METHOD FOR NORMALIZING THE NEUTROPHIL-TO-LYMPHOCYTE RATIO IN CANCER PATIENTS TREATED WITH A SELECTIVE GLUCOCORTICOID RECEPTOR ANTAGONIST

Abstract

Methods are described for treating a cancer patient with a neutrophil-to-lymphocyte ratio (NLR) greater than 3, comprising administering a nonsteroidal glucocorticoid receptor antagonist (GRA) to the cancer patient, effective in reducing the patient's NLR. The methods include administering a nonsteroidal GRA and cancer therapy to the cancer patient, effective in reducing the patient's NLR and enhancing the cancer patient's treatment. The GRA may be administered orally. The nonsteroidal GRA may be a nonsteroidal compound comprising a fused azadecalin heteroarylketone structure (e.g., relacorylant) or a fused octahydro azadecalin structure (e.g., exicorylant).Cancer treatment may include chemotherapy, immunotherapy, radiation therapy, administration of an anti-angiogenic agent, administration of a growth factor inhibitor, and surgery. These methods can enhance cancer treatment, improve the prognosis of cancer patients, improve cancer patient survival, and provide beneficial clinical effects and advantages for the patient.

Description

Method to normalize the neutrophil to lymphocyte ratio in cancer patients with a selective glucocorticoid receptor antagonist Background Cancer is a group of diverse diseases characterized by the uncontrolled growth and spread of abnormal cells. Cancer is a leading cause of death in the United States and around the world. The pathways that regulate cell division and / or cell communication become altered in cancer cells such that they fail or are bypassed by these regulatory mechanisms to control and limit cell growth. Through successive rounds of mutation and natural selection, a group of abnormal cells, usually originating from a single mutant cell, accumulate additional mutations that provide a selective growth advantage over other cells, and thus evolve a cell type that predominates in the cell mass. As cancer cells further evolve, some become locally invasive and then metastasize to colonize tissues other than the tissue of origin of the cancer cell.This property, together with the heterogeneity of the tumor cell population, makes cancer a particularly difficult disease to treat and eradicate. The ratio of the absolute neutrophil count to the absolute lymphocyte count is referred to as the neutrophil-to-lymphocyte ratio (NLR). The NLR is prognostic or predictive of chemotherapy response in multiple oncology settings (An et al., “Elevated neutrophil to lymphocyte ratio predicts survival in advanced pancreatic cancer” Biomarkers. 15(6): 516-522, 2010; Procter 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; 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):56-522, 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). The NLR is also predictive of the response to checkpoint inhibitors, also called immuno-oncology therapeutics, 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 reduction in NLR with cancer treatment is associated with better treatment outcome as compared to those whose NLR does not decrease (Lalani et al., J. ImmunoTherapy Cancer 6:5 (2018)).A neutrophil-to-lymphocyte ratio below a threshold of 3 neutrophils per lymphocyte (NLR < 3) is generally considered low or normal. An NLR less than 3 is associated with better outcomes in multiple oncology settings. High NLR, in contrast, is associated with poorer outcomes. These systemic measurements are consistent with the roles of each cell type in tumor biology: tumor-associated neutrophils mediate tumor progression (Hurt et al. “Cancer-promoting mechanism 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):194–955, 2011). Thus, lowering the NLR to a normal value of less than or equal to approximately 3 might be expected to improve outcomes in multiple oncology settings. The glucocorticoid receptor (GR) is a nuclear hormone receptor that controls the transcription of multiple genes. The GR also controls blood cellular composition through two described mechanisms: cell type-specific apoptosis (Saffar et al., “The Molecular Mechanisms of Glucocorticoids-Mediated Neutrophil Survival” Current Drug Targets. 12(4):556562, 2011) and regulation of genes involved in cellular trafficking between the margins (i.e., lymph nodes and vessels) and 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). The synthetic GR agonist dexamethasone 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 the endogenous GR agonist cortisol, which is the primary etiology 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 Endocrino Metab. 6:312–9, 1946; Masri-lraqi et al., “Elevated White blood cell counts in Cushing's disease: association with hyperthyroidism” 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 (frequently by means of surgical removal of a neoplastic region of the pituitary gland) in patients with Cushing's, circulating neutrophils are decreased and circulating lymphocytes are increased (Masri-lraqi, 2014).Thus, it has been shown that GR agonism increases NLR. GR-mediated signaling pathways have dynamic biological effects involving different components of the immune system, and their in vivo effects are unpredictable. For example, glucocorticoids have been reported to have both immunosuppressive effects—such as suppression of proinflammatory cytokines, promotion of anti-inflammatory cytokines, inhibition of dendritic cells, suppression of natural killer cells, promotion of regulatory T cells, and induction of T cell apoptosis—and enhance immunological effects. See Hinrichs et al., “Glucocorticoids do not inhibit antitumor activity of activated CD8+ T cells.” J. Immunother. 28(6): 517–524 (2005). The effects of GR-mediated signaling pathways in cancer cells are similarly elusive.On the other hand, activating GR signaling pathways is thought to induce apoptosis in certain cancer cell types, e.g., malignant lymphoid cancers (see, e.g., Schlossmacher et al., “Glucocorticoid receptor-mediated apoptosis: mechanisms of resistance in cancer cells,” J. Endocrinol. 211:17-25 (2011)). Moreover, it has also been reported that agents that block the ο^πηη / ζζηζ / Β / γίΛA GR signaling pathway can potentiate chemotherapy in epithelial-derived killer cancer cells (see, e.g., U.S. Pat. No. 9,149,485). The effects, if any, of GR antagonism on the NLR are unknown. Administration of mifepristone (also known as RU-486) ​​to healthy men does not alter neutrophil or lymphocyte abundance in the blood (Laue, 1990). Patients with Addison’s disease frequently have less than normal serum cortisol levels; however, these patients have normal neutrophil abundance and function (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) (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). Thus, the effects, if any, of GR antagonism on the NLR are not known, and there remains a need for improved cancer therapies, including therapies that utilize the prognostic value of the NLR in cancer treatments. Brief Description of the Invention Described in the present application are methods for normalizing the neutrophil-to-lymphocyte ratio (NLR). For cancer patients, an NLR that is higher than normal (greater than 3) is predictive of a poorer prognosis. Lowering the NLR has been correlated with improved outcomes for cancer treatment. Reducing the NLR in cancer patients to a normal value (i.e., less than about 3) improves the prognosis of those patients, improves their response to cancer treatment, improves the results of cancer therapies, may reduce tumor burden, and promotes tumor elimination. As noted above, mifepristone does not alter the abundance of neutrophils or lymphocytes in healthy subjects, and therefore does not affect the NLR in healthy subjects (Laue, 1990). Surprisingly, as described herein, administration of a non-spheroidal ARG is effective in reducing the NLR in cancer patients receiving cancer treatment.The methods described herein include selecting cancer patients who have an NLR of greater than 3 and administering a non-steroidal glucocorticoid receptor (GRA) antagonist, such as relacorilant, in combination with a cancer treatment to normalize (reduce) the NLR in cancer patients with a high NLR receiving cancer treatment. The methods described herein include administering a non-steroidal GRA, such as relacorilant, in combination with a cancer treatment to treat cancer patients with a high NLR. The methods described herein include administering a non-steroidal GRA, such as relacorilant, in combination with a cancer treatment to increase the response to cancer treatment in cancer patients with a high NLR receiving cancer treatment.The methods described herein include administering a non-steroidal ARG, such as relacorilant, in combination with a cancer treatment to reduce tumor burden in cancer patients having a tumor(s) with high NLR and receiving cancer treatment. The methods described herein include administering a non-steroidal ARG, such as relacorilant, in combination with a cancer treatment to promote tumor clearance in cancer patients with high NLR and receiving cancer treatment. The methods described herein include administering a non-steroidal ARG, such as relacorilant, in combination with a cancer treatment to improve the health of cancer patients with high NLR.The methods described herein include administering a non-steroidal GRA, such as relacorilant, in combination with a taxane, such as nab-placitaxel, to a cancer patient with high NLR to decrease the NLR, to improve the patient's response to the taxane, and to improve the health of the cancer patient. In embodiments, the cancer treatment may include the administration of a chemotherapeutic agent (e.g., a taxane, such as nab-paclitaxel, gemcitabine, or another chemotherapeutic agent). In embodiments, the cancer treatment may include the administration of an immunotherapeutic agent (e.g., a checkpoint inhibitor, such as an antibody directed to a selected target protein of PD-1, PD-L1, CTKA4, LAG3, B7-H3, B7-H4, OX-40, CD-137, and TIM3), or other immunotherapy. In embodiments, the cancer treatment may include the administration of radiation therapy (e.g., directing ionizing radiation to a tumor, infusion of a radioactive pharmaceutical composition, implantation of a radiation source, or other radiation therapy). The cancer treatment may include surgery and other cancer treatments, and may include combinations of these cancer treatments. In embodiments of the methods described herein, the non-steroidal GRA is a non-steroidal compound comprising a fused azadecalin structure. In embodiments, the compound comprising a fused azadecalin structure is a compound described and mentioned in U.S. Patent 7,928,237 and U.S. Patent 8,461,172. In embodiments, the compound comprising a fused heteroaryl ketone azadecalin structure is a compound described and mentioned in U.S. Patent 8,859,774. In embodiments, the compound comprising an octahydro fused azadecalin structure is a compound described in U.S. Patent 10,047,082.The entire contents of these patents, and all patents, patent applications, patent publications, and publications discussed herein, both supra and infra, are incorporated herein by reference in their entireties. In embodiments, for example, the non-steroidal GRA is a fused heteroaryl ketone azadecalin compound (e.g., a compound described in U.S. Patent 8,859,774). In particular embodiments, the non-steroidal GRA is (R)-(1-(4-fluorophenyl)-6((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazol[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, also known as “relacorylant” and as “CORT125134” (Example 18 of U.S. Patent 8,859,774), which has the following structure: i Qhbnn / zznz / B / YiAi Relacorilant is chemically distinct from the spheroidal compound mifepristone. Unlike mifepristone, relacorilant does not antagonize the progesterone receptor. Thus, relacorilant (and other fused azadecalin compounds described, for example, in U.S. Patent 8,859,774, U.S. Patent 7,928,237, U.S. Patent 8,461,172, and U.S. Patent 10,047,082 and other patents cited herein) provides a means for selectively antagonizing the glucocorticoid receptor. The effect of relacorilant on the NLR has not been described. In some cases, the selective nonsteroidal anti-inflammatory drug (SARI) is administered orally. In some cases, the selective nonsteroidal anti-inflammatory drug (SARI) is administered by injection, infusion, transdermal application, nebulized suspension, or aerosol dispersion. In some embodiments, the effective amount of the non-steroidal selective GRA is a daily dose of 1 to 100 mg / kg / day. In some embodiments, the dose of the non-steroidal selective GRA is a daily dose of 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 50, 60, 70, 80, 90, or 100 mg / kg / day. In some cases, the GRA is given for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 75, 80 weeks, or until the cancer gets worse (disease progression). The present methods provide improved methods for normalizing (lowering) the NLR in cancer patients with a high NLR receiving cancer treatment; for increasing the response to cancer treatment in cancer patients with a high NLR receiving cancer treatment (e.g., improving the response of a cancer patient with a high NLR to taxane (e.g., nabplacitaxel) chemotherapy); for reducing tumor burden in cancer patients who have a tumor or tumors and with a high NLR and receiving cancer treatment; for promoting tumor clearance in cancer patients with a high NLR receiving cancer treatment; and improving the health of cancer patients with a high NLR receiving cancer treatment.The present methods provide benefits to patients by improving and enhancing cancer treatments, delaying disease progression, improving patient longevity and survival, quality of life, and other beneficial health outcomes. Brief Description of the Drawings Figure 1. Effect of relacorilant on the neutrophil-to-lymphocyte ratio (NLR) of healthy subjects. Dosing and testing schedule for a healthy subjects study. (A) Single ascending dose (SAD) prednisone challenge design. Effect of relacorilant on the neutrophil-to-lymphocyte ratio (NLR) of healthy subjects. Dosing and testing schedule for a healthy subjects study. (B) Multiple ascending dose (MAD) prednisone challenge design. Effect of relacorilant on the neutrophil-to-lymphocyte ratio (NLR) of healthy subjects. Dosing and testing schedule for a healthy subjects study. (C) Figure legend. Figure 2. Patients with advanced solid tumors: Part 1 of the continuous dosing regimen, Segment 1: Dose Discovery; Part 2: Dose Extension. “CORT125134” indicates relacorilant. “PK Drawing” indicates blood samples (“Drawings”) taken for pharmacokinetic measurements. CORT125134 indicates relacorilant. Figure 3. Patients with advanced solid tumors: Intermittent dosing regimen for segment II: Parts 1 and 2: “PK drawing” indicates blood samples (“drawings”) taken for pharmacokinetic measurements. “CORT125134” indicates relacorilant. Figure 4. NLR was measured in 9 healthy subjects administered 25 milligrams (mg) of prednisone, in the absence and presence of relacorilant. A single 500 mg dose of relacorilant reversed the effects of 25 mg of prednisone on NLR in healthy subjects. Figure 5. NLR measured in healthy subjects administered prednisone in the absence and presence of relacorilant. Multiple 250 mg doses (14 consecutive days of 250 mg / day) of relacorilant reversed the effects of 25 mg of prednisone compared with 25 mg of prednisone alone. Figure 6. Multiple doses of 250 mg (14 consecutive days of 250 mg / day) of relacorilant reverse the effects of 25 mg of prednisone on NLR as compared to NLR measured in healthy subjects administered 14 consecutive days of a placebo control prior to prednisone. Figure 7A. NLR is elevated in many cancer patients as compared to NLR in healthy subjects. Figure 7B. 250 mg of relacorilant alone does not change NLR in healthy subjects. Figure 8. Changes associated with AUC (right) or Cmax (left) in NLR over 7 days of relacorilant alone in patients with advanced solid tumors. Figure 9. 8-day dosing with relacorilant + nab-placitaxel reduces NLR in patients with solid tumors. Figure 10. NLR changes in patients with advanced solid tumors and baseline NLR less than or equal to 3 (shown in the graph on the left) as compared with NLR changes in patients with advanced solid tumors and baseline NLR greater than 3 (shown in the graph on the right). Figure 11. NLR decreases (after 7 days of relacorilant alone) in a patient with ovarian cancer who then goes on to achieve complete response to treatment with relacorilant + nabpaclitaxel. i ofrfrnn / zznz / E / YiAi Figure 12. NLR changes from baseline (log2 scale) in patients with progressive disease (PD), stable disease (SD), and partial response or complete response (PR / CR) during the first 8 (left) or 15 (right) days of cycle 1. Horizontal lines represent median values. Detailed Description A. Introduction The methods described herein include selecting cancer patients who have an NLR of greater than 3 and administering a nonsteroidal glucocorticoid receptor (GRA) antagonist, such as relacorilant, in combination with a cancer treatment to normalize (reduce) the NLR in cancer patients with a high NLR and receiving cancer treatment. The neutrophil-to-lymphocyte ratio (NLR) is typically increased in cancer patients, as compared to the NLR observed in healthy individuals. An NLR of greater than 3 is excessive, and is a value frequently found in patients suffering from cancer. Restoring the NLR to healthier values ​​(e.g., to about 3 or less) is indicative of a beneficial response to cancer treatment.Restoring the NLR to healthier values ​​(e.g., to around 3 or less) correlates with improved outcome to cancer treatment as compared to cancer patients who do not show NLR normalization. Normalizing (lowering) the NLR in cancer patients who have an NLR greater than 3 and are receiving cancer treatment is thought to aid cancer treatment, improve cancer treatment outcomes, may reduce tumor burden in cancer patients who have a tumor or tumors, and may promote tumor clearance in cancer patients who have a tumor or tumors, and otherwise aid in achieving a beneficial response to cancer treatment.Antagonism of cortisol activity by administration of a nonsteroidal selective glucocorticoid receptor (NLR) antagonist, such as azadecalin heteroaryl ketone fused NLR, e.g., relacorilant (also named “CORT125134” or “RELA”), in combination with cancer chemotherapy or other cancer treatment is believed to be effective in treating cancer, and in reducing NLR values ​​in the cancer patient receiving the treatment. The applicant describes herein that antagonism of endogenous cortisol activity correlates with response to combination treatment with relacorilant and Nab-placitaxel (NP, or nab-pac). The applicant describes herein that antagonism of endogenous cortisol activity correlates with response to combination treatment with relacorilant and Nab-placitaxel. Glucocorticoids, including endogenous cortisol, promote chemoresistance by upregulating genes that control cell survival pathways such as DUSP1 (“dual specificity Tj phosphatase) 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 selective nonsteroidal ARG, antagonizes the effects of cortisol. Relacorilant+NP achieved disease control at or after 16 weeks in 19 / 49 (39%) patients with refractory advanced solid tumors, including those who progress with taxane earlier in a Phase I clinical study. Biomarkers of cortisol activity are defined after prednisone challenge in healthy subjects and evaluated in patients with solid tumors receiving relacorilant + Nab-paclitaxel Methods: Lymphocyte and neutrophil abundance are determined using standard differential complete blood count tests. Results: In healthy subjects (n=9), administration of 25 milligrams (mg) of prednisone increases the neutrophil-to-lymphocyte ratio (NLR) exactly 4.7-fold. Coadministration of relacorilant reverses this effect. In cancer patients, NLR is significantly elevated at baseline, but is normalized by relacorilant. These results show that relacorilant reverses NLR induction by prednisone in healthy subjects. The increased NLR in cancer patients is reduced by relacorilant. This is consistent with, and suggests, elevated endogenous glucocorticoid receptor (GR) activity in cancer patients. These results show that administration of a non-steroidal selective GRA, such as relacorilant, is effective in normalizing (reducing) elevated NLR in cancer patients with elevated NLR who are receiving cancer treatment. Therefore, administration of a non-steroidal selective GRA to cancer patients with elevated NLR who are receiving cancer treatment can normalize (reduce) elevated NLR in those cancer patients and enhance their cancer treatment, thereby providing clinical benefit to the patients. Thus, the present methods for treating a cancer patient with a neutrophil-to-lymphocyte ratio (NLR) greater than 3 are effective in reducing the patient's NLR and augmenting the cancer patient's treatment. In embodiments, cancer treatment may include chemotherapy, immunotherapy, radiation therapy, administration of an antiangiogenic agent, administration of a growth factor inhibitor, and surgery. The methods may augment cancer treatment, improve the cancer patient's prognosis, delay disease progression, improve the cancer patient's longevity and survival, improve the patient's quality of life, and provide other beneficial health outcomes, beneficial clinical effects, and other advantages to the patient. Definitions: As used herein, the term "subject" or "patient" refers to a human or non-human organism. Thus, the methods and compositions described herein are applicable to both human and veterinary diseases. In certain embodiments, subjects are "patients," that is, living humans receiving medical care for a disease or condition. This includes individuals without a defined disease who are being investigated for signs of pathology. In some cases, a 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 cancer, cervical cancer, ovarian cancer, endometrial cancer (uterine), vulvar cancer, colon cancer, head and neck cancer, lung cancer, sarcoma, hepatocellular tumor, glioblastoma, neuroendocrine tumor, bladder cancer, gallbladder cancer / cholangiocarcinoma, gastric cancer, and mesothelioma. Cancers are characterized by uncontrolled growth and / or spread of abnormal cells. A biopsy is typically taken, and the cell or tissue from the biopsy is examined under a microscope to confirm a suspected condition. In some cases, additional tests need to be performed to confirm a suspected condition. In some cases, additional tests need to be performed on cell proteins, DNA, and RNA to verify the diagnosis. As used herein, the terms "tumor" and "cancer" are used interchangeably and both refer to an abnormal tissue growth resulting from excessive cell division. A tumor that invades surrounding tissue and / or can metastasize is referred to as "malignant." A tumor that does not metastasize is referred to as "benign." As used herein, the term “tumor burden” or “tumor volume” generally refers to the number of cancer cells, the size of a tumor, or the amount of cancer in a subject's body at any given time. Tumor volume can be detected by, for example, measuring the expression of tumor-specific genetic markers, and tumor size can be measured by a number of well-known biochemical or imaging methods, described herein infra. As used herein, the term “checkpoint protein” refers to a protein that is present on the surface of certain cell types, e.g., T lymphocytes and certain tumor cells, and can induce checkpoint signaling pathways and result in modulation 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):36377). Among these, CTLA4, PD-1, and PD-L1 are better studied, and therapies targeting these proteins are more clinically advanced than therapies targeting other checkpoint proteins. As used herein, the term “PD-1” refers to programmed cell death protein 1 (also known as CD279), a cell surface membrane protein of the immunoglobulin superfamily. PD-1 is expressed by B lymphocytes, T lymphocytes, and NK cells. The primary role of PD-1 is to limit T cell activity in peripheral tissues during inflammation in response to infection, as well as to limit autoimmunity. PD-1 expression is induced on activated T cells, and PD-1 binding to one of its endogenous ligands acts to inhibit T cell activation by inhibiting stimulatory kinases. PD-1 also acts to inhibit the TCR “stop signal.” PD-1 is highly expressed on Treg cells (regulatory T cells) and can increase their proliferation in the presence of ligand (Pardoll, 2012, Nature Reviews Cancer 12:252264). As used herein, the term “PD-L1” refers to programmed cell death 1 ligand 1 (also known as CD274 and B7-H1), a ligand for PD-1. PD-L1 is found on activated T cells, B cells, myeloid cells, macrophages, and tumor cells. Although there are two endogenous ligands for PD-1, PD-L1 and PD-L2, anti-tumor therapies have focused on anti-PD-L1. The complex of PD-1 and PD-L1 inhibits the proliferation of CD8+ T lymphocytes and reduces the immune response (Topalian et al., 2012, N. Engl. J. Med. 366:2443-54; Brahmer et al., 2012, N. Engl J. Med. 366:2455-65). As used herein, the term “CTLA4” refers to cytotoxic T cell antigen 4 (also known as CD152), a member of the immunoglobulin superfamily that is expressed exclusively on T cells. CTLA4 acts by inhibiting T cell activation and is reported to inhibit helper T cell activity and enhance the immunosuppressive activity of regulatory T cells. Although the precise mechanism of action of CTL4-A remains under investigation, it has been suggested that it inhibits T cell activation by displacing CD28 onto CD80 and CD86 on antigen-presenting cells, as well as actively delivering inhibitory signals to the T cell (Pardoll, 2012, Nature Reviews Cancer 12:252-264). As used herein, the term “checkpoint inhibitor” refers to any molecule, including antibodies and small molecules, that modulate the immunosuppression pathway induced by one or more checkpoint proteins. A checkpoint inhibitor is typically an antibody (“CIA”) against at least one checkpoint protein. The antibody can block the immunosuppressive activity of the checkpoint protein. A variety of antibodies have been shown to be effective in treating cancers, e.g., antibodies against PD-1, CTLA4, and PD-L1. However, a checkpoint inhibitor can also be a small molecule, a non-protein compound (“NIC”) that blocks the immunosuppression pathway induced by one or more checkpoint proteins. As used herein, the term “antibody” as used herein also includes a full-length antibody as well as an “antigen-binding portion” of an antibody. The term “antigen-binding portion” as used herein refers to one or more fragments of an antibody that retain the ability to specifically bind antigen (e.g., PD-1). Examples of binding fragments encompassed within the term “antigen-binding portion” of an antibody include (i) a Fab fragment, a monovalent fragment consisting of VL, VH, CL, and CH1 domains; (ii) a F(abj2) fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) an Fd fragment consisting of the VH and CH1 domains; (iv) an Fv fragment consisting of the VL and VH domains of a single limb of an antibody; (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Additionally, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they can be joined, using recombinant methods, by a synthetic linker that allows them to be made into a single protein chain in which the paired VL and VH regions form monovalent molecules (known as single chain Fv (scFv); see, for example, Bird et al. (1988) Science 242:423-426; Huston et al. (1988) Proc. Nati. Acad. Sel. USA j Pfrfrnn / zznz / E / YiAi. 85:5879-5883; and Osbourn et al., 1998, Nature Biotechnology 16:778). Single chain antibodies are also proposed to be encompassed within the term “antigen-binding portion” of an antibody. Any specific scFv VH and VL sequences can be linked to the constant region of human immunoglobulin cDNA or genomic sequences to generate expression vectors encoding full-length IgG molecules or other isotypes. VH and VI can also be used in the generation of Fab, Fv, or other immunoglobulin fragments using either protein chemistry or recombinant DNA technology. Other forms of single chain antibodies, such as diabodies, are also encompassed.Diabodies are bivalent, bispecific antibodies in which the VH and VL domains are expressed on a single polypeptide chain, but using a linker that is too short to allow pairing between the two domains on the same chain, thereby forcing the domains to pair with complementary domains on another chain and creating two antigen-binding sites (see, e.g., Holliger, P., et al. (1993) Proc. Nati. Acad. Sci. USA 90:64446448; Poljak, RJ, et al. (1994) Structure 2:1121-1123). Antibodies can be polyclonal or monoclonal: xenogeneic, allogeneic, or syngeneic; or modified forms thereof, e.g., humanized, chimeric, etc. Antibodies directed to checkpoint proteins specifically or substantially specifically bind one or more checkpoint proteins. The term “monoclonal antibodies” refers to a population of antibody molecules that contain only one species of an antigen-binding site capable of immunoreacting with a particular epitope of an antigen, while the term “polyclonal antibodies” and “polyclonal antibody composition” refer to a population of antibody molecules that contain multiple species of antigen-binding sites capable of interacting with a particular antigen. A monoclonal antibody composition typically exhibits a single binding affinity for a particular antigen with which it immunoreacts. As used herein, the term “antibody effective against a checkpoint protein” refers to an antibody that can bind to the checkpoint protein and antagonize the checkpoint protein’s function in suppressing the immune response. For example, an antibody against PD-1 refers to an antibody that can bind to PD-1 and block PD-1’s inhibitory function in the immune response, by, for example, blocking interactions between PD-1 and PD-L1. In some cases, an antibody can be against two checkpoint proteins, that is, it has the ability to bind to two checkpoint proteins and inhibit their function. The term "neutrophil" is used herein as accepted in medical art and refers to the most abundant granulocyte found in mammalian blood. Neutrophils are also known as neutrocytes. As part of the immune system, neutrophils phagocytose foreign cells and foreign bodies found in the blood. The cytoplasm of a neutrophil stains a neutral pink when treated with hemotoxylin and eosin. Neutrophils typically have a banded or segmented nucleus. j ο^πηη / ζζηζ / Β / γίΛΐ The term "lymphocyte" is used herein as accepted in the medical arts and refers to the white blood cells that also form the major portion of cells in lymphoma. Lymphocytes include natural killer cells, T lymphocytes, and B lymphocytes. When a blood sample is stained with Wright's stain, lymphocytes display a large, darkly stained nucleus with little eosinophilic cytoplasm. As used herein, the terms “neutrophil to 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. NLR= (absolute neutrophil count) / (absolute lymphocyte count) The NLR in healthy subjects is generally around 3 or less. An NLR value greater than 3 is considered high. NLR can also be expressed as a percentage change in NLR from baseline (% CfB) using the formula: % CfB in NLR=[(NLR at time2)-(NLR at timei)) / (NLR at timei)] x 100 (where “x” indicates multiplication) Thus, when using this formula for the percentage change in NLR from baseline, any %CfB of NLR that is less than 0% is a decrease in NLR, and any %CfB of NLR greater than 0% is an increase in NLR. NLR can also be expressed as a doubled change in NLR from baseline (doubled CfB) using the formula: Doubled CfB of NLR = (NLR at time2) / (NLR at timei) Thus, when using this formula for doubled change in NLR from baseline, any doubled CfB of NLR that is less than 1 is a reduction in NLR, and any doubled CfB of NLR that is greater than 1 is an increase in NLR. As used herein, the term “normalizing” NLR refers to reducing a high NLR value (greater than 3) to an NLR value of 3, and preferably to NLR values ​​of 3 or less. In most preferred embodiments, the NLR is reduced to a value of less than 3. As used herein, the term “survival” as used, for example, with reference to patient survival, refers to the period of time after initiation of treatment prior to the death of the patient. As used herein, the term “progression-free survival” refers, in patients who originally have a tumor, to the period of time after the start of treatment in which the tumor does not grow significantly (or “progress”). As used herein, the terms “stable response” or “stable response” refer to patients, who originally have a tumor, in which the tumors remain more or less the same size, but may include either a small amount of growth (typically less than 20 or 25%) or a small amount of shrinkage (but less shrinkage that would qualify as a “partial response”). As used herein, the term “partial response” (PR) refers to patients, who originally have a tumor, in whom there is (approximately) at least a 50% decrease in total tumor volume, but with evidence of some residual disease still remaining. In some cases, the residual disease in a deep partial response may actually be tumor death or scarring such that a few patients classified as having a PR may actually have a CR. Also, many patients who have tumor shrinkage during treatment show further tumor shrinkage with continued treatment and may achieve a CR. As used herein, the term “complete response” (CR) refers to patients, who originally had one tumor, in whom all detectable tumor has disappeared as indicated by tests, physical examination, and scan. As used herein, the term “chemotherapy” refers to medical treatments typically used to treat cancer. Chemotherapy treatments include the use of agents that are toxic to cancer tissues and cells, or which act to slow or reduce the growth or spread of cancer tissues and cells. Chemotherapy agents include antineoplastic agents and may be derived from natural compounds (e.g., taxols); may mimic, or may reduce or block the actions of naturally occurring hormones, growth factors, or immunologically active molecules; may be synthetic small molecules; may be antibodies or antibody conjugates; and may be other agents.Exemplary chemotherapy agents include, but are not limited to, taxanes, taxol, docetaxel, paclitaxel, gemcitabine, actinomycin, anthracyclines, doxorubicin, daunorubicin, valrubicin, bleomycin, cisplatin, trastuzumab (Herceptin®), trastuzumab emtasine (Kadcyla®), imatinib (Gleevec®), eribulin (Havalen®), and PARP inhibitors (“PARP” stands for pharmacological inhibitors of poly ADP ribose polymerase), among others known in the art. As used herein, the term “compound” is used to denote a molecular moiety of unique, identifiable chemical structure. A molecular moiety (“compound”) can exist in a free-living form, in which it is not associated with other molecules. A compound can also exist as part of a larger aggregate, in which it is associated with other molecules, but never retains its chemical identity. A solvate, in which the molecular moiety of defined chemical structure (“compound”) is associated with a molecule of a solvent, is an example of an associated form. A hydrate is a solvate in which the associated solvent is water. The statement “compound” refers to the molecular moiety itself (of the described structure), regardless of whether it exists in a free or associated form. As used herein, the term “composition” is intended to encompass a product comprising the specified ingredients such as the recited compounds, their tautomeric forms, their derivatives, their analogues, their stereoisomers, their polymorphs, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions in specified amounts, as well as any product which results, directly or indirectly, from the combination of the specified ingredients in the specified amounts.The term "pharmaceutical composition" in relation to a pharmaceutical composition is intended to encompass a product comprising the active ingredients and the inert ingredient making up the carrier, as well as any product resulting, directly or indirectly, from the combination, complexation or aggregation of any two or more of the ingredients, or from the dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are understood to encompass any composition made by mixing compounds of the present invention and their pharmaceutically acceptable carriers. As used herein, the terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The terms “pharmaceutically acceptable excipient” and “pharmaceutically acceptable carrier” refer to substances that aid in the administration of an active agent to - and for absorption by - a subject and can be included in the compositions of the present invention without causing a significant adverse toxicological effect in the patient. The use of media and agents for pharmaceutically active substances is well known in the art. Except where hereinafter provided that any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated.Complementary active compounds may also be incorporated into the compositions. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, normal saline, lactated Ringer's solution, normal glucose, binders, fillers, disintegrants, lubricants, coatings, sweeteners, flavorings and colors, and the like. One of ordinary skill in the art will recognize that other pharmaceutical excipients are useful in the present invention. As used herein, the terms “administrator,” “administering,” “administered,” or “administering” 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 by mouth, as a pill, capsule, liquid, or in another form suitable for administration by mouth). Oral administration may be buccal (where the compound or composition is held in the mouth, e.g., under the tongue, and absorbed therein). Administration may be by injection, i.e., delivery of the compound or composition by means of a needle, microneedle, jet injector, or other means of puncturing the skin or forcibly passing the compound or composition through the skin of the subject.The injection may be intravenous (i.e., into a vein); intraarterial (i.e., into an artery); intraperitoneal (i.e., into the peritoneum); intramuscular (i.e., into a muscle); or by another injection route. Routes of administration may also include rectal, vaginal, transdermal, via the lungs (e.g., by inhalation), subcutaneous (e.g., by absorption through the skin of an implant containing the compound or composition), or by another route. As used herein, the term “combination therapy” refers to the administration of at least two pharmaceutical agents to a subject to treat a disease. The two agents may be administered simultaneously, or sequentially in any order during the total treatment period or portions thereof. The at least two agents may be administered following the same or different dosage regimens. In some embodiments, one agent is administered following a scheduled regimen while the other agent is administered intermittently. In some embodiments, both agents are administered intermittently. In some embodiments, the pharmaceutical agent, e.g., a non-steroidal SGRA, is administered daily, and the other pharmaceutical agent, e.g., a chemotherapeutic agent, is administered every two, three, or four days. As used herein, the term “co-administrator” refers to administering two compositions simultaneously or within a short time of each other, for example, within about 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of each other. As used herein, the term “effective amount” or “therapeutic amount” refers to an amount of a pharmacological agent effective in treating, eliminating, or mitigating at least one symptom of the disease being treated. In some cases, “therapeutically effective amount” or “effective amount” may refer to an amount of a functional agent in a pharmaceutical composition useful for exhibiting a detectable therapeutic or inhibitory effect. The effect may be detected by an assay method known in the art. The effective amount may be an amount effective to provide a beneficial response in the patient. The effective amount may be an amount effective to invoke an antitumor response. The effective amount may be an amount effective to elicit a humoral and / or cellular immune response in the recipient subject that leads to growth inhibition or death of target cells.For the purpose of this description, the therapeutic amount of the checkpoint inhibitor is an amount that can reduce tumor burden or that leads to other desired beneficial clinical outcomes related to cancer improvement. As used herein, the phrases “not otherwise indicated for treatment with a glucocorticoid receptor modulator” or “not otherwise indicated for treatment with a glucocorticoid receptor antagonist” refer to a patient who is not suffering from any condition recognized by the medical community to be effectively treatable with glucocorticoid receptor antagonists with the exception of hepatic steatosis. Conditions known in the art and accepted by the medical community to be effectively treatable with glucocorticoid receptor antagonists include: psychosis associated with interferon-α therapy, psychotic major depression, dementia, stress disorders, autoimmune disease, neural damage, and Cushing’s syndrome. In some embodiments, the term “consisting essentially of” refers to a composition in a formulation whose active ingredient is solely the stated active ingredient; however, other compounds may be included which are used to stabilize, preserve, etc., the formulation, but are not directly involved in the therapeutic effect of the stated active ingredient. In some embodiments, the term “consisting essentially of” may refer to compositions which contain the active ingredient and components which facilitate the release of the active ingredient. For example, the composition may contain one or more components that provide extended release of the active ingredient over time in the subject. In some embodiments, the term “consisting of” refers to a composition which contains the active ingredient and a pharmaceutically acceptable carrier or excipient. As used herein, the terms “steroid” and “steroids,” and the phrase “spheroidal backbone” in the context of glucocorticoid receptor antagonists containing them, refer to glucocorticoid receptor antagonists that contain modifications of the backbone of cortisol, an endogenous spheroidal glucocorticoid receptor ligand. The backbone of a spheroidal backbone is provided as Formula I: i ofrfrnn / zznz / E / YiAi Formula I: Spheroidal main structure The term “glucocorticosteroid” (“GC”) or “glucocorticoid” refers to a steroid hormone that binds to a glucocorticoid receptor. Glucocorticosteroids are typically characterized by having 21 carbon atoms, an α,β-unsaturated ketone in the A ring, and an α-ketol group attached to the D ring. They differ in the degree of oxygenation or hydroxylation at C-11, C-17, and C-9; see Rawn, “Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives,” in Biochemistry, Daisy et al. (eds.), 1989, p. 567. A mineralocorticoid receptor (MR), also known as glucocorticoid receptor type I (GRI), is activated by aldosterone in humans. The term "cortisol" refers to the naturally occurring glucocorticoid hormone (also known as hydrocortisone), which is produced by the zona fasciculata of the adrenal gland. Cortisol has the following structure: Oh OH I 1HI / Γ T ñ TH The term “mifepristone” refers to 11 p-(4-dimethylaminophenyl)-17p-hydroxy-17a-(1 -propynyl)-estra4,9-dien-3-one), and has the following structure: I \ \\\ Η ^.oh 1HJZ / ii' I h Mifepristone is also referred to as RU486, or RU38.486, or 17-beta-hydroxy-11beta-(4-dimethylaminophenyl)-17-alpha-(1-propynyl)-estra-4,9-di-en-3-one). Mifepristone binds to the glucocorticoid receptor (GR), the progesterone receptor (PR), the androgen receptor (AR), and is thus non-selective for GR. The term “prednisone” refers to the synthetic glucocorticoid 17α,21-dihydroxypregna-1,4-diene3,11,20-trione, which has the following structure: j Pfrfrnn / zznz / B / YiAi As used herein, the term “glucocorticoid receptor” (“GR”) refers to a family of intracellular receptors which specifically bind cortisol and / or cortisol analogs. The glucocorticoid receptor is also referred to as the cortisol receptor. The term includes GR isoforms, recombinant GR, and mutated GR. “Glucocorticoid receptor” (“GR”) refers to the type II GR which specifically binds cortisol and / or cortisol analogs such as dexamethasone (See, e.g., Turner & Muller, J. Mol. Endocrinol. October 1, 2005, 35: 283-292). The term “glucocorticoid receptor modulator” (GRM) refers to any compound that modulates any biological response associated with the binding of GRM to an agonist. For example, a GRM that acts as an agonist, such as dexamethasone, increases tyrosine aminotransferase (TAT) activity in HepG2 cells (a human hepatocellular carcinoma cell line; ECACC, UK). A GRM that acts as an antagonist, such as mifepristone, decreases tyrosine aminotransferase (TAT) activity in HepG2 cells. “Glucocorticoid receptor antagonist” (GRA) refers to any compound which inhibits any biological response associated with GR binding to an agonist. Accordingly, GR antagonists can be identified by measuring a compound’s ability to inhibit the effect of dexamethasone. TAT activity can be measured as reported in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441–2452. A modulator is a compound with an ICso (half-maximal inhibitory concentration) of less than 10 micromolar. See Example 1, infra. As used herein, the term “selective glucocorticoid receptor antagonist” (SGRA) refers to any composition or compound which inhibits any biological response associated with the binding of a GR to an agonist (where inhibition is determined relative to the response in the absence of the compound). By “selective,” the drug preferentially binds to GR more than other nuclear receptors, such as the progesterone receptor (PR), the mineralcorticoid receptor (MR), or the androgen receptor (AR). It is preferred that the selective glucocorticoid receptor antagonist binds to the GR with an affinity that is 10x greater (1 / 10 the Kd value) than its affinity to MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or the MR, AR, and PR.In a preferred embodiment, the selective glucocorticoid receptor antagonist binds GR with an affinity that is 100x greater (1 / 100th the Kd value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or the MR, AR, and PR. In another embodiment, the selective glucocorticoid receptor antagonist binds the GR with an affinity that is 1000x greater (1 / 1000th the Kd value) than its affinity to the MR, AR, or PR, both the MR and PR, both the MR and AR, both the AR and PR, or the MR, AR, and PR. As used herein, the phrase “non-steroidal backbone” in the context of GRAs refers to GRAs that do not share structural homology to, or are not modifications of, cortisol with its steroid backbone containing seventeen carbon atoms, joined in four fused rings. Compounds include synthetic mimetics and protein analogs, which include partially peptidic, pseudopeptide, and non-peptide molecular entities. Non-spheroidal selective GRA compounds include compounds comprising a fused azadecalin structure (which may also be referred to as a fused azadecalin backbone), including compounds comprising a fused heteroaryl ketone azadecalin structure (which may also be referred to as a fused heteroaryl ketone azadecalin structure), and compounds comprising an octahydro fused azadecalin structure (which may also be referred to as an octahydro fused azadecalin backbone). Exemplary non-spheroidal GRA compounds comprising a fused azadecalin structure include those described and mentioned in U.S. Patent Nos. 7,928,237; and 8,461,172.Exemplary non-spheroidal selective GRA compounds comprising a fused heteroaryl ketone azadecalin structure include those described and mentioned in U.S. Patent 8,859,774; U.S. Patent 9,273,047; U.S. Patent 9,707,223; and U.S. Patent 9,956,216. Exemplary non-spheroidal selective GRA compounds comprising an octahydrofused azadecalin structure include those described and mentioned in U.S. Patent 10,047,082. All patents, patent publications, and patent applications described herein, both supra and infra, are incorporated herein by reference in their entirety. In embodiments, the fused heteroaryl ketone azadecalin GRA is the compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazol[3,4-g]isoquinolin-4a-yl)(4-trifluoromethyl)pyridine-2-yl)methanone (Example 18 of U.S. Patent 8,859,774, also known as “relacorylant” and as “CORT125134”), which has the following structure: j Pfrfrnn / zznz / E / YiAi i Qhbnn / zznz / B / YiAi In embodiments, the fused heteroaryl ketone azadecalin GRA is the compound (R)-(1-(4-fluorophenyl)-6-((4-(trifluoromethyl)phenyl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazol-3,4-[isoquinolin-4-yl)(pyridin-2-yl)methanone (Example 1 of U.S. Patent 8,859,774, designated “CORT113176”), which has the following structure: In embodiments, the octahydro-fused azadecalin GRA is the compound ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1H-pyrazol[3.4g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Example 2C of U.S. Patent 10,047,082, referred to as “exicorylant” or “CORT125281”), which has the following structure: In embodiments, 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-pyrazol[3.4g]isoquinolin-4a-yl)(thiazol-4-yl)methanone* (Example 2AJ of U.S. Patent 10,047,082, designated “CORT125329”), which has the following structure: i Qhbnn / zznz / B / YiAi The descriptions of compounds of the present invention are limited by principles of chemical bonding known to those skilled in the art. Accordingly, where a group may be substituted by one or more than one number of substituents, the substitutions are selected to comply with principles of chemical bonding and to produce compounds which are not inherently unstable—and / or may be known to one of ordinary skill in the art to be likely to be unstable under ambient conditions—such as aqueous, neutral, or physiological conditions. B. Glucocorticoid Receptor Antagonists (GRAS) Normalization of NLR can generally be achieved in a cancer patient with elevated NLR who is receiving cancer treatment by administering an effective amount of a nonsteroidal selective glucocorticoid receptor (GRA) antagonist of any chemical structure or mechanism of action. Exemplary non-spheroidal selective GRAs comprising a fused heteroaryl ketone azadecalin structure include those described in U.S. Patent 8,859,774 , which may be as described therein, and are incorporated herein in their entirety. Exemplary GRAs may be SGRAs. In some instances, the GRA comprising a fused heteroaryl ketone azadecalin structure has the following structure: R3 Where R1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O and S, optionally substituted with 1-4 groups each independently selected from R1a; each R1ase is independently selected from the group consisting of hydrogen, C1-C6 alkyl, halogen, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, -CN, N-oxide, C1-C6 cycloalkyl, and C1-C6 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 and heteroaryl rings have 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S; each R2 is independently selected from the group consisting of hydrogen, Cie alkyl, halogen, C-e haloalkyl, C-e alkoxy, C-e haloalkoxy, C-e alkyl-C-e alkoxy, -CN, -OH, -NR2aR2b, -C(O)R2a, -C(O)OR2a, -C(O)NR2aR2b, -SR2a, -S(O)R2a, -S(O)2R2a, C38 cycloalkyl and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 14 R2c groups; Alternatively, two R2 groups attached to the same carbon combine to form an oxo group (=0); alternatively, two R2 groups are combined to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O and S, wherein the heterocycloalkyl ring is optionally substituted with 1 to 3 R2d groups; R2a and R2b are each independently selected from the group consisting of hydrogen and alkyl of O and e; each R2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, -CN, and -NR2aR2b; each R2d independently selected from the group consisting of hydrogen and C1-6 alkyl, or two R2d groups attached to the same ring atom are combined to form (=0); R3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R3a groups; Each R3a is independently selected from the group consisting of hydrogen, halogen, and C1-C3 haloalkyl; and the subscript n is an integer from 0 to 3; or salts and isomers thereof. Exemplary non-spheroidal selective GRAs comprising an octahydrofused azadecalin structure include those described in U.S. Patent 10,047,082 , which may be prepared as described therein and is incorporated herein in its entirety. Exemplary GRAs may be SGRAs. In some instances, the GRA comprising an octahydrofused azadecalin structure has the following structure: i Pfrfrnn / zznz / E / YiAi Pfrfrnn / zznz / E / YiAi Where R1 is selected from the group consisting of pyridine and thiazole, optionally substituted with 1-4 groups each independently selected from R1a, each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, N-oxide and C3-8 cycloalkyl; Ring J is selected from the group consisting of phenyl, pyridine, pyrazole and triazole; each R2 is independently selected from the group consisting of hydrogen, C1e alkyl, halogen, C1e haloalkyl, and -CN; R3aes F; The subscript n is an integer from 0 to 3; Or salts and isomers thereof. C. Identification of Selective Lucocorticoid Receptor Antagonists To determine whether a non-steroidal test compound is a selective non-steroidal GRA (non-steroidal SGRA), the compound is first assayed to measure its ability to bind the GR and inhibit GR-mediated activities, thereby determining whether the compound is a glucocorticoid receptor antagonist. The compound, if confirmed to be a glucocorticoid receptor antagonist, is then subjected to a selectivity test to determine whether the compound can specifically bind to GR as compared to non-GR proteins, such as the estrogen receptor, the progesterone receptor, the androgen receptor, or the mineralocorticoid receptor. In one embodiment, an SGRA binds to GR at a substantially higher affinity, e.g., at least 10-fold higher affinity, than non-GR proteins. An SGRA may exhibit 100-fold, 1000-fold, or greater selectivity for binding the GR relative to binding to non-GR proteins. i. Union The ability of the test compound to bind to the glucocorticoid receptor can be measured using a variety of assays, for example, by screening for 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 a number of ways to perform competitive binding assays. In some embodiments, the glucocorticoid receptor is preincubated with a labeled glucocorticoid receptor ligand and then contacted with a test compound. This type of competitive binding assay may also be referred to herein as a binding displacement assay. A decrease in the amount of labeled ligand bound to the glucocorticoid receptor indicates that the test compound binds to the glucocorticoid receptor.In some cases, the labeled ligand is a fluorescently labeled compound (e.g., a fluorescently labeled steroid or steroid analog). Alternatively, the binding of a test compound to the glucocorticoid receptor can be measured directly with a labeled test compound. This latter type of assay is called a direct binding assay. Both direct binding assays and competitive binding assays can be used in a variety of different formats. The formats can be similar to those used in immunoassays and receptor binding assays. For a description of different formats for binding assays, including competitive binding assays and direct binding assays, see Basic and Clinical Immunology 7th Edition (D. Stites and A. Terr ed.) 1991; Enzyme Immunoassay, E.T. Maggio, ed., CRC Press, Boca Raton, Florida (1980); and “Practice and Theory of Enzyme Immunoassays,” P. Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology, Elsevier Science Publishers BV Amsterdam (1985), each of which is incorporated herein by reference. In solid-phase competitive binding assays, for example, the sample compound may compete with a labeled analyte for specific binding sites on a binding agent bound to a solid surface. In this type of format, the labeled analyte may be a glucocorticoid receptor ligand, and the binding agent may be the glucocorticoid receptor bound to a solid phase. Alternatively, the labeled analyte may be a labeled glucocorticoid receptor, and the binding agent may be a solid-phase glucocorticoid receptor ligand. The concentration of labeled analyte bound to the capture agent is inversely proportional to the test compound's ability to compete in the binding assay. Alternatively, the competitive binding assay can be performed in the liquid phase, and any of a variety of techniques known in the art can be used to separate bound labeled protein from unbound labeled protein. For example, several procedures have been developed to distinguish between bound ligand and excess bound ligand or between bound test compound and excess unbound test compound. These include identification of the bound complex by sedimentation on sucrose gradients, gel electrophoresis, or gel isoelectric focusing; precipitation of the receptor-ligand complex with protamine sulfate or adsorption onto hydroxylapatite; and the removal of unbound compounds or ligands by adsorption onto dextran-coated carbon (DCC) or binding to non-immobilized antibody. After separation, the amount of bound ligand or test compound is determined. Alternatively, a homogeneous binding assay can be performed in which a separation step is not necessary. For example, a label on the glucocorticoid receptor can be altered by the binding of the glucocorticoid receptor to its ligand or test compound. This alteration in the labeled glucocorticoid receptor results in a decrease or increase in the signal emitted by the label, such that measurement of the label at the end of the binding assay allows detection or quantification of the glucocorticoid receptor in the bound state. A wide variety of labels can be used. The component can be labeled by any of several methods. Useful radioactive labels include those incorporating 3H, 125I, 35S, 14C, or 32P. Useful non-radioactive labels include those incorporating fluorophores, chemiluminescent agents, phosphorescent agents, electrochemiluminescent agents, and the like.Fluorescent agents are particularly useful in analytical techniques used to detect changes in protein structure, such as fluorescence anisotropy and / or fluorescence polarization. The choice of label depends on the required sensitivity, ease of conjugation with the compound, stability requirements, and available instrumentation. For a review of various label or signal production systems that can be used, see U.S. Patent 4,391,904, which is incorporated herein by reference in its entirety for all purposes. The label can be coupled directly or indirectly to the desired assay component according to methods well known in the art.In some cases, a test compound is contacted with a GR in the presence of a fluorescently labeled ligand (e.g., a steroid or steroid analog) with a known affinity for the GR, and the amount of bound and free labeled ligand is estimated by measuring the fluorescence polarization of the labeled ligand. ii. Activity 1) HepG2 tyrosine aminotransferase (TAT) assay Compounds that have demonstrated the desired binding affinity for GR are tested for their activity in inhibiting GR-mediated activities. 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 that are suitable for the method described herein have an ICso (half-maximal inhibitory concentration) of less than 10 micromolar. Other assays, including, but not limited to, those described below, may also be performed to confirm the GR modulating activity of the compounds. 2) Cell-based assays Cell-based assays may also be used, which involve whole cells or cell fractions containing glucocorticoid receptors to test for binding of the test compound or modulation of glucocorticoid receptor activity.Exemplary cell types that can be used in accordance with the methods described herein include, for example, any mammalian cells including leukocytes such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes, such as T lymphocytes and B lymphocytes, leukemia cells, Burkitt's lymphoma cells, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiac cells, muscle cells, mammary tumor cells, ovarian cancer carcinomas, cervical carcinomas, glioblastomas, liver cells, kidney ! Qhbnn / 77n7 / B / YIAI cells, and neuronal cells, as well as fungal cells, including yeast. The cells can be primary cells or tumor cells or other types of immortal cell lines. Of course, the glucocorticoid receptor can be expressed in cells that do not express an endogenous version of the glucocorticoid receptor. In some cases, glucocorticoid receptor fragments, as well as protein fusions, can be used for screening. When molecules that compete for binding to glucocorticoid receptor ligands are desired, the GR fragments used are fragments capable of binding the ligands (e.g., dexamethasone). Alternatively, any GR fragment can be used as a target to identify molecules that bind to the glucocorticoid receptor. Glucocorticoid receptor fragments can include any fragment of, for example, at least 20, 30, 40, or 50 amino acids up to a protein containing all but one amino acid of the glucocorticoid receptor. In some embodiments, a reduction in signaling triggered by glucocorticoid receptor activation is used to identify glucocorticoid receptor antagonists. Glucocorticoid receptor signaling activity can be determined in many ways. For example, downstream molecular events can be monitored to determine signaling activity. Downstream events include those activities or manifestations that occur as a result of stimulation of a glucocorticoid receptor. Exemplary downstream events useful in the functional assessment of transcriptional activation and antagonism in unaltered cells include upregulation of a number of glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase).In addition, specific cell types susceptible to GR activation can be used, such as osteocalcin expression in osteoblasts, which is downregulated by glucocorticoids; primary hepatocytes, which exhibit glucocorticoid-mediated upregulation of PEPCK and glucose-6-phosphate (G-6-Pase). GRE-mediated gene expression has also been demonstrated in cell lines transfected using well-known GRE-regulated sequences (e.g., the mouse mammary tumor virus (MMTV) promoter) upstream of a reporter gene construct). Examples of useful reporter gene constructs include luciferase (luc), alkaline phosphatase (ALP), and chloramphenicol acetyl transferase (CAT). Functional assessment of transcriptional repression can be performed in cell lines such as monocytes or human skin fibroblasts.Useful functional assays include those measuring IL-1beta-stimulated IL-6 expression; downregulation of collagen, cyclooxygenase-2, and various chemokines (MCP-1, RANTES); LPS-stimulated cytokine release, e.g., TNFa; or expression of NFkB-regulated genes or AP-1 transcription factors in transfected cell lines. Compounds tested in whole-cell assays can also be tested in a cytotoxicity assay. Cytotoxicity assays are used to determine the extent to which a perceived effect is due to cellular effects of non-glucocorticoid receptor binding. In one exemplary embodiment, the cytotoxicity assay includes contacting a constitutively active cell with the test compound. Any decrease in cellular activity indicates a cytotoxic effect. 3) Additional tests Furthermore, illustrative of the many assays that can be used to identify compositions used in the methods described herein are assays based on in vivo glucocorticoid activities. For example, assays that evaluate the ability of a putative GR modulator to inhibit the uptake of 3H-thymidine into DNA in cells that are stimulated by glucocorticoids can be used. Alternatively, the putative GR modulator can be paired with 3H-dexamethasone to bind to a hepatoma tissue culture GR (see, e.g., Choi, et al., Steroids, 57:313-318, 1992). As another example, the ability of a putative GR modulator to block nuclear binding of the 3H-dexamethasone-GR complex can be used (Alexandrova et al., J. Steroid Biochem. Mol. Biol. 41:723-725, 1992).To further identify putative GR modulators, kinetic assays capable of discriminating between glucocorticoid agonists and modulators by receptor binding kinetics can also be used (as described in Jones, Biochem J. 204:721-729, 1982). In another illustrative example, the assay described by Daune, Molec. Pharm. 13:948-955, 1977; and in U.S. Patent No. 4,386,085, can be used to identify antiglucocorticoid activity. Briefly, thymocytes from adrenalectomized rats are incubated in nutrient medium containing dexamethasone with the test compound (the putative GR modulator) at various concentrations. 3H-uridine is added to the cell culture, which is further incubated, and the extent of incorporation of radiolabel into the polynucleotide is measured. Glucocorticoid agonists decrease the amount of 3H-uridine incorporated. Thus, a GR modulator will oppose this effect. iii. Selectivity The GR antagonists selected above are then subjected to a selectivity assay to determine if they are SGRAs. Typically, selectivity assays include testing a compound that binds the glucocorticoid receptor in vitro for the degree of binding to non-glucocorticoid receptor proteins. Selectivity assays can be performed in vitro or in cell-based systems, as described above. Binding can be tested against any appropriate non-glucocorticoid receptor protein, including antibodies, receptors, enzymes, and the like. In one exemplary embodiment, the non-glucocorticoid receptor binding protein is a cell surface receptor or nuclear receptor. In another exemplary embodiment, the non-glucocorticoid receptor protein is a steroid receptor, such as the estrogen receptor, progesterone receptor, androgen receptor, or mineralocorticoid receptor. The selectivity of the antagonist for the GR relative to the MR can be measured using a variety of assays known to those skilled in the art. For example, specific antagonists can be identified by measuring the ability of the antagonist to bind to the GR j Qhbnn / 77n7 / B / YiAi compared to the MR (see, e.g., U.S. Pat. No. 5,606,021; 5,696,127; 5,215,916; 5,071,773). The analysis can be performed using either a direct binding assay or by assessing competitive binding to purified GR or MR in the presence of a known ligand. In one exemplary assay, cells stably expressing the glucocorticoid receptor or mineralocorticoid receptor (see, e.g., U.S. Pat. No. 5,606,021) at high levels are used as a source of purified receptor. The affinity of the ligand for the receptor is then directly measured.Those GR modulators that exhibit at least a 10-fold, 100-fold, often 1000-fold higher affinity for the GR relative to MR are then selected for use in the methods described herein. The selectivity assay may also include assaying for the ability to inhibit GR-mediated activities, but not MR-mediated activities. One method for identifying a GR-specific modulator is to assess the ability of an antagonist to prevent activation of reporter constructs using transfection assays (see, e.g., Bocquel et al., J. Steroid Biochem Molec. Biol. 45:205-215, 1993; U.S. Patent 5,606,021 ; 5,929,058 ). In an exemplary transfection assay, an expression plasmid encoding the receptor and a reporter plasmid containing a reporter gene linked to receptor-specific regulatory elements are co-transfected into appropriate receptor-negative host cells.The transfected host cells are then cultured in the presence and absence of a hormone, such as cortisol or an analogue thereof, capable of activating the hormone-responsive promoter / enhancer element of the reporter plasmid. The transfected and cultured host cells are then monitored for induction (i.e., the presence) of the product of the reporter gene sequence. Finally, the expression and / or skeletal binding capacity of the hormone receptor protein (encoded by the receptor DNA sequence in the expression plasmid and produced in the transfected and cultured host cells) is measured to determine reporter gene activity in the presence and absence of an antagonist. The antagonistic activity of a compound can be determined in comparison to known GR and MR receptor antagonists (see, e.g., U.S. Patent No. 5,696,127).Efficacy is then reported as the maximum percentage response observed for each compound relative to a reference antagonist compound. GR modulators that exhibit at least 100-fold, often 1000-fold or greater, activity toward the GR relative to the MR, PR, or AR are then selected for use in the methods described herein. D. Pharmaceutical Compositions and Administration In embodiments, the present invention provides a pharmaceutical composition for normalizing NLR in cancer patients who have high NLR and are receiving the cancer treatment, the pharmaceutical composition including a pharmaceutically acceptable excipient and a GRA. In some embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient and a GRA. SGRA. In preferred embodiments, the pharmaceutical composition includes a pharmaceutically acceptable excipient and a non-steroidal SGRA. Non-steroidal SGRAs can be prepared and administered in a wide variety of oral, parenteral, and topical forms. Oral preparations include tablets, pills, powders, dragees, capsules, liquids, lozenges, syrups, slurries, suspensions, etc., suitable for ingestion by the patient. Non-steroidal SGRAs can also be administered by injection, i.e., intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Non-steroidal SGRAs can also be administered by inhalation, e.g., intranasally. Additionally, non-steroidal SGRAs can be administered transdermally. Accordingly, the present invention also provides pharmaceutical compositions that include a pharmaceutically acceptable carrier or excipient and a non-steroidal SGRA. For preparing pharmaceutical compositions of non-spheroidal SGRAs, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, sachets, suppositories, and dispersible granules. A solid carrier can be one or more substances, which may also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. Details of formulation and administration techniques are well described in the scientific and patent literature; see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA ("Remington's"). 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 the carrier that has the necessary binding properties in appropriate proportions and compacted into the desired shape and size. Powders and tablets preferably contain from 5% or 10% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low-melting wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus associated with it. Similarly, sachets and lozenges are included. Tablets, powders, capsules, pills, sachets, and lozenges may be used as solid dosage forms suitable for oral administration. Suitable solid excipients are carbohydrate or protein fillers including, but not limited to, sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose such as methylcellulose, hydroxypropylmethylcellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; as well as proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents, such as cross-linked polyvinylpyrrolidone, agar, alginic acid, or its salt, such as sodium alginate, may be added. Tablet cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dye or pigment products may be added to the tablet or tablet coatings for product identification or to characterize the amount of active compound (i.e., dose). Pharmaceutical preparations described herein may also be used orally using, for example, pressurized capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol. The pressurized capsules may contain GR modulator mixed with a filler or binder such as lactose or starch, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.In soft capsules, GR modulator compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers. Liquid preparations include solutions, suspensions, and emulsions, e.g., water or water / propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in aqueous polyethylene glycol solution. Aqueous solutions suitable for oral use may be prepared by dissolving the active component in water and adding suitable colorings, flavorings, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use may be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and dispersing or wetting agents such as naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long-chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol),a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g., polyoxyethylene sorbitol monooleate), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension 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 formulations may be adjusted for osmolarity. Also included are solid preparations, which can be converted, shortly before use, into liquid preparations for oral administration. 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, solubilizing agents, and the like. Oil suspensions can be formulated by suspending a non-steroidal SGRA in a vegetable oil, such as arachis oil, olive oil, sesame oil, or coconut oil, or in a mineral oil such as liquid paraffin; or a mixture of these. The oil suspensions may contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents may be added to provide a palatable oral preparation, such as glycerol, sorbitol, or sucrose. These formulations can be preserved by the addition of an antioxidant such as ascorbic acid. As an example of an injectable oil vehicle, see Minto, J. Pharmacol. Exp. Ther. 281:93-102, 1997. The pharmaceutical formulations described herein may also be in the form of oil-in-water emulsions. The oil phase may be a vegetable oil or a mineral oil, described above, or a mixture of these.Suitable emulsifying agents include naturally occurring gums, such as acacia and tragacanth gum, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening agents and flavoring agents, as in the formulation of syrups and elixirs. The formulations may also contain a demulcent, a preservative, or a coloring agent. Non-spheroidal SGRAs can be delivered transdermally, topically, or formulated as applicator sticks, solutions, suspensions, emulsions, gels, creams, ointments, pastes, jellies, paints, powders, and sprays. Non-spheroidal SGRAs can also be delivered as microspheres for slow release into the body. For example, the microspheres can be administered by intradermal injection of slowly released drug-containing microspheres subcutaneously (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 produce a steady supply for weeks to months. The pharmaceutical formulations described herein may be provided as a salt and may be formed with many acids, including, but not limited to, hydrochloric, hydrogen sulfide, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. In other instances, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol over a pH range of 4.5 to 5.5, which is buffered prior to use. In another embodiment, the formulations described herein can be delivered by the use of liposomes which fuse with the cell membrane or undergo endocytosis, i.e., by employing ligands attached to the liposome, or attached directly to the oligonucleotide, which bind to cell surface membrane protein receptors resulting in endocytosis. By using liposomes, particularly where the liposome surface carries ligands specific to target cells, or otherwise preferentially directed to a specific organ, one can focus the delivery of the Pfrfrnn / zznz / E / YiAi modulator. GR in target cells in vivo. (See, e.g., 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). The pharmaceutical preparation is preferably in unit-dose form. In this form, the preparation is subdivided into unit doses containing the appropriate amounts of the active ingredient, a nonsteroidal SGRA. The unit-dose form can be a packaged preparation, the package containing discrete quantities of the preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Alternatively, the unit-dose form can be a capsule, tablet, sachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. The amount of active component in a unit dosage preparation may be varied or adjusted from 0.1 mg to 10,000 mg, more typically 1.0 mg to 6,000 mg, more typically 50 mg to 500 mg. Suitable doses also include about 1 mg, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, or 2000 mg, according to the particular application and the potency of the active component. The composition may, if desired, also contain other compatible therapeutic agents. The pharmaceutical preparation is preferably in unit dosage form. In that form, the preparation is subdivided into unit doses containing appropriate amounts of the compounds and compositions of the present invention. The unit dosage form may be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form may be a capsule, tablet, sachet, or lozenge itself, or it may be the appropriate number of any of these in packaged form. Non-steroidal SGRAs can be administered orally. For example, the non-steroidal SGRA can be administered as a pill, capsule, or liquid formulation as described herein. Alternatively, the non-steroidal SGRAs can be provided by parenteral administration. For example, the non-steroidal SGRA can be administered intravenously (e.g., by injection or infusion). Additional methods of administering the compounds described herein, and pharmaceutical compositions or formulations thereof, are described herein. In some embodiments, the nonsteroidal SGRA is administered in one dose. In other embodiments, the nonsteroidal SGRA is administered in more than one dose, e.g., 2 doses, 3 doses, 4 doses, 5 doses, 6 doses, 7 doses, or more. In some cases, the doses are of equivalent amounts. In other cases, the doses are of different amounts. Doses may increase or decrease over the duration of administration. The amount will vary according to, for example, the properties of the nonsteroidal SGRA and the characteristics of the patient. Any suitable dose of non-steroidal SGRA may be used in the methods described herein. The dose of non-steroidal SGRA administered may be at least about 300 milligrams (mg) per day, or about 600 mg / day, e.g., about 600 mg / day, about 700 mg / day, about 800 mg / day, about 900 mg / day, about 1000 mg / day, about 1100 mg / day, about 1200 mg / day, or more. For example, where the non-steroidal SGRA is relacorilant, the dose of non-steroidal SGRA can be, for example, 50 mg / day, or 75 mg / day, or 100 mg / day, or 125 mg / day, or 150 mg / day, or 175 mg / day, or 200 mg / day, or 225 mg / day, or 250 mg / day, or 300 mg / day, or 350 mg / day, or 400 mg / day, or another amount of relacorilant. In embodiments, the non-steroidal SGRA is administered orally. In some embodiments, the non-steroidal SGRA is administered in at least one dose.In other words, the nonsteroidal SGRA may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses per day. In embodiments, the nonsteroidal SGRA is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more doses per day. The subject may be administered at least one dose of nonsteroidal SGRA in one or more doses over, for example, a period of 2-48 hours. In some embodiments, the nonsteroidal SGRA is administered as a single dose.In other embodiments, the non-steroidal SGRA is administered in more than one dose, e.g., 2 doses, 3 doses, 4 doses, 5 doses, or more doses over a period of 2-48 hours, e.g., a 2-hour period, a 3-hour period, a 4-hour period, a 5-hour period, a 6-hour period, a 7-hour period, an 8-hour period, a 9-hour period, a 10-hour period, an 11-hour period, a 12-hour period, a 14-hour period, a 16-hour period, an 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 hours, a 42-hour period, a 44-hour period, a 46-hour period, or a 48-hour period.In some embodiments, the non-steroidal SGRA is administered over 2-48 hours, 2-36 hours, 2-24 hours, 2-12 hours, 2-8 hours, 8-12 hours, 8-24 hours, 8-36 hours, 8-48 hours, 9-36 hours, 9-24 hours, 9-20 hours, 9-12 hours, 12-48 hours, 12-36 hours, 12-24 hours, 18-48 hours, 18-36 hours, 18-24 hours, 24-36 hours, 24-48 hours, 36-48 hours, or 42-48 hours. Single or multiple administrations of formulations may be administered depending on the dose and frequency as required and tolerated by the patient. The formulations may provide a sufficient amount of active agent to effectively treat the disease state. Thus, in one embodiment, the pharmaceutical formulation for oral administration of a non-steroidal SGRA is in a daily amount of between about 0.01 to about 150 mg per kilogram of body weight per day (mg / kg / day). In some embodiments, the daily amount is about 1.0 to 100 mg / kg / day, 5 to 50 mg / kg / day, 10 to 30 mg / kg / day, and 10 to 20 mg / kg / day. Lower doses may be used, particularly when administering the drug to an anatomically isolated site, such as the cerebrospinal fluid (CSF) space, as opposed to administration orally, into the bloodstream, into a body cavity, or into the lumen of an organ.Substantially higher doses may be used in topical administration. Actual methods for preparing parenterally administrable formulations will be known or apparent to those skilled in the art and are described in more detail in publications such as Remington's, supra. See also Nieman, In “Receptor Mediated Antisteroid Action” Agarwal, et al., eds., De Gruyter, New York (1987). The duration of treatment with a non-steroidal SGRA to lower NLR, to treat NLR-high cancer patients, to augment a patient's cancer treatment, to assist with chemotherapy (e.g., taxane-related treatment, e.g., to improve a cancer patient's response to nab-placitaxel treatment) of a cancer patient, or to improve the health of a cancer patient, or to otherwise improve the symptoms of cancer in a cancer patient, may vary according to the severity of the condition in a subject and the subject's response to non-steroidal SGRAs. In some embodiments, the non-steroidal SGRAs may be administered for a period of about 1 week to 104 weeks (2 years), more typical, and about 6 weeks to 80 weeks, more typical, and about 9 to 60 weeks.Suitable administration periods also include 5 to 9 weeks, 5 to 16 weeks, 9 to 16 weeks, 16 to 24 weeks, 16 to 32 weeks, 24 to 32 weeks, 24 to 48 weeks, 32 to 48 weeks, 32 to 52 weeks, 48 ​​to 52 weeks, 48 ​​to 64 weeks, 52 to 64 weeks, 52 to 72 weeks, 64 to 72 weeks, 64 to 80 weeks, 72 to 80 weeks, 72 to 88 weeks, 80 to 88 weeks, 80 to 96 weeks, 88 to 96 weeks, and 96 to 104 weeks. Suitable periods of administration also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96, 100 and 104 weeks. Generally, administration of a non-steroidal SGRA may be continued until a clinically significant reduction or improvement is observed. Treatment with the non-steroidal SGRA according to the invention may last for as long as two years or even longer. In some embodiments, administration of a non-steroidal SGRA is not continuous and may be stopped for one or more time periods, followed by one or more time periods where administration is resumed. Suitable periods where administration is stopped 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 100 weeks. Appropriate periods where administration is stopped also include 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 24, 25, 30, 32, 35, 40, 45, 48, 50, 52, 55, 60, 64, 65, 68, 70, 72, 75, 80, 85, 88, 90, 95, 96 and 100 weeks. The dosage regimen also takes into consideration pharmacokinetic parameters well known in the art, i.e., absorption rate, bioavailability, metabolism, clearance, and the like (see, e.g., Hidalgo-Aragonese (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. Se / 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108; the latter by Remington, supra). The state of the art allows the physician to determine the dosage regimen for each individual patient, the GR modulator, and the disease or condition being treated. j Pfrfrnn / zznz / E / YiAi Non-steroidal SGRAs may be used in combination with other active agents known to be useful in modulating a glucocorticoid receptor, or with complementary agents that may not be effective alone, but may contribute to the efficacy of the active agent. In some embodiments, co-administration includes administering one active agent, a non-spheroidal SGRA, within 0.5, 1, 2, 4, 6, 8, 10, 12, 16, 20, or 24 hours of a second active agent. Co-administration includes administering two active agents simultaneously, approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other), or sequentially in any order. In some embodiments, co-administration may be accomplished by co-formulation, i.e., preparing a single pharmaceutical composition that includes both active agents. In other embodiments, the active agents may be formulated separately. In another embodiment, the active and / or complementary agents may be linked or conjugated to each other. Once a pharmaceutical composition including a nonsteroidal SGRA has been formulated in an acceptable carrier, it can be placed in an appropriate container and labeled for the treatment of an indicated condition. For administration of a nonsteroidal SGRA, the labeling may include, for example, instructions relating to the amount, frequency, and method of administration. The pharmaceutical compositions of the present invention may be provided as a salt and may be formed with many acids, including, but not limited to, hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous solutions or other protonic solvents than are the corresponding free base forms. In other instances, the preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol in a pH range of 4.5 to 5.5, which is buffered prior to use. 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 lumen of an organ. Formulations for administration will typically comprise a solution of the compositions of the present invention dissolved in a pharmaceutically acceptable carrier. Among the acceptable vehicles and solvents that may be employed are water and Ringer's solution, an isotonic sodium chloride. In addition, sterile fixed oils may conveniently be employed as a solvent or suspending medium. For this purpose, any bland, fixed oil may be employed, including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may be similarly used in the preparation of injectables. These solutions are sterile and generally free of undesired matter.These formulations can be sterilized by conventional, well-known sterilization techniques. The formulations may contain pharmaceutically acceptable auxiliary substances as required for approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, for example, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like. The concentration of the compositions of the present invention in these formulations can vary widely, and will be selected primarily on the basis of fluid volumes, viscosities, body weight, and the like, according to the particular mode of administration selected and the needs of the patient. For IV administration, the formulation may be a sterile injectable preparation, such as a sterile injectable aqueous solution or oleaginous suspension.This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parentally acceptable diluent or solvent, such as a 1,3-butanediol solution. E. Cancer Treatments Cancer Chemotherapeutic Agents In modalities, cancer treatment administered to the patient with high NLR may include the administration of a chemotherapeutic agent.Suitable chemotherapeutic agents for use in combination with non-steroidal SGRA to normalize (reduce) NLR in cancer patients with high NLR and receiving cancer treatments include agents that have the property of killing cancer cells or inhibiting cancer cell growth, including but not limited to anti-microtubule agents (e.g., taxanes, vinca alkaloids, and plinabulin), topoisomerase inhibitors and antimetabolites (e.g., nucleoside analogs acting as, for example, Gemcitabine), mitotic inhibitors, alkylating agents, antimetabolites, antitumor antibiotics, mitotic inhibitors, anthracyclines, intercalating agents, agents capable of interfering with a signal transduction pathway, agents that promote apoptosis, proteasome inhibitors, and the like.Additional anticancer agents, such as those described in U.S. Patent Publication No. 20150218274, and also on, for example, the website “chemocare.com” at the page chemotherapy / what-is-chemotherapy / types-of-chemotherapy.aspx, may also be used in the practice of the methods described herein. Antimicrotubule agents include taxanes, vinca alkaloids, and plinabulin. Examples of taxanes that can be used in combination with nonsteroidal anti-inflammatory drugs (NSAIDs) 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), polyglutamate-bound paclitaxel (PG-paclitaxel, poliglumex paclitaxel, CT-2103, XYOTAC, sold by Cell Therapeutic), the tumor-activated prodrug (TAP), ANG105 (Angiopep-2 bound to three paclitaxel molecules, sold by ImmunoGen), paclitaxel-EC-1 (paclitaxel bound to EC-1 peptide that recognizes erbB2; see Li et al., Biopolymers (2007) 87:225-230)), and glucose-conjugated paclitaxel (for example, 2'-paclitaxel methyl 2-glucopyranosyl succinate, see Liu et al., Bioorganic & Medicinal Chemistry Letters (2007) 17:617-620).Exemplary vinca alkaloids that may be used in combination with the nonsteroidal SGRA to treat cancer patients include, but are not limited to, vinorelbine tartrate (Navelbine®), Vincristine (Oncovin®), and Vindesine (Eldisine®)); vinblastine (also known as vinblastine sulfate, vincaleucoblastine, and VLB, Alkaban-AQ®, and Velban®); and vinorelbine (Navelbine®). Plinabulin is a small molecule that blocks microtubule assembly (e.g., polymerization), has antiangiogenic activity (e.g., reduces tumor vascularization), and can induce apoptosis and arrest mitotic growth. Alkylating agents are most active in the resting phase of the cell. These types of drugs are non-specific to the cell cycle. Exemplary alkylating agents that may be used in combination with nonsteroidal SGRA to treat cancer patients include, but are not limited to, nitrogen mustards, ethyleneimine derivatives, alkyl sulfonates, nitrosoureas, and triazenes.Uracil Mustard Procytox®, Revimmune™), ifosfamide (Mitoxana®), melphalan (Alkeran®), Chlorambucil (Leukeran®), pipobroman (Amedl®, Vercyte®), triethylenemelamine (Hemel®, Hexalen®, Hexastat®), triethylenethiophosphoramine, thiotepa (Thioplex®), busulfan JBusilvex®, Myleran®), carmustine (BiCNU®), lomustine (CeeNU®), streptozocin (Zanosar®), and Dacarbazine (DTIC-Dome®). Additional 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 imidazolecarboxamide, DTIC-Dome®); Altretamine (also known as hexamethylmelamine (HMM), Hexalen®); ifosfamide (Ifex®; Prednumustine; Procarbazine (Matulane®); mechlorethamine (also known as nitrogen mustard, mustine and mechloroethamine hydrochloride, Mustargen®); Streptozocin (Zanosart®); thiotepa (also known as thiophosphoamide, TESPA and TSPA, Tioplex®); cyclophosphamide (Endoxan®, Cytoxan®, Neosar®, Procytox®, Revimmune®); and bendamustine HCl (Treanda®).; Antitumor antibiotics are chemoagents derived from natural products produced by species of the soil fungus Streptomyces. These drugs act during multiple phases of the cell cycle and are considered cell cycle-specific. These various types of antitumor antibodies include, but are not limited to, anthracyclines (e.g., doxorubicin, daunorubicin, epirubicin, mitoxantrone, and idarubicin), chromomycins (e.g., dactinomycin and plicamycin), mitomycin, and bleomycin. Antimetabolites are types of chemotherapy treatments that are cell cycle-specific. When cells incorporate these antimetabolite substances into their metabolism, they are unable to divide. This class of chemotherapy agents includes folic acid antagonists such as methotrexate; pyrimidine antagonists such as 5-fluorouracil, floxuridine, cytarabine, capecitabine, and gemcitabine; purine antagonists such as 5-mercaptopurine and 6-thioguanine; and adenosine deaminase inhibitors such as cladribine, fludarabine, nelarabine, and pentostatin. j Pfrfrnn / zznz / E / YiAi Exemplary anthracyclines that may be used in combination with the nonsteroidal SGRA to treat cancer include, for example, doxorubicin (Adriamycin® and Rubex®); bleomycin (Lenoxane®); daunorubicin (dauorubicin hydrochloride, daunomycin and rubidomycin hydrochloride, Cerubidine®); liposomal daunorubicin (daunorubicin citrate liposome, DaunoXome®); mitoxantrone (DHAD, Novantrone®); epirubicin (Ellence); idarubicin (Idamycin®, Idamycin PFS®); mitomycinC (Mutamycin®); geldanamycin; herbimycin; ravidomycin; and desacetylravidomycin. Exemplary proteasome inhibitors that may be used in combination with the non-steroidal SGRA to treat cancer include, but are not limited to, Bortezomib (Velcade, RTM); Carfilzomib (PX-171, (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-morpholinoacetamido)-4-phenlbutanamido)pentanamide); marizomib (NPI-0052); ixazomib citrate (MLN-9708); delanzomib (CEP-18770); and O-methyl-N-[(2-methyl-5thiazol¡l)carbonyl]-L-seryl-O-methyl-N-[(1 S)-2-[(-2R)-2-methyl-2-oxiranyl]-2-oxo-1 -(phenylmethyl)ethyl]-L-serinamide (ONX-0912). In some embodiments, the chemotherapeutic agent is selected from the group consisting of 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, ARO, NPC, campothecin, topotecan, 9-nitrocamptothecin, 9-aminocamptothecin, rubifen, gimatecan, diflomotecan, BN80927, DX-895, Si MAG-CPT, amsacrine, etoposide, etoposide phosphate, teniposide, doxorubicin, paclitaxel, docetaxel, accatin III, 10-deacetyltaxol, 7-xylosyl-10-deacet¡ltaxol, cephalomannin, 10-deacetyl-7-epitaxol, 7-epitaxol, 10-deacetylbaccatin III, 10-deacetyl cephalomannin, irinotecan, albumin-bound paclitaxel, oxaliplatin,Capecitabine, cisplatin, docetaxel, irinotecan liposome, and etoposide, and combinations thereof. In certain 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 body, subject to empirical optimization. In some cases, the chemotherapeutic agent is administered at a dose of about 100 to 1000 mg, e.g., about 200 mg to 800 mg, about 300 mg to 700 mg, or about 400 mg to 600 mg, e.g., about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, or 700 mg. The dosing schedule may vary from, e.g., every week, every five days, every four days, every other day, twice a day, or three times a day.In one embodiment, the chemotherapeutic agent is administered in an oral dose or an intravenous dose of about 100 mg to 600 mg daily, e.g., about 100 mg, 200 mg, 260 mg, 300 mg, 400 mg, or 600 mg daily, every other day, or every fourth day for all or a portion of the treatment period. In some embodiments, the chemotherapeutic agent is a taxane and can be used at any standard dose, e.g., those FDA-approved doses of taxane, in accordance with the methods described herein. In various embodiments, the taxane is nab-paclitaxel, the i Pfrfrnn / zznz / E / YiAi which is administered at a dose in the range of 80 mg to 125 mg per square meter of body surface area as an intravenous infusion over 30 minutes on days 1, 8, and 15 of each 28-day cycle. In still further embodiments, more than one chemotherapeutic agent may be administered simultaneously, or sequentially, in any order during all or part of the treatment period. The two agents may be administered according to the same or different dosage regimens. Immunotherapeutic Agents In embodiments, the cancer treatment administered to the patient with high NLR may include administration of an immunotherapeutic agent. Suitable immunotherapeutic agents for use in combination with the non-steroidal SGRA to normalize (reduce) the NLR in patients with cancer with high NLR and receiving cancer treatments include antibodies against checkpoint proteins, and include small molecule inhibitors of checkpoint activity. A number of the antibodies have already been shown to be effective in treating cancers, for example, antibodies against PD-1, CTLA4, and PD-L1. In embodiments, the cancer treatment administered with a non-steroidal SGRA may include administration of a checkpoint inhibitor, and the checkpoint inhibitor may be a checkpoint inhibitor antibody (CIA). 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 cancer. Exemplary anti-PD-1 antibodies include pembrolizumab (Keytruda®, also known as lambrolizumab and as MK-3475, Merck), nivolumab (Opdivo®, also known as BMS-936558, Bristol Myers Squibb), cemiplimab (Libtayo®, Sanofi), spartalizumab (PDR001, Novartis), AMP-224 (AstraZeneca), AMP-514 (MEDI0680, AstraZeneca), REGN2810 (Regeneren), 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), Dostarlimab (TSR-042, WBP-285, GlaxoSmithKIine), and INCMGA00012 (MGA012, Incyte and Macrogenics). Anti-PD-L1 antibodies have been used for the treatment of non-small cell lung cancer, melanoma, colorectal cancer, renal cell cancer, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, and hematologic 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 envafolimab (KN035, a “nanobody” (camel antibody), Tracon Therapeutics). Anti-CTLA4 antibodies have been used in clinical trials for the treatment of melanoma, prostate cancer, small cell lung cancer, and non-small cell lung cancer. A significant feature of anti-CTL4A is the kinetics of the antitumor effect, with a lag period of up to 6 months after initial treatment required for a physiological response. i Qhbnn / zznz / B / YiAi In some cases, tumors may actually increase in size after treatment is initiated, before a reduction is observed (Pardoll, 2012, Nature Reviews Cancer 12:252–264). Exemplary anti-CTLA4 CIAs include ipilimumab (Yervoy®, Bristol Myers Squibb) and tremelimumab (initially ticilimumab, CP-675,206, AstraZeneca). CIAs against other checkpoint proteins, such as, for example, varlilumab, ARGX-110, LAG3, LAG525, B7-H3, B7-H4, OX-40, CD137, MEDI6383, MEDI6469, MOXR0916 and TIM3, may also be used in combination with the non-steroidal SGRAs herein to treat cancers. The AIDs used in this disclosure may be a combination of different AIDs, especially if the target checkpoint proteins, e.g., PD-1 and CTLA4, suppress the immune response via different signaling pathways. Thus, a combination of AIDs against either checkpoint protein or a single AID targeting both checkpoint proteins may provide an enhanced immune response. Generate CIAs CIAs can be developed using methods well known in the art. See, e.g., Kohler and Milstein, Nature 256:495 (1975) and Coligan et al. (eds.), Current Protocols in Immunology, Vol. 1, pp. 2.5.1-2.6.7 (John Wiley & Sons 1991). Monoclonal antibodies can be obtained by injecting mice with a composition comprising an antigen, e.g., a checkpoint protein or an epitope thereof, removing the vessel to obtain B-lymphocytes, fusing the B-lymphocytes with myeloma cells to produce hybridomas, cloning the hybridomas, selecting positive clones which produce antibodies to the antigen, culturing the clones which produce antibodies to the antigen, and isolating the antibodies from the hybridoma cultures. The produced monoclonal antibodies can be isolated and purified from hybridoma cultures by a variety of well-established techniques. Isolation techniques include Protein-A Sepharose affinity chromatography, size exclusion chromatography, and ion exchange chromatography. See, for example, Coligan on 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 the initial increase of antibodies to a checkpoint protein, antibodies can 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, for example, Leung et al.Hybridoma 13:469 (1994); United States patent application US20140099254 A1. Human antibodies can be produced using transgenic mice that have been genetically engineered to produce human-specific antibodies in response to antigenic challenge using a checkpoint protein. See Green et al., Nature Genet. 7:13 (1994), Lonberg et al., Nature 368:856 (1994). Human antibodies against a checkpoint protein can also be raised by genetic or chromosomal transfection methods, phage display technology, or by activated B cells in vitro. See, e.g., McCafferty et al., 1990, Nature 348:552-553, U.S. Pat. Nos. 5,567,610 and 5,229,275. Modify CIAs CIAs can also be produced by introducing conservative modifications relative to existing CIAs. For example, a modified CIA can comprise heavy and light chain variable regions, and / or an Fc region, that are homologous to the counterparts of a previously produced antibody. The modified CIA that can be used for the method described herein should have the desired functional properties of being able to block the checkpoint signaling pathway. CIAs can also be produced by altering protein modification sites. For example, antibody glycosylation sites can be altered to produce an antibody lacking glycosylation, and the modified CIAs typically have increased affinity of the antibody for the antigen. Antibodies can also be pegylated by reacting with polyethylene glycol (PEG) under conditions in which one or more PEG groups become attached to the antibody. PEGylation can increase the biological half-life of the antibody. Antibodies having the modifications can be used in combination with the selective GFα modulator described herein while retaining the desired functional properties of blocking checkpoint pathways. ii. Small Molecule Non-Protein Checkpoint Inhibitor Compounds (“SPIs”) In another embodiment, the cancer treatment administered with a non-steroidal SGRA may include the administration of a checkpoint inhibitor, and the checkpoint inhibitor may be a CIC. A CIC is a small molecule, non-protein compound that antagonizes an immune suppressive function of a checkpoint protein. Many CICs are known in the art, for example, the small molecule checkpoint inhibitor CA-170 (Aurigine), the peptide checkpoint inhibitors AUNP12 (Aurigene and Laboratoire Pierre-Fabre) and BMS986189 (Bristol Myers Squibb), and those described in U.S. Patent 9,872,852; U.S. Patent 9,422,339; and U.S. Patent Publication 2013-0022629 A1. CISs can also be identified using any of the numerous combinatorial library methods available in the art and described in, for example, European patent application EP2360254. Combinatorial libraries include: biological libraries; spatially parallel solution-phase or solid-phase libraries; synthetic library methods requiring deconvolution; the one-bead compound library method; and synthetic library methods using affinity chromatography screening. The biological library method is limited to peptide libraries, while the other methods are applicable to peptide, non-peptide oligomer, or small molecule libraries of compounds (Lam, KS (1997) Anticancer Drug Des. 12:145). ! Qhbnn / 77n7 / B / YIAI Radiation Cancer Treatments Radiation may be used to treat cancer. In some embodiments, the cancer treatment administered to a patient with a high NLR may include radiation therapy (e.g., directing ionizing radiation at a tumor, infusion of a radioactive pharmaceutical composition, implantation of a radiation source, or other radiation therapy).Radiation treatments suitable for use in combination with non-steroidal SGRA to normalize NLRs in cancer patients who have NLRs and are receiving cancer treatment include targeting radiation at a tumor or cancerous region (which may be referred to as “external beam radiation therapy” or “teletherapy”); implanting radiation-emitting matter in or near a tumor or cancerous region (which may be referred to as “brachytherapy”); administering a radiolabeled pharmaceutical composition effective to direct radiation to a cancerous tumor or cancerous region (e.g., radiolabeled ligand that targets a receptor expressed, and preferentially overexpressed, on cancer cells). Antiangiogenesis Cancer Treatments Antiangiogenic agents reduce or block the formation of new blood vessels and can be used to treat cancer. Antiangiogenic agents are thought to slow, block, or even reverse tumor growth by limiting the blood supply to the tumor. In modalities, cancer treatment administered to the patient with high NLR may include administration of antiangiogenic therapy, for example, including administration of an antiangiogenic agent. Antiangiogenic agents include antibodies that block the action of vascular epithelial growth factor (VEGF), such as bevacizumab (Avastin®); carboxyamidotriazole, itraconazole; angiopoietin 2; soluble VEGF receptor and other “decoy” molecules to which VEGF can bind and thus reduce its binding to, and activation of, endogenous VEGF receptors which can otherwise stimulate angiogenesis; angiostatin; endostatin;interferin-α, interferin-β, and interferin-γ; platelet factor 4; vasostatin; calreticulin; prolactin; osteopontin; secreted protein 1, 2- and 3-nucleotide polypeptide-rich cysteine ​​(SPARC), also known as osteonectin, and as BM-40; and other angiogenesis inhibitors can be used to treat cancer, and are suitable cancer treatments for use in the methods described herein for normalizing (lowering) the NLR in cancer patients who have high NLR and are receiving cancer treatment. Treatments for Growth Factor Inhibition In embodiments, the cancer treatment administered to the patient with high NLR may include administration of a growth factor inhibitor. Administration of growth factor inhibitors, including, for example, epidermal growth factor (EGF) inhibitors, fibroblast growth factor (FGF) inhibitors, and others may comprise a cancer treatment administered to a cancer patient having high NLR, and administration of non-steroidal SGRA and a growth factor inhibitor may be effective to normalize (reduce) NLR in the cancer patient, to augment growth factor treatment, to reduce tumor burden or promote removal of the tumor(s), and otherwise provide clinical benefit to the cancer patient.Growth factor inhibitors include, for example, tyrosine kinase inhibitors (such as, axitinib (Inlyta®), dasatinib (Sprycel®), erlotinib (Tarceva®), imatinib (Glivec®), nilotinib (Tasigna®), pazopanib (Votrient®), and sunitnib (Sutent®); proteasome inhibitors (such as, bortezomib (Velcade ®), histone deacetylase inhibitors (such as, vorinostat (Zolinza®) and Panobinostat (Farydak®); hedgehog pathway inhibitors (such as, vismodegib (Erivedge®); phosphotidyl inosotide 3 kinase (PIP3) inhibitors (such as idelalisib (Zydelig®); mammalian (or mechanistic) target of rapamycin (mTOR) inhibitors (such as, for example temsirolimus (Torisel®) and everolimus (Afinitor®), and others. Surgical Treatments for Cancer In some embodiments, the cancer treatment administered to a patient with a high NLR may include surgical treatment for the cancer. Surgery may be used to treat the cancer by removing a tumor or by removing part of a tumor, in order to reduce the tumor burden of a patient with a tumor. Administration of a nonsteroidal SGRA to normalize NLR in cancer patients with a high NLR may be performed before, during, or after surgery and may assist in normalizing the patient's NLR and may enhance the patient's treatment and overall health. E. Combination Therapies Various combinations of a non-steroidal SGRA and one or more other anticancer therapies may be employed to treat cancer patients, e.g., to reduce NLR in a cancer patient with a high NLR. The term “combination therapy” or “in combination with” is not intended to imply that the therapeutic agents must be administered at the same time and / or formulated to be delivered together, although these delivery methods are within the scope described herein. The non-steroidal SGRA and the chemotherapeutic agent may be administered following the same or different dosage regimens. In some embodiments, the non-steroidal SGRA and the chemotherapeutic agent are administered sequentially in any order for all or portions of the treatment period.In some embodiments, the non-steroidal SGRA and the anti-cancer agent are administered simultaneously or approximately simultaneously (e.g., within about 1, 5, 10, 15, 20, or 30 minutes of each other). Non-limiting examples of combination therapies are as follows, with administration of the non-steroidal SGRA and the chemotherapeutic agent, e.g., non-steroidal SGRA is “A” and the anti-cancer agent or compound, given as part of a chemotherapy regimen, is “B”. A / B / AB / A / BB / B / AA / A / BA / B / BB / A / AA / B / B / BB / A / B / B i Qhbnn / zznz / B / YiAi. B / B / B / AB / B / A / BA / A / B / BA / B / A / BA / B / B / AB / B / A / A Β / Α / Β / Α Β / Α / Α / Β Α / Α / Α / Β Β / Α / Α / Α Α / Β / Α / Α Α / Α / Β / Α The administration of therapeutic compounds or agents to a patient will follow general protocols for the administration of compounds, taking into account the toxicity, if any, of the therapy. Surgical intervention may also be used in combination with the described therapy. The present methods can be combined with other means of cancer treatment such as surgery, radiation, immunotherapy, use of growth factor inhibitors, anti-angiogenesis factors and other treatments, and combinations thereof. F. Evaluate Improvements to Reduce NLR The nonsteroidal SGRA therapy described herein may reduce the NLR in a cancer patient with a high NLR (e.g., an NLR of 3 or greater) and may confer a beneficial clinical outcome to the cancer patient. Methods for measuring responses to cancer therapies are well known to those skilled in the art of cancer therapy, e.g., as described in the Response Evaluation Criteria in Solid Tumours (“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)). In one procedure, NLR is measured by determining the number of neutrophils and lymphocytes in a blood sample obtained from a cancer patient. A decline in NLR levels after treatment with a nonsteroidal anti-inflammatory drug, such as relacorilant, may suggest beneficial treatment for the cancer patient. A patient receiving the therapy described herein may exhibit varying degrees of NLR reduction. In some instances, a patient may exhibit a reduction of about 10% in the NLR measured prior to treatment; in embodiments, the NLR of a patient with a high NLR cancer is reduced by about 15%, or about 20%, or about 25%, or about 30%, or about 33%, or about 35%, or about 40%, or about 45%, or about 50%, or more, from the NLR measured prior to 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. The desired beneficial or clinical outcomes from combination therapy may also include, for example, a reduction in tumor burden; reduced (i.e., slowed to some extent and / or stopped) cancer cell infiltration into peripheral organs; inhibited (i.e., slowed to some extent and / or stopped) tumor metastasis; increased response rates (RR); increased duration of response; some alleviation of one or more of the symptoms associated with the cancer; decreased doses of other medications required to treat the disease; delayed disease progression; and / or prolonged patient survival and / or improved quality of life. Methods for evaluating these effects are well known and / or described in, for example, cancerguide.org / endpoints.html and the RECIST guidelines, supra. i ofrfrnn / zznz / E / YiAi Although the above-mentioned 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 of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit and scope of the appended claims. EXAMPLES The following examples are provided for illustrative purposes only and not as a limitation. Those with experience will readily recognize a variety of noncritical parameters that can be changed or modified to produce essentially similar results. Example 1: AMINOTRANSFERASE AND HEPG2 TYROSINE ASSAY The following protocol describes an assay for measuring TAT induction by dexamethasone in HepG2 cells (a human liver hepatocellular carcinoma cell line; ECACC, UK). HepG2 cells are cultured using MEME media supplemented with 10% (v / v) fetal bovine serum; 2 mM L-glutamine and 1% (v / v) NEAA at 37°C, 5% / 95% (v / v) CO2 / air. HepG2 cells are then counted and adjusted to yield a density of 0.125 x 106cells / ml in RPMI 1640 without phenol red, 10% (v / v) FBS on charcoal strips, 2 mM L-glutamine and seeded at 25,000 cells / well in 200 μl 96-well tissue culture microtiter plates and incubated at 37°C, 5% CO2 for 24 hours. The growth media is then removed and replaced with assay media {RPMI 1640 without phenol red, 2 mM L-glutamine + 10 µM forskolin}. Test compounds are then screened against a 100 nM dexamethasone challenge. Compounds are then serially diluted in a two-log manner in 100% (v / v) dimethyl sulfoxide from a 10 mM stock. An 8-point one-half log dilution curve is then generated followed by a 1:100 dilution in assay medium to give a final 10x assay compound concentration, resulting in the final assay compound concentration being in the range of 10 to 0.003 µM in 0.1% (v / v) dimethyl sulfoxide. Test compounds are preincubated with cells in microtiter plates for 30 minutes at 37°C, 5 / 95 (v / v) CO2 / air, prior to the addition of 100 nM dexamethasone and then subsequently for 20 hours to allow optimal TAT induction. HepG2 cells are then incubated with 30 μI of cell lysis buffer containing a protease inhibitor cocktail for 15 minutes at 4°C. 155 μI of substrate mix containing 5.4 mM tyrosine sodium salt, 10.8 mM alpha-ketoglutarate, and 0.06 mM pyridoxal 5'-phosphate in 0.1 M potassium phosphate buffer (pH7.4) can then be added. After 2 hours of incubation at 37°C, the reaction can be terminated by the addition of 15 μI of 10 M aqueous potassium hydroxide solution, and the plates incubated for an additional 30 minutes at 37°C. The TAT activity product can be measured by absorbance at λ of 340 nm. Pfrfrnn / zznz / E / YiAi IC50 values ​​can be calculated by plotting % inhibition (normalized to 100 nM TAT stimulation by dexamethasone) against compound concentration and fitting the data to a 4-parameter logistic equation. IC50 values ​​can be converted to K¡ (equilibrium dissociation constant) using the Cheng-Prusoff equation, assuming that the antagonists are competitive inhibitors with respect to dexamethasone. Example 2. Effect of Relacorilant on NLR and Cancer Treatment The neutrophil-to-lymphocyte ratio (NLR) in the blood is typically below 3 in healthy subjects (Figure 7A). However, this ratio is well above 3 in many cancer patients, as indicated by the NLR values ​​for patients with solid tumors shown in Figure 7A. In this example, the effects of relacorilant administration on NLR in healthy subjects and in cancer patients are determined. The results of relacorilant administration indicate that relacorilant administration reduces the NLR, and may normalize the NLR, in cancer patients. Methods Healthy subjects Healthy subjects are enrolled in relacorilant study NCT03508635. The single- and multiple-ascending-dose (SAD and MAD) cohorts are administered and analyzed as described in Figure 1, which shows the schedule for dosing and evaluating healthy subjects in this study. Part (A) of Figure 1 shows the single-ascending-dose (SAD) prednisone challenge design of the study. Part (B) of Figure 1 shows the multiple-ascending-dose (MAD) prednisone challenge design of the study. (C) is the figure legend. Intensive NLR sampling is performed at time 0 (morning, predose) and then 2, 4, 8, 12, and 24 hours later. Single NLR samples are collected in the morning predose. The SAD portion of this experiment uses a 500 mg dose, while the MAD uses a single daily dose of 250 mg. Cancer Patients Cancer patients are enrolled in study NCT02762981, a Phase 1 study of relacorilant in combination with nab-paclitaxel in patients with solid tumors, based on the following criteria: Key Inclusion Criteria Included • Consenting patients > 18 years of age with advanced or metastatic solid tumors who have disease progression. • Treated with up to 3 prior lines of therapy in the advanced setting. Prior nabpac is permitted. Pfrfrnn / zznz / E / YiAi • ECOG-PS (Eastern Cooperative Oncology Group Behavioral Status) 0-1 • Adequate renal, hepatic, and bone marrow function • Medial or evaluable disease • For patients enrolled in a dose-specific pancreatic discovery cohort, key inclusion criteria included • Histologically confirmed diagnosis of pancreatic adenocarcinoma. Patients with pancreatic neuroendocrine tumors, pancreatic lymphoma, or ampullary cancer are not eligible. • CA19-9 (or CEA, CA-125, in non-CA 19-1 elevated tumors) measured within 14 days prior to the first dose of study drug. • Metastatic (non-irradiated) lesion that is measurable by RECIST 1.1 Key Exclusion Criteria Included ° Requirement for treatment with oral corticosteroids used chronically or frequently for medical conditions or diseases (e.g., rheumatoid arthritis, immunosuppression after organ transplant). Evaluations Tumor assessments are performed at screening, end of cycle 2, and every 6-8 weeks thereafter with confirmation of tumor response performed as needed per RECIST (version 1.1). Patients are dosed with relacorilant daily (see Figure 2) or intermittently (see Figure 3), and nab-paclitaxel is administered in a 28-day cycle. The abbreviations used in the figures are Nab-Pac, nab-paclitaxel; PK, pharmacokinetics. Introduction of relacorilant includes daily dosing of relacorilant alone (without nab-paclitaxel) for 7 days. Specimen Collection for Drug Concentration Determination Drug concentrations were determined in study NCT02762981. Blood was collected at multiple time points on day 7 of relacorilant dosing. Before collection, blood was chelated with EDTA, centrifuged, and plasma aliquoted. Bioanalytical analyses were performed by MicroConstants (San Diego, CA, USA). Briefly, human plasma samples containing relacorilant and its stable labeled analogue as an internal standard and K3EDTA as the anticoagulant were buffered with ammonium citrate solution and extracted with 2-butane-2-hexane (2.5:97.5, v / v). Samples were vortex mixed, centrifuged, and the lower portion was frozen in a flash freezer. The organic portion was transferred to a clean tube and evaporated under nitrogen. The extracts are dried, reconstituted, and analyzed by reverse-phase HPLC using a Pfrfrnn / zznz / E / YiAi of 61.7 NLR*hour with prednisone alone at 9.6 NLR*hour after prednisone + relacorilant (25 mg of prednisone administered after 14 consecutive days of relacorilant dosing). Second, the effect of 25 mg of prednisone after 14 consecutive days of dosing with placebo (instead of relacorilant) is evaluated in different subjects (Figure 6). The area under the curve is reduced from 72 NLR*hour with prednisone+placebo to 9.6 NLR*hour after prednisone+relacorilant (25 mg of prednisone administered after 14 consecutive days of 250 mg / day relacorilant dosing). Compared with either control, 14 days of relacorilant dosing significantly flattens the effects of prednisone on NLR. Relacorilant Does Not Affect NLR in Healthy Subjects Normalization of the NLR by relacorilant is thought to occur through antagonism of endogenous cortisol. If patients have elevated cortisol activity, relacorilant may be expected to normalize this activity. Alternatively, relacorilant alone may cause neutropenia (reduction in neutrophils) or lymphocytosis (increase in lymphocytes) by antagonizing normal endogenous cortisol. To distinguish these two possibilities, the effects of relacorilant alone were evaluated in healthy subjects with normal endogenous cortisol. After 14 administrations of 250 mg of relacorilant for 14 consecutive days, no change in the NLR was observed in a cohort of seven healthy subjects (Figure 7). None of the healthy subjects had an NLR greater than 3 at baseline. NLR Changes in Patients with Advanced Solid Tumors After Single-Agent Relacorilant The relationship between relacorilant exposure and NLR is evaluated. Exposure (AUC) and Cmax are determined on day 7 and are considered steady state for the 7-day lead-in period. NLR is expressed as the change from baseline (CfB), where a CfB < 0% indicates a decrease in NLR during relacorilant lead-in. In patients with AUCs in the range of 0–8000 hour*ng / ml, there is a trend toward decreased NLR with increasing exposures (Figure 8, left). A similar trend is seen in patients with Cmax in the range of 0–1000 ng / ml (Figure 8, right). None of the patients with an AUC < 2011 ng / hr / ml or Cmax < 442 ng / ml experienced a decrease in NLR during this period. In contrast, 6 / 13 (46%) patients with an AUC between 2011-8000 ng*hr / ml and 6 / 9 (67%) patients with a Cmax between 442-1000 ng / ml experienced a decrease in NLR. The mean change in NLR for patients with an AUC between 3740-8000 ng*hr / ml is -6.1%, representing a decrease in NLR. The mean change in NLR for patients with a Cmax between 595-836 ng / ml is -4.4%, representing a decrease in NLR. Relacorilant + Nab-paclitaxel Normalizes NLR in Patients with Advanced Solid Tumor NLR was measured on cycle 1 day 1 and day 8 of the relacorilant + nab-paclitaxel combination. 35 of 59 patients with advanced solid tumors had an NLR > 3 on cycle 1 day 1. A significant decrease (p = 0.012) in NLR was observed after 8 days of dosing with relacorilant + nab-paclitaxel in these 59 patients (Figure 9). The average NLR on cycle 1 day 1 was 4.4 and decreased to 3.6 by cycle 1 day 8. The reduction in NLR is observed predominantly 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, there was a significant decrease (p=0.029) in NLR over the same dosing period (Figure 10, right). For patients with a baseline NLR >3, the average of 5.6 at cycle 1 was reduced to 4.5 by cycle 1 day 8. Relacorilant + nab-paclitaxel Reduces NLR in a Patient with Ovarian Cancer Who Experiences a Complete Response Patient 038-4004 is a 57-year-old woman with Stage IIIB high-grade papillary serous ovarian cancer who was initially sensitive to treatment with paclitaxel + cisplatin. Her disease then recurred 3 years later and progressed after two subsequent lines of therapy (gemcitabine + carboplatin + bevacizumab and liposomal doxorubicin). The patient experienced a reduction in tumor marker CA125 (1225.9 to 63.7 units / mL) after the first cycle of study treatment with relacorilant + nab-paclitaxel, and achieved complete response radiographically after two cycles of treatment. This patient discontinued study treatment due to toxicity after 5 months, and her disease progressed 8 months after the start of study treatment. During the 7-day relacorilant lead-in, patient 038-4004 experienced a decrease in NLR from 5.5 to 2.5 (Figure 11). This represents a -46% NLR change. NLR above 5 is consistently interpreted as “high,” and NLR below 2.5 is consistently interpreted as “low” in oncology studies evaluating the predictive value of NLR for immunotherapy or chemotherapy outcomes (Sacdalan, 2018; Goldstein, 2015). This represents a -55% NLR change from baseline (CfB) (i.e., a 55% decrease) during relacorilant lead-in. NLR Reduction is Associated with Tumor Response Changes in NLR are compared between patients with distinct tumor response categories as defined by RECIST criteria. Patients are grouped by RECIST criteria for progressive disease (PD), stable disease (SD), and partial and complete response (PR / CR). Patients with PR / CR tend to have a more pronounced reduction in NLR in the first 8 or 15 days of cycle 1 (Figure 12). In those patients who experience progressive disease, the mean NLR at day 15 is 48% higher than the NLR at day 1. In patients who experience partial or complete response, the mean NLR at day 5 is 25% lower than the NLR at day 1. In conclusion, reductions in NLR are associated with a more pronounced response to relacorilant + nab-paclitaxel. i Pfrfrnn / zznz / E / YiAi Conclusions Decreased NLR predicts better outcomes for cancer patients treated with chemotherapy or immunotherapy. Relacorilant, a selective GR antagonist, inhibits the prednisone-induced increase in NLR. Patients with relacorilant pharmacokinetic parameters in the optimal range are more likely to experience a decrease in NLR after 7 days of dosing with relacorilant alone. Relacorilant + nab-paclitaxel decreased NLR in cancer patients with an elevated baseline NLR. Relacorilant had no effect on NLR in healthy subjects or cancer patients with a baseline NLR in the normal range. This observation has not been previously described. Furthermore, this observation may indicate that elevated cortisol activity is partially responsible for the elevated NLR in patients with advanced solid tumors. The results described here demonstrate that relacorilant administration can reduce NLR in cancer patients and normalize NLR in cancer patients. Reducing NLR in cancer patients with elevated NLR is believed to provide therapeutic benefit to these patients. All patents, patent publications, patent applications, and publications cited in this application are hereby incorporated by reference herein in their entirety as if each individual patent, patent publication, patent application, or publication were specifically and individually indicated to be incorporated by reference. Furthermore, although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A method for reducing the neutrophil-to-lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR greater than 3, the method comprising: administering an effective amount of a selective non-steroidal glucocorticoid receptor antagonist (GRA) to the cancer patient, wherein the NLR of the cancer patient is reduced 2. A method for reducing the neutrophil-to-lymphocyte ratio (NLR) in a cancer patient having a tumor and having an NLR greater than 3, the method comprising: administering an effective amount of a cancer treatment and an effective amount of a selective non-steroidal glucocorticoid receptor antagonist (GRA) to the cancer patient, wherein the NLR of the cancer patient is reduced 3. The method according to claim 1 or claim 2, wherein the neutrophil-to-lymphocyte ratio (NLR) of the cancer patient is reduced to approximately 3 or less.

4. The method according to claim 2 or claim 3, wherein the administration of a cancer treatment and the administration of a selective non-steroidal GRA are effective in reducing the patient's tumor burden.

5. The method according to any of claims 1 to 4, wherein the non-steroidal selective GRA comprises a fused azadecalin structure.

6. The method according to claims 1 to 4, wherein the non-steroidal selective GRA is a compound comprising a fused azadecalin heteroaryl ketone structure, the GRA having the formula: 1 ofrfrnn / zznz / E / YiAi wherein R1 is a heteroaryl ring having 5 to 6 ring members and 1 to 4 heteroatoms each independently selected from the group consisting of N, O, and S, optionally substituted with 1-4 groups each independently selected from R1a; each R1a is independently selected from the group consisting of hydrogen, C1-6 alkyl, halogen, C1-6 haloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, -CN, N-oxide, C3-8 cycloalkyl, and C3-8 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 and heteroaryl rings have 5 to 6 ring members and 1 to 4 heteroatoms each, independently selected from the group consisting of N, O, and S; each R2 is independently selected from the group consisting of hydrogen, Ci6 alkyl, halogen, C1-6 haloalkyl, Ci-e alkoxy, C1-6 haloalkoxy, Ci-6 alkyl, Ci-6 alkoxy, -CN, -OH, -NR2aR2b, -C(O)R2a, -C(O)OR2a, -C(O)NR2aR2b, -SR2a, -S(O)R2a, -S(O)2R2a, C3-8 cycloalkyl and C3-8 heterocycloalkyl, wherein the heterocycloalkyl groups are optionally substituted with 14 R2c groups; alternatively, two R2 groups bonded to the same carbon are combined to form an oxo (=O) group;Alternatively, two R2 groups are combined to form a heterocycloalkyl ring having 5 to 6 ring members and 1 to 3 heteroatoms each independently selected from the group consisting of N, O, and S, wherein the heterocycloalkyl ring is optionally substituted with 1 to 3 R2d groups; R2a and R2b are each independently selected from the group consisting of hydrogen and C1-e alkyl; each R2c is independently selected from the group consisting of hydrogen, halogen, hydroxy, C1-6 alkoxy, C1-6 haloalkoxy, CN, and NR2aR2b; each R2d is independently selected from the group consisting of hydrogen and C16 alkyl, or two R2d groups attached to the same ring atom are combined to form (=O); R3 is selected from the group consisting of phenyl and pyridyl, each optionally substituted with 1-4 R3a groups; each R3a is independently selected from the group consisting of hydrogen, halogen, and haloalkyl from Cí e;and the subscript n is an integer from 0 to 3; or salts and isomers thereof.; 7. The method according to claim 6, wherein the non-spheroidal selective GRA is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazol-4-yl)sulfonyl)-4-4a,5,6,7,8-hexahydro-1Hpyrazol[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the structure: 1 Pfrfrnn / zznz / E / YiAi 8. The method according to claim 6, wherein the non-spheroidal selective GRA is (R)-(1 -(4-f I uorof en i I)-6-((4-(trif I uoro metí I )phenyl)sulf onyl)-4-4a, 5,6,7,8-hexahydro-1 H-pyrazol3,4g]¡soquinol¡n-4a-¡l)pyr¡din-2-yl)methanone, which has the structure i Pfrfrnn / zznz / E / YiAi 9. The method according to any one of claims 1 to 4, wherein the non-spheroidal selective GRA comprises a fused octahydro azadecalin structure, the GRA having the formula: wherein R1 is selected from the group consisting of pyridine and thiazole, optionally substituted with 1-4 groups each independently selected from R1a, each R1a being independently selected from the group consisting of hydrogen, Ci 6 alkyl, halogen, Ci-6 haloalkyl, C1-6 alkoxy, Ci haloalkoxy, N-oxide and O cycloalkyl; ring J is selected from the group consisting of phenyl, pyridine, pyrazole and triazole; each R2 is independently selected from the group consisting of hydrogen, Ci6 alkyl, halogen, C1-6 haloalkyl, and -CN; R3a is F; the subscript n is an integer from 0 to 3; Or salts and isomers thereof.

10. The method according to claim 9, wherein the non-steroidal 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,9octahydro-1Hpyrazol-[3,4-g]isoquinolin-4-a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone, which has the structure: i Qhbnn / zznz / B / YiAi 11. The method according to claim 9, wherein the non-spheroidal 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-pyrazol-[3,4-g]isoquinolin-4-a-l)(triazol-4-l)methanone, which has the structure:

12. The method according to any of claims 2 to 4, wherein the cancer treatment comprises the administration of a chemotherapeutic agent.

13. The method according to claim 12, wherein the chemotherapeutic agent is selected from the group consisting of antimicrotubule agents, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress-inducing agents, antimetabolites, mitotic inhibitors, and combinations thereof.

14. The method according to claim 12, wherein the chemotherapeutic agent is an antimicrotubular agent selected from plinabulin and a taxane.

15. The method according to claim 14, wherein the chemotherapeutic agent is nab-paclitaxel.

16. The method according to any of claims 2 to 4, wherein the cancer treatment comprises the administration of an immunotherapeutic agent.

17. The method according to claim 16, wherein the immunotherapeutic agent comprises the administration of an antibody directed against a protein target selected from PD-1, PD-L1, CTKA4, LAG3, B7-H3, B7-H4, OX-40, CD137 and TIM3.

18. The method according to any one of claims 2 to 4, wherein the cancer treatment comprises one or more cancer radiation therapies, the administration of growth factor inhibitors, and the administration of anti-angiogenesis factors.

19. The method according to any one of claims 2 to 18, wherein reducing the NLR is effective in increasing the response to cancer treatment in a cancer patient receiving cancer treatment and having a neutrophil-to-lymphocyte ratio of more than 3, wherein the increase is as compared to the response in the absence of the present method, the method comprising: administering an effective amount of a cancer treatment and an effective amount of a selective non-steroidal glucocorticoid receptor antagonist (GRA) to the cancer patient, wherein the NLR of the cancer patient is reduced and the response to cancer treatment is increased.

20. The method according to claim 19, wherein the non-steroidal selective GRA comprises a fused azadecalin structure.

21. The method according to claim 19 or claim 20, wherein the non-steroidal selective GRA comprises a fused azadecalin heteroarylketone structure.

22. The method according to claim 21, wherein the non-steroidal selective GRA is (R)-(1-(4-fluorophenyl)-6-((1-methyl 1-1H-pyrazol-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazol[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone, which has the structure i ofrfrnn / zznz / E / YiAi 23. The method according to claim 21, 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-pyrazol-3,4g]isoquinolin-4a-yl)(pridin-2-yl)methanone, which has the structure: l· 24. The method according to claim 19 or claim 20, wherein the non-steroidal selective GRA comprises an octahydro fused azadecalin structure.

25. The method according to claim 24, wherein the non-steroidal selective GRA is ((4aR,8aS)-1-(4-fluorophenyl)-6-((2-methyl-2H-1,2,3-tr-azol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9-octahydro-1Hpyrazol-[3,4-g]isoquinolin-4-a-yl)(4-tr-fluoromethyl)pyridine-2-yl)methanone, which has the structure: i ofrfrnn / zznz / E / YiAi 26. The method according to claim 24, wherein the non-steroidal selective GRA is ((4aR,8aS)-1-(4-f luorophenyl)-6-((2-isopropyl-2H-1,2,3-triazol-4-yl)sulfonyl)-4,4a,5,6,7,8,8a,9octahydro-1 H-pyrazole-[3,4-g]isoquinolín-4-a-íl)(thiazol-4-íl)methanone, which has the structure:

27. The method according to claim 19 or claim 20, wherein the cancer treatment comprises the administration of a chemotherapeutic agent.

28. The method according to claim 27, wherein the chemotherapeutic agent is selected from the group consisting of antimicrotubule agents, alkylating agents, topoisomerase inhibitors, endoplasmic reticulum stress-inducing agents, antimetabolites, mitotic inhibitors, and combinations thereof.

29. The method according to claim 27, wherein the chemotherapeutic agent is an antimicrotubular agent selected from plinabulin and a taxane.

30. The method according to claim 29, wherein the chemotherapeutic agent is nab-placitaxel.

31. The method according to claim 19 or claim 20, wherein the cancer treatment comprises the administration of an immunotherapeutic agent.

32. The method according to claim 31, wherein the immunotherapeutic agent comprises the administration of an antibody directed against a protein target selected from PD-1, PD-L1, CTKA4, LAG3, B7-H3, B7-H4, OX-40, CD137 and TIM3.

33. The method according to claim 19 or claim 20, wherein the cancer treatment comprises one or more cancer radiation therapies, administration of growth factor inhibitors, and administration of anti-angiogenesis factors.

34. The method according to any of claims 12 to 15 and 27 to 30, wherein the chemotherapeutic agent is an antimetabolite.

35. The method according to claim 34, wherein the chemotherapeutic agent is gemcitabine.

36. The method according to any of claims 19 to 35, wherein the patient exhibits a partial response to cancer treatment and GRA treatment, wherein the partial response is an improvement as compared to the patient's response to cancer treatment alone, wherein the cancer patient's NLR is reduced and the cancer patient's response to cancer treatment is increased.

37. The method according to any of claims 19 to 35, wherein the patient exhibits a complete response to the cancer treatment and GRA treatment, wherein the complete response is an improvement as compared to the patient's response to the cancer treatment alone, wherein the cancer patient's NLR is reduced and the cancer patient's response to the cancer treatment is increased.

38. The method according to any of claims 1 to 37, wherein the NLR of the cancer patient is reduced after at least 7 days of administration of the selective non-steroidal GRA.