, pyrazoline, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, morpholine, thiomorpholine, dioxane, and dithiane. The heterocycloalkyl may form a ring having 5 to 6 ring members and 1 to 2 heteroatoms, representative members include, but are not limited to, pyrrolidine, piperazine, tetrahydrofuran, tetrahydrothiophene, pyrazoline, imidazolidine, piperazine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, and morpholine.

[0132] "Aryl" refers to an aromatic ring system having any suitable number of ring atoms and any suitable number of rings. Aryl groups can contain any suitable number of ring atoms, such as 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 ring atoms, and 6-10, 6-12, or 6-14 ring members. Aryl groups can be monocyclic, fused to form bicyclic or tricyclic groups, or linked by bonds to form biaryl groups. Representative aryl groups include phenyl, naphthyl, and biphenyl. Other aryl groups include benzyl, which has a methylene linking group. Some aryl groups have 6-12 ring members, such as phenyl, naphthyl, or biphenyl. Other aryl groups have 6-10 ring members, such as phenyl or naphthyl. Some other aryl groups have 6 ring members, such as phenyl. Aryl groups can be substituted or unsubstituted.

[0133] "Heteroaryl" refers to a monocyclic, fused bicyclic, or tricyclic aromatic ring assembly containing 5-16 ring atoms, of which 1-5 are heteroatoms such as N, O, or S. Additional heteroatoms may also be useful, including but not limited to B, Al, Si, and P. The heteroatoms may also be oxidized, such as, but not limited to, N-oxide, -S(O)-, and -S(O)2-. Heteroaryl groups may contain any number of ring atoms, such as 3-6, 4-6, 5-6, 3-8, 4-8, 5-8, 6-8, 3-9, 3-10, 3-11, or 3-12 ring members. The heteroaryl groups may contain any suitable number of heteroatoms, such as 1, 2, 3, 4, or 5; or 1-2, 1-3, 1-4, 1-5, 2-3, 2-4, 2-5, 3-4, or 3-5. Heteroaryl groups can have 5-8 ring members and 1-4 heteroatoms, or 5-8 ring members and 1-3 heteroatoms, or 5-6 ring members and 1-4 heteroatoms, or 5-6 ring members and 1-3 heteroatoms. The heteroaryl groups can include groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused with aromatic ring systems such as phenyl rings to form members, including but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophenes, and benzofurans. Other heteroaryl groups contain heteroaryl rings linked by bonds, such as bipyridine.Heteroaryl groups can be substituted or unsubstituted.

[0134] Said heteroaryl group can be linked through any position of its ring.For example, pyrrole includes 1-, 2- and 3-pyrrole;pyridine includes 2-, 3- and 4-pyridine;imidazole includes 1-, 2-, 4- and 5-imidazole;pyrazole includes 1-, 3-, 4- and 5-pyrazole;triazole includes 1-, 4- and 5-triazole;tetrazole includes 1- and 5-tetrazole;pyrimidine includes 2-, 4-, 5- and 6-pyrimidine;pyridazine includes 3- and 4-pyridazine;1,2,3-triazine includes 4- and 5-triazine;1,2,4-triazine includes 3-, 5- and 6-triazine;1,3,5-triazine includes 2-triazine;thiophene includes 2- and 3-thiophene;furan includes 2- and 3-furan; thiazoles include 2-, 4- and 5-thiazoles; isothiazoles include 3-, 4- and 5-isothiazoles; oxazoles include 2-, 4- and 5-oxazoles; isoxazoles include 3-, 4- and 5-isoxazoles; indoles include 1-, 2- and 3-indoles; isoindoles include 1- and 2-isoindole; quinolines include 2-, 3- and 4-quinolines; isoquinolines include 1-, 3- and 4-isoquinolines; quinazolines include 2- and 4-quinoazolines; cinnolines include 3- and 4-cinnolines; benzothiophenes include 2- and 3-benzothiophenes; and benzofurans include 2- and 3-benzofurans.

[0135] Some heteroaryl groups include those having 5 to 10 ring members and 1 to 3 ring atoms containing N, O, or S, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4-, and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, isoxazole, indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include those having 5 to 8 ring members and 1 to 3 heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. Some other heteroaryl groups include those having 9 to 12 ring members and 1 to 3 heteroatoms, such as indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, cinnoline, benzothiophene, benzofuran, and bipyridine. Still other heteroaryl groups include those having 5-6 ring members and 1-2 ring heteroatoms including N, O or S, such as pyrrole, pyridine, imidazole, pyrazole, pyrazine, pyrimidine, pyridazine, thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole.

[0136] Some heteroaryl groups contain 5-10 ring members and only nitrogen heteroatoms, such as pyrrole, pyridine, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), indole, isoindole, quinoline, isoquinoline, quinoxaline, quinazoline, phthalazine, and cinnoline. Other heteroaryl groups contain 5-10 ring members and only oxygen heteroatoms, such as furan and benzofuran. Some other heteroaryl groups contain 5-10 ring members and only sulfur heteroatoms, such as thiophene and benzothiophene. Still other heteroaryl groups contain 5 to 10 ring members and at least two heteroatoms and include, for example, imidazole, pyrazole, triazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiazole, isothiazole, oxazole, isoxazole, quinoxaline, quinazoline, phthalazine, and cinnoline.

[0137] "Heteroatom" refers to O, S, or N.

[0138] "Salt" refers to the acid or base salt of the compound used in the method of the present invention. Illustrative examples of pharmaceutically acceptable salts are mineral acid (hydrochloric acid, hydrobromic acid, phosphoric acid, etc.) salts, organic acid (acetic acid, propionic acid, glutamic acid, citric acid, etc.) salts, and quaternary ammonium (methyl iodide, ethyl iodide, etc.) salts. It is understood that said pharmaceutically acceptable salts are non-toxic. Further information on suitable pharmaceutically acceptable salts can be found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, which is incorporated herein by reference.

[0139] "Isomers" refer to compounds that have the same chemical formula but are structurally distinguishable.

[0140] "Tautomer" refers to one of two or more structural isomers that exist in equilibrium and are readily converted from one form to another.

[0141] The description of the compounds of the present invention is limited by the principles of chemical bonding known to those skilled in the art. Thus, when groups may be substituted with one or more of a number of substituents, such substitutions are selected to be compatible with the principles of chemical bonding and to produce compounds that are not inherently unstable and / or that would be known to those skilled in the art to be susceptible to instability under ambient conditions, such as aqueous, neutral, or physiological conditions.

[0142] "Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that aid in the administration of and absorption by a subject of an active agent, and may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, antioxidants, isotonic and absorption retardants, and the like, that are compatible with drug administration. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavorings, and pigments, and the like. Those skilled in the art will recognize that other pharmaceutical excipients are useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. The use of any conventional media or agent in the compositions described above is contemplated, except insofar as they are incompatible with such active compounds. Additional active compounds may be incorporated into the compositions described above. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0143] In some embodiments, the methods disclosed herein include combination therapy comprising administering a GRM comprising a fused azadecalin structure; a GRM comprising a heteroaryl ketone fused azadecalin structure; or a GRM comprising an octahydro fused azadecalin structure.

[0144] Exemplary GRMs containing condensed azadecalin structures include those described in U.S. Patent Nos. 7,928,237; and 8,461,172, which may be prepared as disclosed herein, and are incorporated herein in their entirety. Such exemplary GRMs may be SGRMs. In some cases, the GRMs containing condensed azadecalin structures have the following structure, or a salt or isomer thereof:

[0145] [ka]

[0146] During the ceremony, L 1 and L 2 is a member independently selected from a bond and unsubstituted alkylene; R 1 is unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted heterocycloalkyl, -OR 1A , N.R. 1C R 1D , -C(O)NR 1C R 1D , and -C(O)OR 1A where R 1A is a member selected from hydrogen, unsubstituted alkyl, and unsubstituted heteroalkyl; R 1C and R 1D are members independently selected from unsubstituted alkyl and unsubstituted heteroalkyl, which may be joined together to form an unsubstituted ring with the nitrogen to which they are attached, said ring optionally containing an additional ring nitrogen; R 2 has the formula:

[0147] [ka]

[0148] During the ceremony, R 2Gis a member selected from hydrogen, halogen, unsubstituted alkyl, unsubstituted heteroalkyl, unsubstituted cycloalkyl, unsubstituted heterocycloalkyl, -CN, and -CF3; J is phenyl; t is an integer from 0 to 5; X is -S(O2)-; R 5 is 1 to 5 R 5A phenyl optionally substituted with a group; R 5A is hydrogen, halogen, -OR 5A1 , S(O2)NR 5A2 R 5A3 , -CN, and unsubstituted alkyl; R 5A1 is a member selected from hydrogen and unsubstituted alkyl; R 5A2 and R 5A3 is a member independently selected from hydrogen and unsubstituted alkyl.

[0149] In some cases, the fused azadecalin compound is

[0150] [ka]

[0151] It is.

[0152] Exemplary GRMs containing heteroaryl ketone-fused azadecalin structures include those described in U.S. Pat. No. 8,859,774, which may be prepared as disclosed herein, and which is incorporated herein in its entirety. Such exemplary GRMs may be SGRMs. In some cases, the GRMs containing heteroaryl ketone-fused azadecalin structures have the following structure, or a salt or isomer thereof:

[0153] [ka]

[0154] During the ceremony, R 1 is a heteroaryl ring having 5 to 6 ring members and having 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, each heteroaryl ring being independently R 1a may be substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, N-oxide, C 3-8 Cycloalkyl and C 3-8 heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein said heterocycloalkyl ring and heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl and C 3-8 heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of 1 to 4 R 2c may be substituted with a group; Or, two R attached to the same carbon 2 groups combine to form an oxo group (=O); Or, two R 2 groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2d may be substituted with a group; R 2a and R 2b are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 2c are each independently hydrogen, halogen, hydroxy, or C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, and NR 2a R 2b selected from the group consisting of; R 2d are each independently hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Each has 1 to 4 R 3a phenyl and pyridyl, each of which may be substituted with an alkyl group; R 3a are each independently hydrogen, halogen, or C 1-6 haloalkyl; The subscript n is an integer from 0 to 3.

[0155] In some cases, the non-steroidal SGRM is CORT125134, i.e., (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following structure:

[0156] [ka]

[0157] Exemplary GRMs containing an octahydro-fused azadecalin structure include those described in U.S. Pat. No. 10,047,082 and may be prepared as described herein, the disclosure of which is incorporated herein in its entirety. Such exemplary GRMs may be SGRMs. In some cases, the GRMs containing the octahydro-fused azadecalin structure have the following structure, or a salt or isomer thereof:

[0158] [ka]

[0159] During the ceremony, R 1 is a heteroaryl ring having 5-6 ring members and 1-4 heteroatoms each independently selected from the group consisting of N, O, and S, each heteroaryl ring being independently selected from R 1a may be substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of aryl and heteroaryl rings having 5-6 ring members and 1-4 heteroatoms, each independently selected from the group consisting of N, O, and S; R 2 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 cycloalkyl, and C having 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S 3-8 heterocycloalkyl; Alternatively, two R on adjacent ring atoms 2 groups are combined to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, said heterocycloalkyl ring being comprised of 1-3 R 2c may be substituted with a group; R 2a , R 2b , and R 2c are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 3a are each independently a halogen; The subscript n is an integer from 0 to 3.

[0160] In some embodiments, the octahydro-fused azadecalin compound has the following structure, or a salt or isomer thereof:

[0161] [ka]

[0162] During the ceremony, R 1 are each independently R 1a is selected from the group consisting of pyridine and thiazole, optionally substituted with 1 to 4 groups selected from R1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; R 2 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 selected from the group consisting of haloalkyl, and -CN; R 3a is F; The subscript n is an integer from 0 to 3.

[0163] In some cases, the non-steroidal SGRM is exicholant (also known as CORT125281), i.e., ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, having the following structure:

[0164] [ka]

[0165] In some cases, the non-steroidal SGRM is CORT125329, i.e., ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, having the following structure: [ka]

[0166] (Identification of selective glucocorticoid receptor modulators (SGRMs)) To determine whether a test compound is an SGRM, the compound is first subjected to an assay that measures its ability to bind to the GR and inhibit GR-mediated activity, and determines whether the compound is a glucocorticoid receptor modulator. If the compound is confirmed to be a glucocorticoid receptor modulator, it is then subjected to a selectivity test that determines whether the compound can specifically bind to GR compared to non-GR proteins such as estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor. In some embodiments, the SGRM binds to GR with substantially higher affinity than non-GR proteins, for example, at least 10-fold higher affinity. The SGRM may show 100-fold, 1000-fold, or more selectivity for binding to GR compared to binding to non-GR proteins.

[0167] join The ability of a test compound to bind to the glucocorticoid receptor can be measured using various assays, for example, by screening the ability of the test compound to compete with a glucocorticoid receptor ligand, such as dexamethasone, for binding to the glucocorticoid receptor. Those skilled in the art will recognize that there are numerous ways to perform such competitive binding assays. In some embodiments, the glucocorticoid receptor is pre-incubated with a labeled glucocorticoid receptor ligand and then contacted with a test compound. This type of competitive binding assay may also be referred to herein as a binding displacement assay. A decrease in the amount of labeled ligand that binds to the glucocorticoid receptor indicates that the test compound binds to the glucocorticoid receptor. In some cases, the labeled ligand is a fluorescently labeled compound (e.g., a fluorescently labeled steroid or steroid analog). Alternatively, the binding of a test compound to the glucocorticoid receptor can be measured directly by a labeled test compound. This latter type of assay is referred to as a direct binding assay.

[0168] Both direct and competitive binding assays can be used in a variety of different formats. The formats can be similar to those used in immunoassays and receptor binding assays. For a description of different formats for binding assays, including competitive and direct binding assays, see Basic and Clinical Immunology 7th Edition (D. Stites and See, A. Terr, ed.) 1991; Enzyme Immunoassay, E.T. Maggio, ed., CRC Press, Boca Raton, Florida (1980); and "Practice and Theory of Enzyme Immunoassays", P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers BV Amsterdam (1985), each of which is incorporated herein by reference.

[0169] In a solid-phase competitive binding assay, for example, a sample compound may compete with a labeled analyte for specific binding sites in a binding agent bound to a solid surface. In this type of format, the labeled analyte may be a glucocorticoid receptor ligand and the binding agent may be a glucocorticoid receptor bound to a solid phase. Alternatively, the labeled analyte may be a labeled glucocorticoid receptor and the binding agent may be a solid phase glucocorticoid receptor ligand. The concentration of labeled analyte bound to the capture agent is inversely proportional to the ability of the test compound to compete in the binding assay.

[0170] Alternatively, the competitive binding assay may be performed in liquid phase, and any of a variety of techniques known in the art may be used to separate bound from unbound labeled protein. For example, several procedures have been developed to distinguish between bound and excess bound ligand or between bound and excess unbound test compound. These include identification of bound complexes by precipitation in sucrose gradients, gel electrophoresis, or gel isoelectric focusing; precipitation of receptor-ligand complexes with protamine sulfate or adsorption on hydroxyapatite; and removal of unbound compounds or ligands by adsorption on dextran-coated charcoal (DCC) or binding to immobilized antibodies. After separation, the amount of bound ligand or test compound is determined.

[0171] Alternatively, homogeneous binding assays may be performed that do not require a separation step. For example, the label on the glucocorticoid receptor may be modified by the binding of the glucocorticoid receptor to its ligand or test compound. This modification on the labeled glucocorticoid receptor results in a decrease or increase in the signal emitted by the label, such that measurement of the label at the end of the binding assay allows detection or quantification of the glucocorticoid receptor in the bound state. A wide variety of labels may be used. Components may be labeled by any one of several methods. Useful radioactive labels include: 3 H, 125 I, 35 S, 14 C, or 32 P. Useful non-radioactive labels include those incorporating fluorophores, chemiluminescent agents, phosphorescent agents, electrochemiluminescent agents, and the like. Fluorescent agents are particularly useful in analytical techniques used to detect shifts in protein structure, such as fluorescence anisotropy and / or fluorescence polarization. The choice of label depends on the sensitivity required, ease of conjugation with the compound, stability requirements, and available instrumentation. For a review of various labeling or signal generating systems that may be used, see U.S. Pat. No. 4,391,904, the contents of which are incorporated herein by reference for all purposes. The label may be directly or indirectly coupled to the desired components of the assay according to methods well known in the art. In some cases, a test compound is contacted with the GR in the presence of a fluorescently labeled ligand (e.g., a steroid or steroid analog) with known affinity for GR, and the amount of bound and free labeled ligand is estimated by measuring the fluorescence polarization of the labeled ligand.

[0172] Activity 1) HepG2 tyrosine aminotransferase (TAT) assay Compounds that demonstrate the desired binding affinity to GR are tested for their activity in inhibiting GR-mediated activity. The compounds are typically subjected to a tyrosine aminotransferase assay (TAT assay) to assess the ability of the test compound to inhibit the induction of tyrosine aminotransferase activity by dexamethasone. See Example 1. GR modulators that are suitable for the methods disclosed herein have an IC of less than 10 micromolar. 50 (half-maximal inhibitory concentration). Other assays, including but not limited to those described below, can also be developed to confirm the GR modulating activity of the compounds.

[0173] 2) Cell-based assays Cell-based assays on whole cells or cell fractions containing glucocorticoid receptors can also be used to assay for binding of test compounds or modulation of the activity of the glucocorticoid receptor.Exemplary cell types that can be used by the methods of the present invention include any mammalian cell, including, for example, leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes such as T cells and B cells, leukemia cells, Burkitt's lymphoma cells, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiac cells, muscle cells, breast tumor cells, ovarian cancer carcinomas, cervical carcinomas, glioblastomas, liver cells, kidney cells, and neuronal cells, as well as fungal cells, including yeast.Cells can be primary cells or tumor cells or other types of immortal cell lines.Of course, the glucocorticoid receptor can be expressed in cells that do not express an endogenous version of the glucocorticoid receptor.

[0174] In some cases, fragments of the glucocorticoid receptor as well as protein fusions can be used for screening.When a molecule that competes for binding with glucocorticoid receptor ligand is desired, the GR fragment used is a fragment that allows binding of the ligand (e.g., dexamethasone).Alternatively, any fragment of GR can be used as a target to identify molecules that bind the glucocorticoid receptor.Glucocorticoid receptor fragments can include, for example, any fragment of at least 20, 30, 40, 50 amino acids, up to a protein that contains all but one amino acid of the glucocorticoid receptor.

[0175] In some embodiments, the reduction of signal transduction triggered by glucocorticoid receptor activation is used to identify glucocorticoid receptor modulators. The glucocorticoid receptor signal transduction activity can be determined in many ways. For example, downstream molecular events can be monitored to measure signal transduction activity. Downstream events include those activities or symptoms that occur as a result of glucocorticoid receptor stimulation. Exemplary downstream events useful in functional evaluation of transcription activation and antagonism in unaltered cells include upregulation of a number of glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase). In addition, certain cell types that are susceptible to GR activation may be used, such as osteocalcin expression in primary hepatocytes that show glucocorticoid-mediated upregulation of osteoblasts; PEPCK and glucose-6-phosphate (G-6-Pase) that are downregulated by glucocorticoids. GRE-mediated gene expression has also been demonstrated in transfected cell lines using well-known GRE regulatory sequences (e.g., mouse mammary tumor virus promoter (MMTV) transfected upstream of a reporter gene construct). Examples of useful reporter gene constructs include luciferase (luc), alkaline phosphatase (ALP) and chloramphenicol acetyltransferase (CAT). Functional evaluation of transcriptional repression can be performed in cell lines such as monocytes or human dermal fibroblasts. Useful functional assays include those measuring IL-1beta-stimulated IL-6 expression; downregulation of collagenase, cyclooxygenase-2 and various chemokines (MCP-1, RANTES); LPS-stimulated cytokine release, e.g., TNFα; or expression of genes regulated by NFkB or AP-1 transcription factors in transfected cell lines.

[0176] Compounds tested in whole cell assays can also be tested in cytotoxicity assays. Cytotoxicity assays are used to determine the extent to which observed effects are due to non-glucocorticoid receptor binding cellular effects. In some exemplary embodiments, the cytotoxicity assays include contacting constitutively active cells with the test compound. Any reduction in cellular activity indicates a cytotoxic effect.

[0177] 3) Further Assays Further examples of the many assays that can be used to identify the composition that is utilized in the method of the present invention include assays based on glucocorticoid activity in vivo.For example, the assay that evaluates the ability of putative GR modulator to inhibit the incorporation of 3H-thymidine into DNA in cells stimulated by glucocorticoids can be used.Alternatively, the putative GR modulator can compete with 3H-dexamethasone for binding to hepatoma tissue culture GR (see, for example, Choi, et al., Steroids 57:313-318, 1992).As another example, the ability of putative GR modulator to block the nuclear binding of 3H-dexamethasone-GR complex can be used (Alexandrova et al., J.Steroid Biochem.Mol.Biol.41:723-725, 1992). To further identify putative GR modulators, kinetic assays that utilize receptor-binding kinetics to distinguish between glucocorticoid agonists and regulators may be used (described in Jones, Biochem J. 204:721-729, 1982).

[0178] In another illustrative example, the assay described by Daune, Molec. Pharm. 13:948-955, 1977; and in U.S. Patent No. 4,386,085, can be used to identify anti-glucocorticoid activity. Briefly, thymocytes from adrenalectomized rats are incubated with varying concentrations of the test compound (the putative GR modulator) in nutrient medium containing dexamethasone. 3 H-uridine is added to the cell cultures, which are further incubated, and the extent of incorporation of the radiolabel into the polynucleotides is measured. 3 GR modulators counter this effect by decreasing the amount of H-uridine.

[0179] Selectivity The GR modulators selected above are then subjected to a selectivity assay to determine whether they are SGRMs. Typically, the selectivity assay involves testing the compounds that bind to the glucocorticoid receptor in vitro for the degree of binding to the non-glucocorticoid receptor protein. The selectivity assay can be performed in vitro or in a cell-based system as described above. Binding can be tested against any suitable non-glucocorticoid receptor protein, including antibodies, receptors, enzymes, and the like. In some exemplary embodiments, such non-glucocorticoid receptor binding proteins are cell surface receptors or nuclear receptors. In other exemplary embodiments, the non-glucocorticoid receptor proteins are steroid receptors, such as estrogen receptors, progesterone receptors, androgen receptors, or mineralocorticoid receptors.

[0180] The selectivity of an antagonist for GR over MR can be measured using various assays known to those skilled in the art. For example, a specific antagonist can be identified by measuring the ability of the antagonist to bind to GR compared to MR (see, e.g., U.S. Pat. Nos. 5,606,021; 5,696,127; 5,215,916; and 5,071,773). Such analysis can be performed either using a direct binding assay or by evaluating competitive binding to purified GR or MR in the presence of a known ligand. In an exemplary assay, cells stably expressing high levels of glucocorticoid receptor or mineralocorticoid receptor (see, e.g., U.S. Pat. No. 5,606,021) are used as a source of purified receptor. The affinity of the ligand to the receptor is then measured directly. Those GR modulators that exhibit at least a 10-fold, 100-fold, and often 1000-fold greater affinity for GR compared to their affinity for MR are then selected for use in the methods of the invention.

[0181] The selectivity assay may also include assaying for the ability to inhibit GR-mediated activity but not MR-mediated activity. One way to identify such GR-specific regulators is to use transfection assays to evaluate the ability of antagonists to prevent the activation of a reporter construct (see, for example, Bocquel et al, J.Steroid Biochem Molec.Biol.45:205-215,1993; U.S. Patent Nos. 5,606,021 and 5,929,058). In an exemplary transfection assay, an expression plasmid encoding the receptor and a reporter plasmid containing a reporter gene linked to a receptor-specific regulatory element are co-transfected into a suitable receptor-negative host cell. The transfected host cell is then cultured in the presence and absence of a hormone, such as cortisol or its analog, to activate the hormone-responsive promoter / enhancer element of the reporter plasmid. The transfected and cultured host cells are then monitored for induction (i.e., presence) of the product of the reporter gene sequence. Finally, the expression and / or steroid binding capacity of the hormone receptor protein (encoded by the receptor DNA sequence in the expression plasmid and produced in the transfected and cultured host cells) is measured by determining the activity of the reporter gene in the presence and absence of an antagonist. The antagonist activity of a compound can be determined in comparison to known antagonists of the GR and MR receptors (see, for example, U.S. Pat. No. 5,696,127). Efficacy is then reported as the percent maximum response observed for each compound compared to a reference antagonist compound. GR modulators that show at least 100-fold, and often 1000-fold or more activity against GR compared to MR, PR, or AR are then selected for use in the methods disclosed herein.

[0182] Cancer Diagnosis Cancer is characterized by the uncontrolled growth and / or spread of abnormal cells. Typically, a biopsy is taken and cells or tissue from the biopsy are examined under a microscope to confirm the suspected condition. In some cases, further tests need to be performed on the cells' proteins, DNA, and RNA to verify the diagnosis.

[0183] Identifying checkpoint inhibitor-sensitive cancers In some embodiments of the present invention, the method is used to treat patients with at least one checkpoint inhibitor-sensitive cancer. A checkpoint inhibitor-sensitive cancer is one that is responsive to a checkpoint inhibitor, i.e., administration of one or more checkpoint inhibitors can reduce tumor burden or achieve beneficial or desired clinical results related to cancer improvement. For example, administration of the checkpoint inhibitor can cause one or more of the following: reduction in cancer cell count; reduction in tumor size; inhibition (i.e., slowing down to a certain extent and / or stopping) of cancer cell invasion into surrounding organs; inhibition (i.e., slowing down to a certain extent and / or stopping) of tumor metastasis; inhibition of tumor growth to a certain extent; and / or alleviation to a certain extent of one or more symptoms associated with the disorder; reduction in tumor size; reduction in symptoms resulting from the disease; improvement in the quality of life of those suffering from the disease; reduction in the dose of other medicines required to treat the disease; delay in the progression of the disease; and / or prolongation of the patient's survival.

[0184] Checkpoint inhibitor-sensitive tumors often have high expression of ligands, such as PD-L1 or B7, which bind to checkpoint proteins, PD-1 or CTLA-4, respectively. These interactions suppress immune responses against tumor cells. As disclosed herein, administration of a GRM or SGRM is believed to induce checkpoint inhibitor sensitivity in tumors that are otherwise relatively insensitive to checkpoint inhibitors, or to improve checkpoint inhibitor sensitivity in tumors. Non-limiting examples of checkpoint inhibitor-sensitive tumors and tumors that can be induced to become checkpoint inhibitor sensitive include lung cancer, liver cancer, ovarian cancer, cervical cancer, skin cancer, bladder cancer, colon cancer, breast cancer, glioma, renal carcinoma, gastric cancer, esophageal cancer, oral squamous cell carcinoma, head / neck cancer, melanoma, sarcoma, renal cell tumor, hepatocellular tumor, glioblastoma, neuroendocrine tumor, bladder cancer, pancreatic cancer, gallbladder cancer, gastric cancer, prostate cancer, endometrial cancer, thyroid cancer, and mesothelioma.

[0185] iii. Identification of GR expression In some embodiments, the checkpoint inhibitor-sensitive cancer is a GR + Cancer. GR expression in cancer cells can be examined by using one or more of the conventional biochemical analyses. In some embodiments, GR expression is determined by detecting GR transcription expression using methods such as microarray and RT-PCR. In other embodiments, GR expression is determined by detecting protein expression using methods such as Western blot analysis and immunohistochemical staining. In still other embodiments, the GR expression is determined using a combination of these methods.

[0186] In some preferred embodiments, immunohistochemical staining is performed and the H-score method is used to quantify the expression of GR in cancer tissue. In one example assay, formalin-fixed and paraffin-embedded tumor tissue sections are deparaffinized and treated with an antigen retrieval solution to make the glucocorticoid receptor easily accessible to the anti-GR antibody. The anti-GR antibody is then incubated with the tissue section, and the antibody that binds to GR in the tissue section is detected by adding a horseradish peroxidase (HRP)-conjugated secondary antibody that recognizes the anti-GR antibody. The HRP in this secondary antibody conjugate catalyzes a colorimetric reaction, which upon contact with an appropriate substrate, produces staining where GR is present. In one approach, the intensity levels of GR staining are represented by 0 for negative staining, 1+ for weak staining, 2+ for moderate staining, and 3+ for strong hypochromic staining. See www.ihcworld.com / ihc_scoring.htm. The intensity levels are then calculated based on the GR intensity levels of each intensity level. + The percentage of cells is multiplied and the results for all intensity levels are summed to produce an H-score between 0 and 300. In one embodiment, cancer types with an H-score above a predefined threshold are classified as GR + In some preferred embodiments, the threshold is 150. In some other embodiments, the GR + Cancers are those with at least 10% of tumor cells that exhibit GR staining at any intensity. Using an H-score threshold of 150, many cancer types exhibit GR staining. + See Table 1 below. The majority of these cancer types are checkpoint inhibitor sensitive cancers as shown by published clinical trial results. See website "clinicaltrials.gov."

[0187] (Checkpoint inhibitors) The methods disclosed herein use at least one SGRM in combination with at least one checkpoint inhibitor to treat cancer. In some embodiments, the checkpoint inhibitor is an antibody ("CIA") against at least one checkpoint protein. In some embodiments, the checkpoint inhibitor is a small molecule non-protein compound ("CIC") that blocks an immunosuppressive pathway triggered by one or more checkpoint proteins.

[0188] i. Checkpoint Inhibitor Antibodies ("CIAs") In one embodiment, the method of treating cancer comprises administering an SGRM in combination with a checkpoint inhibitor antibody. Such an antibody can block the immunosuppressive activity of the checkpoint protein. A number of such antibodies, for example, antibodies against PD-1, CTLA4, and PD-L1, have already been shown to be effective in treating cancer.

[0189] Anti-PD-1 antibodies have been used to treat melanoma, non-small cell lung cancer, bladder cancer, prostate cancer, colon cancer, head and neck cancer, triple-negative breast cancer, leukemia, lymphoma, and renal cell carcinoma. Exemplary anti-PD-1 antibodies include lambrolizumab (MK-3475, MERCK), nivolumab (BMS-936558, BRISTOL-MYERS SQUIBB), AMP-224 (MERCK), and pidilizumab (CT-011, CURETECH LTD.).

[0190] Anti-PD-L1 antibodies have been used to treat non-small cell lung cancer, melanoma, colorectal cancer, renal cell carcinoma, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, and hematological malignancies. Exemplary anti-PD-L1 antibodies include MDX-1105 (MEDAREX), MEDI4736 (MEDImmune), MPDL3280A (GENENTECH), and BMS-936559 (BRISTOL-MYERS SQUIBB).

[0191] Anti-CTLA4 antibodies have been used in clinical trials for the treatment of melanoma, prostate cancer, small cell lung cancer, and non-small cell lung cancer. A notable feature of anti-CTLA4A is the kinetics of anti-tumor effects, which require a lag period of up to 6 months for physiological response after initial treatment. In some cases, tumors may actually increase in size after treatment begins before shrinkage is observed (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Exemplary anti-CTLA4CIA include ipilimumab (Bristol-Myers Squibb) and tremelimumab (PFIZER).

[0192] CIAs against other checkpoint proteins, such as LAG3, B7-H3, B7-H4 and TIM3, can also be used in combination with the SGRMs disclosed herein to treat cancer.

[0193] The CIA used in the present disclosure may be a combination of different CIAs, especially when the target checkpoint proteins, e.g., PD-1 and CTLA4, suppress the immune response through different signaling pathways. A combination of multiple CIAs against any of the checkpoint proteins or a single CIA against both checkpoint proteins may provide an improved immune response.

[0194] (CIA Creation) CIA can be expressed using methods well known in the art. See, for example, Kohler and Milstein, Nature 256:495 (1975), and Coligan et al. (eds.), CURRENT PROTOCOLS IN IMMUNOLOGY, VOL.1, pages 2.5.1-2.6.7 (John Wiley & Sons 1991). Monoclonal antibodies can be obtained by injecting a mouse with an antigen, such as a checkpoint protein or a composition containing an epitope thereof, removing the spleen to obtain B lymphocytes, fusing the B lymphocytes with myeloma cells to produce hybridomas, cloning the hybridomas, selecting positive clones that produce antibodies to the antigen, culturing the clones that produce antibodies to the antigen, and isolating the antibodies from the hybridoma culture.

[0195] The monoclonal antibodies produced can be isolated and purified from the hybridoma cultures by a variety of established techniques. Such isolation techniques include affinity chromatography with protein-A sepharose, size-exclusion chromatography, and ion-exchange chromatography. See, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3. See also Baines et al., "Purification of Immunoglobulin G (IgG)" in METHODS IN MOLECULAR BIOLOGY, VOL. 10, pages 79-104 (The Humana Press, Inc. 1992). After initial development of antibodies to checkpoint proteins, the antibodies can be sequenced and then prepared by recombinant techniques. Humanization and chimerization of mouse antibodies and antibody fragments are well known to those skilled in the art. See, for example, Leung et al. al. Hybridoma 13:469 (1994); U.S. Patent Application Publication No. 20140099254A1.

[0196] Human antibodies can be produced using transgenic mice that have been genetically engineered to produce specific human antibodies in response to challenge with checkpoint proteins. See Green et al., Nature Genet. 7:13 (1994); Lonberg et al., Nature 368:856 (1994). Human antibodies against checkpoint proteins can also be constructed by genetic or chromosomal transfection methods, phage display techniques, or in vitro activated B cells. See, e.g., McCafferty et al., 1990, Nature 348:552-553; U.S. Patent Nos. 5,567,610 and 5,229,275.

[0197] (CIA modification) CIAs can also be produced by introducing conservative modifications to existing CIAs. For example, modified CIAs can contain heavy and light chain variable regions and / or Fc regions that are homologous to counterparts of the antibodies produced above. Modified CIAs that can be used in the methods disclosed herein must retain the desired functional property of being able to block checkpoint signaling pathways.

[0198] CIAs can also be produced by modifying protein modification sites. For example, the glycosylation site of an antibody can be modified to produce an antibody lacking glycosylation, and such modified CIAs typically increase the affinity of the antibody to the antigen. Antibodies can also be PEGylated by reacting with polyethylene glycol (PEG) under conditions that result in one or more PEG groups being attached to the antibody. PEGylation can increase the biological half-life of the antibody. Antibodies with such modifications can also be used in combination with selective GR modulators disclosed herein, so long as they retain the desired functional property of blocking checkpoint pathways.

[0199] ii. Small Molecule Non-Protein Checkpoint Inhibitor Compounds ("CICs") In some other embodiments, the method of treating cancer, for example, checkpoint inhibitor-sensitive cancer, uses SGRM in combination with CIC. CIC is a small molecule non-protein compound that antagonizes the immunosuppressive function of checkpoint protein. Many CICs are known in the art, for example, those described in PCT publications WO2015034820, WO20130144704, and WO2011082400.

[0200] CICs may also be identified using any of a number of approaches in combinatorial library methods known in the art and disclosed, for example, in European Patent Application EP2360254. Such combinatorial libraries include biological libraries; spatially addressable parallel solid-phase or solution-phase libraries; synthetic library methods requiring deconvolution; "one bead one compound" library methods; and synthetic library methods using affinity chromatography selection. The biological library approach above is limited to peptide libraries, while the other four approaches are applicable to peptide, non-peptide oligomer or small molecule libraries of compounds (Lam, KS (1997) Anticancer Drug Discovery and Development, Vol. 11, No. 1, 2002). Des. 12:145).

[0201] iii. Evaluation of the functional properties of candidate checkpoint inhibitors A number of well-known assays can be used to assess whether a candidate, i.e., an antibody raised by immunizing an animal with an antigen that includes a checkpoint protein, an epitope of a checkpoint protein, or a test compound from a combinatorial library, as disclosed above, is an antibody checkpoint inhibitor. Non-limiting example assays include binding assays (e.g., enzyme-linked immunosorbent assay (ELISA), radioimmunoassay (RIA)), fluorescence-activated cell sorting (FACS) analysis, cell-based assays, and in vivo assays.

[0202] Binding Assay In some embodiments, the assay is a direct binding assay. The checkpoint protein can be coupled with a radioisotope or enzyme label such that binding of the checkpoint protein and the candidate can be measured by detecting the labeled checkpoint protein in a complex. For example, a checkpoint protein can be coupled with 125 I, 35 S, 14 C, or 3 Candidates can be labeled either directly or indirectly with H, and such radioisotopes are detected by direct counting of radioactive emission or by scintillation counting. Determining the ability of candidates to bind to their cognate checkpoint proteins can be accomplished, for example, by measuring direct binding. Alternatively, checkpoint protein molecules can be enzymatically labeled, for example, with horseradish peroxidase, alkaline phosphatase, or luciferase, and binding of the candidate to the target checkpoint protein is determined by conversion of an appropriate substrate to product.

[0203] Enzyme-linked immunosorbent assays (ELISAs) are commonly used to assess the binding specificity of CIA candidates to their target checkpoint proteins. In a typical assay, microtiter plates are coated with checkpoint proteins by coating overnight at 37° C. with 5 μg / ml of checkpoint protein. Serum samples containing candidate CIAs are diluted in PBS, 5% serum, 0.5% Tween-20 and incubated in the wells at room temperature for 1 hour, followed by the addition of anti-human IgG Fc and IgG F(ab')-horseradish peroxidase in the same diluent. After 1 hour at room temperature, enzyme activity is assessed by the addition of ABTS substrate (Sigma, St. Louis Mo.) and read at 415-490 nm after 30 minutes.

[0204] The binding kinetics (e.g., binding affinity) of the candidates can also be assessed by standard assays known in the art, such as Biacore analysis (Biacore AB, Uppsala, Sweden). In one exemplary assay, purified recombinant human checkpoint proteins are covalently coupled to a CM5 chip (a carboxymethyldextran coated chip) via primary amines using standard amine coupling chemistry and a kit provided by Biacore. Binding is performed in HBS EP buffer (Biacore) at a concentration of 267 nM at a flow rate of 50 μl / min. The kinetics of the checkpoint protein-candidate association are followed for 3 minutes and the dissociation kinetics are followed for 7 minutes. Association and dissociation curves are fitted to a 1:1 Langmuir binding model using BIA evaluation software (Biacore AB). To minimize the influence of binding strength on the estimation of the binding constant, only the initial segments of the data corresponding to the association and dissociation phases are used for the fit. The K of the interaction is D , K on and K off A preferred checkpoint inhibitor is one that is more potent than 1×10 -7 It can bind to these target checkpoint proteins with a Kd of less than or equal to M.

[0205] For checkpoint proteins that block immune responses through binding to a ligand, further binding assays can be used to test the ability of the candidate to block the binding of the ligand to the checkpoint protein. In one exemplary assay, flow cytometry is used to test the blocking of the binding of a ligand (e.g., PD-L1) to a checkpoint protein (e.g., PD-1) expressed in transfected CHO cells. Various concentrations of the candidate are added to a suspension of cells expressing the checkpoint protein and incubated at 4°C for 30 minutes. Unbound inhibitors are washed away, and FITC-labeled ligand protein is added to the tube and incubated at 4°C for 30 minutes. FACS analysis is performed using a FACScan flow cytometer (Becton Dickinson, San Jose, Calif.). The mean fluorescence intensity (MFI) of the staining of the cells indicates the amount of ligand that binds to the checkpoint protein. A reduced MFI in the sample spiked with the candidate indicates that the candidate is effective in blocking the binding of the ligand to the target checkpoint protein.

[0206] For example, a homogeneous time-resolved fluorescence (HTRF) binding assay, as described in PCT Publication WO2015034820, may also be used to assay the ability of the candidate to block checkpoint protein-ligand interactions. In one embodiment, the CIC used in the above method is an IC measured by a PD-1 / PD-L1 homogeneous time-resolved fluorescence (HTRF) binding assay. 50 A value of 10 pM or less, for example, 0.01 to 10 pM, preferably 1 pM or less, for example, 0.01 to 1 pM, can inhibit PD-1 / PD-L1 interaction.

[0207] (Cell-based assays) In some alternative embodiments, the assay to assess whether a candidate is a checkpoint inhibitor is a cell-based assay. The mixed lymphocyte reaction (MLR) assay, described in U.S. Pat. No. 8,008,449, is routinely used to measure T cell proliferation, IL-2 and / or IFN-γ production. In one exemplary assay, human T cells are transfected with human CD4 + Candidates are purified from PBMCs using T cell enrichment columns (R&D systems). Candidates are added to multiple T cell cultures at different concentrations. The cells are cultured at 37°C for 5 days and 100 μl of medium is taken from each culture for cytokine measurement. IFN-gamma and other cytokine levels are measured using OptEIA ELISA kits (BD Biosciences). The cells are cultured at 37°C for 5 days and 100 μl of medium is taken from each culture for cytokine measurement. IFN-gamma and other cytokine levels are measured using OptEIA ELISA kits (BD Biosciences). 3 The cells are labeled with H-thymidine, cultured for an additional 18 hours, and analyzed for cell proliferation. Results showing that cultures containing the candidate exhibit increased T cell proliferation, increased production of IL-2 and / or IFN-gamma compared to controls indicate that the candidate is effective in inhibiting a checkpoint protein of the T cell immune response.

[0208] In vivo assay In another embodiment, the assay used to evaluate whether a candidate is a checkpoint inhibitor is an in vivo assay. In one exemplary assay, 6-8 week old female AJ mice (Harlan Laboratories) are randomized into 6 groups by body weight. On day 0, the mice are injected with 2×10 mAbs dissolved in 200 μl of DMEM medium into the right flank. 6 of SA1 / N fibrosarcoma cells are implanted subcutaneously. The mice are treated with PBS vehicle or the candidate at the indicated dosage. The animals are dosed by intraperitoneal injection with approximately 200 μl of PBS containing the candidate or vehicle on days 1, 4, 8, and 11. The mice are monitored twice weekly for tumor growth for approximately 6 weeks. The tumors are measured three-dimensionally (height x width x length) using electronic calipers, and tumor volume is calculated. The tumors are then allowed to grow to the tumor endpoint (1500 mm3 Mice are euthanized when the tumor reaches a volume below 1500 mm or when the mice exhibit greater than 15% weight loss. 3 Results showing a longer mean time to reach CR2+ / CR4 indicates that the candidate has activity in inhibiting cancer growth.

[0209] Combination therapy The methods disclosed herein include, in some cases, combination therapy in which both an SGRM and a checkpoint inhibitor are administered to a subject afflicted with a tumor burden due to the presence of a checkpoint inhibitor-sensitive cancer. In some embodiments, the methods disclosed herein include combination therapy in which both an SGRM and a checkpoint inhibitor are administered to a subject afflicted with a tumor burden of a tumor type that is not conventionally considered to be a checkpoint inhibitor-sensitive cancer but that can be induced to become sensitive to a checkpoint inhibitor by administration of a GRM or SGRM. In some embodiments, the combination therapy includes co-administration of a checkpoint inhibitor and an SGRM sequentially in any order over all or part of the treatment period.

[0210] In some cases, the SGRM and the checkpoint inhibitor are administered according to the same or different dosing regimen. For example, the GRM or SGRM can be administered alone for 1 day, or 2 days, or 3 days, or 1 week, or other lead-in period, and then the checkpoint inhibitor can be administered following the lead-in period of the first GRM or SGRM. In some cases, the SGRM is administered according to a planned regimen while the checkpoint inhibitor is administered intermittently. In some cases, the checkpoint inhibitor is administered according to a planned regimen while the SGRM is administered intermittently. In some cases, both the SGRM and the checkpoint inhibitor are administered intermittently. In some embodiments, the SGRM is administered daily, and the checkpoint inhibitor, e.g., a checkpoint inhibitor, is administered weekly, every other week, once every 3 weeks, once every 4 weeks, or at other intervals. In some embodiments, the SGRM is administered daily for a lead-in period of 1, 2, 3, 4, 5, 6, 7, or other days, and then the checkpoint inhibitor, e.g., a checkpoint inhibitor, is administered weekly, every other week, once every three weeks, once every four weeks, or other intervals. Administration of the GRM or SGRM can continue daily or on other schedules during the time of intermittent administration of the checkpoint inhibitor.

[0211] In some cases, the SGRM and the checkpoint inhibitor are administered sequentially or simultaneously once or twice per month, three times per month, every other week, once per week, twice per week, three times per week, four times per week, five times per week, six times per week, every other day, daily, twice per day, three times per day or more frequently for a period ranging from about 1 day to about 1 week, from about 2 weeks to about 4 weeks, from about 1 month to about 2 months, from about 2 months to about 4 months, from about 4 months to about 6 months, from about 6 months to about 8 months, from about 8 months to about 1 year, from about 1 year to about 2 years, or from about 2 years to about 4 years or more.

[0212] In some embodiments, the combination therapy includes co-administering an SGRM and a checkpoint inhibitor, hi some embodiments, co-administering a checkpoint inhibitor and an SGRM includes administering the two agents simultaneously or approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other).

[0213] Duration The duration of treatment with the SGRM and checkpoint inhibitor to reduce tumor burden can vary depending on the severity of the condition in the subject and the subject's response to the combination therapy. In some embodiments, the SGRM and / or the checkpoint inhibitor can be administered for a period of about 1 week to 104 weeks (2 years), more typically about 6 weeks to 80 weeks, and most typically about 9 to 60 weeks. Suitable administration periods also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable administration periods also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, 100, and 104 weeks. In general, administration of SGRM and / or checkpoint inhibitor should be continued until a desired clinically significant reduction or improvement is observed. Treatment with SGRM and checkpoint inhibitor according to the present invention can last for 2 years or even longer. In some embodiments, the duration of administration of the SGRM is the same as that of the checkpoint inhibitor. In some embodiments, the duration of administration of the SGRM is shorter or longer than that of the checkpoint inhibitor.

[0214] In some embodiments, administration of the SGRM or checkpoint inhibitor may be stopped for one or more periods, rather than continuously, and then administration may be resumed for one or more periods. Suitable periods for stopping administration include 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-100 weeks. Suitable periods for which administration will cease also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, and 100 weeks.

[0215] (Assessment of Improvement in Tumor Burden Reduction) The combination therapy disclosed herein can reduce tumor burden.Methods for measuring these responses are well known to those skilled in the art of cancer treatment, for example, as described in the Response Evaluation Criteria in Solid Tumors ("RECIST") guidelines available at http: / / ctep.cancer.gov / protocolDevelopment / docs / recist_guideline.pdf.

[0216] In one approach, the tumor burden is measured by assaying the expression of tumor-specific gene markers. This approach is particularly useful for metastatic tumors or tumors that are not easily measurable, such as bone marrow cancer. Tumor-specific gene markers are proteins or other molecules that are unique to cancer cells or more abundant than non-cancerous cells. For example, see WO2006104474. Non-limiting examples of tumor-specific gene markers include alpha-fetoprotein (AFP) for liver cancer, beta-2-microglobulin (B2M) for multiple myeloma; beta-human chorionic gonadotropin (beta-hCG) for choriomas and germ cell tumors; CA19-9 for pancreatic, gallbladder, bile duct, and gastric cancer; CA-125 and HE4 for ovarian cancer; carcinoembryonic antigen (CEA) for colorectal cancer; chromogranin A (CgA) for neuroendocrine tumors; fibrin / fibrinogen for bladder cancer; prostate-specific antigen (PSA) for prostate cancer; and thyroglobulin for thyroid cancer. See http: / / www.cancer.gov / about-cancer / diagnosis-staging / diagnosis / tumor-markers-fact-sheet.

[0217] Methods for measuring the expression level of tumor-specific gene markers are well known. In some embodiments, the mRNA of the gene marker is isolated from blood samples or tumor tissues, and real-time reverse transcription polymerase chain reaction (RT-PCR) is performed to quantify the expression of the gene marker. In some embodiments, Western blot or immunohistochemistry analysis is performed to evaluate the protein expression of the tumor-specific gene marker. Typically, the level of the tumor-specific gene marker is measured in multiple samples taken over the course of the combination therapy of the present invention, and a decrease in the level correlates with a decrease in tumor burden.

[0218] In another approach, the reduction of tumor burden by the combination therapy disclosed herein is shown by the reduction of tumor size or the reduction of cancer volume in the body.The measurement of tumor size is typically achieved by imaging-based techniques.For example, computed tomography (CT) scan can provide accurate and reliable anatomical information on the progression of disease as well as the shrinkage or growth of tumors, by identifying either the growth of existing lesions or the occurrence of new lesions or tumor metastasis.

[0219] In another approach, reduction in tumor burden can be assessed by functional and metabolic imaging techniques. These techniques can provide earlier assessment of treatment response by observing changes in perfusion, oxygenation and metabolism. For example, 18 F-FDG PET uses radiolabeled glucose analog molecules to assess tissue metabolism. Tumors typically have high uptake of glucose, and changes in values ​​corresponding to a decrease in tumor tissue metabolism indicate a reduction in tumor burden. A similar imaging technique is disclosed in Kang et al., Korean J.Radiol.(2012) 13(4) 371-390.

[0220] Patients undergoing the combination therapy disclosed herein may show varying degrees of tumor burden reduction. In some cases, patients may show complete response (CR), also referred to as "no evidence of disease (NED)". CR means that all detectable tumors as shown by tests, physical examinations and scans have disappeared. In some cases, patients undergoing the combination therapy disclosed herein may experience partial response (PR), which roughly corresponds to at least a 50% reduction in total tumor volume, but some evidence of residual disease still remains. In some cases, the residual disease in deep partial response may actually be dead tumor or scar, such that some patients classified as having a PR are actually those who have a CR. Also, many patients who show a reduction upon treatment may show further reduction and achieve a CR with continued treatment. In some cases, patients undergoing the combination therapy may experience minor response (MR), which roughly means that the amount of reduction is more than 25% of the total tumor volume, but less than 50% which makes it a PR. In some cases, patients receiving the combination therapy may show stable disease (SD), where the tumors remain roughly the same size. SD may include either a small amount of growth (typically less than 20 or 25%) or a small amount of shrinkage (either less than PR unless a minor response occurs, in which case SD is typically defined as less than 25%).

[0221] The desired beneficial or desired clinical outcome from the combination therapy may also include, for example, a reduction (i.e., slowing and / or stopping to a certain extent) of cancer cell invasion into surrounding organs; an inhibition (i.e., slowing and / or stopping to a certain extent) of tumor metastasis; an increase in the response rate (RR); an increase in the duration of response; an alleviation to a certain extent of one or more symptoms associated with cancer; a reduction in the dose of other medications required to treat the disease; a delay in disease progression; and / or an increase in the survival and / or improvement in the quality of life of the patient. Methods for assessing these effects are well known and / or disclosed, for example, at http: / / cancerguide.org / endpoints.html and in the RECIST guidelines (see above).

[0222] Pharmaceutical Compositions and Administration GRMs and SGRMs (as used herein, GRMs and SGRMs include nonsteroidal GRMs and nonsteroidal SGRMs) can be prepared and administered in a wide variety of oral, parenteral and topical dosage forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, gels, syrups, slurries, suspensions, and the like, suitable for ingestion by a patient. GRMs and SGRMs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. GRMs and SGRMs can also be administered by inhalation, e.g., intranasally. Additionally, GRMs and SGRMs can be administered transdermally. Thus, the present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and a GRM or SGRM.

[0223] For preparing pharmaceutical compositions from GRMs and SGRMs, pharma- ceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details concerning techniques for formulation and administration are well described in the scientific and patent literature, see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's").

[0224] In powders, the carrier is a finely divided solid that is in admixture with the finely divided active ingredient, GRM or SGRM. In tablets, the active ingredient is mixed with the carrier having the required binding properties in suitable proportions and compacted in the shape and size desired.

[0225] The powders and tablets preferably contain 5% to 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, cocoa butter, and the like. The term "preparation" is intended to include formulations of the active compound together with an encapsulating material as a carrier to form an capsule, in which the active ingredient, with or without other carriers, is enclosed by the carrier, thereby bringing them together. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

[0226] Suitable solid additives are carbohydrate or protein fillers, including, but not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starches derived from corn, wheat, rice, potato, or other plants; celluloses, such as methylcellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums, including arabic and tragacanth; and proteins, such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate.

[0227] Dragee cores are provided with suitable coatings such as gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and concentrated sugar solutions that may contain suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active compound (i.e., dosage). The pharmaceutical preparations of the present invention may also be used orally using push-fit capsules, for example made of gelatin, as well as soft sealed capsules made of gelatin and a coating, for example, glycerol or sorbitol. Push-fit capsules may contain the GR modulator mixed with a filler or binder, such as lactose or starch, a lubricant, such as talc or magnesium stearate, and, optionally, a stabilizer. In soft capsules, such GR modulator compounds may be dissolved or suspended in a suitable liquid, such as fatty acid oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0228] Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water / propylene glycol solutions.For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

[0229] Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active ingredient in water with viscous materials such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The said aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, aspartame or saccharin. The osmolarity of the preparation may be adjusted.

[0230] Also included are solid form preparations that are intended to be converted shortly before use into liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active ingredient, colorants, flavorants, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, and the like.

[0231] Oil suspensions can be formulated by suspending the SGRM in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or a mineral oil, such as liquid paraffin; or a mixture thereof. The oil suspensions can contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as glycerol, sorbitol, or sucrose, can be added to provide a palatable oral preparation. These preparations can be preserved by the addition of an antioxidant, such as ascorbic acid. For examples of injectable oil vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations of the present invention can also be in the form of oil-in-water emulsions. The oil phase can be a vegetable oil or a mineral oil, or a mixture thereof. Suitable emulsifying agents include naturally occurring gums such as gum acacia and gum tragacanth, naturally occurring phospholipids such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide such as polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents, as in the formulation of syrups and elixirs. Such formulations may also contain analgesics, preservatives, or coloring agents.

[0232] GRMs and SGRMs can be delivered transdermally and topically, formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0233] GRMs and SGRMs may also be delivered as microspheres for sustained release in the body. For example, microspheres may be administered via intradermal injection of drug-containing microspheres for sustained subcutaneous release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995); as biodegradable and injectable gel formulations (see, e.g., Gao Pharm. Res. 12:857-863, 1995); or as microspheres for oral administration (see, e.g., Eyles, J. Pharm. Pharmacol. 49:669-674, 1997). Both transdermal and intradermal routes allow constant delivery over a period of weeks or months.

[0234] The pharmaceutical formulations of the present invention may be provided as salts and may be formed with a number of acids, including but not limited to hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the preparations may be lyophilized powders in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, in a pH range of 4.5-5.5, and combined with a buffer prior to use.

[0235] In some other embodiments, the formulations of the present invention can be delivered by using liposomes that fuse with or are incorporated into cell membranes, i.e., by using ligands attached to the liposomes or directly attached to the oligonucleotides that bind to cell surface membrane protein receptors resulting in endocytosis.By using liposomes, it is possible to focus the in vivo delivery of GR modulators to the target cells, especially when the liposome surface carries ligands specific to the target cells or otherwise preferentially targets a particular organ. (See, for example, Al-Muhammed, J.Microencapsul.13:293-306,1996; Chonn, Curr.Opin.Biotechnol.6:698-708,1995; Ostro, Am.J.Hosp.Pharm.46:1576-1587,1989).

[0236] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the active ingredient, GRM or SGRM. The unit dosage form may be a packaged preparation containing discrete amounts of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0237] The amount of active ingredient in a unit dose preparation may vary or be adjusted from 0.1 mg to 10,000 mg, more typically from 1.0 mg to 6,000 mg, and most typically from 50 mg to 500 mg. Suitable dosages include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg, depending on the particular application and the potency of the active ingredient. The composition may also contain other compatible therapeutic agents, if desired.

[0238] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate amounts of the compounds and compositions of the present invention. The unit dosage form can be a packaged preparation containing discrete quantities of the preparation, such as packaged tablets, capsules, and powders in vials or ampoules. The unit dosage form can also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these in packaged form.

[0239] The GRM can be administered orally. For example, the GRM can be administered as a pill, capsule, or liquid formulation as described herein. Alternatively, the GRM can be provided via parenteral administration. For example, the GRM can be administered intravenously (e.g., by injection or infusion). Further methods of administration of the compounds described herein, and pharmaceutical compositions or formulations thereof, are described herein.

[0240] In some embodiments, the GRM is administered in one dose. In other embodiments, the GRM is administered in more than one dose, for example, two doses, three doses, four doses, five doses, six doses, seven doses, or more. In some cases, the doses are of equivalent amounts. In other cases, the doses are of different amounts. The doses may increase or decrease over the duration of administration. The amounts vary, for example, according to the properties of the GRM and the characteristics of the patient.

[0241] Any suitable GRM dose can be used in the methods disclosed herein. The dose of GRM administered can be at least about 300 milligrams (mg) per day, or about 600 mg / day, for example, about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1100 mg / day, about 1200 mg / day, or more. For example, when the GRA is mifepristone, the GRM dose can be, for example, 300 mg / day, or 600 mf / day, or 900 mg / day, or 1200 mg / day of mifepristone. In some embodiments, the GRM is administered orally. In some embodiments, the GRM is administered in at least one dose. In other words, the GRM may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses, hi some embodiments, the GRM is administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses.

[0242] The patient may be administered at least one dose of the GRM, one or more doses, for example, over a period of 2 to 48 hours. In some embodiments, the GRM is administered in a single dose. In other embodiments, the GRM is administered in more than one dose, for example, two doses, three doses, four doses, five doses, or more, over a period of 2 to 48 hours, for example, a 2 hour period, a 3 hour period, a 4 hour period, a 5 hour period, a 6 hour period, a 7 hour period, a 8 hour period, a 9 hour period, a 10 hour period, a 11 hour period, a 12 hour period, a 14 hour period, a 16 hour period, a 18 hour period, a 20 hour period, a 22 hour period, a 24 hour period, a 26 hour period, a 28 hour period, a 30 hour period, a 32 hour period, a 34 hour period, a 36 hour period, a 38 hour period, a 40 hour period, a 42 hour period, a 44 hour period, a 46 hour period, or a 48 hour period. In some embodiments, the GRM is administered over a period of 2-48 hours, 2-36 hours, 2-24 hours, 2-12 hours, 2-8 hours, 8-12 hours, 8-24 hours, 8-36 hours, 8-48 hours, 9-36 hours, 9-24 hours, 9-20 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 18-48 hours, 18-36 hours, 18-24 hours, 24-36 hours, 24-48 hours, 36-48 hours, or 42-48 hours.

[0243] Single or multiple doses of the formulation may be administered depending on the dosage and frequency required and tolerated by the patient. The formulation may provide a sufficient amount of active agent to effectively treat a disease state. Thus, in certain embodiments, the daily dosage of the pharmaceutical formulation for oral administration of GRM is about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In some embodiments, the daily dosage is about 1.0 to 100 mg / kg / day, 5 to 50 mg / kg / day, 10 to 30 mg / kg / day, and 10 to 20 mg / kg / day. Lower dosages may be used, particularly when such drugs are administered to anatomically isolated sites such as the cerebrospinal fluid (CSF) space, into the bloodstream, into a body cavity, or into the lumen of an organ, as opposed to oral administration. Substantially higher dosages may be used in local administration. Actual methods for preparing parenterally administrable formulations will be known or apparent to those skilled in the art and are described in more detail in publications such as Remington's (supra). See also Nieman, in "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0244] The duration of treatment with a GRM or SGRM can vary depending on the severity of the condition in the subject and the response of the subject to the GRM or SGRM. In some embodiments, the GRM and SGRM can be administered for a period of about 1 week to 104 weeks (2 years), more typically about 6 weeks to 80 weeks, and most typically about 9 to 60 weeks. Suitable administration periods also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable administration periods also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, 100, and 104 weeks. In general, administration of a GRM or SGRM should be continued until a desired clinically significant reduction or improvement is observed. Treatment with said GRM or SGRM according to the present invention may be sustained for 2 years or even longer.

[0245] In some embodiments, administration of the GRM or SGRM may be stopped for one or more periods, rather than continuously, and then administration may be resumed for one or more periods. Suitable periods for which administration may be stopped include 5-9 weeks, 5-16 weeks, 9-16 weeks, 16-24 weeks, 16-32 weeks, 24-32 weeks, 24-48 weeks, 32-48 weeks, 32-52 weeks, 48-52 weeks, 48-64 weeks, 52-64 weeks, 52-72 weeks, 64-72 weeks, 64-80 weeks, 72-80 weeks, 72-88 weeks, 80-88 weeks, 80-96 weeks, 88-96 weeks, and 96-100 weeks. Suitable periods for which administration will cease also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, and 100 weeks.

[0246] Dosing regimens also take into account pharmacokinetic parameters well known in the art, i.e., rate of absorption, bioavailability, metabolism, clearance, etc. (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; Remington, supra, more recently). The clinician, with the aid of state of the art techniques, is able to determine the dosage regimen for each individual patient, GR modulator and disease or condition being treated.

[0247] SGRMs may be used in combination with other active agents known to be useful in modulating the glucocorticoid receptor, or with adjunct agents that may not be effective alone but may contribute to the efficacy of the active agents.

[0248] In some embodiments, co-administration includes administering one active agent, GRM or SGRM, within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration can be achieved by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents can be formulated separately. In other embodiments, the active agents and / or adjuncts can be linked or conjugated to each other.

[0249] After the pharmaceutical compositions containing the GR modulators of the present invention have been formulated in an acceptable carrier, they can be placed in an appropriate container and labeled for treatment of a designated condition. For administration of a GRM or SGRM, such labeling can include, for example, instructions regarding the amount, frequency and method of administration.

[0250] The pharmaceutical compositions of the present invention may be provided as salts and may be formed with a number of acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. Salts tend to be more soluble in aqueous or other protic solvents than the corresponding free base form. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, in a pH range of 4.5-5.5, and combined with a buffer prior to use.

[0251] In another embodiment, the composition of the present invention is useful for parenteral administration, such as intravenous (IV) administration or administration into a cavity or into a cavity of an organ. The formulation for administration may generally comprise a solution of the composition of the present invention dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that may be used include water and Ringer's solution, isotonic sodium chloride. In addition, sterile fixed oils may be conventionally used as a solvent or suspending medium. For this purpose, any sterile fixed oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid may be used in the preparation of injectables as well. These solutions are sterile and generally free of undesirable substances. These formulations may be sterilized by conventional well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances required for approximate physiological conditions, such as pH adjusting agents and buffers, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the composition of the present invention in these preparations can vary widely and is selected mainly based on body fluid volume, viscosity, body weight, etc., according to the specific administration form selected and the patient's requirements. For IV administration, the preparation can be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension can be formulated according to known techniques using these suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0252] (Combination therapy) Various combinations of GRM or SGRM and chemotherapeutic agents, checkpoint inhibitors, or other treatments (e.g., cancer treatments), or combinations of such agents and compounds, may be used to treat patients. By "combination therapy" or "combination with," it is not intended to imply that the therapeutic agents must be administered simultaneously and / or formulated for delivery together, but these delivery methods are within the scope described herein. The GRM or SGRM and the chemotherapeutic or other agent may be administered according to the same or different dosing regimens. In some embodiments, the GRM or SGRM and the chemotherapeutic or other agent are administered sequentially in any order over the entire or part of the treatment period. In some embodiments, the GRM or SGRM and the chemotherapeutic or other agent are administered simultaneously or approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other). A non-limiting example of a combination therapy is as follows, with administration of the GRM or SGRM and a chemical agent, e.g., the GRM or SGRM is "A" and the chemotherapeutic or other agent given as part of the treatment regimen is "B":

[0253] A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B

[0254] B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A

[0255] B / A / B / AB / A / A / BA / A / A / BB / A / A / AA / B / A / AA / A / B / A

[0256] AAA (B / A AAAAAAAAAAAAAAAAAAAAA) n (where "n" indicates that the bracketed cycle may be repeated at the physician's discretion).

[0257] Administration of the therapeutic compound or agent to the patient will follow standard protocols for the administration of such compounds, taking into account any toxicities of the treatment. Surgical interventions may also be applied in combination with the described treatments.

[0258] The method may be combined with other means of treatment, such as surgery, radiation, targeted therapy, immunotherapy, the use of growth factor inhibitors, or anti-angiogenic factors.

[0259] All patents, patent publications, publications, and patent applications cited in this specification are hereby incorporated by reference in their entirety into this specification, as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference.

[0260] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of this invention that certain changes and modifications may be made therein without departing from the spirit or scope of the appended claims. EXAMPLES

[0261] The following examples are offered by way of illustration only, and not by way of limitation. Those of skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially similar results.

[0262] Example 1. HepG2 Tyrosine Aminotransferase (TAT) Assay The following protocol describes an assay to measure induction of TAT by dexamethasone in HepG2 cells (human hepatoma cell line; ECACC, UK). HepG2 cells are cultured in MEME medium supplemented with 10% (v / v) fetal bovine serum; 2 mM L-glutamine and 1% (v / v) NEAA at 37° C., 5% / 95% (v / v) CO2 / air. The HepG2 cells are then counted and cultured at 0.125×10 in RPMI 1640 with 10% (v / v) charcoal-stripped FBS, 2 mM L-glutamine and phenol red-free. 6 The density of cells / ml is adjusted and seeded into 96-well sterile tissue culture microtiter plates at 25,000 cells / well in 200 μl and incubated at 37° C., 5% CO 2 for 24 hours.

[0263] Growth medium is then removed and replaced with assay medium {RPMI 1640, 2 mM L-glutamine + 10 μM forskolin, without phenol red}. Test compounds are then screened against a 100 nM dexamethasone challenge. Compounds are then serially half-log diluted from a 10 mM stock in 100% (v / v) dimethyl sulfoxide. An 8-point half-log dilution curve is then generated, followed by a 1:100 dilution in assay medium to give 10× the final assay compound concentration, resulting in final assay compound concentrations that are in the range of 10-0.003 μM in 0.1% (v / v) dimethyl sulfoxide.

[0264] Test compounds are pre-incubated in microtiter plates at 37° C., 5 / 95 (v / v) CO 2 / air for 30 min before addition of 100 nM dexamethasone, followed by 20 h to allow optimal TAT induction.

[0265] HepG2 cells are then lysed with 30 μl of cell lysis buffer containing a protease inhibitor cocktail for 15 minutes at 4° C. Then 155 μl of substrate mixture containing 5.4 mM tyrosine sodium salt, 10.8 mM alpha-ketoglutarate and 0.06 mM pyridoxal 5′ phosphate in 0.1 M potassium phosphate buffer (pH 7.4) can be added. After 2 hours of incubation at 37° C., the reaction can be terminated by the addition of 15 μl of 10 M aqueous potassium hydroxide solution, and the plate can be incubated for another 30 minutes at 37° C. TAT activity product can be measured by absorbance at λ340 nm.

[0266] I C 50 Values ​​can be calculated by plotting % inhibition (normalized to 100 nM dexamethasone TAT stimulation) versus compound concentration and fitting this data to a four parameter logistic equation: IC 50 Values ​​can be converted to Ki (equilibrium dissociation constant) using the Cheng-Prusoff equation, assuming that the antagonist is a competitive inhibitor with respect to dexamethasone.

[0267] Example 2. Relacorilant stimulates anti-tumor immune responses Because response to immune checkpoint inhibitors (ICIs) is associated with tumor immune infiltration and PD-L1 expression, we first assessed whether GR expression is observed in the same types of tumors that are susceptible to response to ICIs. In melanoma and TNBC tumors, CD3+ T cell infiltration correlated with GR expression (Figure 1). GR expression also correlated with T cell proliferation, which suppresses cytotoxic T cell function. reg The results also correlated with FOXP3+ cells, a marker for cancer. Analysis of transcriptome data from the National Cancer Institute's The Cancer Genome Atlas (TCGA; accessible at the National Cancer Institute's "cancer.gov" website at the page "about-nci / organization / ccg / research / structural-genomics / tcga") showed that GR expression correlated with markers of immune suppressive cells. An overall correlation of GR and PDL1 was observed (p<2×10 -16 ), adrenal, bladder, and pancreatic cancers. Figure 2 shows that GR expression correlates with PD-L1 expression. Using xCell (Aran, Genome Biology 2017) to estimate the abundance of different cell types within individual tumors, we observed a positive correlation between GR and CD8+ T cells, Tregs, and Th2 cells. Figure 3A shows that GR expression correlates positively with CD8+ T cells and regulatory T cells (Tregs). Figure 3B shows that GR expression correlates positively with T H 1 Negatively correlated with T cells and T H 2 positively correlates with T cell proliferation and Treg expression. Tregs have been shown to limit the ability of CD8+ T cells to activate and eliminate tumors. These data suggest that GR is elevated in tumors with suppressed T cell infiltration, a tumor category that is generally considered to be good candidates for ICI therapy.

[0268] Cortisol inhibits activation of human PBMCs, and activation is restored by relacorilant To understand the molecular consequences of GC activity on T cell activation, the effects of cortisol and lelacorilant were evaluated on stimulated human PBMCs. The 400 nM cortisol concentration typically found in human serum strongly suppressed almost all phenotypic effects of stimulation with either phytohemagglutinin (PHA) or αCD3+IL-12. Expression of CD137 (aka 41-BB) in CD8+ cells was reduced by cortisol and restored by lelacorilant. Figure 4 shows the restoration of T cell activation by lelacorilant in the presence of physiological levels of cortisol. Expression of CD137 (aka 41-BB) in CD8+ cells was reduced by cortisol and restored by lelacorilant. Similar trends were observed for other T cell subsets stimulated with PHA or αCD3+IL-12 (Figures 5 and 6), including CD8+ and CD4+ expressing LAG3 and CTLA4. FIG. 5 shows the suppression of CD3+ cell surface receptors by cortisol and the restoration of CD3+ cell surface receptors by lelacorilant upon stimulation with phytohemagglutinin (PHA). As also shown in FIG. 4, inflammatory cytokines such as TNF-α were induced by stimulation, suppressed by cortisol, and restored by lelacorilant. A similar pattern was observed for cytokines and chemokines induced by stimulation, including IFNγ, IL-1β, IL-1α, and IL-6 (FIGS. 6A and 6B). FIGS. 6A and 6B show the suppression of cytokines and chemokines by cortisol and the restoration of cytokine / chemokine levels by lelacorilant upon stimulation with phytohemagglutinin (PHA) (FIG. 6A) or αCD3 (FIG. 6B). (Supernatant IL-12 measurements were excluded from the analysis shown in FIG. 6B because the stimulation included recombinant IL-12.) Physiological levels of cortisol suppressed cytokines and chemokines, and this suppression was reversed by relacorilant. These results demonstrate a broad immunosuppressive effect on T cell activation mediated by cortisol at normal physiological concentrations, and these effects were reversed by relacorilant.

[0269] Relacorilant enhances T cell function and αPD1 responses in a syngeneic mouse model The inhibitory effect of cortisol on CD8+ cytotoxic T cells and the ability of relacorilant to promote T cell activation were evaluated in the EG7 syngeneic mouse model. EG7 tumor cells express ovalbumin and the model was cultured with either WT or OT-1 / Rag - / - The OT-1 / Rag - / - Only mice harbor T cells expressing a transgenic ovalbumin-specific TCR. - / - In this background, untreated mice were also able to control tumor growth for 17-20 days (Figure 7). The combination of PD1 antagonist antibody (RMP1-14) and Relacorilant was evaluated in the EG7 tumor model. Relacorilant significantly increased the efficacy of anti-PD1 antibody in this model. Because mice do not have comparable levels of cortisol synthesis to humans, cortisol was administered in the drinking water at 100 mg / L, resulting in a mean serum cortisol level of 447 nM (data not shown). Cortisol administration resulted in rapid tumor growth (Figure 7). Premature death occurred in 2 / 5 cortisol-treated mice and 0 / 5 control mice. All cortisol-treated mice had measurable tumors by day 10, whereas 2 / 5 control mice had no detectable tumors at days 10-20. The OT-1 / Rag - / - When mice were given cortisol + / - lelacorilant, 2 / 7 histologically confirmed complete remission was observed in the cortisol + lelacorilant treatment group, but none of the cortisol-only groups had remission. In contrast, administration of cortisol in the drinking water of wild-type (WT) mice had no effect on tumor control or growth (data not shown). Together, these data suggest that cortisol suppresses tumor elimination by cytotoxic CD8+ T cells and that lelacorilant restores cytotoxic CD8+ T cell function.

[0270] The combination of PD1 antagonist antibody (RMP1-14) and Relacorilant was evaluated in the EG7 tumor model. This more established model was used because many reports have evaluated αPD1 effects on EG7 cells in WT mice without added cortisol. Relacorilant or αPD1 alone had no significant effect in this model. The combination of Relacorilant and αPD1 suppressed tumor growth (Figure 8). By day 14, tumors had grown to 1800 mm 3 Mice had larger tumors than 8 / 10 in the αPD1 alone treatment group compared to 2 / 10 in the αPD1 + Relacorilant group. 3 Time to progression was also significantly better in the Relacorilant + αPD1 group compared to the αPD1 alone group (Figure 8). Evaluation of individual mouse tumor volume trajectories indicates that this malignancy model is significantly controlled from days 10 to 20. The effect of Relacorilant was reversed by excess cortisol administration and tumor growth was restored, demonstrating that the Relacorilant effect is specific to antagonism of cortisol activity. Final serum collected on days 11 to 21 of the study showed that TNFα levels were increased by the addition of Relacorilant but suppressed by the addition of cortisol. Consistent with the effects observed in isolated human peripheral blood mononuclear cells (PBMCs), the ability of Relacorilant to promote T cell function and pro-inflammatory cytokine secretion is recapitulated in this model.

[0271] Systemic effects of relacorilant in phase I studies in patients with solid tumors demonstrate antagonism of endogenous GR activity Since GR is a broad regulator of immune suppressive transcriptional programs, we first evaluated the transcriptional effects of prednisone and / or lelacorilant in whole blood. In a phase I study of healthy volunteers, a 25 mg dose of prednisone resulted in a large transcriptional effect 4 hours after the dose. This defined a gene set of prednisone-induced genes in whole blood. In a phase I study of lelacorilant + nab-paclitaxel in patients with solid tumors, the prednisone-induced genes were primarily suppressed. Significant overlap in the two gene sets was observed only in patients who benefited from treatment, defined as best overall response of SD or good by RECIST. In patients with progressive disease, there was no significant overlap between genes induced by prednisone and genes suppressed after dosing with lelacorilant + nab-paclitaxel. Figure 10 shows that treatment with the combination of lelacorilant + nab-paclitaxel suppressed gene expression in patients with solid tumors. Repressed genes included genes expressing IL8 (CXCL8), IDO1, and EP4 (PTGER4) (n=46). Neutrophil-to-lymphocyte ratios (NLR) also normalized in these patients (p=0.01). The canonical GR-regulated genes dusp1 and ptgs2 (COX2) were repressed in patients who received relacorilant plus nab-paclitaxel. Among the most repressed genes after treatment with relacorilant and nab-paclitaxel were cxcl8 (IL-8), ido1, and ptger4 (EP4). Reduction of cxcl8 transcripts resulted in post-treatment readouts below the limit of measurement. These three genes are known to have a role in suppressing cytotoxic T-cell responses. The overall transcriptional effect of relacorilant in whole blood is both reciprocal to the prednisone effect and characteristic of processes that might be expected to promote effective cytotoxic T-cell responses.

[0272] Since GR activity has previously been shown to alter blood cellular composition, we evaluated the effect of lelacorilant on neutrophil and lymphocyte abundance. Baseline neutrophil-to-lymphocyte ratios predict response to checkpoint inhibitors, and reduction of the NLR is also associated with improved outcomes (Lalani et al. Journal for ImmunoTherapy of Cancer (2018) 6:5). First, we demonstrated that lelacorilant does not affect the NLR in healthy volunteers with normal cortisol levels. In healthy volunteers, prednisone resulted in a rapid and sharp increase in the NLR. This effect was reversed when lelacorilant was co-administered with prednisone. These data demonstrate that lelacorilant does not affect the NLR in healthy individuals (under conditions where stress or disease states are not expected to elevate cortisol levels) and that lelacorilant can reverse glucocorticoid agonism on the NLR. In patients with advanced solid tumors, we observed that the baseline NLR was higher than in healthy subjects. There was an overall decrease in the NLR in all patients over the first 8 or 15 days. This decrease was more pronounced in patients with elevated baseline NLR (NLR>3), whereas no significant change in NLR was observed in patients with normal NLR at baseline (NLR≦3). The decrease in NLR over the first 15 days of treatment was consistent with the C-relacorilant effect of relacorilant. max The NLR correlated with GR agonism but not with paclitaxel, suggesting that the above effects were primarily driven by GR antagonism. There was a non-significant trend toward more pronounced clinical benefit in patients with decreased NLR. These data demonstrate that the NLR is increased by GR agonists and decreased by GR antagonists.

[0273] In a small Phase I solid tumor study, one patient achieved a complete response per RECIST 1.1 after treatment with relacorilant + nab-paclitaxel. This observation was unexpected given the patient history and previous lines of treatment. Figure 11 shows a summary of the effects on selected biomarkers in a patient with a complete response (CR) to treatment with relacorilant + nab-paclitaxel. This patient showed a decrease in neutrophil-to-lymphocyte ratio (NLR), as well as changes in CD4+ cells, CD8+ cells, CD3+ T cells, expression of ptgs2 and dusp1, and other changes. (C1D1 indicates day 1 of cycle 1 of treatment; C1D15 indicates day 15 of cycle 1 of treatment; C4D1 indicates day 1 of cycle 4 of treatment, and EOT indicates end of treatment.) In this patient, the NLR decreased from 5.5 (elevated) to 2.5 (normal) 8 days after treatment (top left of Figure 11). This improvement in NLR was accompanied by a reduction in the GR-regulated transcripts ptgs2 and dusp1 (Figure 11, bottom left). The abundance of these transcripts later rebounded above baseline as disease progressed, treatment with relacorilant was discontinued, and dexamethasone was eventually administered. reg A decrease in CD4+ T cells (as % of mononuclear CD45+) and increases in CD3+ (as % of CD3+), CD4+ (as % of CD3+), and CD8+ (as % of CD3+) were observed (Figure 11, top right). Plasma IFN-γ was slightly increased, whereas IL-10 was decreased in this patient (Figure 11, bottom right). These observations are consistent with immune activation and antagonism of cortisol activity.

[0274] Based on this observation, we evaluated immune responses in other patients with long-lasting responses to Relacorilant + nab-paclitaxel. As is common in ICI trials, a small group (10 of 57 evaluable patients) had sustained benefit (Figure 12). This was particularly surprising given the disease state and, in some cases, the duration of response to nab-paclitaxel treatment (Figure 12). Blood CD3+ cells and plasma IFNγ levels increased in these patients. This was consistent with the increase in blood T reg , plasma IL-10 levels, and the transcription of GR-regulated genes (Figure 13).

[0275] As shown in Figure 13, there is evidence of immune activation in patients with exceptional and durable responses to Relacorilant + nab-paclitaxel. These patients exhibited these trends in plasma / whole blood: Among the trends seen in such patients were decreased NLR (D8 p=0.006; D15 p=0.02); reg Increased CD3+ cell counts (p=0.06); decreased GR-regulated gene expression (ptgs2) in early whole blood that rebounded at EOT (p=0.008); increased IFNγ (p=0.03 excluding high outliers); and decreased IL-10 (p=0.03). These trends were not observed across the broader study population. Furthermore, NLR in these notable responders decreased from baseline to C1D8 and C1D15 (Figure 13). Together, these observations suggest that a long duration of benefit was associated with the immune response to relacorilant + nab-paclitaxel.

[0276] conclusion Relacorilant is a potent and selective GR antagonist with proven systemic GR antagonism in healthy volunteers and patients with advanced solid tumors. GR expression is abundant in human tumors and immune cells, and high tumor GR levels are associated with high immune infiltration and PDL1 expression. Physiological concentrations of cortisol broadly inhibit human PBMC activation in vitro, and Relacorilant relieves this inhibition. The combination of Relacorilant with αPD1 was demonstrated in the syngeneic mouse model EG7. The systemic effects of Relacorilant were consistent with the reciprocal effects of GR agonists in Phase I studies in solid tumor patients and healthy volunteers.

[0277] Important correlates of response to immune checkpoint inhibitors (ICIs) have been clinically demonstrated. Immune infiltration within tumors (often referred to as “hot” tumors) and PDL1 expression in tumors tend to predict better response to checkpoint inhibitors, and GR abundance correlates with both. This suggests that there are overlapping tumor subsets with high GR, immune infiltration, and PDL1 expression. GR antagonism may reactivate these infiltrated, suppressed immune cells. Induction of proinflammatory signals such as TNF-α and IFN-γ, in concert with suppression of immunosuppressive signals such as IL-8, EP4, and IDO1, has been associated with ICI responses. While endogenous cortisol regulates these pathways in a direction expected to reduce ICI responses, relacorilant has the opposing effect. Low NLR predicts response to checkpoint inhibitors, and relacorilant reduces NLR in cancer patients with elevated baseline NLR. Therefore, the effect of relacorilant would be to suppress pathological endogenous cortisol activity and promote ICI responses.

[0278] Whereas elevated endogenous cortisol activity has previously been reported in patients with cancer, the Relacorilant data confirm that endogenous cortisol activity can be antagonized. Normalization of the NLR by GR antagonists suggests that elevated NLR in cancer patients may be driven, in part, by elevated cortisol activity. The elevated NLR was not caused by administration of synthetic GR agonists, as treatment with synthetic GR agonists was prohibited in this study. Similarly, antagonism of GR-regulated genes by Relacorilant in patients demonstrating benefit in Relacorilant + nab-paclitaxel suggests that some endogenous GR agonist activity was present prior to treatment. Baseline synthetic steroid use has been associated with inferior outcomes with ICIs, so elevated baseline cortisol activity may be responsible for limited ICI response in some patients.

[0279] Example 3. Reversal of Cortisol Effects in Solid Tumors by Relacorilant Introduction: Cortisol, an endogenous glucocorticoid receptor (GR) agonist, controls a broad range of transcriptional programs that affect T cell activation, proinflammatory cytokine secretion, and immune cell trafficking. By selectively antagonizing GR, relacorilant may reverse the immunosuppressive effects of cortisol in solid tumor cancers.

[0280] Methods: Immune cell abundance and GR expression were assessed by IHC in The Cancer Calculations were based on Genome Atlas (TCGA) data. Human PBMCs were stimulated with αCD3+IL-12+ / -Cortisol or Cortisol+Relacorilant. Mice bearing EG7 tumors were treated with αPD1 (RMP1-14) (ip (intraperitoneal) Q5D (every 5 days)) + / - Relacorilant (QD) (daily). Whole blood mRNA was measured via Nanostring, hematology was performed using a standard whole blood count assay, and cytokines were assessed by immunoassay in study NCT02762981.

[0281] Results: GR expression was observed in human tumors and immune cells. Its abundance was H 2. Tregs and PDL1 + It was positively correlated with the tumor infiltration of T cells (P<.001). H 1 cells (P<.001). + Cortisol inhibited, and leracorilant restored, T cell activation (P < .001) and proinflammatory cytokine secretion (TNFα P = .006, IFNγ P < .05). In an EG7 syngeneic model, leracorilant increased αPD1 potency (P = .007) and reduced circulating IL-10 (P < .002). In patients with advanced solid tumors, leracorilant plus nab-paclitaxel systemically suppressed expression of a canonical GR-regulated gene (ptgs2 P < .001) and genes encoding potential immunomodulatory drug targets (cxcl8, ptger4, ido1; P < .001) (Figure 10, n = 46). In a small subset of patients (n = 11), sustained clinical responses were associated with increases in T cell counts (P = .06) and IFNγ (P = .03), as well as decreases in Tregs. Neutrophil-to-lymphocyte ratio (NLR) was also normalized in these patients (p=0.01).

[0282] Conclusions: Evidence of T cell activation by Relacorilant was observed in PBMCs, syngeneic mouse tumors, and in patients with durable responses in a phase 1 study, supporting the hypothesis that Relacorilant may reverse endogenous cortisol-mediated immunosuppression in solid tumor cancers.

[0283] Example 4. Short-term Relacorilant Effects in T-Cells A short-term (7-day) EG7 pharmacodynamic study was performed in female B6 CD45.1 mice to evaluate the effect of Relacorilant + αPD1 on T cell proliferation and activation. Spleens and tumor sections from B6 CD45.1 female mice inoculated subcutaneously with E.G7-OVA mouse lymphoma cells and treated with CORT125134 (30 mg / kg, orally, once daily for 7 days) and RMP1-14 (10 mg / kg, intraperitoneally, every 5 days for a total of 2 doses), alone and in combination, were analyzed using flow cytometry. Unlike previous studies, cell and cytokine analysis was performed in parallel before differences in tumor volume were detected (Figure 14). Therefore, changes in tumor volume may not affect the cytokine or T cell measurements in this study. There were no adverse effects of treatment on clinical symptoms or body weight changes.

[0284] Antigen-specific T cells are important mediators of anti-tumor immune responses. The EG7 model expresses the model antigen ovalbumin. Antigen-specific T cells can be quantified by measuring T cells that recognize ovalbumin. Cells that bind T cell markers (e.g., anti-CD3 and anti-CD8) and bind labeled ovalbumin tetramer are considered antigen-specific T cells. Antigen-specific T cells were increased in the spleen and tumor by the combination of Relacorilant + αPD1 (Figure 15). CD69 expression, a marker of T cell activation, in splenic CD8+ T cells was also increased by the combination (Figure 16). Relacorilant or αPD1 alone was sufficient to induce PD1 expression in splenic CD8- T cells (Figure 16). CD3+CD8+ T cells were increased in the spleen by the combination (Figure 16). TNFα in serum was increased by the combination (Figure 17). While αPD1 alone increased IL-6 levels, the combination of Relacorilant + αPD1 achieved antigen-specific T cell potency and proliferation without increasing IL-6 (Figure 17). The observed in vivo effects, including T cell activation and TNFα secretion, are consistent with the in vitro effects observed in isolated human PBMCs.

[0285] Conclusion: Administration of Relacorilant with αPD1 increased the number of antigen-specific T cells in the spleen and tumors in WT mice, as well as CD69 expression in the spleen. This combination was effective in increasing the number of antigen-specific T cells without raising IL-6. Combination therapy of RMP1-14 / CORT125134 (10 / 30 mg / kg) resulted in a significant (p≦0.05) increase in OVA tetramer+ as a percentage of CD8+ cells in tumors compared to vehicle control and the RMP1-14 and CORT125134 monotherapy alone, as well as significantly (p≦0.05) higher levels of CD8+OVA tetramer+ as a percentage of CD3+ cells compared to vehicle control. The RMP1-14 and CORT125134 monotherapy and the RMP1-14 / CORT125134 combination therapy resulted in a significant (p≦0.05) increase in PD-1+ as a percentage of CD8+ cells in the spleen compared to vehicle controls. The combination therapy also led to significantly (p≦0.05) higher levels of CD3+CD8+ as a percentage of CD45.1+ cells in the spleen compared to vehicle controls and RMP1-14 monotherapy. These effects, including T cell activation and TNFα secretion, are consistent with the in vitro effects observed in isolated human PBMCs.

[0286] All patents, patent publications, publications, and patent applications recited in this specification are hereby incorporated by reference in their entirety into this specification, as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In addition, although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those skilled in the art in light of the teachings of the present invention that certain changes and modifications can be made without departing from the spirit or scope of the appended claims.

[0287] Exemplary aspects of the invention are described below. <1> 1. A method of improving immune function in a cancer patient having a solid tumor, comprising administering to the cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal selective glucocorticoid receptor modulator (SGRM), thereby improving the patient's immune function. <2> the improved immune function is effective to produce an anti-cancer effect in a patient having a solid tumor, thereby slowing tumor growth, halting tumor growth, reducing tumor burden, or a combination thereof; <1> 2. A method for improving immune function as described in claim 1. <3> the improved immune function comprises increased CD8+ T cell activation compared to CD8+ T cell activation prior to administration of the nonsteroidal SGRM; <1> or <2> The method according to <4> the improved immune function comprises increased proinflammatory cytokine secretion compared to the proinflammatory cytokine secretion prior to administration of the nonsteroidal SGRM. <1> or <2> The method according to <5> the improved immune function comprises increased TNFα secretion compared to TNFα secretion prior to administration of the nonsteroidal SGRM; <1> or <2> The method according to <6> the improved immune function comprises increased IFNγ secretion compared to IFNγ secretion prior to administration of the non-steroidal SGRM. <1> or <2> The method according to <7> the immune function is improved for a number of days selected from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days or more following administration of the nonsteroidal SGRM; <1> ~ <6> 2. The method according to claim 1 , <8> The non-steroidal SGRM is a compound comprising a heteroaryl ketone-fused azadecalin structure having the formula: <1> ~ <6> Either way: [ka] During the ceremony R 1is a heteroaryl ring having 5 to 6 ring members and having 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, each heteroaryl ring being independently R 1a may be substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, N-oxide, C 3-8 Cycloalkyl and C 3-8 heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein said heterocycloalkyl ring and heteroaryl ring have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; R 2 are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, C 1-6 Alkyl-C 1-6 Alkoxy, CN, OH, NR 2a R 2b , C(O)R 2a , C(O)OR 2a , C(O)NR 2a R 2b , S.R. 2a , S(O)R 2a , S(O)2R 2a , C 3-8 Cycloalkyl and C 3-8 heterocycloalkyl groups, wherein the heterocycloalkyl groups are selected from the group consisting of 1 to 4 R 2c may be substituted with a group; Or, two R attached to the same carbon 2 groups combine to form an oxo group (=O); Or, two R2 groups combine to form a heterocycloalkyl ring having 5-6 ring members and 1-3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2d may be substituted with a group; R 2a and R 2b are each independently hydrogen and C 1-6 selected from the group consisting of alkyl; R 2c are each independently hydrogen, halogen, hydroxy, or C 1-6 Alkoxy, C 1-6 Haloalkoxy, CN, and NR 2a R 2b selected from the group consisting of; R 2d are each independently hydrogen and C 1-6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O); R 3 Each has 1 to 4 R 3a phenyl and pyridyl, each of which may be substituted with an alkyl group; R 3a are each independently hydrogen, halogen, or C 1-6 haloalkyl; The subscript n is an integer from 0 to 3. <9> The nonsteroidal SGRM is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, referred to as relacorilant, and having the structure: <8> The method described above. [ka] <10> The nonsteroidal SGRM is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,-7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, designated CORT122928, having the structure: <8> The method according to [ka] <11> The non-steroidal SGRM is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazoloP,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone, designated CORT113176, having the structure: <8> The method according to [ka] <12> The non-steroidal SGRM is an octahydro-fused azadecalin structure compound having the formula: <1> ~ <6> 2. The method according to claim 1 , [ka] During the ceremony, R 1 are each independently R 1a is selected from the group consisting of pyridine and thiazole, optionally substituted with 1 to 4 groups selected from R 1a are independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 1-6 Haloalkoxy, N-oxide, and C 3-8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; R 2 are each independently hydrogen, C 1-6 Alkyl, halogen, C 1-6 selected from the group consisting of haloalkyl, and -CN; R 3a is F; The subscript n is an integer from 0 to 3. <13> The nonsteroidal SGRM is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, referred to as an exicholant, and having the structure <12> The method according to [ka] <14> The nonsteroidal SGRM is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(thiazol-2-yl)methanone, designated "CORT125329," having the structure: <12> The method according to [ka] <15> the cancer treatment comprises administering a chemotherapeutic agent; <1> ~ <14> 2. The method according to claim 1 , <16> the chemotherapeutic agent is selected from the group consisting of taxanes, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, antimetabolites, mitotic inhibitors, and combinations thereof; <15> The method according to <17> the chemotherapeutic agent is a taxane; <15> The method according to <18> The chemotherapeutic agent is nab-paclitaxel; <17> The method according to <19> the cancer treatment comprises administering an immunotherapeutic agent; <1> ~ <14> 2. The method according to claim 1 , <20> the immunotherapy comprises administering an antibody checkpoint inhibitor directed to a protein target selected from PD-1, PD-L1, CTLA-4, LAG3, B7-H3, B7-H4, OX-40, CD137, and TIM3; <19> The method according to <21> The cancer treatment comprises one or more of cancer radiation therapy, administration of a growth factor inhibitor, and administration of an anti-angiogenic factor; <1> ~ <14> 2. The method according to claim 1 , <22> The selective glucocorticoid receptor modulator is a selective glucocorticoid receptor antagonist. <1> ~ <21> 2. The method according to claim 1 ,

Claims

1. 1. A medicament for use in a method for reducing regulatory T cells in a cancer patient having a solid tumor, comprising a nonsteroidal selective glucocorticoid receptor antagonist (SGRA), (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, designated relacorilant, having the structure The method includes administering to the cancer patient an effective amount of a cancer treatment and an effective amount of the non-steroidal SGRA, thereby reducing regulatory T cells in the patient. The said medicine. 【Chemistry 1】

2. The method of claim 1, wherein the use is effective to increase CD8+ T cell activation compared to CD8+ T cell activation before administration of the non-steroidal SGRA.

3. The method of claim 1, wherein the use is effective to increase pro-inflammatory cytokine secretion compared to the pro-inflammatory cytokine secretion prior to administration of the non-steroidal SGRA.

4. The method of claim 1, wherein said use is effective to increase TNFα secretion compared to TNFα secretion before administration of said non-steroidal SGRA.

5. The method of claim 1, wherein the use is effective to increase IFNγ secretion compared to IFNγ secretion before administration of the non-steroidal SGRA.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the use is effective to reduce regulatory T cells following administration of the non-steroidal SGRA for a number of days selected from 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 10 days, 14 days or more.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer treatment comprises administering a chemotherapeutic agent.

8. The pharmaceutical composition of claim 7, wherein the chemotherapeutic agent is selected from the group consisting of taxanes, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, antimetabolites, mitotic inhibitors, and combinations thereof.

9. The pharmaceutical composition of claim 7 , wherein the chemotherapeutic agent is a taxane.

10. The pharmaceutical composition of claim 9, wherein the chemotherapeutic agent is nab-paclitaxel.

11. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer treatment comprises administering an immunotherapeutic agent.

12. The pharmaceutical of claim 11, wherein the immunotherapeutic agent comprises administering an antibody checkpoint inhibitor directed against a protein target selected from PD-1, PD-L1, CTLA-4, LAG3, B7-H3, B7-H4, OX-40, CD137, and TIM3.

13. The pharmaceutical composition according to any one of claims 1 to 6, wherein the cancer treatment comprises one or more of cancer radiation therapy, administration of a growth factor inhibitor, and administration of an anti-angiogenic factor.

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