Methods for normalizing neutrophil / lymphocyte ratio in cancer patients using selective glucocorticoid receptor antagonists

Abstract

A method for treating a cancer patient with a neutrophil-to-lymphocyte ratio (NLR) greater than 3 is disclosed, comprising administering a nonsteroidal glucocorticoid receptor antagonist (GRA) to the cancer patient, which is effective in reducing the NLR in the patient. The method comprises administering the nonsteroidal GRA to the cancer patient and administering a cancer treatment, which is effective in reducing the NLR in the patient and enhancing the treatment of the cancer patient. The GRA may be administered orally. The nonsteroidal GRA may be a nonsteroidal compound containing a heteroaryl ketone-fused azadecalin structure (e.g., relacolinant) or a nonsteroidal compound containing an octahydro-fused azadecalin structure (e.g., exicolinant). The cancer treatment includes chemotherapy, immunotherapy, radiation therapy, administration of antiangiogenic agents, administration of growth factor inhibitors, and surgery. The method enhances cancer treatment, improves the prognosis of cancer patients, improves survival rates, and provides beneficial clinical effects and benefits to patients.

Description

[Background technology]

[0001] Cancer is a diverse group of diseases characterized by the uncontrolled proliferation and metastasis of abnormal cells. Cancer is the leading cause of death in the United States and worldwide. In cancer cells, pathways that control cell division and / or cell-cell communication become altered in such a way that the effect of these control mechanisms in controlling and limiting cell proliferation is disabled or bypassed. Through successive rounds of mutation and natural selection, a population of abnormal cells (usually arising from a single mutant cell) accumulates additional mutations that confer a selective proliferation advantage over other cells, thereby evolving into a cell type that is dominant in the cell population. As cancer cells further evolve, some of them become locally invasive and subsequently metastasize to colonizing tissues other than the tissue of origin of the cancer cells. This characteristic, together with the heterogeneity of the tumor cell population, makes cancer a particularly difficult disease to treat and eradicate.

[0002] The ratio of absolute neutrophil count to absolute lymphocyte count is called the neutrophil / lymphocyte ratio (NLR). NLR is a prognostic or predictive factor for response to chemotherapy in multiple cancer treatments (An et al., “Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer” Biomarkers. 15(6):516-522, 2010; Proctor et al., “A derived neutrophil to lymphocyte ratio predicts survival in patients with cancer” Br J Cancer. 107(4):695-699, 2012; Xue et al., “Neutrophil-to-lymphocyte ratio for predicting palliative chemotherapy outcomes in advanced pancreatic cancer patients” Cancer Med. 3(2):406-15, 2014; Stotz et al., “Increased neutrophil-lymphocyte ratio is a poor prognostic factor in patients with primary operable and inoperable pancreatic cancer. Br J Cancer” 109(2):416-421, 2013). 2013; Teo et al., “Prognostic role of neutrophil-to-lymphocyte ratio in advanced pancreatic ductal adenocarcinoma: impact of baseline fluctuation and changes during chemotherapy” Tumori. 99(4):516-522, 2013; Wang et al., “Comparison of the prognostic values ​​of various inflammation-based factors in patients with pancreatic cancer” Med Oncol. 29(5):3092-3100, 2012). NLR is also predictive of response to checkpoint inhibitors, also called immune cancer therapy, such as PD-1 inhibitors (Sacdalan et al., “Prognostic utility of baseline neutrophil-to-lymphocyte ratio in patients receiving immune checkpoint inhibitors: a review and meta-analysis” OncoTargets and Therapy. 11:955-65, 2018). In patients with metastatic renal cell carcinoma, a decrease in NLR due to cancer treatment was associated with better treatment outcomes compared to patients whose NLR did not decrease (Lalani et al., J. ImmunoTherapy Cancer 6:5 (2018)). Neutrophil / lymphocyte ratios below the threshold of 3 neutrophils per lymphocyte (NLR<3) are usually considered low or normal. An NLR below 3 is associated with better outcomes in several cancer treatments. Conversely, a high NLR is associated with poorer outcomes. These systemic measurements are consistent with the role of each cell type in tumor biology: tumor-associated neutrophils mediate tumor progression (Hurt et al. “Cancer-promoting mechanisms of tumor-associated neutrophils” Am J Surg. 214(5):938-944, 2017), whereas tumor-infiltrating lymphocytes promote tumor clearance (Mahmoud et al., “Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer” J Clin Oncol.29(15):1949-55, 2011). Therefore, lowering the NLR to normal levels of about 3 or lower would be expected to improve outcomes in the treatment of several cancers.

[0003] The glucocorticoid receptor (GR) is a nuclear hormone receptor that regulates the transcription of multiple genes. GR also regulates blood cellular composition through two previously described mechanisms: cell type-specific apoptosis (Saffar et al., "The Molecular Mechanisms of Glucocorticoids-Mediated Neutrophil Survival" Current Drug Targets. 12(4): 556-562, 2011) and the regulation of genes involved in cell trafficking between the peripheral zone (i.e., lymph nodes and spleen) and the circulating blood (Burton et al., "Regulation of L-selectin and CD18 on bovine neutrophils by glucocorticoids: effects of cortisol and dexamethasone" J Leukocyte Biol. 57(2):317-25, 1995). Dexamethasone, a synthetic GR agonist, increases circulating neutrophils and decreases circulating lymphocytes (Mishler and Emerson, "Development of Neutrophilia by serially increasing doses of dexamethasone" Br J Hematol. 36(2):249-57, 1977).Excessive production of cortisol, an endogenous GR agonist, which is the primary pathogenesis of Cushing's disease, increases circulating neutrophils and decreases circulating lymphocytes (de la Balze et al., “Differential blood counts in certain adrenal cortical disorders (Cushing's syndrome, Addison's disease and panhypopituitarism)” J Clin Endocrinol Metab. 6:312-9, 1946; Masri-Iraqi et al., “Elevated white blood cell counts in Cushing's disease: association with hypercortisolism” Pituitary. 17:436-440, 2014; Tatsi et al., “Decreased lymphocytes and increased risk for infection are common in endogenous pediatric Cushing syndrome. Pediatric Res. 83(2):431-437, 2018). When cortisol levels are normalized in Cushing's patients (often by surgical removal of tumorous areas of the pineal gland), circulating neutrophils decrease and circulating lymphocytes increase (Masri-Iraqi, 2014). Thus, excessive physiological GR receptor agonism has been shown to elevate the NLR.

[0004] GR-mediated signaling pathways have dynamic biological effects that involve various components of the immune system, and their effects in vivo are unpredictable. For example, glucocorticoids have been reported to have both immunosuppressive and immunoenhancing effects, such as suppressing inflammatory cytokines, promoting anti-inflammatory cytokines, inhibiting dendritic cells, suppressing natural killer cells, promoting regulatory T cells, and inducing T cell apoptosis. See Hinrichs et al., "Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells." J. Immunother. 28 (6): 517-524 (2005). GR-mediated signaling pathways on cancer cells are similarly difficult to understand. On the other hand, activation of the GR signaling pathway is believed to induce apoptosis in certain types of cancer cells, such as malignant lymphatic cancers (see, for example, Schlossmacher et al., “Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells” J. Endocrinol. 211:17-25 (2011)). On the other hand, it has also been reported that drugs that inhibit the GR signaling pathway can enhance chemotherapeutic effects in killing cancer cells of epithelial origin (see, for example, U.S. Patent No. 9,149,485).

[0005] The effect, if any, of GR antagonism on the NLR is unknown. Administration of mifepristone (also known as RU-486) ​​to healthy men does not alter the blood abundance of neutrophils or lymphocytes (Laue, 1990). Addison's disease patients often have lower than normal serum cortisol levels, but these patients have normal neutrophil abundance (de la Balze, "Differential blood counts in certain adrenal cortical disorders (Cushing's syndrome, Addison's disease and panhypopituitarism)" J Clin Endocrinol Metab. 6:312-9, 1946) and function (Bancos et al., "Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality" Eur J Endocrinol. 176(4):471-480, 2017).

[0006] Thus, the effect, if any, of GR antagonism on NLRs is unknown, and there remains a need for improved cancer therapies, including those that exploit the prognostic value of NLRs in cancer treatment. Summary of the Invention [Means for solving the problem]

[0007] Applicant discloses a method for normalizing the neutrophil / lymphocyte ratio (NLR). For cancer patients, a higher than normal NLR (greater than 3) predicts poor prognosis. A reduction in the NLR is associated with improved outcome of cancer treatment. Reducing the NLR in cancer patients to normal values ​​(i.e., less than about 3) can improve the prognosis of these patients, improve the patient's response to cancer treatment, improve the outcome of cancer therapy, reduce tumor burden, and facilitate tumor removal. As mentioned above, mifepristone does not affect the NLR in healthy subjects, as it does not alter the abundance of neutrophils or lymphocytes in healthy subjects (Laue, 1990). Surprisingly, as disclosed herein, administration of a nonsteroidal GRA was effective in reducing the NLR in cancer patients undergoing cancer treatment.

[0008] The methods disclosed herein include selecting a cancer patient with an NLR greater than 3 and administering a nonsteroidal glucocorticoid receptor antagonist (GRA), such as relacorilant, in combination with a cancer treatment to normalize (reduce) the NLR in a cancer patient undergoing cancer treatment and with a high NLR. The methods disclosed herein include administering a nonsteroidal GRA, such as relacorilant, in combination with a cancer treatment to treat a cancer patient undergoing cancer treatment and with a high NLR. The methods disclosed herein include administering a nonsteroidal GRA, such as relacorilant, in combination with a cancer treatment to enhance the response to the cancer treatment in a cancer patient undergoing cancer treatment and with a high NLR. The methods disclosed herein include administering a nonsteroidal GRA, such as relacorilant, in combination with a cancer treatment to reduce tumor burden in a cancer patient undergoing cancer treatment and with a tumor or tumors and with a high NLR. The methods disclosed herein include administering a nonsteroidal GRA, such as relacorilant, in combination with a cancer treatment to promote tumor clearance in a cancer patient undergoing cancer treatment and with a high NLR. The methods disclosed herein include administering a nonsteroidal GRA, such as relacorilant, in combination with a cancer treatment to improve the health of cancer patients with high NLR.The methods disclosed herein include administering a nonsteroidal GRA, such as relacorilant, in combination with a taxane, such as nab-paclitaxel, to cancer patients with high NLR to reduce the NLR, improve the patient's response to the taxane, and improve the health of the cancer patient.

[0009] In some embodiments, the cancer treatment may include administration of a chemotherapeutic agent (e.g., a taxane such as nab-paclitaxel, gemcitabine, or other chemotherapeutic agent). In some embodiments, the cancer treatment may include administration of an immunotherapeutic agent (e.g., a checkpoint inhibitor, such as an antibody against a protein target selected from PD-1, PD-L1, CTKA4, LAG3, B7-H3, B7-H4, OX-40, CD137, and TIM3, or other immunotherapy). In some embodiments, the cancer treatment may include administering radiation therapy (e.g., directing ionizing radiation to the tumor, injecting a radiopharmaceutical composition, implanting a radiation source, or other radiation therapy). The cancer treatment may include surgery and other cancer treatments, or a combination of these cancer treatments.

[0010] In some embodiments of the methods disclosed herein, the non-steroidal GRA is a non-steroidal compound comprising a fused azadecalin structure. In some embodiments, the compound comprising a fused azadecalin structure is a compound described and disclosed in U.S. Patent No. 7,928,237 and U.S. Patent No. 8,461,172. In some embodiments, the compound comprising a heteroaryl ketone fused azadecalin structure is a compound described and disclosed in U.S. Patent No. 8,859,774. In some embodiments, the compound comprising an octahydro fused azadecalin structure is a compound described and disclosed in U.S. Patent No. 10,047,082. The entire contents of these patents, as well as all patents, patent applications, patent publications, and publications described herein, both supra and infra, are incorporated herein by reference in their entirety.

[0011] In some embodiments, for example, the nonsteroidal GRA is a heteroaryl ketone-fused azadecalin compound (e.g., a compound disclosed in U.S. Pat. No. 8,859,774). In a specific embodiment, the nonsteroidal GRA 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, also known as "Relacorilant" and as "CORT125134" (Example 18 of U.S. Pat. No. 8,859,774), having the following structure: [ka]

[0012] Lelacorilant is chemically different from mifepristone, which is a steroidal compound.Unlike mifepristone, Lelacorilant does not antagonize progesterone receptor.Therefore, Lelacorilant (and other condensed azadecalin compounds disclosed in, for example, U.S. Patent No. 8,859,774, U.S. Patent No. 7,928,237, U.S. Patent No. 8,461,172, and U.S. Patent No. 10,047,082, and other patents cited herein) provides a means to selectively antagonize glucocorticoid receptor.The effect of Lelacorilant on NLR has not been described before.

[0013] In some cases, the selective nonsteroidal GRA is administered orally. In some cases, the selective nonsteroidal GRA is administered by injection, infusion, transdermal application, atomized suspension, or aerosol spray.

[0014] In some cases, the effective amount of the nonsteroidal selective GRA is a daily dose of 1-100 mg / kg per day, hi some embodiments, the dose of the nonsteroidal selective GRA is a daily dose of 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg per day. In some cases, the GRA is administered for 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or more, 7 weeks or more, 8 weeks or more, 9 weeks or more, 10 weeks or more, 11 weeks or more, 12 weeks or more, 13 weeks or more, 14 weeks or more, 15 weeks or more, 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more, 25 weeks or more, 30 weeks or more, 35 weeks or more, 40 weeks or more, 45 weeks or more, 50 weeks or more, 55 weeks or more, 60 weeks or more, 65 weeks or more, 70 weeks or more, 75 weeks or more, 80 weeks or more, or until the cancer gets worse (disease progression).

[0015] The present methods provide improved methods of normalizing (reducing) NLR in cancer patients undergoing cancer treatment who have high NLR, enhancing the response to cancer treatment in cancer patients undergoing cancer treatment who have high NLR (e.g., improving the response of cancer patients who have high NLR to taxane (e.g., nab-paclitaxel) chemotherapy), reducing tumor burden in cancer patients who have a tumor or tumors and who have high NLR and are undergoing cancer treatment, promoting tumor removal in cancer patients undergoing cancer treatment who have high NLR, and improving the health of cancer patients undergoing cancer treatment who have high NLR. The present methods provide benefits to patients by improving and enhancing cancer treatment, slowing disease progression, improving patient lifespan and survival, quality of life, and other beneficial health outcomes. [Brief description of the drawings]

[0016] [Figure 1] Effect of Relacorilant on Neutrophil / Lymphocyte Ratio (NLR) in Healthy Subjects. Dosing and evaluation schedules for the healthy subject study. (A) Single ascending dose (SAD) prednisone dosing regimen. (B) Multiple ascending dose (MAD) prednisone dosing regimen. (C) Figure legend. [Diagram 2] Patients with Advanced Solid Tumors: Segment I Continuous Dosing Regimen, Part 1: Titration, Part 2: Extension. "CORT125134" refers to relacorilant. "PK Collect" refers to blood samples collected for pharmacokinetic measurements ("Collect"). "CORT125134" refers to relacorilant. [Diagram 3] Patients with Advanced Solid Tumors: Segment II Intermittent Dosing Regimen: Part 1 and Part 2. "PK Collection" refers to blood samples collected for pharmacokinetic measurements ("Collection"). "CORT125134" refers to relacorilant. [Figure 4] The NLR was measured in nine healthy subjects who received 25 milligrams (mg) of prednisone in the absence and presence of Relacorilant. A single dose of 500 mg of Relacorilant attenuated the effect of 25 mg of prednisone on the NLR in healthy subjects. [Diagram 5] NLR was measured in healthy subjects receiving prednisone in the absence and presence of Relacorilant. Multiple doses of 250 mg Relacorilant (250 mg per day for 14 consecutive days) attenuated the effect of 25 mg prednisone compared with 25 mg prednisone alone. [Figure 6] Multiple doses of 250 mg of relacorilant (250 mg per day for 14 consecutive days) attenuated the effect of 25 mg of prednisone on the NLR compared with the NLR measured in healthy subjects who received a placebo control for 14 consecutive days prior to prednisone. [Figure 7A] Compared with the NLR in healthy subjects, the NLR is elevated in many cancer patients. [Figure 7B] 250 mg of relakolinant alone does not alter the NLR in healthy subjects. [Figure 8] AUC (right) or Cmax (left) were related to changes in NLR during 7 days of relacorilant alone in patients with advanced solid tumors. [Figure 9] Administration of relacorilant plus nab-paclitaxel for 8 days reduces NLR in patients with solid tumors. [Figure 10] FIG. 1 shows the change in NLR in patients with advanced solid tumors with a baseline NLR of 3 or less (shown in the graph on the left) compared with the change in NLR in patients with advanced solid tumors with a baseline NLR of >3 (shown in the graph on the right). [Figure 11] In ovarian cancer patients who achieved a complete response to treatment with Relacorilant plus nab-paclitaxel, the NLR decreased (after 7 days of Relacorilant alone). [Figure 12] Figure 1 shows the change in NLR (in log2 units) from baseline during the first 8 days (left) or 15 days (right) of cycle 1 in patients with progressive disease (PD), stable disease (SD), and partial or complete response (PR / CR). The horizontal line represents the median. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] A. Introduction The method disclosed herein includes selecting cancer patients with an NLR greater than 3, and administering a nonsteroidal glucocorticoid receptor antagonist (GRA), such as relacorilant, in combination with a cancer treatment to normalize (reduce) the NLR in cancer patients undergoing cancer treatment who have high NLR. The neutrophil / lymphocyte ratio (NLR) is usually elevated in cancer patients compared to the NLR observed in healthy individuals. An NLR greater than 3 is excessive and is a value often found in patients suffering from cancer. Restoration of the NLR to a healthier value (e.g., about 3 or less) is indicative of a beneficial response to cancer treatment. Restoration of the NLR to a healthier value (e.g., about 3 or less) is associated with improved treatment outcomes for cancer treatment compared to cancer patients who do not show normalization of the NLR. It is believed that normalizing (reducing) the NLR in cancer patients undergoing cancer treatment, with an NLR greater than 3, can aid in cancer treatment, improve the outcome of cancer treatment, reduce tumor burden in cancer patients with a tumor or multiple tumors, facilitate tumor removal in cancer patients with a tumor or multiple tumors, or aid in achieving a beneficial response to cancer treatment. Antagonism of cortisol activity by administration of a nonsteroidal selective glucocorticoid receptor antagonist (GRA), such as a heteroaryl ketone fused azadecalin GRA, for example, Relacorilant (also called "CORT125134" or "RELA"), in combination with cancer chemotherapy or other cancer treatment, is believed to be effective in treating cancer patients and in reducing NLR levels in cancer patients undergoing treatment. Applicant discloses herein that antagonism of endogenous cortisol activity is associated with response to combination treatment with Relacorilant and Nab-paclitaxel (NP or nab-pac). Applicants disclose herein that antagonism of endogenous cortisol activity is associated with response to combination treatment with Relacorilant and Nab-paclitaxel.

[0018] Glucocorticoids, including endogenous cortisol, promote chemotherapy resistance through upregulation of genes that control cell survival pathways, such as DUSP1 ("dual specificity phosphatase 1") and SGK1 ("serum / glucocorticoid regulated kinase 1") (DUSP1: Accession No. NM_004417.2, NSID No. NM_004417.2:987; SGK1: Accession No. NM_005627.2, NSID No. NM_005627.2:1790). Relacorilant, a nonsteroidal selective GRA, antagonizes the effects of cortisol. Relacorilant+NP achieved disease control at or beyond week 16 in 19 / 49 (39%) patients with refractory advanced solid tumors in a phase 1 study, including patients who had progressed on prior taxane therapy. Biomarkers of cortisol activity were defined following prednisone administration in healthy subjects and assessed in patients with solid tumors receiving Relacorilant + Nab-paclitaxel.

[0019] method: Lymphocyte and neutrophil abundance was determined using a standard differential complete blood count test.

[0020] result: In healthy subjects (n=9), administration of 25 milligrams (mg) of prednisone actually increased the neutrophil-to-lymphocyte ratio (NLR) by 4.7-fold; this effect was reversed by coadministration of relacorilant. In cancer patients, the NLR was significantly elevated at baseline but was normalized by relacorilant.

[0021] These results indicate that relacorilant attenuates prednisone-induced NLR induction in healthy subjects. Elevated NLR in cancer patients was reduced by relacorilant, consistent with and suggesting elevated endogenous glucocorticoid receptor (GR) activity in cancer patients.

[0022] These results indicate that administration of a nonsteroidal selective GRA, such as relaxorilant, was effective in normalizing (reducing) high NLR in cancer patients undergoing cancer treatment who have high NLR. Thus, administration of a nonsteroidal selective GRA to cancer patients undergoing cancer treatment who have high NLR can normalize (reducing) high NLR in such cancer patients and enhance cancer treatment, thereby providing clinical benefit to the patients.

[0023] Thus, the present methods for treating cancer patients with a neutrophil / lymphocyte ratio (NLR) greater than 3 are effective in reducing the patient's NLR and enhancing the treatment of the cancer patient. In some embodiments, the cancer treatment may include chemotherapy, immunotherapy, radiation therapy, administration of antiangiogenic agents, administration of growth factor inhibitors, and surgery. The methods may enhance cancer treatment, improve the prognosis of the cancer patient, slow disease progression, improve the lifespan and survival of the cancer patient, improve the quality of life of the patient, and provide other beneficial health outcomes, beneficial clinical effects, and other benefits to the patient.

[0024] B. Definition The term "subject" or "patient" as used herein refers to a human or non-human organism. Thus, the methods and compositions described herein are applicable to human and animal diseases. In some embodiments, the subject is a "patient", i.e., a living human undergoing medical care for a disease or condition. This includes people without a clear illness who are being investigated for signs of a medical condition. In some cases, the subject may suffer from one or more types of cancer simultaneously. Cancers include, but are not limited to, prostate cancer, breast cancer, renal cell carcinoma, melanoma, pancreatic cancer, adrenocortical carcinoma, cervical cancer, ovarian cancer, endometrial (or uterine) cancer, vulvar cancer, colorectal cancer, head and neck cancer, lung cancer, sarcoma, hepatocellular tumor, glioblastoma, neuroendocrine tumor, bladder cancer, gallbladder / cholangiocarcinoma, gastric cancer, and mesothelioma.

[0025] Cancer is characterized by the uncontrolled growth and / or spread of abnormal cells. Usually, a biopsy is taken and cells or tissues from the biopsy are examined under a microscope to confirm the suspected condition. In some cases, additional tests on the cells' proteins, DNA, and RNA must be performed to verify the diagnosis.

[0026] As used herein, the terms "tumor" and "cancer" are used interchangeably and both refer to an abnormal growth of tissue resulting from excessive cell division. Tumors that can invade surrounding tissues and / or metastasize are said to be "malignant." Tumors that do not metastasize are said to be "benign."

[0027] "Tumor burden" or "tumor burden" as used herein generally refers to the number of cancer cells, tumor size, or amount of cancer in a subject's body at a given time. Tumor burden can be detected, for example, by measuring the expression of tumor-specific gene markers and by measuring tumor size by a number of known biochemical or imaging methods disclosed herein below.

[0028] The term "checkpoint protein" as used herein refers to a protein present on the surface of certain types of cells, such as T cells and certain tumor cells, that can induce checkpoint signaling pathways leading to the regulation of immune responses. Commonly known checkpoint proteins include CTLA4, PD-1, PD-L1, LAG3, B7-H3, B7-H4, TIM3, CD160, CD244, VISTA, TIGIT, OX-40, CD137, and BTLA (Pardoll, 2012, Nature Reviews Cancer 12:252-264; Baksh, 2015, Semin Oncol. 2015 Jun;42(3):363-77). Of these, CTLA4, PD-1, and PD-L1 are the most well-studied, and therapies targeting these proteins are more clinically advanced than those targeting other checkpoint proteins.

[0029] The term "PD-1" as used herein 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 surrounding tissues during inflammation in response to infection and to limit autoimmunity. PD-1 expression is induced on activated T cells, and upon binding to one of its endogenous ligands, PD-1 functions to inhibit T cell activity by inhibiting stimulatory kinases. PD-1 also functions to inhibit TCR "stop signals." PD-1 is highly expressed on Treg cells (regulatory T cells) and can increase their proliferation in the presence of ligand (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0030] The term "PD-L1" as used herein refers to programmed cell death 1 ligand 1 (also known as CD274 and B7-H1), a ligand for PD-1. PD-L1 is present on activated T cells, B cells, myeloid cells, macrophages, and tumor cells. There are two endogenous ligands for PD-1 (PD-L1 and PD-L2), but antitumor therapy has focused on anti-PD-L1. The complex of PD-1 and PD-L1 inhibits the proliferation of CD8+ T cells and reduces immune responses (Topalian et al., 2012, N. Engl J. Med. 366:2443-54; Brahmer et al., 2012, N. Engl J. Med. 366:2455-65).

[0031] The term "CTLA4" as used herein refers to cytotoxic T-lymphocyte antigen 4 (also known as CD152), a member of the immunoglobulin superfamily that is exclusively expressed on T cells. CTLA4 has been reported to function to inhibit T cell activation, inhibit helper T cell activity, and enhance the immunosuppressive activity of regulatory T cells. Although the exact mechanism of action of CTL4-A is under investigation, it has been suggested that CTL4-A inhibits T cell activation by outcompeting CD28 in binding to CD80 and CD86 on antigen-presenting cells and actively transmitting an inhibitory signal to T cells (Pardoll, 2012, Nature Reviews Cancer 12:252-264).

[0032] The term "checkpoint inhibitor" as used herein refers to any molecule, including antibodies and small molecules, that modulates the immunosuppressive pathway induced by one or more checkpoint proteins. A checkpoint inhibitor is usually an antibody ("CIA") against at least one checkpoint protein. Such an antibody can block the immunosuppressive activity of a checkpoint protein. A number of such antibodies have been shown to be effective in the treatment of cancer, for example, antibodies against PD-1, CTLA4, and PD-L1. However, a checkpoint inhibitor may also be a small molecule non-protein compound ("CIC") that blocks the immunosuppressive pathway induced by one or more checkpoint proteins.

[0033] The term "antibody" as used herein includes full length antibodies and "antigen-binding portions" of antibodies. The term "antigen-binding portion" as used herein refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen (e.g., PD-1). Examples of binding fragments encompassed by the term "antigen-binding portion" 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 comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VL 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 (VL and VH) of the Fv fragment are encoded by separate genes, they can be linked by a synthetic linker that allows them to be produced, using recombinant techniques, as a single protein chain in which the VL and VH regions pair to form a monovalent molecule (also known as single-chain Fvs (scFvs); 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 by the term "antigen-binding portion" of an antibody. Any VH and VL sequence of a particular scFv can be linked to cDNA or genomic sequences of human immunoglobulin constant regions to produce expression vectors encoding complete IgG molecules or other isotypes. The VH and VI may also be used in the production of Fab, Fv, or other immunoglobulin fragments using protein chemistry or recombinant DNA techniques. Other forms of single chain antibodies, such as diabodies, are also encompassed.Bispecific antibodies are bispecific antibodies in which the VH and VL domains are expressed as a single peptide chain, with a linker that is too short to allow pairing between the two domains on the same chain, allowing these domains to pair with one another's complementary domains to create two antigen-binding sites (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).

[0034] Antibodies may be polyclonal or monoclonal, and may be xeno-, allo- or syngeneic, or modified forms thereof (e.g., humanized, chimeric, etc.). Antibodies against checkpoint proteins bind specifically or substantially specifically to one or more checkpoint proteins. The term "monoclonal antibody" refers to a population of antibody molecules that contain only one type of antigen-binding site capable of immune-responding to a particular epitope of an antigen. In contrast, the terms "polyclonal antibody" and "polyclonal antibody composition" refer to a population of antibody molecules that contain multiple types of antigen-binding sites capable of interacting with a particular antigen. A monoclonal antibody composition typically exhibits a single binding affinity for the particular antigen to which it immune-responds.

[0035] The term "antibody effective against checkpoint protein" as used herein refers to an antibody that can bind to a checkpoint protein and antagonize the function of the checkpoint protein in suppressing immune response. For example, an antibody against PD-1 refers to an antibody that can bind to PD-1 and inhibit the suppressive function of PD-1 in immune response, for example, by inhibiting the interaction between PD-1 and PD-L1. In some cases, the antibody may be against two checkpoint proteins, i.e., it has the ability to bind to two checkpoint proteins and suppress their functions.

[0036] The term "neutrophil" as used herein is generally accepted in the medical field and refers to the most abundant granulocyte in mammalian blood. Neutrophils are also known as neutrocytes. As part of the immune system, neutrophils phagocytose foreign cells and substances present in the blood. The cytoplasm of neutrophils stains medium pink when treated with hematoxylin and eosin stain. Neutrophils usually have rod-shaped or segmented nuclei.

[0037] The term "lymphocytes" as used herein is generally accepted in the medical field and refers to white blood cells that form the majority of cells in lymph. Lymphocytes include natural killer cells, T cells, and B cells. When blood samples are stained with Wright's stain, lymphocytes exhibit large, deeply staining nuclei with little eosinophilic cytoplasm.

[0038] As used herein, the terms "neutrophil / lymphocyte ratio" and "NLR" refer to the ratio of the number of neutrophil cells divided by the number of lymphocyte cells in a blood sample obtained from a subject.

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[0039] As used herein, the term "normalize" the NLR refers to reducing an elevated (greater than 3) NLR value to an NLR value of 3, preferably to an NLR value of 3 or less. In the most preferred embodiment, the NLR is reduced to a value less than 3.

[0040] As used herein, for example with respect to patient survival, the term "survival" refers to the period of time after initiation of treatment before the death of the patient.

[0041] As used herein, the term "progression-free survival" refers to the period of time after initiation of treatment during which the tumor does not significantly grow (or "progress") in a patient who originally had the tumor.

[0042] The term "stable response" or "stable response" as used herein refers to a patient who originally had a tumor in which the tumor has remained roughly the same size, but which may include either a small amount of growth (usually less than 20% or 25%) or a small amount of shrinkage (albeit less than would be considered a "partial response").

[0043] As used herein, the term "partial response" (PR) refers to a patient with an original tumor who has experienced (approximately) a 50% or greater reduction in total tumor volume, but still has some evidence of residual disease. In some cases, the residual disease in a deep response may actually be dead tumor or scar, and a small number of patients classified as having a PR may actually have a CR. Also, many patients who show tumor shrinkage during treatment may show further tumor shrinkage and achieve a CR with continued treatment.

[0044] The term "complete response" (CR) as used herein refers to a patient who originally had a tumor who has had the disappearance of all detectable tumor as demonstrated by laboratory tests, physical examination, and imaging.

[0045] The term "chemotherapy" as used herein refers to medical procedures that are typically used to treat cancer. Chemotherapy includes the use of drugs that are toxic to cancerous tissues or cells, or that act to slow or reduce the growth and spread of cancerous tissues or cells. Chemotherapeutic agents include anti-cancer drugs, which may be derived from natural compounds (e.g., taxol), may mimic, or reduce or inhibit the action of natural hormones, growth factors, or immunologically active molecules, may be synthetic small molecules; may be antibodies or antibody conjugates; or may be other drugs. Exemplary chemotherapeutic agents include, but are not limited to, taxanes, taxol, docetaxel, paclitaxel, gemcitabine, actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, bleomycin, cisplatin, trastuzumab (Herceptin®), trastuzumab emtansine (Kadcyla®), imatinib (Gleevec®), eribulin (Halaven®), and PARP inhibitors ("PARP" stands for pharmacological inhibitors of poly ADP-ribose polymerase), among others, well known in the art.

[0046] The term "compound" as used herein is used to refer to a molecular moiety of a unique and identifiable chemical structure. The molecular moiety ("compound") may exist in the form of a free species, not bound to other molecules. The compound may exist as part of a larger aggregate bound to other molecule(s) but still retaining its chemical identity. A solvate, in which a molecular moiety of a defined chemical structure ("compound") is bound to a molecule(s) of solvent, is an example of such a bound form. A hydrate is a solvate in which the bound solvent is water. The reference "compound" refers to the molecular moiety itself (of the described structure), whether in free or bound form.

[0047] The term "composition" as used herein is intended to encompass products containing specific components in specific amounts, such as the compounds, their tautomeric forms, their derivatives, their analogs, their stereoisomers, their polymorphs, their pharma- ceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharma- ceutically acceptable solvates and pharma- ceutical acceptable compositions, as well as any products resulting directly or indirectly from the combination of the specific components in the specific amounts. Such terms in relation to pharmaceutical compositions are intended to encompass products containing the active ingredient(s) and the inactive ingredient(s) constituting the carrier, as well as any products resulting directly or indirectly from the combination, complexation, or aggregation of any two or more components, or from the dissociation of one or more components, or from any other type of reaction or interaction of one or more components. Thus, the pharmaceutical compositions of the present invention are intended to encompass any compositions produced by mixing the compounds of the present invention with their pharma- ceutical acceptable carriers.

[0048] The terms "pharmaceutically acceptable additives" and "pharmaceutically acceptable carriers" as used herein are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, as well as isotonic and absorption delaying agents, etc., that are compatible with drug administration. The terms "pharmaceutically acceptable additives" and "pharmaceutically acceptable carriers" 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 toxic effects to the patient. The use of such solvents and agents for pharmaceutically active substances is well known in the art. Except in the case where any conventional solvent or agent is incompatible with the active agent, its use in the composition is contemplated. Additional active compounds may be incorporated into the composition. Non-limiting examples of pharmaceutically acceptable additives include water, NaCl, saline, lactated Ringer's solution, normal sucrose, normal glucose, binders, excipients, disintegrants, lubricants, coatings, sweeteners, flavorings, and colorings. Those of skill in the art will recognize that other pharmaceutical excipients are useful in the present invention.

[0049] The terms "administer", "administering", "administered" or "administration" as used herein refer to providing a compound or composition 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 by buccal administration (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., delivery of the compound or composition via a needle, microneedle, pressurized syringe, or other means of piercing the skin or forcing the compound or composition through the skin of the subject. Injection may be intravenous (i.e., injection into a vein), intraarterial (i.e., injection into an artery), intraperitoneal (i.e., injection into the abdominal cavity), intramuscular (injection into a muscle), or other injection route. Routes of administration include rectal, intravaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneous (e.g., by absorption into the skin from an implant containing the compound or composition), or other routes.

[0050] The term "combination therapy" as used herein refers to the administration of two or more pharmaceutical agents to a subject to treat a disease. The two agents may be administered simultaneously or sequentially in any order during all or part of the treatment period. The two or more agents may be administered according to the same or different dosing schedules. In some cases, one agent is administered according to a regular treatment schedule and the other agent is administered intermittently. In some cases, both agents are administered intermittently. In some embodiments, one agent (e.g., a nonsteroidal SGRA) is administered daily and the other agent (e.g., a chemotherapeutic agent) is administered every second, third, or fourth day.

[0051] As used herein, the term "co-administration" refers to administration of two compositions at the same time or within a short time of each other, for example, within about 0.5 hours, within about 1 hour, within about 2 hours, within about 4 hours, within about 6 hours, within about 8 hours, within about 10 hours, within about 12 hours, within about 16 hours, within about 20 hours, or within about 24 hours of each other.

[0052] The term "effective amount" or "therapeutic amount" as used herein refers to an amount of a pharmaceutical agent effective in treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, a "therapeutically effective amount" or "effective amount" may refer to an amount of a functional agent or pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. An effective amount may be an amount effective to produce a beneficial response in a patient. An effective amount may be an amount effective to induce an anti-tumor response. An effective amount may be an amount effective to induce a humoral and / or cellular immune response in a recipient subject that results in growth inhibition or death of target cells. For purposes of this disclosure, a therapeutic amount of a checkpoint inhibitor is an amount that may reduce tumor burden or produce other desired beneficial clinical outcomes related to cancer amelioration.

[0053] As used herein, the phrases "not specific for treatment with a glucocorticoid receptor modulator" or "not specific for treatment with a glucocorticoid receptor antagonist" refer 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 fatty liver. Conditions known in the art and recognized by the medical community as being effectively treatable with a glucocorticoid receptor antagonist include psychosis associated with interferon-alpha treatment, major depression due to psychosis, dementia, stress-related disorders, autoimmune disorders, neurological damage, and Cushing's syndrome.

[0054] In some embodiments, the term "consisting essentially of" refers to a composition in a formulation where the only active ingredient is the indicated active ingredient, while other compounds may be included that are intended to stabilize, preserve, etc. the formulation, but are not directly involved in the therapeutic effect of the indicated active ingredient. In some embodiments, the term "consisting essentially of" may refer to a composition that includes an active ingredient and a component that facilitates release of the active ingredient. For example, the composition may include one or more components that provide a sustained release of the active ingredient to the subject over an extended period of time. In some embodiments, the term "consisting essentially of" refers to a composition that includes an active ingredient and a pharma- ceutically acceptable carrier or excipient.

[0055] As used herein, the terms "steroid" and "steroids," and the expression "steroid backbone" in the context of glucocorticoid receptor antagonists that include them, refer to glucocorticoid receptor antagonists that contain modifications of the basic structure of cortisol, the endogenous steroidal glucocorticoid receptor ligand. The basic structure of the steroid backbone is defined by Formula I: [ka]

[0056] The term "glucocorticosteroids" ("GC") or "glucocorticoids" refers to steroid hormones that bind to the glucocorticoid receptor. Glucocorticosteroids are generally characterized by having 21 carbons, an α,β-unsaturated ketone in ring A, and an α-ketone group attached to ring D. They vary in the degree of oxygenation or hydrogenation at C-11, C-17, and C-19 (see Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives," in Biochemistry, Daisy et al. (eds.), 1989, pg. 567).

[0057] The mineralocorticoid receptor (MR), also known as the type I glucocorticoid receptor (GRI), is activated by aldosterone in humans.

[0058] The term "cortisol" refers to the naturally occurring glucocorticoid hormone (also known as hydrocortisone) produced by the zona fasciculata of the adrenal gland. Cortisol has the following structure: [ka]

[0059] The term "mifepristone" refers to 11β-(4-dimethylaminophenyl)-17β-hydroxy-17α-(1-propynyl)-estra-4,9-dien-3-one), having the following structure: [ka] Mifepristone is a steroid used in the treatment of rheumatoid arthritis. It is also used in the treatment of rheumatoid arthritis. + Mifepristone is also known as glucocorticoid receptor (GR), progesterone receptor (PR), and androgen receptor (AR), and is therefore not GR selective.

[0060] The term "prednisone" refers to the synthetic glucocorticoid 17α,21-dihydroxypregna-1,4-diene-3,11,20-trione, having the following structure: [ka]

[0061] The term "glucocorticoid receptor" ("GR") as used herein refers to a family of intracellular receptors that specifically bind cortisol and / or cortisol analogs. Glucocorticoid receptors are also referred to as cortisol receptors. The term includes isoforms of GR, recombinant GR, and mutant GR. "Glucocorticoid receptor" ("GR") refers to type II GR that specifically binds cortisol and / or cortisol analogs such as dexamethasone (see, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005 35 283-292).

[0062] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates any biological response associated with the binding of an agonist to GR. For example, GRMs that function as agonists, such as dexamethasone, increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human hepatocellular carcinoma cell line, ECACC, UK). GRMs that act as antagonists, such as mifepristone, decrease the activity of tyrosine aminotransferase (TAT) in HepG2 cells.

[0063] "Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits any biological response associated with the binding of an agonist to GR. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the effects of dexamethasone. TAT activity can be measured as reviewed in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. Modulators can be measured by measuring the IC 50 (50% inhibitory concentration) is less than 10 micromolar. See Example 1 below.

[0064] As used herein, the term "selective glucocorticoid receptor antagonist" (SGRA) refers to any composition or compound that inhibits any biological response associated with the binding of GR to an agent (inhibition is determined relative to the response in the absence of the compound). By "selective", the agent preferentially binds to GR rather than other nuclear receptors such as the progesterone receptor (PR), mineralocorticoid receptor (MR), or androgen receptor (AR). A selective glucocorticoid receptor antagonist has 10-fold or greater affinity (1 / 10th the 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 a more preferred embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 100-fold greater (1 / 100th the K value) than it does to MR, AR, or PR, or both MR and PR, or both MR and AR, or both AR and PR, or MR, AR, and PR. d In another embodiment, the selective glucocorticoid receptor antagonist binds to GR with an affinity that is 1000-fold or greater (1 / 1000th of a K value) than that for MR, AR, or PR, both MR and PR, both MR and AR, both AR and PR, or MR, AR, and PR. d The GR binds with an affinity of 0.1 μg / L (value).

[0065] As used herein, the expression "non-steroidal backbone" in the context of GRA refers to GRA that does not share structural homology with or is not a modification of cortisol, which has a steroidal backbone containing 17 carbon atoms bonded to four fused rings. Such compounds include synthetic mimetics and analogs of proteins, including partially peptidic, pseudopeptidic, and nonpeptidic molecular entities.

[0066] Nonsteroidal selective GRA compounds include compounds that contain fused azadecalin structures (sometimes called fused azadecalin skeletons), including compounds that contain heteroaryl-ketone fused azadecalin structures (sometimes called heteroaryl-ketone fused azadecalin skeletons) and compounds that contain octahydro fused azadecalin structures (sometimes called octahydro fused azadecalin skeletons). Exemplary nonsteroidal selective GRA compounds that contain fused azadecalin structures include those described and disclosed in U.S. Patent Nos. 7,928,237 and 8,461,172. Exemplary nonsteroidal selective GRA compounds that contain heteroaryl-ketone fused azadecalin structures include those disclosed in U.S. Patent Nos. 8,859,774, 9,273,047, 9,707,223, and 9,956,216. Exemplary nonsteroidal selective GRA compounds containing an octahydro-fused azadecalin structure include those described and disclosed in U.S. Patent No. 10,047,082. All patents, patent publications, and patent applications disclosed herein, above and below, are hereby incorporated by reference in their entirety.

[0067] In one embodiment, the heteroaryl-ketone fused azadecalin GRA 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 compound having the following structure (Example 18 of U.S. Pat. No. 8,859,774, also known as "Relacorilant" and "CORT125134"). [ka]

[0068] In one embodiment, 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)(pyridin-2-yl)methanone having the following structure (Example 1 of U.S. Pat. No. 8,859,774, referred to as "CORT113176"). [ka]

[0069] In one embodiment, the octahydro-fused azadecalin GRA 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 compound having the following structure (Example 2C of U.S. Pat. No. 10,047,082, referred to as "exicholant" or "CORT125281"). [ka]

[0070] In one embodiment, the octahydro-fused azadecalin GRA is the compound ((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-4-yl)methanone* having the following structure (Example 2AJ of U.S. Pat. No. 10,047,082, referred to as "CORT125329"). [ka]

[0071] The description of the compounds of the present invention is limited to the principles of chemical bonding known to those skilled in the art. Thus, a group may be substituted with one or more substituents, which are selected to produce compounds that conform to the principles of chemical bonding and are not inherently unstable, and / or that would be known to those skilled in the art to be potentially unstable under ambient conditions, such as aqueous, neutral, or physiological conditions.

[0072] C. Glucocorticoid receptor antagonists (GRAs) In general, normalization of the NLR in cancer patients undergoing cancer treatment in whom the NLR is elevated can be achieved by administration of an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA) of any chemical structure or mechanism of action.

[0073] Exemplary nonsteroidal selective GRAs that contain heteroaryl ketone fused azadecalin structures include those described in U.S. Patent No. 8,859,774, which can be prepared as disclosed in U.S. Patent No. 8,859,774, the entirety of which is incorporated herein by reference. Such exemplary GRAs may be SGRAs. In some cases, the GRAs that contain heteroaryl ketone fused azadecalin structures have the following structure, or are salts or isomers thereof: [ka] During the ceremony, R 1 is R 1a is a 5- or 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, which may be substituted by 1 to 4 groups independently selected from R 1a are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN, N-oxide, C3-C8 cycloalkyl, and C3-C8 heterocycloalkyl; Ring J is selected from the group consisting of a cycloalkyl ring, a heterocycloalkyl ring, an aryl ring, and a heteroaryl ring, wherein the heterocycloalkyl ring and the heteroaryl ring are 5-6 membered rings having 1-4 heteroatoms each independently selected from the group consisting of N, O, and S. R 2 are respectively hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 alkyl-C1-C6 alkoxy, -CN, -OH, -NR 2a R 2b , -C(O)R 2a , -C(O)OR 2a , -C(O)NR 2a R 2b , -SR 2a , -S(O)R 2a , -S(O)2R 2a , C 3-8 cycloalkyl, and C-C heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of 1 to 4 R 2C optionally substituted with a group, Alternatively, two R's linked to the same carbon 2 The groups combine to form an oxo group (=O), Or, two R 2 groups combine to form a 5-6 membered heterocycloalkyl ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2d optionally substituted with a group, R 2a and R 2b are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; R 2c are hydrogen, halogen, hydroxy, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN, and -NR 2a R 2b each independently selected from the group consisting of R 2dare each independently selected from the group consisting of hydrogen and C1-C6 alkyl, or two R 2d The groups combine to form (=O), R 3 is 1 to 4 R 3a is selected from the group consisting of phenyl and pyridyl, each of which may be substituted with a group; R 3a are each independently selected from the group consisting of hydrogen, halogen, and C1-C6 haloalkyl; The subscript n is an integer between 0 and 3.

[0074] Exemplary nonsteroidal selective GRAs containing octahydro-fused azadecalin structures include those described in U.S. Patent No. 10,047,082, which can be prepared as disclosed therein, the entirety of which is incorporated herein by reference.Such exemplary GRAs may be SGRAs.In some cases, the GRAs containing octahydro-fused azadecalin structures have the following structure, or are salts or isomers thereof: [ka] During the ceremony, R 1 is R 1a is selected from the group consisting of pyridine and thiazole, each of which may be substituted with 1 to 4 groups independently selected from R 1a are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, N-oxide, and C3-C8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole, and triazole; R 2 are each independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, and -CN; R 3a is F, The subscript n is an integer from 0 to 3.

[0075] D. Identification of Selective Glucocorticoid Receptor Antagonists To determine whether a nonsteroidal test compound is a nonsteroidal selective GRA (nonsteroidal SGRA), the compound is first assayed for its ability to bind to GR and inhibit GR-mediated activity to determine whether the compound is a glucocorticoid receptor antagonist. If the compound is identified as a glucocorticoid receptor antagonist, it is subjected to a selectivity test to determine 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 one embodiment, the SGRA binds to GR with a sufficiently high affinity, for example, with an affinity 10-fold or more higher than non-GR proteins. The SGRA may exhibit 100-fold, 1000-fold, or more selectivity for binding to GR compared to binding to non-GR proteins.

[0076] i. 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 many 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 the 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 bound to the glucocorticoid receptor indicates that the bound 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 a fluorescently labeled steroid analog). Alternatively, the binding of the test compound to the glucocorticoid receptor can be measured directly using a labeled test compound. The latter type of assay is referred to as a direct binding assay.

[0077] Both direct and competitive binding assays can be used in a variety of different formats. The formats may be the same as those used in immunoassays and receptor binding assays. For a description of different formats of binding assays, including competitive and direct binding assays, see Basic and Clinical Immunology 7th Edition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, ET 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.

[0078] In a solid-phase competitive binding assay, for example, a sample compound can compete with a labeled analyte for a specific binding site on a binding agent bound to a solid surface. In this type of format, the labeled analyte can be a glucocorticoid receptor ligand, and the binding agent can be a glucocorticoid receptor bound to a solid phase. Alternatively, the labeled analyte can be a labeled glucocorticoid receptor, and the binding agent can be a solid-phase glucocorticoid receptor ligand. The concentration of the labeled analyte bound to the capture agent is inversely proportional to the competitive ability of the test compound in the binding assay.

[0079] Alternatively, competitive binding assays may be performed in liquid phase, and bound labeled protein may be separated from unbound labeled protein using various techniques known in the art. For example, several means have been developed to distinguish between bound and excess bound ligand, or between bound and excess unbound test compound. These include sedimentation in sucrose gradients, gel electrophoresis, or gel isoelectric focusing; precipitation of receptor-ligand complexes with protamine sulfate or adsorption onto hydroxyapatite; and identification of bound complexes by removal of unbound compound or unbound ligand by adsorption onto dextran-coated charcoal (DCC) or binding to immobilized antibodies. Following separation, the amount of bound ligand or test compound is determined.

[0080] Alternatively, homogeneous binding assays may be performed in which no separation step is required. For example, the label on the glucocorticoid receptor may be altered by binding of the glucocorticoid receptor to its ligand or test compound. This change in the labeled glucocorticoid receptor results in a decrease or increase in the signal emitted by the label, and measurement of the label at the end of the binding assay allows detection or quantification of the bound glucocorticoid receptor. A wide variety of labels may be used. Compounds may be labeled in any of several ways. Useful radioactive labels include: 3 H, 125 I, 35 S, 14C, or 32 Useful non-radioactive labels include those incorporating fluorophores, chemiluminescent agents, phosphorescent agents, and electrochemiluminescent agents. 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 to the compound, stability requirements, and available measurement means. For a review of various labeling and signal generating systems that can be used, see U.S. Pat. No. 4,391,904, which is incorporated herein by reference in its entirety for all purposes. The label may be linked directly or indirectly to the desired analytical component by methods well known in the art. In some cases, the test compound is contacted with 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 or free labeled ligand is estimated by measuring the fluorescence polarization of the labeled ligand.

[0081] ii.Activity 1) HepG2 tyrosine aminotransferase (TAT) analysis Compounds that demonstrate the desired binding affinity to GR are then tested for their ability to inhibit GR-mediated activity. Compounds are typically subjected to a tyrosine aminotransferase assay (TAT assay), which evaluates the ability of a test compound to inhibit the induction of tyrosine aminotransferase activity by dexamethasone. See Example 1. GR modulators suitable for the methods disclosed herein have an IC of less than 10 micromolar. 50 (50% inhibitory concentration). Other assays, including but not limited to those described below, can also be developed to confirm the GR modulating activity of compounds.

[0082] 2) Cell-based analysis Cell-based assays involving whole cells or cell fractions containing glucocorticoid receptors can also be used to analyze the binding or activity modulation of test compounds to glucocorticoid receptors.Exemplary cell types that can be used in the methods disclosed herein 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 carcinomas, cervical carcinomas, glioblastomas, liver cells, kidney cells, and neuronal cells, as well as fungal cells, including yeast.The cells can be primary cells, tumor cells, or other types of immortalized cell lines.Of course, glucocorticoid receptors can be expressed in cells that do not express endogenous glucocorticoid receptors.

[0083] In some cases, fragments of the glucocorticoid receptor and protein fusions can be used for screening. If a molecule that competes with the glucocorticoid receptor ligand for binding is desired, the GR fragment used is a fragment that can bind to the ligand (e.g., dexamethasone). Alternatively, any fragment of GR can be used as a target to identify molecules that bind to the glucocorticoid receptor. The glucocorticoid receptor fragment can include any fragment, for example, 20 amino acids or more, 30 amino acids or more, 40 amino acids or more, 50 amino acids or more, up to a protein that contains all but one amino acid of the glucocorticoid receptor.

[0084] In some embodiments, the reduction of signal transduction caused by glucocorticoid receptor activation is used to identify glucocorticoid receptor antagonists. The signal transduction activity of glucocorticoid receptor can be determined in many ways. For example, downstream molecular events can be monitored to determine signal transduction activity. Downstream events include activation or symptoms resulting from stimulation of glucocorticoid receptor. Exemplary downstream events useful in functional evaluation of transcriptional activation and antagonism in unmodified cells include upregulation of a number of glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase). In addition, certain cell types that are sensitive to GR activation may be used, such as osteocalcin expression in osteoblasts, which shows glucocorticoid-mediated downregulation, and primary hepatocytes, which show glucocorticoid-mediated upregulation of PEPCK and glucose-6-phosphate (G-6-Pase). GRE-mediated gene expression has also been demonstrated in transgenic cell lines using well-known GRE-regulated sequences (e.g., the mouse mammary tumor virus cell 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 assays measuring IL-1β-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 transgenic cell lines.

[0085] Compounds tested in whole cell assays may also be tested in cytotoxicity assays. Cytotoxicity assays are used to determine to what extent a perceived effect is due to non-glucocorticoid receptor binding cellular effects. In an exemplary embodiment, the cytotoxicity assay involves contacting constitutively active cells with the test compound. Any reduction in cellular activity indicates a cytotoxic effect.

[0086] 3) Additional analysis Other examples of the many assays that can be used to identify compositions that can be used in the methods disclosed herein are assays based on glucocorticoid activity in vivo.For example, an assay can be used that evaluates the ability of a putative GR regulator to inhibit glucocorticoid-stimulated incorporation of 3H-thymidine into cellular DNA.Alternatively, a putative GR regulator competes with 3H-dexamethasone for binding to hepatoma tissue culture GR (see, for example, Choi, et al., Steroids 57:313-318, 1992).As another example, a putative GR regulator can be used to inhibit the nuclear binding of 3H-dexamethasone-GR complex (Alexandrova et al., J. Steroid Biochem. Mol. Biol. 41:723-725, 1992). To further identify putative GR modulators, kinetic analyses capable of distinguishing between glucocorticoid agonists and glucocorticoid modulators by receptor binding kinetics (as described in Jones, Biochem J. 204:721-729, 1982) can also be used.

[0087] In another example, the assays described in Daune, Molec. Pharm. 13:948-955, 1977, and U.S. Pat. No. 4,386,085, can be used to identify anti-glucocorticoid activity. Briefly, thymocytes from adrenalectomized rats are cultured in nutrient medium containing dexamethasone with various concentrations of a test compound (a putative GR modulator). The cell cultures are 3H-uridine is added, incubated further, and the extent of incorporation of the radiolabel into polynucleotides is measured. 3 H-uridine reduces the amount of H-uridine, so GR modulators would counter this effect.

[0088] iii.Selectivity The GR antagonists selected above are then subjected to a selectivity analysis to determine whether they are SGRAs. Typically, the selectivity analysis involves testing the compounds that bind to glucocorticoid receptors in vitro for the degree of binding to non-glucocorticoid receptor proteins. As described above, the selectivity analysis may be performed in vitro or in a cell-based system. Binding may be tested against any suitable non-glucocorticoid receptor protein, such as antibodies, receptors, and enzymes. In an exemplary embodiment, the non-corticoid receptor binding protein is a cell surface receptor or a nuclear receptor. In another exemplary embodiment, the non-glucocorticoid receptor protein is a steroid receptor, such as an estrogen receptor, a progesterone receptor, an androgen receptor, or a mineralocorticoid receptor.

[0089] The selectivity of an antagonist for GR compared to MR can be measured using various assays known in the art. For example, a particular 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 an assay can be performed using either 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 the 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 for the receptor is then measured directly. Those GR modulators that show 10-fold or more, 100-fold or more, and often 1000-fold or more, higher affinity for GR compared to MR are then selected for use in the methods disclosed herein.

[0090] Selectivity assays may also include assaying for the ability to inhibit GR-mediated but not MR-mediated activity. One way to identify such GR-specific modulators is to assess the ability of antagonists to inhibit the activation of a reporter construct using a transfection assay (see, e.g., Bocquel et al, J. Steroid Biochem Molec. Biol. 45:205-215, 1993; U.S. Pat. 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 cotransfected 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 an analog thereof, capable of activating the hormone-responsive promoter / enhancer sequence of the receptor plasmid. The transfected and cultured host cell is then monitored for induction (i.e., presence) of the product of the reporter gene sequence. Finally, the expression and / or steroid binding capacity of hormone receptor protein (encoded by the receptor DNA sequence on an expression plasmid and produced in transfected and cultured host cells) is measured by determining the activity of the reporter gene in the presence and absence of the antagonist. The antagonist activity of the compound may 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 maximum percent response observed for each compound relative to the reference antagonist compound. GR modulators that show 100-fold or more, 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.

[0091] D. Pharmaceutical Compositions and Administration In some embodiments, the present invention provides a pharmaceutical composition for normalizing NLR in a cancer patient undergoing cancer treatment in which the NLR is elevated, the pharmaceutical composition comprising a pharma- ceutical acceptable excipient and a GRA. In some embodiments, the pharmaceutical composition comprises a pharma- ceutical acceptable excipient and an SGRA. In a preferred embodiment, the pharmaceutical composition comprises a pharma- ceutical acceptable excipient and a non-steroidal SGRA.

[0092] Nonsteroidal SGRAs 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 the patient. Nonsteroidal SGRAs can also be administered by injection, i.e., intravenously, intramuscularly, intradermally, subcutaneously, intraduodenally, or intraperitoneally. Nonsteroidal SGRAs can also be administered by inhalation, e.g., intranasally. Additionally, nonsteroidal SGRAs can be administered transdermally. Thus, the present invention also provides pharmaceutical compositions comprising a pharma- ceutically acceptable carrier or excipient and a nonsteroidal SGRA.

[0093] For preparing pharmaceutical compositions from nonsteroidal SGRAs, 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 also function as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or encapsulating materials. Details of techniques for formulation and administration are fully described in the scientific and patent literature (see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington")).

[0094] In powders, the carrier is a finely divided solid which is a mixture with the finely divided active ingredient, a nonsteroidal SGRA. In tablets, the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

[0095] The powders and tablets preferably contain 5% or 10% to 70% of the active ingredient. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low melting wax, and cocoa butter. The term "preparation" is intended to include the formulation of the active ingredient with an encapsulating material as a carrier to provide a capsule, in which the active ingredient is surrounded by and bound by a carrier, with or without other carriers. Similarly, cachets and lozenges are also included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid preparations suitable for oral administration.

[0096] Suitable solid excipients are carbohydrate and protein excipients, including, but not limited to, sugars including lactose, sucrose, mannitol, or sorbitol; starches of corn, wheat, rice, potato, or other vegetables; celluloses such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums including gum arabic and gum tragacanth; and proteins such as gelatin and collagen. If desired, disintegrating and solubilizing agents may be added, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or a salt of alginic acid, such as sodium alginate.

[0097] Dragee cores are provided with suitable coatings such as concentrated sugar solutions, lacquer solutions, and suitable organic solvents or solvent mixtures, which may contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the amount of active ingredient (i.e., dosage). The pharmaceutical preparations disclosed herein may also be used orally using, for example, push-fit capsules made of gelatin, as well as soft sealed capsules made of gelatin and a coating such as glycerol or sorbitol. Push-fit capsules may contain the GR modulator mixed with excipients or binders such as lactose or starch, lubricants such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the GR modulator compound may be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol, with or without stabilizers.

[0098] 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.

[0099] Aqueous solutions suitable for oral use can be prepared by dissolving the active ingredient in water and adding suitable colorants, flavorings, stabilizers and thickeners as required. Aqueous suspensions suitable for oral use can be prepared 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 natural phospholipids (e.g., lecithin), condensation products of fatty acids and alkylene oxides (e.g., polyoxyethylene stearate), condensation products of long-chain fatty alcohols and ethylene oxide (e.g., heptadecaethyleneoxycetanol), condensation products of partial esters derived from fatty acids and hexitols and ethylene oxide (e.g., polyoxyethylene sorbitol monooleate), or condensation products of partial esters derived from fatty acids and hexitol anhydrides and ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). 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 preparations may be adjusted for osmolality.

[0100] Also included are solid form preparations that are converted into liquid form preparations immediately before use for oral administration.Such liquid forms include solutions, suspensions and emulsions.These preparations may contain, in addition to the active ingredient, colorants, flavorings, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizers, etc.

[0101] Oil suspensions may be formulated by suspending the nonsteroidal SGRAs in a vegetable oil, such as peanut oil, olive oil, sesame oil, or coconut oil, or in a mineral oil, such as liquid paraffin, or a mixture thereof. Oil suspensions may contain thickening agents, such as beeswax, hard paraffin, or cetyl alcohol. Sweeteners, such as glycerol, sorbitol, or sucrose, may be added to provide a palatable oral preparation. These preparations may be preserved by the addition of an antioxidant, such as ascorbic acid. For examples of injectable oily vehicles, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical preparations disclosed herein may be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil, as described above, or a mixture thereof. Suitable emulsifying agents include natural gums (acacia and tragacanth), natural phospholipids (e.g., soybean lecithin), esters or partial esters derived from fatty acids and hexitol anhydrides (e.g., sorbitan monooleate), and condensation products of these partial esters with ethylene oxide (e.g., polyoxyethylene sorbitan monooleate). Emulsifying agents may also contain sweetening and flavoring agents in the formulation of syrups and elixirs. Such formulations may also contain a demulcent, preservative, or coloring agent.

[0102] Nonsteroidal SGRAs can be delivered transdermally, topically, and formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and aerosols.

[0103] Nonsteroidal SGRAs can also be delivered as microspheres for sustained release in the body. For example, the microspheres can be administered by intradermal injection of drug-containing microspheres for subcutaneous sustained release (see Rao, J. Biomater Sci. Polym. Ed. 7:623-645, 1995), as biodegradable 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 provide constant delivery for weeks to months.

[0104] The pharmaceutical formulations disclosed herein may be provided as salts, which may be formed with many acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, butyric acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be soluble in aqueous or other protic solvents and are the corresponding free base forms. In other cases, the preparations may be lyophilized powders in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, with a pH range of 4.5-5.5, and mixed with a buffer prior to use.

[0105] In another embodiment, the formulations disclosed herein can be delivered using liposomes that fuse with or are incorporated into cell membranes, for example, by using ligands that are bound to the liposomes or directly bound to oligonucleotides, which bind to cell surface membrane protein receptors and cause endocytosis. Liposomes can be used to focus the delivery of GR modulators into target cells in vivo, especially when the liposome surface carries target cell-specific ligands or ligands that selectively target specific organs (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).

[0106] Pharmaceutical preparations are preferably in unit dosage form.In such form, the preparation is divided into unit doses containing an appropriate amount of the active ingredient nonsteroidal SGRA.The unit dosage form may be a packaged preparation, such as a packaged tablet, capsule, and powder in a vial or ampoule, where the package contains a discrete amount of the preparation.The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or any of the appropriate number of these packaged forms.

[0107] The quantity of active ingredient in a unit dose preparation may vary or be adjusted from 0.1 mg to 10000 mg, more typically from 1.0 mg to 6000 mg, most typically from 50 mg to 500 mg. Suitable doses include about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, about 1000 mg, about 1100 mg, about 1200 mg, about 1300 mg, about 1400 mg, about 1500 mg, about 1600 mg, about 1700 mg, about 1800 mg, about 1900 mg, or about 2000 mg, depending on the particular application and the potency of the active ingredient. If desired, the composition can also contain other compatible therapeutic agents.

[0108] The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is divided into unit doses containing appropriate amounts of the compounds and compositions of the present invention. The unit dosage form may be a packaged preparation, such as packaged tablets, capsules, and powders in vials or ampoules, where the package contains a discrete amount of the preparation. The unit dosage form may also be a capsule, tablet, cachet, or lozenge itself, or the appropriate number of any of these packaged forms.

[0109] The nonsteroidal SGRAs may be administered orally. For example, the nonsteroidal SGRAs may be administered in pill, capsule, or liquid form as described herein. Alternatively, the nonsteroidal SGRAs may be provided parenterally. For example, the nonsteroidal SGRAs may be administered intravenously (e.g., by injection or infusion). Alternative methods of administration of the compositions described herein, and pharmaceutical compositions or formulations thereof, are described herein.

[0110] In some embodiments, the nonsteroidal SGRA is administered in one dose. In other embodiments, the nonsteroidal SGRA 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 multiple doses are of equal amounts. In other cases, the multiple doses are of different amounts. The dose may increase or decrease over the period of administration. The amount will vary, for example, according to the properties of the nonsteroidal SGRA and the characteristics of the patient.

[0111] Any suitable nonsteroidal SGRA dose may be used in the methods disclosed herein. The dose of nonsteroidal SGRA administered may be about 300 milligrams (mg) or more per day, or about 600 mg or more per day, for example, about 600 mg per day, about 700 mg per day, about 800 mg per day, about 900 mg per day, about 1000 mg per day, about 1100 mg per day, about 1200 mg per day, or more. For example, when the nonsteroidal SGRA is relacorilant, the nonsteroidal SGRA dose may be, for example, 50 mg per day, 75 mg per day, 100 mg per day, 125 mg per day, 150 mg per day, 175 mg per day, 200 mg per day, 225 mg per day, 250 mg per day, 300 mg per day, 350 mg per day, 400 mg per day, or other amounts of relacorilant. In some embodiments, the nonsteroidal SGRA is administered orally. In some embodiments, the nonsteroidal SGRA is administered in one or more doses. In other words, the nonsteroidal SGRA may be administered in one, two, three, four, five, six, seven, eight, nine, ten, or more doses per day. In some embodiments, the nonsteroidal SGRA is administered orally 1 dose, 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, 8 doses, 9 doses, 10 doses, or more per day.

[0112] The subject may be administered one or more doses of the nonsteroidal SGRA in a single dose or multiple doses, for example, over a period of 2 to 48 hours. In some embodiments, the nonsteroidal SGRA is administered as a single dose. In other embodiments, the nonsteroidal SGRA is administered in one or more doses, for example, two, three, four, five, or more doses, 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 nonsteroidal SGRA is administered over a 2 to 48 hour period, over a 2 to 36 hour period, over a 2 to 24 hour period, over a 2 to 12 hour period, over a 2 to 8 hour period, over a 8 to 12 hour period, over a 8 to 24 hour period, over a 8 to 36 hour period, over a 8 to 48 hour period, over a 9 to 36 hour period, over a 9 to 24 hour period, over a 9 to 20 hour period, over a 9 to 12 hour period, over a 12 to 48 hour period, over a 12 to 36 hour period, over a 12 to 24 hour period, over a 18 to 48 hour period, over a 18 to 36 hour period, over a 18 to 24 hour period, over a 24 to 36 hour period, over a 24 to 48 hour period, over a 36 to 48 hour period, or over a 42 to 48 hour period.

[0113] Depending on the dosage and frequency required and tolerated by the patient, single or multiple doses of the formulation may be administered. The formulation should provide a sufficient amount of active agent to effectively treat the disease state. Thus, in certain embodiments, the pharmaceutical formulation for oral administration of nonsteroidal SGRAs is a daily dose of about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In some embodiments, the daily dose is about 1.0 to about 100 mg / kg / day, about 5 to about 50 mg / kg / day, about 10 to about 30 mg / kg / day, about 10 to about 20 mg / kg / day. In contrast to oral administration, administration into the bloodstream, or administration into a body cavity or organ cavity, lower doses may also be used, especially when the agent is administered to an anatomically isolated site such as the cerebrospinal fluid (CSF) space. In local administration, substantially higher doses may be used. 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, supra. See also Nieman, In "Receptor Mediated Antisteroid Action," Agarwal, et al., eds., De Gruyter, New York (1987).

[0114] The duration of treatment with nonsteroidal SGRAs for reducing the NLR, for treating cancer patients with high NLR, for enhancing cancer treatment in patients, for supporting chemotherapy in cancer patients (e.g., taxane-related treatments to improve the response of cancer patients with high NLR to nab-paclitaxel), or for improving the health of cancer patients, or for improving the symptoms of cancer in cancer patients, may vary depending on the severity of the subject's symptoms and the subject's response to the nonsteroidal SGRA. In some embodiments, the nonsteroidal SGRAs may 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 weeks to 60 weeks. Suitable periods of administration 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 durations of administration include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, 100 weeks, and 104 weeks. Usually, administration of the nonsteroidal SGRA should be continued until a clinically significant decrease or improvement is observed. Treatment with the nonsteroidal SGRA of the present invention may continue for a period of 2 years or more.

[0115] In some embodiments, administration of the nonsteroidal SGRA is not continuous, but may be stopped for one or more periods followed by one or more periods when administration is resumed. 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 is to cease also include 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks, 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 24 weeks, 25 weeks, 30 weeks, 32 weeks, 35 weeks, 40 weeks, 45 weeks, 48 ​​weeks, 50 weeks, 52 weeks, 55 weeks, 60 weeks, 64 weeks, 65 weeks, 68 weeks, 70 weeks, 72 weeks, 75 weeks, 80 weeks, 85 weeks, 88 weeks, 90 weeks, 95 weeks, 96 weeks, and 100 weeks.

[0116] The dosing regimen also takes into account pharmacokinetic parameters well known in the art, such as absorption rate, bioavailability, metabolism, and clearance (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, for the latest). The current state of the art allows the clinician to determine the dosing regimen for the individual patient, GR modulator, and disease or condition being treated.

[0117] Nonsteroidal SGRAs may be used in conjunction 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 effectiveness of the active agent.

[0118] In some embodiments, co-administration includes administration of one type of active agent, a nonsteroidal SGRA, within 0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 16 hours, 20 hours, or 24 hours of a second active agent. Co-administration includes administration of two active agents simultaneously, at about the same time (e.g., within about 1 minute, within about 5 minutes, within about 10 minutes, within about 15 minutes, within about 20 minutes, or within about 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 another embodiment, the active agents can be formulated separately. In other embodiments, the active agents and / or auxiliary agents can be linked or bound to each other.

[0119] After the pharmaceutical composition comprising the nonsteroidal SGRA has been formulated in an acceptable carrier, it may be transferred into an appropriate container and labeled for treatment of an indicated condition. For administration of the nonsteroidal SGRA, such labeling may include, for example, instructions regarding the amount, frequency, and method of administration.

[0120] The pharmaceutical compositions of the present invention may be provided as salts, which may be formed with many acids, including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, butyric acid, tartaric acid, malic acid, succinic acid, etc. Salts tend to be soluble in aqueous or other protic solvents and are the corresponding free base forms. In other cases, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol, with a pH range of 4.5-5.5, and mixed with a buffer prior to use.

[0121] In another embodiment, the compositions of the present invention are useful for parenteral administration, such as intravenous (IV) administration or administration into a body cavity or organ cavity. The compositions for administration will usually comprise a solution of the compositions of the present invention dissolved in a pharma- ceutically acceptable carrier. Acceptable solvents or vehicles that may be used are water and Ringer's solution, which is an isotonic saline solution. In addition, sterile fixed oils may be used in a conventional manner 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. These solutions are sterile and usually free of undesirable substances. These preparations may be sterilized by conventional, well-known sterilization techniques. The preparations may contain pharma-ceutically acceptable auxiliary substances required to approximate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of the composition of the present invention in these formulations may vary and will be selected primarily based on the volume of liquid, viscosity, body weight, etc., according to the particular administration method selected and the patient's requirements. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous or oily suspension. This suspension may be formulated according to well-known techniques using suitable dispersing or wetting agents. The sterile injectable preparation may be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution of 1,3-butanediol.

[0122] E. Cancer Treatment Cancer chemotherapy agents In some embodiments, cancer treatment for patients with high NLR may include the administration of chemotherapy. Chemotherapeutic agents suitable for combination with nonsteroidal SGRAs to normalize (reduce) NLR in cancer patients undergoing cancer treatment with high NLR include agents that have the property of killing cancer cells or inhibiting the proliferation of cancer cells, including but not limited to microtubule inhibitors (e.g., taxanes, vinca alkaloids, and plinabulin), topoisomerase inhibitors and antimetabolites (e.g., nucleoside analogs acting on their own, e.g., gemcitabine), mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, anthracyclines, intercalating agents, agents capable of inhibiting signal transduction pathways, agents promoting apoptosis, and proteosome inhibitors. Other anti-cancer agents, such as those disclosed in U.S. Patent Publication No. 20150218274 and at the "chemocare.com" website, for example, at page chemotherapy / what-is-chemotherapy / types-of-chemotherapy.aspx, may also be used in the practice of the methods disclosed herein.

[0123] Microtubule inhibitors include taxanes, vinca alkaloids, and plinabulin. Exemplary taxanes that can be combined with nonsteroidal SGRAs to treat cancer patients include, but are not limited to, paclitaxel and docetaxel. Non-limiting examples of paclitaxel agents include nanoparticle albumin-bound paclitaxel (ABRAXANE, sold by Abraxis Bioscience), docosahexaenoic acid-bound paclitaxel (DHA-paclitaxel, Taxoprexin, sold by Protarga), polyglutamic acid-bound paclitaxel (PG-paclitaxel, paclitaxel poliglumex, CT-2103, XYOTAX, sold by Cell Therapeutic), tumor-activated prodrug (TAP), ANG105 (Angiopep-2 bound to three molecules of paclitaxel, sold by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound to the erbB2-recognition peptide EC-1; Li et al., Biopolymers (2007) 87:225-230), and paclitaxel-EC-1 and glucose-conjugated paclitaxel (e.g., 2'-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620). Exemplary vinca alkaloids that may be combined with nonsteroidal SGRAs to treat cancer patients include, but are not limited to, vinorelbine tartrate (Navelbine®), vincristine (Oncovin®), and vindesine (Eldisine®); vinblastine (also known as vinblastine sulfate, vincaleukoblastine and VLB, Alkaban-AQ® and Velban®); and vinorelbine (Navelbine®). Plinabulin is a small molecule that inhibits microtubule assembly (eg, polymerization), has anti-angiogenic activity (eg, reduces tumor angiogenesis), and can induce apoptosis and mitotic arrest.

[0124] Alkylating agents are most active in the resting phase of cells. These classes of agents are cell cycle non-specific. Exemplary alkylating agents that may be combined with nonsteroidal SGRAs to treat cancer patients include, but are not limited to, nitrogen mustards, ethylenimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes: uracil mustard (Aminouracil Mustard®, Chlorethaminacil®, Demethyldopan®, Desmethyldopan®, Haemanthamine®, Nordopan®, Uracil nitrogen mustard, etc.). Mustard®, Uracillost®, Uracilmostaza®, Uramustin®, Uramustine®), chlormethine (Mustargen®), cyclophosphamide (Cytoxan®, Neosar®, Clafen®, Endoxan®, Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), chlorambucil (Leukera n®), pipobroman (Amedel®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, thiotepa (Thioplex®), busulfan (Busilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and dacarbazine (DTIC-Dome®).Other exemplary alkylating agents include, but are not limited to, oxaliplatin (Eloxatin®); temozolomide (Temodar® and Temodal®); dactinomycin (also known as actinomycin-D, Cosmegen®); melphalan (also known as L-PAM, L-sarcolysin, and phenylalanine mustard, Alkeran®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); carmustine (BiCNU®); bendamustine (Treanda®); busulfan (Busulfex® and Myleran®); carboplatin (Paraplatin®); lomustine (also known as CCNU, CeeNU®); cisplatin (also known as CDDP, Platinol® and Platinol®-AQ); chlorambucil (Leukeran®) cyclophosphamide (Cytoxan® and Neosar®); dacarbazine (also known as DTIC, DIC, and imidazole carboxamide, DTIC-Dome®); altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®); prednisolone; procarbazine (Matulane®); mechlorethamine (nitrogen mustard, mustine, and These include mechlorethamine hydrochloride, also known as Mustargen®; streptozocin (Zanosar®); thiotepa (also known as thiophosphoamide, TESPA, and TSPA, Thioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine HCl (Treanda®).

[0125] Antitumor antibiotics are chemical agents derived from natural products produced by the soil fungus Streptomyces species. These agents function in multiple phases of the cell cycle and are believed to be cell cycle specific. There are several types of antitumor antibiotics, including, but not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), chromomycins (e.g., dactinomycin and plicamycin), mitomycin, and bleomycin.

[0126] Antimetabolites are a type of chemotherapy that is cell cycle specific. When cells incorporate these antimetabolites into their cell metabolism, the cells cannot divide. These types of chemotherapy drugs include folate antagonists such as methotrexate; pyrimidine antagonists such as 5-fluorouracil, floxuridine, cytarabine, capecitabine, and gemcitabine; purine antagonists such as 6-mercaptopurine and 6-thioguanine; and adenosine deaminase inhibitors such as cladribine, fludarabine, nelarabine, and pentostatin.

[0127] Exemplary anthracyclines that may be used in combination with nonsteroidal SGRAs in the treatment of cancer patients include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (Lenoxane®); daunorubicin (daunorubicin hydrochloride, daunomycin, and rubidomycin hydrochloride, Cerubidine®); liposomal daunorubicin (daunorubicin citrate liposomal, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence); idarubicin (Idamycin®, Idamycin PFS®); mitomycin C (Mutamycin®); geldanamycin; herbimycin; rabidomycin; and desacetylrabidomycin.

[0128] Exemplary proteosome inhibitors that may be combined with nonsteroidal SGRAs in treating cancer patients include, but are not limited to, bortezomib (Velcade®); carfilzomib (PX-171-007, (S)-4-methyl-N--((S)-1-(((S)-4-methyl-1-((R)-2-methyloxiran-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholino)-1-oxo-3-phenylpropan-2-yl); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); and O-methyl-N-[(2-methyl-5-thiazolyl)carbonyl]-L-seryl-O-methyl-N-[(1S)-2-[(-2R)-2-methyl-2-oxiranyl]-2-oxo-1-(phenylmethyl)ethyl]-L-serinamide (ONX-0912).

[0129] In some embodiments, the chemotherapeutic agent is chlorambucil, cyclophosphamide, ifosfamide, melphalan, streptozocin, carmustine, lomustine, bendamustine, uramustine, estramustine, carmustine, nimustine, ranimustine, mannosulfan Busulfan, dacarbazine, temozolomide, thiotepa, altretamine, 5-fluorouracil (5-FU), 6-mercaptopurine (6-MP), capecitabine, cytarabine, floxuridine, fludarabine, gemcitabine, hydroxyurea, methotrexate, pemetrexed, daunorubicin, doxorubicin, epirubicin, idarubicin, SN-38, ARC, NPC, camptothecin, topotecan, 9-nitrocamptothecin, 9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-895 If, MAG-CPT, amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, paclitaxel, docetaxel, baccatin III, 10-deacetyltaxol, 7-xylosyl-10-deacetyltaxol, cephalomannine, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, 10-deacetylcephalomannine, irinotecan, albumin-bound paclitaxel, oxaliplatin, capecitabine, cisplatin, docetaxel, irinotecan liposomal, and etoposide, and combinations thereof.

[0130] In some embodiments, the chemotherapeutic agent is administered at a dose and schedule that may be guided by doses and schedules approved by the U.S. Food and Drug Administration (FDA) or other regulatory agencies, with empirical optimization being performed. In some cases, the chemotherapeutic agent is administered at a dose of about 100 mg to about 1000 mg, e.g., about 200 mg to about 800 mg, about 300 mg to about 700 mg, or about 400 mg to about 600 mg, e.g., about 200 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, or about 700 mg. The administration schedule may vary, e.g., from weekly, once every 5 days, once every 4 days, every other day, to daily, twice a day, or three times a day. In certain embodiments, the chemotherapeutic agent is administered at about 100 mg to about 600 mg per day, e.g., about 100 mg, about 200 mg, about 260 mg, about 300 mg, about 400 mg, or about 600 mg per day, in oral or intravenous doses, every other day or once every four days, for all or a portion of the treatment period. In some embodiments, the chemotherapeutic agent is a taxane, and any standard dose, e.g., FDA approved taxane dose, may be used in accordance with the methods disclosed herein. In various embodiments, the taxane is nab-paclitaxel, and is administered at a dose of 1 mg / kg or more. 2 It is administered as an intravenous infusion over 30 minutes on days 1, 8, and 15 of every 28-day cycle at doses ranging from 80 mg to 125 mg per 1000 mg of body surface area.

[0131] In yet other embodiments, two or more chemotherapeutic agents may be administered simultaneously or sequentially in any order for all or part of the treatment period. The two agents may be administered according to the same dosing schedule or different dosing schedules.

[0132] Immunotherapy In some embodiments, the cancer treatment administered to patients with high NLR may include the administration of an immunotherapeutic agent. Immunotherapeutic agents suitable for combination with nonsteroidal SGRAs to normalize (reduce) NLR in cancer patients undergoing cancer treatment with high NLR include antibodies against checkpoint proteins, including small molecule inhibitors of checkpoint activity. Many such antibodies have already been shown to be effective in the treatment of cancer, for example, antibodies against PD-1, CTLA4, and PD-L1. In some embodiments, the cancer treatment administered with nonsteroidal SGRAs may include the administration of a checkpoint inhibitor, which may be a checkpoint inhibitor antibody (CIA).

[0133] Anti-PD-1 antibodies have been used to treat melanoma, non-small cell lung cancer, bladder cancer, prostate cancer, colorectal cancer, head and neck cancer, triple-negative breast cancer, leukemia, lymphoma, and renal cell carcinoma. Exemplary anti-PD-1 antibodies include pembrolizumab (also known as lambrolizumab and MK-3475, Keytruda®, Merck), nivolumab (also known as BMS-936558, Opdivo®, Bristol Myers Squibb), cemiplimab (Libtayo®, Sanofi), spartalizumab (PDR001, Novartis), AMP-224 (AstraZeneca), AMP-514 (MEDI0680, AstraZeneca), REGN2810 (Regeneron), tislelizumab (BGB-A317, BeiGene), BGB-A317 (BeiGene), pidilizumab (CT-011, Curetech LTD), JTX-4014 (Jounce Therapeutics), camrelizumab (SHR1210, Jiangsu HengRui Medicine Co., Ltd.), sintilimab; (IBI308, Eli Lilly), toripalimab (JS001, Shanghai Junshi Biosciences), dostallimab (TSR-042, WBP-285, GlaxoSmithKline), and INCMGA00012 (MGA012, Incyte and Macrogenics).

[0134] Anti-PD-L1 antibodies have been used to treat non-small cell lung cancer, melanoma, colorectal cancer, renal cell cancer, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, and hematological malignancies. Exemplary anti-PD-L1 antibodies include atezolizumab (Tecentriq®, Roche), avelumab (Bavencio®, MSB0010718C, MerckKGaA and Pfizer), durvalumab (Imfinzi®, AstraZeneca), MDX-1105 (Bristol Myers Squibb), MEDI4736 (Medimmune), MPDL3280A (Roche), BMS-936559 (Bristol Myers Squibb), cosibelimab (CK-301 (Checkpoint Therapeutics) and embafolimab (KN035, a "nanobody" (camel antibody), Tracon Therapeutics).

[0135] 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. An important feature of anti-CTLA4A is the kinetics of the antitumor effect, with a lag phase of up to 6 months required for physiological response after the first treatment. In some cases, tumor size actually increases after treatment initiation before shrinkage is observed (Pardoll, 2012, Nature Reviews Cancer 12:252-264). Exemplary anti-CTLA4 CIAs include ipilimumab (Yervoy®, Bristol Myers Squibb) and tremelimumab (formerly ticilimumab, CP-675,206, AstraZeneca).

[0136] For example, CIAs against other checkpoint proteins such as valilumab, ARGX-110, LAG3, LAG525, B7-H3, B7-H4, OX-40, CD137, MEDI6383, MEDI6469, MOXR0916, and TIM3 may also be combined with the non-steroidal SGRAs disclosed herein to treat cancer.

[0137] The CIAs used in the present disclosure may be in combination with different CIAs, especially when the target checkpoint proteins (e.g., PD-1 and CTLA4) suppress the immune response through different signaling systems. Thus, a combination of CIAs against either checkpoint protein, or a single CIA against both checkpoint proteins, may result in an enhanced immune response.

[0138] The Creation of the CIA CIAs can be developed 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 a composition containing an antigen (e.g., a checkpoint protein or an epitope thereof), removing the spleen to harvest B lymphocytes, fusing the B lymphocytes with myeloma cells to generate hybridomas, cloning the hybridomas, selecting positive clones that produce antibodies against the antigen, culturing the clones that produce antibodies against the antigen, and isolating the antibodies from the hybridoma culture.

[0139] 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 using Protein A Sepharose, size exclusion chromatography, and ion exchange chromatography. See, e.g., Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3. Also, see 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 raising of antibodies against checkpoint proteins, the antibodies may be sequenced and subsequently prepared by recombinant techniques. Humanization and chimerization of murine antibodies and antibody fragments are well known to those skilled in the art. See, e.g., Leung et al. Hybridoma 13:469 (1994); U.S. Patent Application Publication No. 20140099254.

[0140] Human antibodies can be produced using transgenic mice genetically engineered to produce specific human antibodies in response to antigenic 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.

[0141] CIA Modifications CIAs may be generated by introducing conservative modifications to existing CIAs. For example, modified CIAs contain heavy and light chain variable regions and / or Fc regions that are homologous to the counterparts of the antibodies generated above. Modified CIAs that can be used in the methods disclosed herein must retain the desired functional properties that allow them to inhibit checkpoint signaling pathways.

[0142] 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 usually have increased affinity of the antibody for the antigen. Antibodies can also be pegylated by reacting with polyethylene glycol (PEG) under conditions that allow one or more PEG groups to bind 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 inhibiting checkpoint pathways.

[0143] ii. Small Molecule Non-Protein Checkpoint Inhibitor Compounds ("CICs") In other embodiments, the cancer treatment performed with the nonsteroidal SGRA may include administration of a checkpoint inhibitor, and the checkpoint inhibitor may be a CIC. A CIC is a small molecule non-protein compound that antagonizes the immunosuppressive function of checkpoint proteins. Many CICs are known in the art, such as the small molecule checkpoint inhibitor CA-170 (Aurigene), the peptide checkpoint inhibitor AUNP12 (Aurigene and Laboratoire Pierre-Fabre) and BMS-986189 (Bristol Myers Squibb), and those disclosed in U.S. Patent No. 9,872,852, U.S. Patent No. 9,422,339, and U.S. Patent Application Publication No. 2013-0022629.

[0144] CICs can be identified using any of a number of approaches in combinatorial library methods known in the art, for example, those disclosed in EP 2360254. Combinatorial libraries include biological libraries, spatially addressable parallel solid-phase or parallel liquid-phase libraries, synthetic libraries that require deconvolution methods, "one bead one compound" library methods, and synthetic library methods that use affinity chromatography selection. The biological library approach is limited to peptide libraries, while the other four approaches are applicable to peptide libraries, non-peptide oligomer libraries, or small molecule libraries of compounds (Lam, KS (1997) Anticancer Drug Des. 12:145).

[0145] Radiation Cancer Therapy Radiation may be used to treat cancer. In some embodiments, cancer treatments for patients with high NLR include administering radiation therapy (e.g., directing ionizing radiation to tumors, injecting radiopharmaceutical compositions, implanting radioactive sources, or other radiation therapy). Suitable radiation therapies for use in combination with nonsteroidal SGRAs to normalize NLR in cancer patients with NLR undergoing cancer treatment include directing radiation to tumors or cancerous regions (sometimes called "external beam radiation therapy" or "teletherapy"), implanting radiation-emitting materials in or near tumors or cancerous regions (sometimes called "brachytherapy"), and administering radiolabeled pharmaceutical compositions effective for directing radiation to cancer tumors or cancerous regions (e.g., radiolabeled ligands targeting receptors expressed, preferably overexpressed, in cancer cells).

[0146] Antiangiogenic Cancer Therapy Antiangiogenic agents reduce or inhibit the formation of new blood vessels and may be used in cancer treatment. Antiangiogenic agents are believed to slow, inhibit, or reverse tumor growth by restricting the blood supply to the tumor. In some embodiments, cancer treatment for patients with high NLR may include administering antiangiogenic therapy, including, for example, administering antiangiogenic agents. Antiangiogenic agents include antibodies that inhibit the action of anti-vascular endothelial growth factor (VEGF), such as, for example, bevacizumab (Avastin®); carboxyamidotriazoles, itraconazole; angiopoietin-2; soluble VEGF receptors and other "decoy" molecules that can reduce the binding and activation of endogenous VEGF receptors to which VEGF can bind and promote angiogenesis; angiostatin; endostatin; interferon-α, interferon-β, and interferon-γ; platelet factor 4; vasostatin; calreticulin; prolactin; osteopontin; secreted protein rich in cysteine ​​(SPARC), also known as osteonectin and BM-40; and other angiogenesis inhibitors that can be used to treat cancer, and are suitable cancer treatments for use in the methods disclosed herein for normalizing (reducing) the NLR in cancer patients undergoing cancer treatment in whom the NLR is elevated.

[0147] Growth factor inhibitor therapy In some embodiments, cancer treatments administered to patients with high NLR may include administration of growth factor inhibitors. For example, administration of growth factor inhibitors, including epidermal growth factor (EGF), fibroblast growth factor (FGF), and others, may include cancer treatments administered to cancer patients with high NLR, and administration of non-steroidal SGRAs and growth factor inhibitors may be effective in normalizing (reducing) NLR in cancer patients, improving growth factor therapy, reducing tumor burden, or promoting tumor removal, providing beneficial clinical benefits to patients. Growth factor inhibitors include, for example, tyrosine kinase inhibitors (e.g., axitinib (Inlyta®), dasatinib (Sprycel®), erlotinib (Tarceva®), imatinib (Glivec®), nilotinib (Tasigna®), pazopanib (Votrient®), and sunitinib (Sutent®)); proteasome inhibitors (e.g., bortezomib (Velcade®); histone deacetylase inhibitors (e.g., , vorinostat (Zolinza®) and panobinostat (Farydak®); hedgehog pathway inhibitors (such as vismodegib (Erivedge®); phosphatidylinositide 3 kinase (PIP3) inhibitors (such as idelalisib (Zydelig®)); mammalian (or mechanistic) target of rapamycin (mTOR) inhibitors (such as temsirolimus (Torisel®) and everolimus (Afinitor®)); and others.

[0148] Surgical cancer treatment In some embodiments, cancer treatment for patients with high NLR may include surgical treatment for cancer. Surgery may be used to treat cancer by removing tumors or removing parts of tumors to reduce tumor burden in patients with tumors. Administration of nonsteroidal SGRAs to normalize NLR in cancer patients with high NLR may be performed before, during, or after surgery, and may help normalize NLR in patients, improving the treatment and health of cancer patients.

[0149] F. Combination Therapy Various combinations of nonsteroidal SGRAs and one or more cancer therapies may be used to treat cancer patients, for example to reduce NLR in cancer patients with elevated NLR. "Combination therapy" or "combination with" is not intended to imply that the therapeutic agents must be administered simultaneously and / or formulated for simultaneous delivery, although these delivery methods are within the scope disclosed herein. The nonsteroidal SGRA and chemotherapeutic agent may be administered according to the same dosing regimen or different dosing regimens. In some embodiments, the nonsteroidal SGRA and chemotherapeutic agent are administered sequentially in any order during all or part of the treatment period. In some embodiments, the nonsteroidal SGRA and anti-cancer agent are administered simultaneously or nearly simultaneously (e.g., within about 1 minute, within about 5 minutes, within about 10 minutes, within about 15 minutes, within about 20 minutes, or within about 30 minutes of each other). For example, in the case of administration of a nonsteroidal SGRA and a chemotherapeutic agent, a non-limiting example of a combination therapy is as follows, where the nonsteroidal SGRA is "A" and the anti-cancer agent or compound administered as part of the chemotherapy regimen is "B":

[0150] [Table 1]

[0151] Administration of the therapeutic compound or agent to the patient will follow standard protocols for the administration of such compounds, taking into account the toxicity, if any, of the treatment. In combination with the described treatments, surgical interventions may also be applied.

[0152] The present methods may be combined with other means of cancer treatment, such as surgery, radiation, immunotherapy, the use of growth factor inhibitors, the use of anti-angiogenic factors, and the use of other therapies, as well as combinations thereof.

[0153] Evaluation of improvements in the control of G.NLR The nonsteroidal SGRA therapy disclosed herein reduces the NLR in cancer patients with high NLR (e.g., NLR ≥ 3), providing beneficial clinical outcomes to such cancer patients. Methods for measuring response to cancer treatment 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 (Eisenhauer et al., "New Response Evaluation Criteria in Solid Tumours: Revised RECIST Guidelines (version 1.1) Eur. J. Cancer 45:228-247 (2009)).

[0154] In one approach, NLR is measured by determining the number of neutrophils and lymphocytes in blood samples obtained from cancer patients. A decrease in NLR levels after treatment with nonsteroidal SGRAs (e.g., relaxylorant) may suggest a beneficial treatment for cancer patients.

[0155] Patients undergoing the treatments disclosed herein may show varying degrees of NLR reduction. In some cases, patients may show about a 10% reduction in NLR measured before treatment. In some embodiments, the NLR of cancer patients with high NLR is reduced by about 15%, about 20%, about 25%, about 30%, about 33%, about 35%, about 40%, about 45%, about 50%, or more from the NLR measured before treatment. In preferred embodiments, the NLR is reduced to 3 or less, and in most preferred embodiments, the NLR is reduced to less than 3.

[0156] In addition, the desired beneficial or desired clinical outcome of the combination therapy may include, for example, a reduction in tumor burden, a reduction (i.e., slowing and / or stopping to some extent) of cancer cell invasion into surrounding organs, an inhibition (i.e., slowing and / or stopping to some extent) of tumor metastasis, an increase in the response rate (RR), a prolongation of the duration of response, a reduction to some extent of one or more symptoms associated with cancer, a reduction in the dose of other drugs required to treat the disease, a delay in disease progression, and / or an increase in the survival rate and / or an improvement in the quality of life of the patient. Methods for assessing these effects are well known and / or are disclosed, for example, at cancerguide.org / endpoints.html and in the RECIST guidelines mentioned above.

[0157] Although the foregoing invention has been described in 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 present disclosure that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. EXAMPLES

[0158] The following examples are offered for purposes of illustration only, and not for purposes of limitation. Those of ordinary skill in the art will readily recognize a variety of non-critical parameters that could be changed or modified to yield essentially the same results.

[0159] 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 at 37°C, 5% / 95% (v / v) CO2 / air in MEME medium supplemented with 10% (v / v) fetal bovine serum, 2 mM L-glutamine, and 1% (v / v) NEAA. HepG2 cells are then counted and cultured at 0.125 x 10 per ml in phenol red-free RPMI 1640, charcoal stripped FBS, 2 mM L-glutamine. 6 The cells are adjusted to a concentration of 25,000 cells per well and seeded into 96-well sterile tissue culture microtiter plates at 25,000 cells per well in 200 μl and incubated at 37° C., 5% CO 2 for 24 hours.

[0160] Growth medium is then removed and replaced with assay medium (RPMI 1640 without phenol red, 2 mM L-glutamine + 10 μM forskolin). Test compounds are then screened against an exposure of 100 nM dexamethasone. Compounds are then serially half log diluted from a 10 mM stock into 100% (v / v) dimethyl sulfoxide. An 8-point half log dilution curve is then generated, followed by a 1:100 dilution into assay medium resulting in 10x final analytical samples of compound concentrations ranging from 10 to 0.003 μM in 0.1% (v / v) dimethyl sulfoxide.

[0161] Test compounds are pre-incubated with cells in microtiter plates at 37° C., 5 / 95 (v / v) CO2 / air for 30 min, followed by 20 h, prior to addition of 100 nM dexamethasone to induce optimal TAT.

[0162] HepG2 cells are then lysed with 30 μl of cell lysis buffer containing a protein inhibitor cocktail for 15 min at 4° C. Then 155 μl of substrate mixture containing 5.4 mM tyrosine sodium salt, 10.8 mM α-ketoglutaric acid, and 0.06 mM pyridoxal 5′-phosphate in 0.1 M potassium phosphate buffer (pH 7.4) may be added. After 2 h of incubation at 37° C., the reaction may be terminated by the addition of 15 μl of 10 M aqueous potassium hydroxide solution, and the plate was incubated for an additional 30 min at 37° C. TAT activity product may be measured by absorbance at λ of 340 nm.

[0163] I C 50 IC values ​​can be calculated by plotting percent inhibition (normalized to 100 nM dexamethasone TAT stimulation) against compound concentration and fitting the data to a four-parameter logistic equation. 50 Values ​​can be converted to Ki (equilibrium dissociation constant) using the Cheng-Prusoff equation, assuming that the antagonist is a competitive inhibitor for dexamethasone.

[0164] Example 2. Effects of Relacorilant on NLR and Cancer Treatment The neutrophil / lymphocyte ratio (NLR) in blood is usually less than 3 in healthy subjects (FIG. 7A). However, this ratio is much greater than 3 in many cancer patients, as indicated by the NLR value for patients with solid tumors shown in FIG. 7A. In this example, the effect of administering relacorilant on NLR was determined in healthy subjects and cancer patients. Such results of administering relacorilant suggest that administration of relacorilant can reduce NLR and normalize NLR in cancer patients.

[0165] method Healthy subjects Healthy subjects participated in the NCT03508635 study of Relacorilant. Single-dose ascending dose cohorts and multiple-dose ascending dose cohorts (SAD and MAD) were administered and analyzed as described in Figure 1, which shows the schedule of administration and evaluation of healthy subjects in this study. Figure 1 (A) shows the single-dose ascending dose (SAD) prednisone dosing schedule of the study. Figure 1 (B) shows the multiple-dose ascending dose (MAD) prednisone dosing schedule of the study. Figure 1 (C) shows the figure legend.

[0166] Focused NLR sampling was performed at time 0 (morning, pre-dose), followed by 2, 4, 8, 12, and 24 hours. A single NLR sample was taken in the morning pre-dose. The SAD portion of the study used a 500 mg dose, while the MAD used a 250 mg dose once daily.

[0167] Cancer patients Cancer patients enrolled in NCT02762981, a Phase 1 / 2 study of relacorilant in combination with nab-paclitaxel in patients with solid tumors, based on the following classification:

[0168] Important selection criteria included -Informed patients aged 18 years or older with progressive, advanced or metastatic solid tumors who have given their consent Treated with ≤3 lines of prior therapy in the progressive setting. Prior nab-paclitaxel was permitted. -ECOG-PS (Eastern Cooperative Oncology Group Performance Status) 0-1 Proper kidney, liver and bone marrow function Measurable or evaluable disease

[0169] Key inclusion criteria for participation in specific dose-finding pancreatic cohorts included A histologically confirmed diagnosis of pancreatic adenocarcinoma. Patients with pancreatic neuroendocrine tumors, lymphoma of the pancreas, or ampullary carcinoma are not eligible. CA19-9 (or CEA, or CA-125 in tumors not expressing elevated CA19-9) measured within 14 days prior to the first dose of study drug -Measurable (non-irradiated) metastases by RECIST 1.1

[0170] Important exclusion criteria included The need for chronic or frequent treatment with oral corticosteroids for a medical condition or disease (e.g., rheumatoid arthritis, immunosuppression after organ transplantation)

[0171] evaluation Tumor assessments were performed at the completion of cycle 2 and at screening every 6 to 8 weeks thereafter, with confirmation of response based on RECIST (version 1.1) as needed.

[0172] Patients received Relacorilant daily (see Figure 2) or intermittently (see Figure 3) and nab-paclitaxel on a 28-day cycle. Abbreviations used in the figures: nab-Pac, nab-paclitaxel; PK, pharmacokinetics.

[0173] The lead-in of relacorilant involved daily administration of relacorilant alone (without nab-paclitaxel) for 7 days.

[0174] Collecting specimens for drug concentration determination Drug concentrations were determined in the NCT02762981 study. Blood was collected at multiple time points on day 7 of Relacorilant administration. Upon collection, blood was chelated with EDTA, centrifuged, and plasma was divided into aliquots. Biochemical analysis was performed by MicroConstants (San Diego, CA, USA). Briefly, human plasma samples containing Relacorilant and its stable labeled analogues as internal standards and K3EDTA as an anti-aggregant were buffered with ammonium citrate solution and extracted with 2-butanol:hexane (2.5:97.5, v / v). Samples were vortex mixed, centrifuged, and the bottom portion was frozen in an ultra-low temperature freezer. The organic portion was transferred to a sterile tube and evaporated under nitrogen at 4°C. Extracts were dried, reconstituted, and analyzed by reversed-phase HPLC using an ACE UltraCore SuperPhenylHexyl column. The mobile phase was nebulized with heated nitrogen in a Z-spray source / interface set to Lectrospray in positive ionization mode. Ionized compounds were detected using MS / MS.

[0175] Specimen collection for CBC Blood was drawn on the days identified in Figures 1-3. Blood was also drawn the morning before dosing. Cells from whole blood were incubated with counterstain to identify cell types. A differential complete blood count (CBC) enumerated neutrophils, lymphocytes, monocytes, eosinophils, and basophils using standard methods.

[0176] Data analysis The NLR was calculated using the following formula:

number

number

[0177] Using this formula, any NLR CfB less than 0% is a decline in NLR. NLR may also be expressed as a fold change from baseline (CfB) using the following formula:

number

[0178] Using this formula, any NLR CfB factor less than 1 is a decrease in the NLR.

[0179] Statistical significance was assessed using standard T-tests, and p-values ​​reported were reproduced. Pharmacokinetic analysis was performed by Corcept Therapeutics using Phoenix WinNonlin Version 8.1 (Satala, NJ, USA). In summary, for relacorilant, AUC 0-24 and C max Pharmacokinetic parameters, including , were assessed using noncompartmental analysis (Model 200) based on intensive PK sampling over 24 hours following administration of Relacorilant on day 7 of the lead-in phase.

[0180] result Relacorilant inhibits prednisone-induced increases in NLR in healthy subjects A single dose of 25 mg prednisone caused an acute increase in NLR in nine healthy subjects. NLR rose from less than 2 at baseline to greater than 6 8 hours after prednisone. NLR returned to baseline after 24 hours. A single dose of 500 mg relacorilant administered with prednisone significantly blunted this NLR effect (Figure 4). The area under the curve for prednisone alone was 54.6 NLR*hr, which was reduced to 12.5 NLR*hr with a single dose of relacorilant.

[0181] The NLR effect of prednisone after 14 consecutive days of 250 mg per day of relacorilant was also evaluated. Two controls were included. The first evaluated the effect of 25 mg prednisone alone in the same subjects (day -5, Figure 5). The area under the curve decreased from 61.7 NLR*hr with prednisone alone to 9.6 NLR*hr after prednisone + relacorilant (14 consecutive days of relacorilant followed by 25 mg prednisone). The second evaluated the effect of 25 mg prednisone after 14 consecutive days of placebo (in place of relacorilant) in a different subject (Figure 6). The area under the curve decreased from 72 NLR*hr with prednisone plus placebo to 9.6 NLR*hr with prednisone plus lelacorilant (14 consecutive days of lelacorilant 250 mg per day followed by 25 mg prednisone). Compared with either control, 14 days of lelacorilant significantly blunted the NLR effect of prednisone.

[0182] Relacorilant does not affect the NLR in healthy subjects The normalization of NLR by lelacorilant is believed to occur through antagonism of endogenous cortisol. If a patient has elevated cortisol activity, lelacorilant may be expected to normalize this activity. Alternatively, lelacorilant alone may cause neutropenia (a decrease in neutrophils) or lymphocytosis (an increase in lymphocytes) through antagonism of normal endogenous cortisol. To distinguish between these two possibilities, the effect of lelacorilant alone in healthy subjects with normal endogenous cortisol was evaluated. After 14 doses of 250 mg lelacorilant on 14 consecutive days, no changes in NLR were observed in a cohort of seven healthy subjects (Figure 7). None of the healthy subjects had an NLR greater than 3 at baseline.

[0183] NLR changes in patients with advanced solid tumors following single-agent relacorilant The relationship between relacorilant administration and NLR was evaluated. maxwas determined and considered to be at steady state for the 7-day induction phase. NLR was expressed as change from baseline (CfB), with a CfB of less than 0% indicating that the NLR had decreased during the induction phase. In patients with AUC in the range of 0-8000hr*ng / ml, there was a trend for NLR to decrease with increasing exposure (Figure 8, left). max A similar trend was observed in patients with IL-1 in the range of 0–1000 ng / ml ( Fig. 8 , right ).

[0184] AUC < 2011ng*hr / ml or C max None of the patients with an AUC < 442ng / ml showed a decrease in NLR during this period. In contrast, 6 / 13 (46%) of patients with an AUC of 2011-8000ng*hr / ml and C max Six-nine (67%) patients with AUC between 442 and 1000 ng / ml had a decrease in NLR. For patients with AUC between 3740 and 8000 ng*hr / ml, the mean change in NLR was -6.1%, indicating a decrease in NLR. max The mean change in NLR for patients with a serum NLR between 595 and 836 ng / ml was -4.4%, indicating a decline in NLR.

[0185] Relacorilant plus nab-paclitaxel normalizes the NLR in patients with advanced solid tumors NLR was measured on days 1 and 8 of cycle 1 of the combination of relacorilant + nab-paclitaxel. Thirty-five to fifty-nine patients with advanced solid tumors had an NLR greater than 3 on day 1 of cycle 1. In these 59 patients, a significant (p=0.012) decrease in NLR was observed 8 days after administration of relacorilant + nab-paclitaxel (Figure 9). The mean NLR on day 1 of cycle 1 was 4.4, decreasing to 3.6 on day 8 of cycle 1.

[0186] The decrease in NLR was observed primarily in patients with a baseline NLR >3. For the 24 patients with a baseline NLR ≤3, there was no significant change in NLR over the 8-day dosing period (Figure 10, left). For the 35 patients with a baseline NLR >3, the NLR decreased significantly (p=0.029) over the same dosing period (Figure 10, right). For patients with a baseline NLR >3, the mean of 5.6 on day 1 of cycle 1 decreased to 4.5 on day 8 of cycle 1.

[0187] Relacorilant plus nab-paclitaxel reduces NLR in ovarian cancer patients with complete response Patient 038-4004 is a 57-year-old woman with recurrent stage IIIB high-grade papillary serous ovarian cancer that was initially sensitive to treatment with paclitaxel plus cisplatin. Her disease subsequently recurred 3 years later and progressed after two subsequent lines of treatment (gemcitabine + carboplatin + bevacizumab and liposomal doxorubicin). The patient experienced a decline in the tumor marker CA125 (from 1225.9 units / mL to 63.7 units / mL) after the first cycle of study treatment with relacorilant + nab-paclitaxel and achieved a radiographic complete response after two cycles of treatment. The patient discontinued study treatment after 5 months due to toxicity, and her disease progressed 8 months after initiating study treatment.

[0188] During the 7-day induction phase of Relacorilant, patient 038-4004 experienced a decrease in NLR from 5.5 to 2.5 (Figure 11). This represents an NLR change of -46%. In oncology studies evaluating the predictive value of NLR for immunotherapy or chemotherapy outcomes, an NLR greater than 5 is always interpreted as "high" and an NLR less than or equal to 2.5 is always interpreted as "low" (Sacdalan, 2018; Goldstein, 2015). This represents an NLR change from baseline (CfB) of -55% (i.e., a 55% decrease) during the induction phase of Relacorilant.

[0189] NLR loss is associated with tumor response Changes in NLR were compared between patients with different categories of tumor response as defined by RECIST criteria. Patients were classified by RECIST criteria as progressive disease (PD), stable disease (SD), and partial or complete response (PR / CR). Patients with PR / CR tended to have a more pronounced decrease in NLR during the first 8 or 15 days of the first cycle (Figure 12). In patients with progressive disease, the mean NLR at day 15 was 48% higher than the NLR at day 1. In patients with partial or complete response, the mean NLR at day 15 was 25% higher than the NLR at day 1. In conclusion, a decrease in NLR is associated with a more pronounced response to relacorilant + nab-paclitaxel.

[0190] conclusion A decrease in NLR predicts better outcomes for cancer patients treated with chemotherapy or immunotherapy. The selective GR antagonist, lelacorilant, inhibits the increase in NLR caused by prednisone. Patients with optimal pharmacokinetic parameters of lelacorilant were more likely to have a decrease in NLR 7 days after administration of lelacorilant alone. Lelacorilant plus nab-paclitaxel decreased NLR in cancer patients with high baseline NLR. Lelacorilant had no effect on NLR in healthy subjects or cancer patients with baseline NLR in the normal range. This observation has not been described before. Furthermore, this observation may suggest that increased cortisol activity contributes to the increase in NLR in patients with advanced tumors.

[0191] The results disclosed herein demonstrate that administration of relakolinant can reduce the NLR in cancer patients and normalize the NLR in cancer patients. Such reduction of the NLR in cancer patients with elevated NLR is believed to provide a therapeutic benefit to such patients.

[0192] All patents, patent publications, patent applications, and publications cited in this application are incorporated herein by reference in their entirety to the same extent as if each individual patent, patent publication, patent application, or publication was specifically and individually indicated to be incorporated by reference. Moreover, although the foregoing invention has been described in 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 present disclosure that certain changes and modifications can be made without departing from the spirit or scope of the appended claims. The present disclosure also includes the following aspects. <1> 1. A method of reducing the neutrophil / lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR greater than 3, comprising: administering to the cancer patient an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA); This reduces the NLR in the cancer patient. The method. <2> 1. A method of reducing the neutrophil / lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR greater than 3, comprising: administering to the cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA); This reduces the NLR in the cancer patient. The method. <3> The neutrophil / lymphocyte ratio (NLR) of the cancer patient is reduced to about 3 or less. <1> or <2> The method described above. <4> administering the cancer treatment and administering a nonsteroidal selective GRA is effective to reduce tumor burden in the patient. <2> or <3> The method described above. <5> The non-steroidal selective GRA comprises a fused azadecalin structure. <1> ~ <4> 2. The method according to claim 1 , <6> The non-steroidal selective GRA is a compound comprising a heteroaryl ketone fused azadecalin structure, or a salt or isomer thereof, and the GRA has the formula: <1> ~ <4> 2. The method according to claim 1 , [ka] During the ceremony, R 1 is R 1a is a 5- or 6-membered heteroaryl ring having 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S, which may be substituted by 1 to 4 groups independently selected from R 1a are hydrogen and C 1 -C 6 Alkyl, halogen, C 1-C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, CN, N-oxide, C 3 -C 8 Cycloalkyl and C 3 -C 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 the heterocycloalkyl ring and the heteroaryl ring are 5-6 membered rings having 1-4 heteroatoms each independently selected from the group consisting of N, O, and S. R 2 are hydrogen and C 1 -C 6 Alkyl, halogen, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, C 1 -C 6 Alkyl-C 1 -C 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) 2 R 2a 、C 3 -C 8 Cycloalkyl and C 3 -C 8 heterocycloalkyl, wherein the heterocycloalkyl group is selected from the group consisting of 1 to 4 R 2C optionally substituted with a group, Alternatively, two R's linked to the same carbon 2 The groups combine to form an oxo group (=O), Or, two R 2 groups combine to form a 5-6 membered heterocycloalkyl ring having 1-3 heteroatoms independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is 2d optionally substituted with a group, R 2a and R 2b is hydrogen and C 1 -C 6 each independently selected from the group consisting of alkyl, R 2c are hydrogen, halogen, hydroxyl, and C1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, CN, and NR 2a R 2b each independently selected from the group consisting of R 2d are hydrogen and C 1 -C 6 alkyl, or two R attached to the same ring atom 2d The groups combine to form (=O), R 3 is 1 to 4 R 3a is selected from the group consisting of phenyl and pyridyl, each of which may be substituted with a group; R 3a are hydrogen, halogen, and C, respectively. 1 -C 6 haloalkyl; The subscript n is an integer from 0 to 3. <7> The nonsteroidal selective GRA 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 having the following structure: <6> The method described above.

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Claims

1. A pharmaceutical for reducing a neutrophil / lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR of greater than 3, comprising: The medicament comprises an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA), The nonsteroidal selective GRA 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, having the structure: 【Chemistry 1】 Or, The said medicament, wherein the non-steroidal selective GRA is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone having the following structure: 【Chemistry 2】

2. A pharmaceutical for reducing a neutrophil / lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR of greater than 3, comprising: The medicament comprises an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA), The nonsteroidal selective GRA 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 having the structure: 【Chemistry 3】 Or, The non-steroidal selective GRA 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-4-yl)methanone having the following structure. 【Chemistry 4】

3. The pharmaceutical described in claim 1 or claim 2, wherein the neutrophil / lymphocyte ratio (NLR) of the cancer patient is reduced to about 3 or less.

4. A pharmaceutical for reducing a neutrophil / lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR of greater than 3, comprising: the medicament is used in a method comprising administering to the cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA), thereby decreasing the NLR in the cancer patient; The nonsteroidal selective GRA 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, having the structure: 【Chemistry 5】 Or, The said medicament, wherein the non-steroidal selective GRA is (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1-H-pyrazolo[3,4-g]isoquinolin-4a-yl)(pyridin-2-yl)methanone having the following structure: 【Chemistry 6】

5. A pharmaceutical for reducing a neutrophil / lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR of greater than 3, comprising: the medicament is used in a method comprising administering to the cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA), thereby decreasing the NLR in the cancer patient; The nonsteroidal selective GRA 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 having the structure: 【Chemistry 7】 Or, The non-steroidal selective GRA 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-4-yl)methanone having the following structure. 【Chemistry 8】

6. The pharmaceutical composition of claim 4 or claim 5, wherein the neutrophil / lymphocyte ratio (NLR) of the cancer patient is reduced to about 3 or less.

7. The method of any one of claims 4 to 6, wherein performing the cancer treatment and administering a non-steroidal selective GRA is effective in reducing tumor burden in the patient.

8. the reduction in the NLR is effective to enhance a response to cancer treatment in a patient undergoing cancer treatment who has a neutrophil / lymphocyte ratio of greater than 3, said enhancement being compared to the response in the absence of administration of the medicament; The method comprises: administering to said cancer patient an effective amount of a cancer treatment and an effective amount of a nonsteroidal selective glucocorticoid receptor antagonist (GRA); This reduces the NLR in the cancer patient, thereby enhancing the response of the cancer patient to cancer treatment. The pharmaceutical composition according to any one of claims 4 to 7.

9. The method according to any one of claims 4 to 8, wherein the cancer treatment comprises administration of a chemotherapeutic agent.

10. The pharmaceutical composition of claim 9, wherein the chemotherapeutic agent is selected from the group consisting of microtubule inhibitors, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress inducers, metabolic antagonists, mitotic inhibitors, and combinations thereof.

11. The pharmaceutical of claim 9, wherein the chemotherapeutic agent is a microtubule inhibitor selected from plinabulin and a taxane.

12. The pharmaceutical composition of claim 11, wherein the chemotherapeutic agent is nab-paclitaxel.

13. The pharmaceutical composition according to any one of claims 4 to 8, wherein the cancer treatment comprises administration of an immunotherapeutic agent.

14. The pharmaceutical of claim 13, wherein the immunotherapeutic agent comprises an antibody against a protein target selected from PD-1, PD-L1, CTKA4, LAG3, B7-H3, B7-H4, OX-40, CD137, and TIM3.

15. The pharmaceutical composition according to any one of claims 4 to 8, 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.

16. The pharmaceutical composition according to any one of claims 9 to 12, wherein the chemotherapeutic agent is an antimetabolite.

17. The pharmaceutical composition of claim 16, wherein the chemotherapeutic agent is gemcitabine.

18. the patient has a partial response to the cancer treatment and the GRA treatment, wherein the partial response is an improvement compared to the patient's response to the cancer treatment alone; This reduces the NLR in the cancer patient, thereby enhancing the response of the cancer patient to cancer treatment. The pharmaceutical composition according to any one of claims 8 to 17.

19. The patient has a complete response to the cancer treatment and the GRA treatment, wherein the complete response is an improvement compared to the patient's response to the cancer treatment alone; This reduces the NLR in the cancer patient, thereby enhancing the response of the cancer patient to cancer treatment. The pharmaceutical composition according to any one of claims 8 to 17.

20. The pharmaceutical agent according to any one of claims 1 to 19, wherein the NLR of the cancer patient is decreased after administration of the nonsteroidal selective GRA for at least 7 days.

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