Intermittent administration of glucocorticoid receptor modulators for the treatment of ovarian cancer and other cancers.

Abstract

The present invention provides methods and compositions for treating cancer (for example, ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer). [Solution] This disclosure relates to intermittent administration of a glucocorticoid receptor modulator for the treatment of ovarian cancer and other cancers.

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority and benefits of U.S. Provisional Patent Application No. 63 / 244,825 filed on 16 September 2021, U.S. Provisional Patent Application No. 63 / 324,873 filed on 29 March 2022, U.S. Provisional Patent Application No. 63 / 345,682 filed on 25 May 2022, and International Application PCT / US2021 / 050617 filed on 16 September 2021, all of which are incorporated herein by reference in their entirety. [Background technology]

[0002] Glucocorticoid receptors ("GRs") are present in almost all body tissues. Cortisol, an endogenous hormone that acts via GRs, influences many biological systems and may play a role in cancer progression. For example, cortisol and GR-mediated signaling can affect inflammation and the immune system. However, it is unclear whether these effects promote or inhibit cancer growth. Many tumor types express GRs, and some tumors (e.g., ovarian cancer tumors) have high GR expression, but the modulating effects of GR-mediated signaling pathways on cancer progression and cancer treatment are unknown, and the importance of GR-mediated signaling pathways in cancer progression and cancer treatment remains unclear.

[0003] Cancers such as ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer, as well as other cancers of the female reproductive organs and tissues, and peritoneal cancer, account for a significant proportion of cancers that affect women (peritoneal cancer is rare in men). These and other cancers may be hormone-sensitive.

[0004] Such cancers are often diagnosed only at an advanced stage. Treatment options are limited, and the prognosis for patients with these cancers is poor. Conventional treatment options for such cancers include surgery and chemotherapy (radiotherapy, also known as "brightening therapy," is rarely used for such patients). In some cases, such cancers may be resectable at diagnosis, but most patients with these cancers are treated with chemotherapy, such as platinum-based chemotherapy. Chemotherapy agents typically rely on causing systemic DNA damage and chromosomal destabilization, which can reduce the proliferation of cancer cells, promote or induce apoptosis in tumor cells, and ultimately lead to the destruction of cancer cells.

[0005] Ovarian cancer can be a devastating disease, for example. While the majority of ovarian cancer patients initially respond to chemotherapy (often platinum-based chemotherapy), the recurrence rate is high, and the majority of ovarian cancer patients experience relapse (Kemp et al., Int J Women's Health 5:45-51 (2013): around 80% relapse within 18 months; Luvero et al., Crit Rev Oncol / Hematol 140:28-38 (2019)). Unfortunately, the response rate to chemotherapy in these recurrent patients may be low, and may only result in short progression-free survival (Luvero et al., Therap Adv Med Oncol 6(5):229-239 (2014)). Overall survival after recurrence of less than one year is standard for recurrent ovarian cancer.

[0006] Additional therapies are limited to patients with platinum-resistant ovarian cancer. Only a small fraction of such patients respond to standard chemotherapy (Luvero et al. 2014). Additional treatment options include surgery, chemotherapy, molecular targeted therapies (anti-angiogenic agents and PARP inhibitors), and radiation (alone or in combination). For recurrent patients who have received initial treatment for recurrent platinum-resistant ovarian cancer, paclitaxel, liposomal doxorubicin, topotecan, or gemcitabine plus carboplatin, administered as monotherapy or in combination with bevacizumab, are approved and are the most commonly used treatments in this situation (Luvero, 2014; Pujade-Lauraine, et al. J Clin Oncol 37:2437-2448 (2019)). Chemotherapy plus bevacizumab showed the best results in patients who had received fewer than two regimens previously, did not have refractory disease, and did not have a history of bowel obstruction within 6 months of treatment (Pujade-Lauraine et al., J Clin Oncol 32:1302-1308 (2014)). In patients with platinum-resistant ovarian cancer or refractory disease, standard treatment is limited to the sequential use of chemotherapy that has not been previously administered. However, the outcomes of these additional chemotherapy options are generally poor.

[0007] There is a great unmet need for effective and well-tolerated treatments for ovarian cancer, cervical cancer, vaginal cancer, vulvar cancer, fallopian tube cancer, uterine cancer, and other tumors of the female reproductive organs and tissues, as well as peritoneal cancer. There is a great unmet need for effective and well-tolerated treatments for women with platinum-resistant ovarian cancer. [Overview of the project]

[0008] Novel methods for treating cancer, and novel uses of glucocorticoid receptor modulator (GRM) compounds, such as nonsteroidal GRMs containing heteroarylketone condensed azadecalin compounds, for treating cancer are disclosed herein.

[0009] The applicant discloses a method for treating cancer, comprising intermittently administering GRM to a cancer patient undergoing cancer chemotherapy. GRM may be administered orally. The method comprises intermittently administering an effective amount of GRM to a patient having cancer, wherein the patient requires and is undergoing cancer chemotherapy for cancer, and the cancer chemotherapy involves administering cancer chemotherapy agents according to a chemotherapy administration schedule that includes at least one day without administration of the cancer chemotherapy agents between days of administration of the cancer chemotherapy agents. As disclosed herein, the intermittent GRM administration comprises at least a first round of GRM administration and a second round of GRM administration, with the first and second rounds separated by at least one day without GRM administration. The first round of GRM administration may consist of an administration of GRM over one day, two consecutive days, three consecutive days, or a longer consecutive period. The second round of GRM administration may consist of an administration of GRM over one day, two consecutive days, three consecutive days, or a longer consecutive period. The first and second rounds do not need to be the same length.

[0010] Intermittent administration of GRM to patients also receiving cancer chemotherapy may include administering GRM on days coordinated with the cancer chemotherapy administration schedule. Rounds of GRM administration may be administered on days relevant to the patient's cancer chemotherapy administration schedule, or on days determined by the patient's cancer chemotherapy administration schedule. For example, rounds of GRM administration may be administered to the patient before, during (e.g., on the same day as) or after the administration of chemotherapy agents.

[0011] In some embodiments, the GRM administration round may be started or completed at least one day before the patient is administered the chemotherapy agent. In some embodiments, the GRM administration round may be started or completed on the day the patient is administered the chemotherapy agent. In some embodiments, the GRM administration round may be started or completed at least one day after the patient is administered the chemotherapy agent.

[0012] The applicant further discloses the use of GRM for use in the treatment of cancer in accordance with the methods disclosed herein. For example, such use includes intermittently administering GRM to a cancer patient receiving cancer chemotherapy agents on multiple days in accordance with an administration schedule that requires at least one day between days on which the cancer chemotherapy agents are administered to the patient. Intermittent GRM administration to a patient also receiving cancer chemotherapy may include administering GRM on days coordinated with the administration schedule of cancer chemotherapy. In embodiments, intermittent GRM administration includes administering GRM on the same days that cancer chemotherapy agents are administered to the patient. If cancer chemotherapy agents are not administered to the patient, intermittent GRM administration may include administering GRM on one or more days. Intermittent GRM administration may include administering GRM on the same days that cancer chemotherapy agents are administered to the patient, and on one or more days if cancer chemotherapy agents are not administered to the patient.

[0013] In embodiments, the GRM is a non-steroidal GRM. In the methods and uses disclosed herein, the non-steroidal GRM is a compound comprising a heteroarylketone condensed azadecalin structure. In embodiments, the GRM is a heteroarylketone condensed azadecalin structure disclosed in U.S. Patent No. 8,859,774 (the contents of which are incorporated herein by reference in their entirety). The heteroarylketone condensed azadecalin GRM may be a liracorilant having the following structure: (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone ("liracorilant"). [ka] Lilacolinant is also known as CORT125134 and is disclosed as Example 18 of U.S. Patent No. 8,859,774.

[0014] The cancer chemotherapeutic agents used herein include all antineoplastic agents such as chemotoxic compounds and chemotoxic preparations that are normally toxic to cancer cells (and often non-cancerous cells as well), antiproliferative agents, and antimetastatic agents, as well as antibodies, checkpoint inhibitors, and other agents and treatments that inhibit, halt, or reverse cancer growth or metastasis in cancer patients, either alone or in combination with other agents. The cancer chemotherapeutic agent may be a taxane, for example, paclitaxel or nab-paclitaxel.

[0015] Cancers that can be treated by the novel methods disclosed herein include cancers of the female reproductive organs and tissues, as well as peritoneal cancers. Such cancers include, for example, ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, and peritoneal cancer. In some embodiments, the novel methods relate to ovarian cancer, including platinum-resistant ovarian cancer. In some embodiments, the novel methods relate to cervical cancer. In some embodiments, the novel methods relate to uterine cancer. In some embodiments, the novel methods relate to fallopian tube cancer. In some embodiments, the novel methods for treating cancer relate to peritoneal cancer.

[0016] The novel and surprising methods of treatment and uses disclosed herein are believed to provide improved and effective treatment for cancer patients suffering from cancers of the peritoneum or female genitalia and female reproductive tissues, including, for example, ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, and vulvar cancer. The results of clinical trials disclosed herein (see, for example, the trial of relacorilant in combination with nab-paclitaxel for patients with recurrent platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer, NCT03776812) demonstrate that these methods (including the combined administration of taxane chemotherapy and the GR modulator relacorilant to patients suffering from female genital cancers and patients suffering from primary peritoneal cancer) provide a greater benefit than taxane chemotherapy alone. For example, the intermittent administration of relacorilant with nab-paclitaxel resulted in a clinically meaningful benefit without an increased burden of side effects as compared to nab-paclitaxel monotherapy. Such benefits included an improvement in progression-free survival (PFS) with a hazard ratio (HR) of 0.66 (P = 0.038; median PFS 5.6 vs. 3.8 months) as compared to nab-paclitaxel monotherapy alone, an improvement in duration of response (DoR) with an HR of 0.36 (P = 0.006; median DoR 5.6 vs. 3.7 months), and an improvement in overall survival (OS) with an HR of 0.67 (P = 0.066; median OS 13.9 vs. 12.2 months).

[0017] As noted above, there is a great and unmet need for effective and well-tolerated treatment of cancers, including platinum-resistant cancers such as ovarian cancer, cervical cancer, vaginal cancer, vulvar cancer, fallopian tube cancer, uterine cancer, and other tumors of the female genitalia and female reproductive tissues, as well as peritoneal cancer. The methods and uses are believed to provide improved treatment of cancers such as peritoneal cancer and cancers of the female genitalia and female reproductive tissues.

Brief Description of the Drawings

[0018] [Figure 1]It is a schematic diagram of the second - phase clinical trial protocol of Example 1. 178 patients with platinum - resistant or platinum - refractory ovarian cancer, primary peritoneal cancer, or fallopian tube cancer were randomized 1:1:1 to receive either nab - paclitaxel administration (100 milligrams per square meter (mg / m2), 60 patients, "comparison"), continuous administration of relacorilant with nab - paclitaxel (80 mg / m2; 58 patients; "continuous"), or intermittent administration of relacorilant with nab - paclitaxel (80 mg / m2; 60 patients; "intermittent"). Patients receiving continuous administration of relacorilant were administered 1 hundred milligrams (mg / day) of relacorilant per day (a gradual increase up to 150 mg / day of the discretionary relacorilant dosage was allowed). Patients receiving intermittent administration of relacorilant were administered 150 mg of relacorilant on the day before, the day of, and the day after nab - paclitaxel administration. If a patient's disease progressed during platinum - based therapy, or the treatment - free interval after platinum - based therapy was less than six months (i.e., the patient relapsed and thus required additional platinum - based treatment less than six months after the completion of the previous platinum - based treatment round), the patient was considered platinum - resistant. If a patient's disease progressed during or within one month of the last platinum - based treatment, the patient was considered "platinum - refractory". (Platinum - refractory patients are a subgroup of platinum - resistant patients)

[0019] [Figure 2] Shows the characteristics of the patients enrolled in each of the three patient groups in the study. All patients except one had received taxane treatment before enrolling in the study (one patient in the "intermittent" group had not received taxane treatment in the past).

[0020] [Figure 3] Shows the aggregation of the breakdown of patients up to the time of the primary (provisional) analysis (data as of March 22, 2021).

[0021] [Figure 4A]This shows the progression-free survival (PFS) duration for three patient groups at the data point collected up to the first cutoff date of March 22, 2021. Patients treated with nab-paclitaxel and intermittent lirachorilant had significantly improved PFS compared to nab-paclitaxel monotherapy (hazard ratio (HR) 0.66, log-rank test P=0.038; unadjusted for multiplicity). Their median PFS was 5.6 months, 1.8 months longer than the 3.8 months in the nab-paclitaxel monotherapy group. Each event refers to a patient who experienced either disease progression (based on RECIST v1.1) or death, whichever occurred first. In a subgroup of patients excluding those with refractory underlying diseases and those who had previously received four or more lines of treatment, intermittent lirachorilant plus nab-paclitaxel showed improved progression-free survival (PFS) compared to nab-paclitaxel monotherapy, with an HR of 0.58, a 95% CI of 0.37–0.91, a log-rank p-value of 0.0162, and a median PFS of 5.6 months compared to 3.8 months.

[0022] [Figure 4B] This shows the progression-free survival (PFS) period analyzed for a subgroup of patients without platinum-refractory underlying disease who had previously received 1-3 lines of therapy for cancer, including bevacizumab.

[0023] [Figure 5]The duration of response (DoR) for each of the three patient groups at the data point collected up to the initial cutoff date of March 22, 2021, is shown. Compared to nab-paclitaxel monotherapy, patients receiving nab-paclitaxel intermittently with liracoralant showed a significantly improved duration of response (P=0.006; HR 0.36), but the objective response rate (ORR) was similar across all three groups (intermittent: n=20 (35.7%); continuous: n=19 (35.2%); comparative: n=19 (35.8%)). In a subgroup excluding patients with refractory underlying disease and those who had previously received four or more lines of treatment, the DoR of intermittent lirachorilant plus nab-paclitaxel compared to nab-paclitaxel alone was improved from 3.6 months to 5.6 months, with an HR of 0.26, a 95% CI of 0.11–0.62, a log-rank test p=0.0009, and a median DoR of 3.6 months.

[0024] [Figure 6A] The data shows the duration of overall survival (OS) for each of the three patient groups at the data point collected up to the late cutoff date of March 7, 2022 (which was predetermined to reach at least 120 OS events). These data demonstrate improved OS in patients receiving intermittent liracoralant with nab-paclitaxel compared to patients receiving nab-paclitaxel alone, as indicated by a hazard ratio (HR) of 0.67 (P=0.066) for intermittent liracoralant + nab-paclitaxel and an HR of 0.85 (P=0.447) for continuous liracoralant + nab-paclitaxel. Therefore, patients in the intermittent liracoralant group had a 33% lower risk of death compared to patients in the comparison group. The median overall survival (OS) was 12.2 months in patients who received nab-paclitaxel but not liracorilant, compared to 13.9 months in patients who received liracorilant intermittently. Each event represents the death of one patient. See also Figures 7B and 7C.

[0025] [Figure 6B]This shows the overall survival (OS) period analyzed for a subgroup of patients without platinum-refractory underlying disease who had previously received 1 to 3 lines of therapy for cancer, including bevacizumab.

[0026] [Figure 7A] This table compares progression-free survival (PFS), objective response rate (ORR), duration of response (DR), and overall survival (OS) observed in three patient groups during the trial. Note that this figure shows PFS, ORR, DoR, and OS data at the initial cutoff date of March 22, 2021. Additional overall survival results were continued to be collected after this initial cutoff date (see Figures 6 and 7B above). Patients who did not respond to first-line platinum-based therapy prior to the trial were considered to have "platinum-refractory underlying disease." These patients have a particularly poor prognosis. PFS, ORR, DoR, and OS were calculated for all 178 patients in this trial ("Overall" column) and for the 167 patients who did not have "platinum-refractory underlying disease" ("Excluding Platinum-Refractory Underlying Disease" column). Both analyses showed that intermittent administration of lirachorilant during taxane chemotherapy cycles significantly improved PFS and DoR compared to taxane chemotherapy alone.

[0027] [Figure 7B] This report summarizes progression-free survival (PFS), duration of response (DR), and overall survival (OS) data for a subgroup of patients without platinum-refractory primary disease who had previously received 1-3 lines of therapy. This subgroup showed greater improvements in PFS, DoR, and OS compared to nab-paclitaxel monotherapy. The final OS analysis data cutoff date was March 7, 2022.

[0028] [Figure 7C]The following shows OS data up to the cutoff date of March 7, 2022, in a subgroup excluding patients with platinum-refractory underlying disease and those who had previously received four or more lines of therapy. Excluding women with platinum-refractory underlying disease and those who had already received four or more lines of therapy, women intermittently treated with lirachorilant had a 48% reduced risk of death compared to women treated with nab-paclitaxel monotherapy (hazard ratio: 0.52; p-value: 0.010). The median OS was 13.9 months compared to 12.2 months for women treated with nab-paclitaxel monotherapy.

[0029] [Figure 7D] This section presents a summary of progression-free survival (PFS), duration of response (DR), and overall survival (OS) data for a subgroup of patients without platinum-refractory primary disease who had previously received 1-3 lines of therapy, including previous bevacizumab treatment. This subgroup showed even greater improvements in PFS, DoR, and OS than those observed in other subgroup analyses (for the group that did not require previous bevacizumab treatment, see, for example, Figure 7B).

[0030] [Figure 8] This section presents a summary of the comparison of the number of specific clinical conditions observed in the three patient groups during the trial. The safety and tolerability of treatment with lilacolinant and nab-paclitaxel were comparable to the safety and tolerability of treatment with nab-paclitaxel alone.

[0031] [Figure 9A]This shows a comparison of glucocorticoid receptor (GR) encoding mRNA levels in ovarian cancer patients treated with nab-paclitaxel monotherapy compared to ovarian cancer patients treated with liracorilant in addition to nab-paclitaxel. GR expression was observed in 96% of evaluable ovarian tumors in our phase 2 trial. High GR expression was associated with poor response in the nab-paclitaxel monotherapy group. In contrast, high GR expression was associated with partial or complete response in both liracorilant + nab-paclitaxel groups (top). In patients with high GR, the rate of partial or complete response was twice as high in the liracorilant + nab-paclitaxel group compared to the nab-paclitaxel monotherapy group (bottom).

[0032] [Figure 9B] The results for "GR-inducible genes" (defined as 239 genes induced by a single dose of prednisone when measured in whole blood obtained from separate healthy volunteer studies) are shown. In patients (triangle) who received both liracoralant and nab-paclitaxel (either continuously or intermittently), mRNA expression was suppressed in 221 of these 239 GR-inducible genes from day 1 to day 15 of cycle 1. Of the 239 genes previously shown to be GR target genes, 221 were suppressed after liracoralant + nab-paclitaxel treatment. A significantly smaller number of GR target genes were suppressed by nab-paclitaxel alone (P<0.00001).

[0033] [Figure 9C] This shows three GR target genes, including SGK1 (P=0.0089), PIK3CG (P=0.0045), and GSK3B (P=0.0175), that were repressed not by NP alone but by RELA+NP.

[0034] [Figure 9D]This shows mRNA level measurements in 137 pre-treatment tumor specimens, including tumors from patients treated with nab-paclitaxel alone and tumors from patients treated with nab-paclitaxel and lilacolinant. The median values ​​for each of the 444 genes were initially determined (left). NR3C1 mRNA was highly expressed in all tumors tested. The median value of NR3C1 fell within the 83rd percentile of the overall gene distribution.

[0035] [Figure 10A]This is a schematic diagram of the planned clinical trial protocol for Example 2. The target enrollment is 360 patients with carcinoma, ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, with high-grade serous epithelial (grade 3), high-grade endometrioid, and ≥30% endometrioid epithelial tumor component, and who have progressed within 6 months after the last dose of platinum-based therapy. Women with recurrent ovarian cancer, primary peritoneal cancer, or fallopian tube cancer that is resistant to platinum-based chemotherapy after at least one treatment, and whose histological subtypes include high-grade serous epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer; high-grade endometrioid; and carcinosarcoma with ≥30% endometrioid epithelial tumor component. These criteria are expected to exclude patients with platinum-refractory primary disease from the study. The primary endpoint to be measured is progression-free survival (PFS) as determined by blinded independent central review (BICR) based on RECIST v.1.1. Secondary efficacy endpoints will include overall survival (OS), progression-free survival (PFS) based on RECIST v.1.1 (as determined by the principal investigator), best overall response (BOR), duration of response (DR) based on RECIST v.1.1, clinical return based on RECIST v.1.1, and combined responses based on RECIST v.1.1 + GCIG (Gynecological Cancer InterGroup) criteria. Safety endpoints will include patient safety, patient quality of life (QOL), Ca-125, pharmacodynamics, and pharmacokinetics.Patients may receive either (A) intermittent administration of liracoralant (150 mg orally) with nab-paclitaxel (80 mg / m2; 180 patients), where nab-paclitaxel is administered on days 1, 8, and 15 of a 28-day cycle, and liracoralant is administered on days 1, 2, 7-9, 14-16, and 28, or (B) "Investigator's choice" by the treating physician, where patients receive liposomal doxorubicin on day 1 of a 28-day cycle. Patients will be randomized in a 1:1 ratio to receive either 40 mg / m2 intravenously (iv); paclitaxel (80 mg / m2; iv) on days 1, 8, 15, and 22 of a 28-day cycle; nab-paclitaxel (100 mg / m2, iv) on days 1, 8, and 15 of a 28-day cycle; or topotecan (4 mg / m2, iv) on days 1, 8, and 15 of a 28-day cycle, or 1.25 mg / m2, iv) on days 1-5 of each of a 21-day cycle.

[0036] [Figure 10B] This is a schematic diagram of the ROSELLA (NCT05257408) trial, an initiated and ongoing randomized, controlled, two-arm, open-label, multicenter phase 3 trial of intermittent lirachorilant plus nab-paclitaxel. [Modes for carrying out the invention]

[0037] The applicant has surprisingly discovered that intermittent administration of a glucocorticoid receptor modulator (GRM) in combination with cancer chemotherapy provides greater benefits to cancer patients than chemotherapy alone. Intermittent administration of a GRM with a taxane provides greater benefits to cancer patients than taxane monotherapy. For example, the applicant has surprisingly discovered that intermittent administration of the nonsteroidal GRM liracoralant in combination with taxane chemotherapy (e.g., nab-paclitaxel) results in cancer patients with, for example, extended response duration and progression-free survival compared to taxane monotherapy. For example, as disclosed herein, intermittent administration of liracoralant on the day before, on the day of, and the day after weekly administration of nab-paclitaxel (over three consecutive weeks of a four-week cycle, and over multiple such cycles, as demonstrated in the examples herein) provides greater benefits to cancer patients than similar nab-paclitaxel treatment in the absence of liracoralant. These greater benefits include improved progression-free survival, improved duration of response, and other benefits in patients with ovarian cancer, fallopian tube cancer, peritoneal cancer, and other cancers.

[0038] This surprising result differs from previous findings indicating that continued administration of liracorilant in combination with nab-paclitaxel may provide benefits. A phase 1 trial of liracorilant plus nab-paclitaxel demonstrated clinical activity in patients with metastatic PDAC, ovarian cancer, and other solid tumors. The combination of liracorilant plus nab-paclitaxel provided longer-term benefits than previous nab-paclitaxel monotherapy and resulted in sustained disease control in patients with ovarian cancer, fallopian tube cancer, and primary peritoneal cancer (Munster et al. 2019). The applicant hereby discloses that, in contrast to continuous administration of GRM with taxane chemotherapy, intermittent administration of GRM with taxane chemotherapy surprisingly provided additional benefits compared to no GRM administration.

[0039] The methods and uses disclosed herein involve intermittent administration of an effective dose of GRM to a subject that is effective in treating the target cancer. In some embodiments, the GRM is a selective glucocorticoid receptor modulator (SGRM). In some embodiments, the methods disclosed herein involve intermittent administration of an effective dose of non-steroidal GRM ("non-steroidal" means that the GRM does not contain a steroid structure) to a subject that is effective in treating the target cancer.

[0040] In some embodiments, GRM is a nonsteroidal compound comprising a heteroarylketone condensed azadecalin structure, as described and disclosed in U.S. Patent No. 8,859,774. In some embodiments, GRM is a heteroarylketone condensed azadecalin compound disclosed in U.S. Patent No. 8,859,774. Pharmaceutical compositions for use disclosed herein may contain a nonsteroidal GRM compound comprising a heteroarylketone condensed azadecalin structure. In some embodiments, the GRM is a heteroarylketone condensed azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone ("Lilacorilant") having the following structure. [ka] Lilacorilant is disclosed in Example 18 of U.S. Patent No. 8,859,774 and is also known as CORT125134. Lilacorilant is a GRM that does not significantly affect progesterone receptors, mineralocorticoid receptors, androgen receptors, or estrogen receptors. Therefore, lilacorilant is an SGRM. In some embodiments, lilacorilant is administered orally.

[0041] Intermittent administration refers to administering a pharmaceutical composition at intervals longer than one day. In some embodiments, the time interval between administrations may be two days, several days, one week, several weeks, one month, several months, or longer. The time interval between administrations may be regular (e.g., the time interval between administrations is always the same number of days) or irregular (e.g., the time interval between some pairs of administrations of the pharmaceutical composition may be different in number of days from the time interval between other pairs of administrations of the pharmaceutical composition). In some embodiments, the time interval between a first administration of the pharmaceutical composition and a second administration does not need to be the same as the time interval between a second administration of the pharmaceutical composition and a third administration, or between a third administration and a fourth administration, or between other subsequent administrations of the pharmaceutical composition.

[0042] In some embodiments of the methods and uses disclosed herein, intermittent administration includes administering an effective dose of a GRM (e.g., lirachorilant), such as a nonsteroidal GRM, over two consecutive days, waiting for a certain period ("intermittent period"), and then administering an effective dose of the GRM again over two consecutive days. The intermittent period may be, for example, one week, two weeks, three weeks, four weeks, or longer. The intermittent period may be two days or several days, or a number of days that is not equal to an integer number of weeks. In some embodiments of the methods disclosed herein, intermittent administration includes administering an effective dose of a GRM (e.g., lirachorilant), such as a nonsteroidal GRM, over three consecutive days, waiting for an intermittent period, and then administering an effective dose of the GRM again over three consecutive days. The intermittent period may be, for example, one week, two weeks, three weeks, four weeks, or longer. In some embodiments of the methods disclosed herein, intermittent administration includes administration of an effective amount of a GRM (e.g., lirachorilant), such as a nonsteroidal GRM, once a week, once every two weeks, once a month, twice a month, or three times a month. In some embodiments of the methods disclosed herein, intermittent administration includes administration of an effective amount of a GRM (e.g., lirachorilant), such as a nonsteroidal GRM, every other day.

[0043] For example, intermittent administration of GRMs such as heteroarylketone condensed azadecalin GRM may include administration on the day the cancer chemotherapeutic agent is administered to the patient. Intermittent administration of GRMs such as heteroarylketone condensed azadecalin GRM may further include administration on the day before or the day after the cancer chemotherapeutic agent is administered to the patient, and may include administration of nonsteroidal GRMs on the day before, the day, and the day after the cancer chemotherapeutic agent is administered to the patient. Intermittent administration of heteroarylketone condensed azadecalin GRM may include four or more days between administrations of heteroarylketone condensed azadecalin GRM on which heteroarylketone condensed azadecalin GRM is not administered.

[0044] Novel methods and uses disclosed herein may be used to treat cancer patients who are also receiving cancer chemotherapy. In some embodiments of the methods disclosed herein, intermittent administration of a GRM (e.g., liracoralant), such as a nonsteroidal GRM, can be timed according to the administration schedule of cancer chemotherapy agents to the patient. For example, the GRM may be administered the day before, on the day of, or the day after administration of cancer chemotherapy agents to the patient. The GRM may be administered on two or more of the days before, on, or the day after administration of cancer chemotherapy agents to the patient. In some embodiments of the methods and uses disclosed herein, intermittent GRM administration includes administering an effective amount of a GRM (e.g., liracoralant), such as a nonsteroidal GRM, on the day before, on the day of, and the day after administration of cancer chemotherapy agents to the patient. The cancer chemotherapy agent may be a taxane, such as paclitaxel or nab-paclitaxel.

[0045] In some embodiments of the methods disclosed herein, intermittent administration includes administering an effective dose of a GRM (e.g., liracoralant), such as a nonsteroidal GRM, on the day before administering the cancer chemotherapeutic agent to the patient. The cancer chemotherapeutic agent may be, for example, a taxane such as paclitaxel or nab-paclitaxel. In some embodiments of the methods disclosed herein, intermittent administration includes administering an effective dose of a GRM (e.g., liracoralant), such as a nonsteroidal GRM, on the day of administering the cancer chemotherapeutic agent to the patient. The cancer chemotherapeutic agent may be, for example, a taxane such as paclitaxel or nab-paclitaxel. In some embodiments of the methods disclosed herein, intermittent administration includes administering an effective dose of a GRM (e.g., liracoralant), such as a nonsteroidal GRM, on the day following the administration of the cancer chemotherapeutic agent to the patient. The cancer chemotherapeutic agent may be, for example, a taxane such as paclitaxel or nab-paclitaxel.

[0046] Novel methods and uses disclosed herein, including intermittent administration of GRMs such as nonsteroidal GRMs, may be used to treat patients with ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, peritoneal cancer, or other cancers. Such intermittent administration of an effective amount of a GRM, such as a nonsteroidal GRM (e.g., liracorilant), in combination with cancer chemotherapy, is effective in treating cancer. Pharmaceutical compositions for use disclosed herein may contain nonsteroidal GRM compounds (e.g., liracorilant) containing a heteroarylketone condensed azadecalin structure.

[0047] GRMs, such as nonsteroidal GRMs, may be administered orally. In some embodiments, lilacolinant is administered orally. In some cases, GRMs, such as nonsteroidal GRMs, are administered by injection, infusion, or other means.

[0048] In some cases, the effective dose of GRM is 1 mg / kg to 100 mg / kg per day, and GRM is administered together with at least one chemotherapeutic agent. In some embodiments, the dose of GRM is 1 mg / kg, 2 mg / kg, 4 mg / kg, 6 mg / kg, 8 mg / kg, 10 mg / kg, 12 mg / kg, 14 mg / kg, 16 mg / kg, 18 mg / kg, 20 mg / kg, 30 mg / kg, 40 mg / kg, 50 mg / kg, 60 mg / kg, 70 mg / kg, 80 mg / kg, 90 mg / kg, or 100 mg / kg per day. In some cases, GRM may be administered for 1 week or more, 2 weeks or more, 3 weeks or more, 4 weeks or more, 5 weeks or more, 6 weeks or more, 7 weeks or more, 8 weeks or more, 9 weeks or more, 10 weeks or more, 11 weeks or more, 12 weeks or more, 13 weeks or more, 14 weeks or more, 15 weeks or more, 16 weeks or more, 17 weeks or more, 18 weeks or more, 19 weeks or more, 20 weeks or more, 25 weeks or more, 30 weeks or more, 35 weeks or more, 40 weeks or more, 45 weeks or more, 50 weeks or more, 55 weeks or more, 60 weeks or more, 65 weeks or more, 70 weeks or more, 75 weeks or more, or 80 weeks or more, according to an intermittent dosing regimen.

[0049] The cancer chemotherapeutic agents (also called chemotherapeutic agents) used herein may be any chemotherapeutic agent suitable for use in the treatment of cancer, for example, any chemotherapeutic agent suitable for use in the treatment of ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer. The cancer chemotherapeutic agent may be, for example, a chemotoxic compound, an antiproliferative agent, an antimetastatic agent, an antibody, or other agent or treatment that can inhibit, halt, or reverse the growth or progression of cancer, either alone or in combination with other agents. In some embodiments of the methods and uses disclosed herein, the cancer chemotherapeutic agent may be a taxane. The taxane may be, for example, paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, or ortataxel. In some embodiments, the cancer chemotherapeutic agent is a taxane containing paclitaxel, for example, nab-paclitaxel.

[0050] Accordingly, the applicant discloses a method for treating cancer, comprising intermittently administering an effective amount of GRM to a patient having cancer, wherein the patient is in need of and receiving cancer chemotherapy for the cancer, the treatment comprising administering cancer chemotherapy agents according to an administration schedule, the administration schedule requiring that there be at least one day without administration of the cancer chemotherapy agents between days on which the cancer chemotherapy agents are administered to the patient, wherein the intermittent administration comprises administering the GRM on the same days on which the cancer chemotherapy agents are administered to the patient, thereby treating the cancer. In some embodiments, the GRM is a nonsteroidal GRM such as heteroarylketone condensed azadecalin GRM (e.g., liracorilant).

[0051] In some embodiments of the methods disclosed herein, the GRM is also administered the day after the cancer chemotherapy agent is administered to the patient. In some embodiments of the methods disclosed herein, the GRM is also administered the day before the cancer chemotherapy agent is administered to the patient. In some embodiments of the methods disclosed herein, the GRM is administered the day before, the day of, and the day after the cancer chemotherapy agent is administered to the patient. In some embodiments, the GRM is a nonsteroidal GRM (e.g., liracorilant), such as heteroarylketone condensed azadecalin GRM.

[0052] The applicant also discloses herein the use of GRMs, non-steroidal GRMs such as heteroarylketone condensed azadecalin GRM (e.g., liracorilant) in any of the methods disclosed herein for treating cancer. Such use includes the use of such GRMs in the manufacture of pharmaceuticals for treating cancer according to the methods disclosed herein. In some embodiments of the methods and uses disclosed herein, the administration schedule for cancer chemotherapy includes administering a cancer chemotherapy agent on day 1, and administering the cancer chemotherapy agent again on a day following day 1, with an interval of one or more days between day 1 and the day following day (i.e., not the day after the first day) during which the cancer chemotherapy agent is not administered. For example, in some embodiments of the methods and uses disclosed herein, the administration schedule for cancer chemotherapy includes administration of a cancer chemotherapy agent on day 1, and administration of a cancer chemotherapy agent again on a day seven days after day 1, with no administration of the cancer chemotherapy agent on the day between day 1 and the day seven days after day 1.

[0053] In other embodiments of the methods disclosed herein, the cancer chemotherapy agent is administered to the patient over three consecutive weeks according to a cancer chemotherapy administration schedule. In yet another embodiment of the methods disclosed herein, the cancer chemotherapy agent is administered to the patient over three consecutive weeks according to a cancer chemotherapy administration schedule, and then not administered in the week following the last week of the three consecutive weeks. In some embodiments, the cancer chemotherapy agent is administered to the patient over three consecutive weeks according to a cancer chemotherapy administration schedule, and then not administered in the week following the last week of the three consecutive weeks, and then the weekly administration regimen is repeated over a further three consecutive weeks.

[0054] The applicant further discloses the use of a pharmaceutical composition for treating cancer, the cancer treatment comprising intermittently administering an effective amount of a GRM, such as heteroarylketone condensed azadecalin GRM, to a patient having cancer, the patient requiring and receiving cancer chemotherapy for the cancer, the treatment comprising administering the cancer chemotherapy agent according to a chemotherapy administration schedule, the administration schedule requiring that there be at least one day without administration of the cancer chemotherapy agent between days on which the cancer chemotherapy agent is administered to the patient, the intermittent administration comprising administering the GRM on the same day that the cancer chemotherapy agent is administered to the patient, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM such as heteroarylketone condensed azadecalin GRM (e.g., liracorilant).

[0055] In some embodiments of use disclosed herein, the cancer to be treated may be, for example, ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer. In some embodiments, the cancer is platinum-resistant fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer. In some embodiments of use disclosed herein, the cancer chemotherapeutic agent may be a taxane. In some embodiments of use, the taxane may be, for example, paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, or ortataxel. In some embodiments, the cancer chemotherapeutic agent is a taxane containing paclitaxel, for example, nab-paclitaxel.

[0056] In some embodiments of use disclosed herein, GRM (such as nonsteroidal GRMs, e.g., heteroarylketone condensed azadecalin GRM) is also administered the day after the cancer chemotherapy agent is administered to the patient. In some embodiments of use disclosed herein, heteroarylketone condensed azadecalin GRM is also administered the day before the cancer chemotherapy agent is administered to the patient. In some embodiments of use disclosed herein, heteroarylketone condensed azadecalin GRM is administered the day before, the day of, and the day after the cancer chemotherapy agent is administered to the patient.

[0057] In some embodiments of use disclosed herein, the administration schedule for cancer chemotherapy includes administration of the cancer chemotherapy agent on day 1 and administration of the cancer chemotherapy agent again on the day 7 days after day 1, with no administration of the cancer chemotherapy agent on the days between day 1 and the day 7 days after day 1.

[0058] In other embodiments of the use disclosed herein, the cancer chemotherapy agent is administered to the patient over three consecutive weeks according to a cancer chemotherapy administration schedule. In yet another embodiment of the use disclosed herein, the cancer chemotherapy agent is administered to the patient over three consecutive weeks according to a cancer chemotherapy administration schedule, and then not administered in the week following the last week of the three consecutive weeks. In some embodiments of the use disclosed herein, the cancer chemotherapy agent is administered to the patient over three consecutive weeks according to a cancer chemotherapy administration schedule, and then not administered in the week following the last week of the three consecutive weeks, and then the weekly administration regimen is repeated over a further three consecutive weeks.

[0059] B. Definition As used herein, the terms “tumor” and “cancer” are interchangeable and both refer to the abnormal growth of tissue resulting from excessive cell division. A “malignant” tumor can invade surrounding tissue (such invasion of a tumor is called “locally advanced”). A malignant tumor that leaves the organ of origin is a metastatic malignant tumor.

[0060] As used herein, the term “first-line treatment” refers to the treatment administered to a patient first (for example, at the time of cancer diagnosis). Other terms commonly used in relation to “first-line treatment” include induction therapy, primary therapy, and primary treatment.

[0061] As used herein, the terms “overall survival” and “overall survival rate” (OS) refer to the number or percentage of patients in the treatment group who are still alive after the start of treatment, for a certain period of time, or at a selected point in time.

[0062] As used herein, the term “progression-free survival” (“PFS”) refers to the length of time during and after treatment in which the cancer does not worsen (“progress,” for example, the tumor does not grow significantly in size or metastasize). Progression-free survival is an indicator of how well the treatment is working.

[0063] As used herein, the terms “response” and “response rate” refer to improvement related to the treatment, or delay or cessation of disease progression. For example, a patient who shows improvement during or after the treatment, such as a reduction in the severity of symptoms, a slowing or cessation of tumor growth, an improvement in quality of life, or other improvements, is said to respond to the treatment.

[0064] As used herein, the terms “objective response” and “objective response rate” (ORR) refer to a measurable response, i.e., a measurable improvement associated with the treatment. ORR is defined as the percentage of patients whose tumor size decreased over a given dose and minimum duration. See Response Evaluation Criteria in Solid Tumors (“RECIST”) guidelines version 1.1 (available via the World Wide Web at URL: ctep.cancer.gov / protocolDevelopment / docs / recist_guideline.pdf).

[0065] As used herein, the term “duration of response” (DoR) refers to the length of time a patient experiences improvement related to a treatment.

[0066] As used herein, the terms “partial response” and “partial remission” (PR) refer to a reduction of at least 30% in the total diameter (SOD) of the target lesion, with reference to baseline SOD in response to treatment.

[0067] As used herein, the terms “complete response” and “complete remission” (CR) refer to the disappearance of all signs of cancer in response to treatment, i.e., the absence of detectable evidence of tumor. CR is generally measured by imaging (e.g., CT scan) or histopathological evaluation (e.g., bone marrow biopsy or breast cancer mastectomy specimen).

[0068] As used herein, the term “recurrence” means the recurrence of cancer or the reappearance or increase of cancer symptoms following a period in response to treatment.

[0069] As used herein, the term "platinum-resistant" refers to cancer that recurs or progresses within a certain period after successful treatment (e.g., partial or complete response) with platinum-containing chemotherapy (e.g., cisplatin or carboplatin). For example, ovarian cancer that recurs within six months after treatment with platinum-containing chemotherapy is considered platinum-resistant.

[0070] As used herein, the term “platinum-refractory” refers to cancer that does not respond to treatment with anticancer drugs containing the metal platinum, such as cisplatin and carboplatin. Disease that progresses or recurs immediately after previous platinum-based therapy indicates a lack of response to treatment. Some patients with “platinum-refractory underlying disease” do not respond to initial treatment with platinum-based cancer therapy. Other patients may initially respond to platinum-based cancer therapy but do not respond to additional platinum-based cancer therapy upon cancer recurrence. Platinum-resistant patients are a subgroup of platinum-refractory patients.

[0071] As used herein, the term “hazard ratio” (HR) refers to a measure that compares the response of patients in a group of patients who received a particular treatment (e.g., survival) at any given time point to the response of patients in a control group who received a different treatment or placebo (e.g., survival). Patient survival may be measured, for example, as progression-free survival, overall survival, or other survival measures. A hazard ratio of 1 means there is no difference in survival between the two groups. A hazard ratio greater than or less than 1 means that survival was better in one of the groups. For example, if the HR is calculated as the overall survival of the experimental group compared to the overall survival of the control group, then HR < 1 indicates that the overall survival of the experimental group was longer. More generally, a hazard ratio refers to a measure over time that compares how often a particular event occurs in one group to how often a particular event occurs in another group.

[0072] As used herein, the term “ascites” usually refers to an abnormal accumulation of fluid in the abdomen.

[0073] As used herein, the terms “cancer chemotherapeutic,” “cancer chemotherapeutic agent,” “cancer therapeutic,” “cancer chemotherapy agent,” and “chemotherapy agent” refer to any antineoplastic agent, compound, and composition used to treat cancer. As used herein, in addition to chemotoxic compounds and chemotoxic preparations that are normally toxic to cancer cells (and often to non-cancerous cells as well), cancer chemotherapeutic agents and treatments with such agents may also include antibody therapies, toxic or antibiotic compounds and preparations that are normally toxic to cancer cells (and often to non-cancerous cells as well), antiproliferative agents (that reduce the growth or replication of cancer cells), antimetastatic agents (that reduce metastasis), and other agents and treatments that inhibit, halt, or reverse the growth or progression of cancer in cancer patients. Cancer chemotherapeutic agents may be used alone or in combination with other cancer chemotherapeutic agents or other agents.

[0074] Cancer chemotherapy agents include, but are not limited to, doxorubicin, vincristine, cyclophosphamide, fluorouracil (e.g., 5-fluorouracil (5-FU)), topotecan, interferon, platinum derivatives, taxanes (e.g., paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel), vinca alkaloids (e.g., vinblastine), anthracyclines (e.g., doxorubicin), epipodophyllotoxin (e.g., etoposide), cisplatin, methotrexate, actinomycin D, dorastatin 10, trimethrexate, methoprine, daunorubicin, teniposide, alkylating agents (e.g., chlorambucil), 5-fluorouracil, camptothecin, and cisplatin, as well as anti-inflammatory agents, such as colchicine in particular.

[0075] As used herein, the term “taxane” refers to a class of diterpene compounds having a taxadiene core. Many taxanes are useful as cancer chemotherapy agents, typically acting as mitotic inhibitors and antimicrotubule agents. Taxanes include paclitaxel (e.g., TAXOL (Paclitaxel; Bristol-Myers Squibb Oncology, Princeton, New Jersey)), nab-paclitaxel (ABRAXANE®, “Abx”; also known as nab-paclitaxel, albumin-modified nanoparticle formulation of paclitaxel (American Pharmaceutical Partners, Schönberg Ill.)), TAXOTERE® (Docetaxel; Sanofi-Aventis), larotaxel, tesetaxel, cabazitaxel, and ortataxel.

[0076] As used herein, the term "bevacizumab" refers to an antibody drug that binds to vascular endothelial growth factor (VEGF), a protein. Bevacizumab is used alone or in combination with other drugs to treat various types of cancer, including, for example, ovarian cancer, cervical cancer, colorectal cancer, lung cancer, and other cancers. Bevacizumab is thought to treat cancer by inhibiting the growth of new blood vessels. Bevacizumab is marketed under trade names such as Avastin, Mvasi, and Zirabev.

[0077] As used herein, the terms “PARP inhibitor” and “poly(ADP-ribose) polymerase inhibitor” refer to substances that inhibit or block the enzyme poly(ADP-ribose) polymerase (PARP). PARP inhibitors may be used in combination with other cancer chemotherapy agents. PARP is considered an important cellular tool in repairing DNA damage. One objective of many cancer chemotherapy agents is to damage the DNA of cancerous cells. PARP inhibitors are thought to treat cancer by inhibiting DNA repair in cancer cells treated with cancer chemotherapy agents.

[0078] As used herein, the terms “adverse event” and “adverse effect” refer to any unexpected medical problem experienced by a patient during treatment with a drug or other therapy, including, for example, during treatment with an experimental procedure in a clinical trial. Adverse events may be mild, moderate, or severe and may be caused by something other than the drug or therapy being administered. Adverse events that may be observed in cancer patients include, for example, neutropenia, anemia, neuropathy (such as peripheral neuropathy), fatigue, swelling, ascites, nausea, vomiting, and other events or symptoms.

[0079] As used herein, the terms “safety” and “safety” in relation to clinical trials refer to the risk, amount, or number of adverse events in a clinical trial, typically a clinical trial comparing the effect of a test treatment to the effect of a standard treatment. A new drug, new treatment, or new treatment method is considered “safe” (similar means that the number of adverse events is not significantly greater than the number of adverse events associated with the standard treatment).

[0080] As used herein, the terms “patient” and “subject” refer to a person who is receiving, scheduled to receive, or has received treatment for a disease or condition.

[0081] As used herein, the terms “effective dose” or “therapeutic dose” refer to the amount of a pharmacological agent effective in treating, eliminating, or alleviating at least one symptom of the disease being treated. In some cases, “therapeutic effective dose” or “effective dose” may refer to the amount of a functional agent or pharmaceutical composition useful in exhibiting a detectable therapeutic or inhibitory effect. The effect can be detected by any assay method known in the art. The effective dose may be the amount effective in inducing an antitumor response. For the purposes of this disclosure, the effective dose of GRM or the effective dose of a chemotherapeutic agent is the amount, when used in combination with the chemotherapeutic agent or GRM, that results in a desired beneficial clinical outcome related to improvement of cancer. Such desired beneficial clinical outcomes may be, for example, slowing or cessation of tumor growth, a reduction in tumor size or tumor volume, improvement of symptoms or comorbidities, or a reduction in the number of adverse events, such as neutropenia, anemia, neuropathy, or fatigue, an improvement in quality of life, or other improvements.

[0082] As used herein, the terms “administer,” “administering,” “administered,” or “administered” mean giving a compound or composition (e.g., those described herein) to a subject or patient. Administration may be by oral administration (i.e., the subject receives the compound or composition orally as a pill, capsule, liquid, or in any other form suitable for oral administration). Oral administration may be buccal (the compound or composition is held in the mouth, for example, under the tongue, where it is absorbed). Administration may be by injection, i.e., delivery of the compound or composition by needle, microneedle, pressure syringe, or by puncturing the skin or by any other means of forcing the compound or composition through the skin of the subject. Injection may be intravenous (i.e., intravenous), intraarterial (i.e., intraarterially), intraperitoneal (i.e., intraperitoneally), intramuscular (i.e., intramuscularly), or by any other route of infusion. Routes of administration may include rectal, vaginal, percutaneous, pulmonary (e.g., by inhalation), subcutaneous (e.g., by injection, or by absorption into the skin from an implant containing the compound or composition), or other routes.

[0083] Terms such as "measure," "measure a level," and "measure the level" refer to determining, detecting, or quantifying the amount, level, or concentration of a target analyte. The target analyte may be, for example, mRNA from a sample obtained from a subject, or a hormone (e.g., cortisol or ACTH), or another target analyte. The sample may be, for example, a blood sample. The level can be measured from a fraction of the sample. For example, the level of the analyte can be measured in the plasma fraction of a blood sample, in the serum fraction of a blood sample, or, in some embodiments, in whole blood.

[0084] As used herein, the term “sample” refers to a biological sample obtained from a human subject. Such samples are typically taken from the subject and, if obtained, completely separated from the subject (i.e., they are in vitro samples). A sample may be any cell, tissue, or bodily fluid sample obtained from a human subject. A sample may be, for example, a blood sample, a saliva sample, a urine sample, or any other sample obtained from a patient. A sample may be subjected to various treatment, storage, or processing procedures before being analyzed according to the methods described herein. In general, the terms “sample” or “multiple samples” are not intended to be limited by their source, origin, method of procurement, treatment, processing, storage, or analysis, or any modification. Thus, in embodiments, a sample is an in vitro sample and can be analyzed using in vitro methods. The methods disclosed herein are in vitro methods when used with samples obtained from and taken from human subjects.

[0085] As used herein, the term "AUC" means the area under the concentration-time curve and serves as a measure of the level of a drug in an administered subject. Drug levels may be measured in samples obtained from a patient, such as whole blood, plasma, serum, urine, saliva, or other samples.

[0086] When used herein, "C max The term "drug" refers to the maximum observed concentration of the drug in a subject to which the drug was administered or in a sample obtained from that subject. max This can be measured, for example, in whole blood samples, plasma samples, serum samples, urine samples, saliva samples, or other samples.

[0087] As used herein, the term “exposure” refers to the amount of drug available to the body that can produce activity after administration of the drug to a patient. Not all drugs administered to a patient are available for clinical action (for example, some drugs may be excreted, metabolized, or otherwise unavailable), so drug exposure may not be equivalent to the dose. Exposure is measured by AUC or C max These can be measured by various methods, and both provide objective measurements of the drug in the patient.

[0088] As used herein, the term “combination therapy” refers to the administration of at least two different medications to a patient for the treatment of a disease. The two medications may be administered simultaneously or sequentially in any order for the entire duration or part of the treatment period. The at least two medications may be administered according to the same or different dosing regimens. In some cases, one medication may be administered according to a planned regimen, while the other is administered intermittently. In some cases, both medications may be administered intermittently.

[0089] As used herein, terms such as “co-administration,” “concomitant administration,” “combined administration,” and “combination treatment” refer to the administration of at least two drugs to a subject for the treatment of a disease or condition. The two drugs may be administered simultaneously or sequentially in any order for the entire duration or part of the treatment period. The at least two drugs may be administered according to the same or different administration regimens. Such drugs may include, for example, lirachorilant and another drug that may be useful in treating cancer, or another therapeutic agent. In some cases, one drug may be administered intermittently. In some cases, both drugs may be administered intermittently. In some cases, the first drug may be administered once a week for a period of one, two, or three weeks, and the second drug may be administered on one or more of the days preceding, on the day following, and the day after the administration of the first drug.

[0090] As used herein, the term “compound” is used to indicate a molecular portion of a unique, identifiable chemical structure. A molecular portion (“compound”) may exist in the form of a free species that is not associated with other molecules. A compound may also exist as part of a larger aggregate that is associated with other molecules but nevertheless retains its chemical identity. A solvate, in which the molecular portion of a defined chemical structure (“compound”) is associated with molecules of a solvent, is an example of such an associated form. A hydrate is a solvate in which the associated solvent is water. The description of “compound” refers to the molecular portion (of the described structure) itself, whether it exists in a free or associated form.

[0091] As used herein, the term “pharmaceutically acceptable carrier” is intended to include any solvent, dispersion, coating, antimicrobial and antifungal agent, isotonic agent, and absorption retarder, etc., that is suitable for pharmaceutically active substances. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active compound, it is intended to be used in the composition. Co-active compounds may also be incorporated into the composition.

[0092] As used herein, the terms “steroid” and “steroids,” and the phrase “steroid skeleton,” include a steroid skeleton containing 17 carbon atoms linked by four fused rings, having the following structure: [ka] Cortisol contains a steroid skeleton, is a steroid compound, and is a steroid hormone.

[0093] As used herein, the term "non-steroidal skeleton" in the context of GRM refers to a GRM that does not share structural homology with, or is not a modification of, other compounds containing a cortisol or steroidal skeleton. Non-steroidal compounds lack a steroidal skeleton.

[0094] As used herein, the term “glucocorticoid” (“GC”) includes any compound known in the art that binds to and activates glucocorticoid receptors. Thus, GCs are glucocorticoid receptor agonists, and other terms for GC include corticoid, corticosteroid, steroid, and glucocorticosteroid. “Glucocorticosteroid” refers to a steroid hormone or steroid molecule that binds to glucocorticoid receptors. In humans and many other mammals, the major GC is cortisol, while in rodents, for example, corticosterone plays this role. Other GCs include, for example, dexamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone, beclametasone, and other natural and synthetic compounds. Glucocorticoids are typically characterized by having 21 carbon atoms, an α,β-unsaturated ketone in ring A, and an α-ketol group bound to ring D. These differ in the degree of oxygenation or hydroxylation at C-11, C-17, and C-19 (Rawn, “Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives,” in Biochemistry, Daisy et al.(eds.), 1989, pg.567).

[0095] As used herein, the term “glucocorticoid receptor” (“GR”) refers to type II GR, a family of intracellular receptors that specifically bind to cortisol and / or cortisol analogs such as dexamethasone (see, for example, Turner & Muller, J.Mol.Endocrinol.October 1, 2005 35 283–292). Glucocorticoid receptors are also referred to as cortisol receptors. This term includes isoforms of GR, recombinant GR, and mutant GR. The gene encoding GR is called NR3C1.

[0096] The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates GC binding to GR. For example, GRMs that act as agonists, such as dexamethasone, increase the activity of tyrosine aminotransferase (TAT) in HepG2 cells (human hepatocellular carcinoma cell line; ECACC, UK). GRMs that act as antagonists, such as mifepristone, decrease the activity of tyrosine aminotransferase (TAT) in HepG2 cells. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452.

[0097] As used herein, the term “selective glucocorticoid receptor modulator” (SGRM) refers to any composition or compound that modulates the binding of glucocorticoids (GCs) to GRs, or any biological response associated with the binding of GRs to an agonist. Being “selective” means that the drug preferentially binds to GRs over other nuclear receptors such as progesterone receptors (PROs), mineralocorticoid receptors (MRs), or androgen receptors (ARs). A selective glucocorticoid receptor modulator has an affinity (K) that is 10 times greater than its affinity for MRs, ARs, or PROs. d It is preferable to bind to GR at 1 / 10 of the value. The lilacolinant is SGRM.

[0098] A "glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits GC binding to GR. Therefore, GR antagonists can be identified by measuring the compound's ability to inhibit the binding of dexamethasone to GR. TAT activity can be measured as outlined in the literature by A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRAs have an IC50 of less than 10 micromoles. 50 This is a compound having (maximum half-molecule inhibitory concentration). See Example 1 of U.S. Patent No. 8,859,774, the full details of which are incorporated herein by reference. GRA is GRM.

[0099] Compounds containing a heteroarylketone condensed azadecalin structure (which may also be called a heteroarylketone condensed azadecalin skeleton) may be nonsteroidal compounds, GRM compounds, or SGRM compounds. Exemplary heteroarylketone condensed azadecalin compounds are described in U.S. Patent No. 8,859,774. In some embodiments, the heteroarylketone condensed azadecalin GRM for use in the methods and applications disclosed herein is the compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone (Example 18 of U.S. Patent No. 8,859,774), also known as "Lilacorilant" and "CORT125134". [ka]

[0100] As used herein, the term “composition” is intended to encompass products containing specific components such as the above compounds in specific amounts, their tautomers, their derivatives, their analogues, their stereoisomers, their polymorphs, their deuterated species, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates, and pharmaceutically acceptable compositions, as well as any products obtained directly or indirectly from combinations of such specific components in specific amounts. Such terminology relating to pharmaceutical compositions is intended to encompass products containing the active component and the inactive component constituting the support, as well as any products arising directly or indirectly from combinations, complexation, or aggregation of any two or more components, or from the dissociation of one or more of the components, or from one or more other types of reactions or interactions of the components. Accordingly, the pharmaceutical compositions of the present invention are intended to encompass any compositions prepared by mixing the compounds of the present invention and their pharmaceutically acceptable supporters.

[0101] In some embodiments, the term "essentially consisting of" means that the formulation composition contains only the active ingredient shown, but may also contain other compounds for purposes such as stabilizing or preserving the formulation, but which do not directly contribute to the therapeutic effect of the active ingredient. In some embodiments, the term "essentially consisting of" may mean that the composition contains an active ingredient and components that promote the release of the active ingredient. For example, the composition may contain one or more components that cause the active ingredient to be released gradually over time to a target. In some embodiments, the term "consisting of" means that the composition contains an active ingredient and a pharmaceutically acceptable carrier or formulation additive.

[0102] "pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that can be included in the composition of the present invention without causing significant adverse toxicity to the patient, thereby assisting the administration and absorption of the active agent to the subject. As used herein, these terms are intended to include any solvent, dispersion medium, coating, antimicrobial and antifungal agent, antioxidant, isotonic agent and absorption retarder, etc., that is suitable for pharmaceutically acceptable administration. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, ordinary physiological saline, lactated Ringer's solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavorings, and colorants. Those skilled in the art will recognize that other pharmaceutically acceptable excipients are useful in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active compound, it is intended to be used in the composition. Co-active compounds can also be incorporated into the composition. Those skilled in the art will recognize that other pharmaceutical additives are useful in the present invention.

[0103] Methods for identifying or characterizing GRM compounds are known in the art. GRMs bind to GR and modulate its activity. For example, GRMs can antagonize GR activity by inhibiting the GR binding of other agents that activate GR. Such modulation can be detected by observing GR-mediated activity. Compounds that exhibit a desired binding affinity to GR can be tested for their activity in inhibiting GR-mediated activity. Compounds are typically subjected to a tyrosine aminotransferase assay (TAT assay) to evaluate the ability of the test compound to inhibit the induction of tyrosine aminotransferase activity by dexamethasone. GR modulators suitable for the methods disclosed herein have an IC50 of less than 10 micromoles. 50It has (maximum half-dose inhibitory concentration). Other assays, including but not limited to those described below, can also be performed to confirm the GR-modulating activity of the compound.

[0104] Cell-based assays, including whole cells or cell fractions containing glucocorticoid receptors, can also be used to assay the modulation of glucocorticoid receptor binding or activity of test compounds. Exemplary cell types that can be used according to the methods of the present invention include, for example, any mammalian cells including neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells, and lymphocytes such as T cells and B cells, leukocytes, leukemia cells, Burkitt lymphoma cells, tumor cells (including mouse mammary gland tumor virus cells), endothelial cells, fibroblasts, cardiac cells, muscle cells, breast cancer cells, ovarian cancer cells, cervical cancer cells, glioblastoma cells, hepatocytes, renal cells, and nerve cells, as well as fungal cells including yeast. The cells may be primary cells, tumor cells, or other types of immortal cell lines. Naturally, glucocorticoid receptors may be expressed in cells that do not express endogenous glucocorticoid receptors.

[0105] In some embodiments, a decrease in signaling induced by glucocorticoid receptor activation is used to identify glucocorticoid receptor modulators. The signaling activity of the glucocorticoid receptor can be determined in many ways. For example, signaling activity can be determined by monitoring downstream molecular events. Downstream events include activity or signs resulting from stimulation of the glucocorticoid receptor. Exemplary downstream events useful in the functional evaluation of transcriptional activation and antagonistism in immutable cells include the upregulation of numerous glucocorticoid response element (GRE)-dependent genes (PEPCK, tyrosine aminotransferase, aromatase). Furthermore, specific cell types sensitive to GR activation may be used, such as osteocalcin expression in osteoblasts, which are downregulated by glucocorticoids, and 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 with well-known GRE regulatory sequences (e.g., mouse mammary cancer virus promoter (MMTV) transfected upstream of a reporter gene construct). Examples of useful reporter gene constructs include luciferase (luc), alkaline phosphatase (ALP), and chloramphenicol acetyltransferase (CAT). Functional evaluation of transcriptional repression can be performed in cell lines such as monocytes or human dermal fibroblasts. Useful functional assays include those measuring the expression of genes regulated by IL-1β-stimulated IL-6 expression, collagenase, cyclooxygenase-2, and various chemokines (MCP-1, RANTES), LPS-stimulated cytokine release (e.g., TNFα), or NFκB or AP-1 transcription factors in transfected cell lines.

[0106] Compounds tested in whole-cell assays can also be tested in cytotoxic assays. Cytotoxic assays are used to determine the extent to which the recognized effect is attributable to the effect on non-glucocorticoid receptor-binding cells. In some exemplary embodiments, a cytotoxic assay involves contacting constitutively active cells with the test compound. Any decrease in cell activity indicates a cytotoxic effect.

[0107] Other examples of the many assays that can be used to identify the compositions utilized in the method of the present invention include assays based on in vivo glucocorticoid activity. For example, an assay may be used to evaluate the ability of a putative GR modulator to inhibit the uptake of 3H-thymidine into DNA in glucocorticoid-stimulated cells. Alternatively, a putative GR modulator may compete with 3H-dexamethasone for binding to GR in liver cancer tissue cultures (see, e.g., Choi, et al., Steroids 57:313-318, 1992). Another example is the ability of a putative GR modulator to block the nuclear binding of the 3H-dexamethasone-GR complex (Alexandrova et al., J.Steroid Biochem.Mol.Biol.41:723-725, 1992). To further identify the putative GR modulator, kinetic assays can also be used that utilize receptor binding kinetics to distinguish between glucocorticoid agonists and modulators (described in Jones, Biochem J.204:721-729, 1982).

[0108] In another exemplary example, anti-glucocorticoid activity can be identified using the assay described in Daune, Molec. Pharm. 13:948-955, 1977, and U.S. Patent No. 4,386,085. Briefly, adrenalectomized rat thymocytes are incubated with various concentrations of the test compound (putative GR modulator) in dexamethasone-containing nutrient medium. 3H-uridine is added to the cell culture, which is then incubated, and the degree of incorporation of the radiolabel into the polynucleotide is measured. The glucocorticoid agonist is incorporated. 3 It reduces the amount of H-uridine. Therefore, GR antagonists counteract this effect.

[0109] Pharmaceutical composition and administration In embodiments, the present invention provides a method for treating cancer, comprising intermittent administration of a pharmaceutical composition containing a pharmaceutically acceptable formulation additive and a heteroarylketone condensed azadecalin GRM (e.g., liracorilant) in conjunction with a cancer chemotherapy regimen. In some embodiments, the pharmaceutical composition containing liracorilant includes those disclosed in U.S. Patent Application Publication No. 2020 / 0197372, the entirety of which is incorporated herein by reference.

[0110] Any appropriate dose of GRM may be used in the methods and uses disclosed herein. The dose of GRM administered may be at least about 10 mg / day, about 25 mg / day, about 40 mg / day, about 50 mg / day, about 60 mg / day, about 70 mg / day, about 80 mg / day, about 100 mg / day, about 110 mg / day, about 120 mg / day, about 130 mg / day, about 140 mg / day, about 150 mg / day, about 160 mg / day, about 170 mg / day, about 180 mg / day, about 190 mg / day, about 200 mg / day, about 225 mg / day, about 250 mg / day, or more. In some embodiments, GRM is administered in at least one dose on the day of administration to the cancer patient. In some embodiments, GRM can be administered to cancer patients in single, double, triple, quadruple, quintuple, six, seven, eight, nine, ten, or more doses on the day of administration.

[0111] A pharmaceutical composition containing a heteroarylketone condensed azadecalin GR modulator can be formulated in an acceptable carrier, placed in a suitable container, and labeled for cancer treatment when administered, for example, in conjunction with a regimen containing cancer chemotherapy agents. In the case of administration of heteroarylketone condensed azadecalin GRM, such labeling may include, for example, instructions regarding the dosage, frequency, and method of administration.

[0112] The duration of treatment with heteroarylketone condensed azadecalin GRM and cancer chemotherapy agents for the treatment of cancer may vary depending on the severity of the patient's condition and the patient's response. In some embodiments, GRM may be administered in conjunction with a cancer chemotherapy regimen for periods of about 1 week to about 104 weeks (2 years), or about 4 weeks to about 80 weeks, or about 3 weeks to about 60 weeks. For example, these periods may include at least a few days or a week when the patient is not receiving GRM, at least a week when the patient is not receiving cancer treatment agents, or at least a week when the patient is not receiving either GRM or cancer treatment agents.

[0113] For example, a cancer chemotherapy regimen may be one in which the patient receives one, two, three, or more cycles of chemotherapy, and a chemotherapy cycle may include administration of a chemotherapeutic agent one day per week for three consecutive weeks, followed by one week (or longer) without administration of the chemotherapeutic agent. Administration of GRM with such a cancer chemotherapy regimen may include administering GRM to the patient on the day the patient receives the chemotherapeutic agent. Administration of GRM with such a cancer chemotherapy regimen may include administering GRM to the patient on the day the patient receives the chemotherapeutic agent, and on the day before, the day after, or both of the day before and the day after the day the patient receives the chemotherapeutic agent.

[0114] The administration of therapeutic compounds or drugs to patients shall follow general protocols for the administration of such compounds, taking into consideration any potential toxicity of the therapy. Surgical interventions may also be applied in combination with the therapies described above.

[0115] This method can be used in combination with other therapeutic means such as surgery, radiation, targeted therapy, immunotherapy, the use of growth factor inhibitors, or anti-angiogenic agents. [Examples]

[0116] The following examples are provided for illustrative purposes only and not for limitation. Those skilled in the art will readily recognize various non-essential parameters that can be changed or modified to produce essentially similar results.

[0117] Example 1: Intermittent administration of liracorilant with NAB-paclitaxel improves progression-free survival and overall survival in patients with platinum-resistant ovarian cancer. Unless otherwise specified, the data and analyses presented herein are from a primary analysis (provisional or initial analysis) based on 154 progression-free survival (PFS) events and 76 overall survival (OS) events recorded up to March 22, 2021. Further OS analyses were performed (as specified) after achieving 120 or more OS events (up to March 7, 2022). Subgroup analyses were also performed by excluding seven patients with platinum-refractory primary disease from the intermittent lirachorilant group with nab-paclitaxel and one patient with platinum-refractory primary disease from the comparison group (nab-paclitaxel only).

[0118] The effects of adding GRM administration to cancer chemotherapy were investigated in a clinical trial. Daily GRM administration may result in continuous antagonism of GR-mediated chemotherapy resistance pathways, but higher doses of GRM administered intermittently may produce greater GR antagonism before and after maximum chemotherapy exposure. To determine whether different GRM administration schemes may have different effects on treatment outcomes, and if so, which scheme may provide superior benefits, some patients were treated with continuous lirachorilant administration, while others were treated with intermittent lirachorilant administration.

[0119] A three-group, randomized, open-label, comparative phase 2 trial was conducted to compare clinical findings from patients treated with nab-paclitaxel with similar findings from patients treated with liracorilant. This example presents results from this trial, which demonstrated that intermittent administration of liracorilant in combination with nab-paclitaxel improves progression-free survival (PFS) in cancer patients. Such patients included those with recurrent platinum-resistant ovarian cancer and other cancers (including fallopian tube cancer, high-grade serous or endometrioid epithelial ovarian cancer, or ovarian carcinosarcoma, and primary peritoneal cancer). Patients were classified as platinum-refractory (patients who did not respond to platinum-based therapy or who relapsed within one month of treatment with platinum-based therapy) or platinum-resistant (patients who relapsed within six months of treatment with platinum-based therapy). Patients enrolled in this trial had received at least one line of therapy and were either “recurrent” (i.e., “platinum-resistant” with a platinum-free interval of 6 months or less) or had progressive disease (i.e., platinum-refractory) during or immediately after platinum-based therapy. Patients with platinum-resistant underlying disease (progression within 6 months of the last dose of first-line platinum-containing chemotherapy) were eligible for this trial.

[0120] In this trial, cancer patients, including those with ovarian cancer, fallopian tube cancer, peritoneal cancer, and other cancers, were enrolled for comparison between nab-paclitaxel monotherapy and two methods of administering relacorilant together with nab-paclitaxel treatment. A schematic description of the clinical trial protocol is shown in Figure 1. 178 patients with platinum-resistant or platinum-refractory ovarian cancer, primary peritoneal cancer, or fallopian tube cancer were randomized 1:1:1 to receive either nab-paclitaxel alone (60 patients in the nab-paclitaxel monotherapy group, called the "comparison" group), continuous administration of relacorilant together with nab-paclitaxel (58 patients in the "continuous" group), or intermittent administration of relacorilant together with nab-paclitaxel (60 patients in the "intermittent" group). Patients in these groups were all treated with a 28-day chemotherapy cycle in which nab-paclitaxel was administered on days 1, 8, and 15.

[0121] Patients in the comparison group were administered nab-paclitaxel at 100 milligrams per square meter (mg / m 2 ) and no relacorilant was administered. The results of the comparison group were used as a reference for comparison with the other groups. Patients in the continuous group were administered 80 mg / m 2While also receiving nab-paclitaxel, patients were given liracorilant once daily (initially 100 mg per day (mg / day), with discretionary dose escalation up to 150 mg / day permitted from cycle 2 onward for patients who appeared to tolerate higher doses based on their response to the initial 100 mg dose). Dose escalation was managed as follows: If unacceptable grade 2, grade 3, or grade 4 toxicity during the first cycle did not require a reduction or omission of either liracorilant or nab-paclitaxel doses, the liracorilant dose was escalated to 125 mg once daily, starting on day 1 of cycle 2. For patients receiving an escalation of liracoralant to 125 mg, if intolerable grade 2, or grade 3 or 4 toxicity does not require dose reduction or omission of either liracoralant or nab-paclitaxel in cycle 2, the liracoralant dose should be escalated to 150 mg once daily, starting on day 1 of cycle 3. If the dose was not escalated in cycle 1 or 2, the dose should not be escalated in subsequent cycles.

[0122] Patients in the intermittent group receive 80 mg / m² on days 1, 8, and 15 of the 28-day cycle. 2 Patients received nab-paclitaxel and were administered 150 mg of liracorilant once daily on the day before, the day of, and the day after nab-paclitaxel administration (except that patients were not given liracorilant the day before the first nab-paclitaxel administration). In other words, patients in the intermittent group received 150 mg of liracorilant once daily on days 1 and 2 of the monthly cycle; once daily on days 7, 8, and 9; once daily on days 14, 15, and 16; and again on day 28, while nab-paclitaxel was administered on days 1, 8, and 15 of the aforementioned monthly cycle.

[0123] Independent comparisons were made between the intermittent trial group and the continuous trial group. The primary endpoint of this trial was progression-free survival as defined by the Response Evaluation Criteria in Solid Tumors ("RECIST") version 1.1 guidelines (available via the World Wide Web at the following URL: http: / / ctep.cancer.gov / protocolDevelopment / docs / recist_guideline.pdf). Secondary endpoints included objective response rate, duration of response, overall survival, and safety of the combination therapy of nab-paclitaxel and lirachorilant. All efficacy objectives and corresponding endpoints, responses, and disease progression assessments listed below were evaluated according to RECIST v1.1.

[0124] As described above, patients enrolled in this study had received multiple lines of prior therapy (median 3 lines and up to 5 lines), including previous taxane therapy, previous bevacizumab therapy, and previous PARP inhibitor therapy. Many of the ovarian cancer patients in this study were platinum-resistant (more than 35% of patients were platinum-refractory). Patients with platinum-refractory underlying disease accounted for a large proportion of the intermittent group. All but one patient had previously received taxane therapy, more than half had previously received bevacizumab, and slightly more than one-third had previously received PARP inhibitors. Additional information regarding the characteristics of the patients enrolled in the study and their responses to the treatments applied to them is presented in Figure 2 for the total number of patients (rightmost column) and for each of the three groups: intermittent liracorilant, continuous liracorilant, and nab-paclitaxel monotherapy (comparison group) (data as of March 22, 2021). Stratification factors were recurrence within 6 months of the most recent taxane and the presence of ascites. Molecular profiling results were available for some patients. The proportion of patients in this subset with BRCA1 or BRCA2 mutations is shown at the bottom of the table in Figure 2.

[0125] Exposure and peak concentrations were measured for both nab-paclitaxel and liracoralant. Overall, there was significant variability in exposure to liracoralant and nab-paclitaxel, which is consistent with the pharmacokinetic profiles of both compounds and the outpatient nature of the study design. The full range of nab-paclitaxel exposure largely overlapped across all three groups. (AUC and C) were measured for safety endpoints. max The assessment of exposure to lilacolinant and nab-paclitaxel (measured by [method / tool]) showed that there was a large overlap between exposure in the presence or absence of adverse events.

[0126] Figure 3 shows information regarding the breakdown of patients enrolled in the trial as of March 22, 2021. For example, Figure 3 shows the percentage of patients who discontinued the study treatment at some point during the trial, regardless of whether they received treatment with nab-paclitaxel monotherapy (comparison) or liracoralant and nab-paclitaxel (intermittent or continuous liracoralant). As expected, the majority of discontinuations were due to disease progression, with only about 10% due to adverse events. In addition to the number and percentage of patients in each group who discontinued the study treatment, Figure 3 presents the number and percentage of patients who discontinued treatment due to disease progression, adverse events, death, or other reasons.

[0127] Figure 4 shows the duration of progression-free survival (PFS) for the three patient groups as of March 22, 2021. Importantly, the hazard ratio (HR) for PFS was improved in patients treated with nab-paclitaxel plus intermittent liracoralant compared to patients treated with nab-paclitaxel monotherapy, with an HR of 0.66 (95% CI: 0.44–0.98). The median PFS for patients treated with nab-paclitaxel and intermittent liracoralant ("intermittent") was 5.6 months, which was 1.8 months longer than the median PFS for patients treated with nab-paclitaxel monotherapy ("comparison"). The number of platinum-refractory patients was well balanced across all study groups, although the intermittent group had a higher proportion of patients with platinum-refractory underlying disease. In particular, an analysis excluding patients with platinum-refractory underlying diseases, which have a poor prognosis, showed an improved hazard ratio for PFS (0.66 vs. 0.64) and a strong trend toward improved overall survival with intermittent regimens, with a hazard ratio of 0.55 and a P-value of 0.056. The subgroup of patients without platinum-refractory underlying diseases who had previously received 1-3 lines of therapy ("Phase 3 population") included 137 patients, of which 46 received nab-paclitaxel (80 mg / m²). 2 ) + intermittent lirachorilant (150 mg once daily on the day before, the day of, and the day after nab-paclitaxel), and 50 people received nab-paclitaxel monotherapy (100 mg / m²). 2 Patients received ) as treatment. Nab-paclitaxel was administered on days 1, 8, and 15 of each 28-day cycle. In a subgroup excluding patients with refractory underlying disease and patients who had previously received four or more lines of treatment, intermittent lirachorilant + nab-paclitaxel showed improved PFS compared to nab-paclitaxel monotherapy, with an HR of 0.58, a 95% CI of 0.37–0.91, a log-rank test P=0.0162, and a median PFS of 5.6 months compared to 3.8 months.

[0128] The median PFS for women in the continuation group was 1.5 months longer than that of the comparison group. This PFS also showed a numerical improvement compared to nab-paclitaxel monotherapy, with a hazard ratio of 0.83, although it was not statistically significant at the P<0.05 level. Therefore, these PFS results indicate that intermittent administration of lirachorilant with nab-paclitaxel administration provided superior therapeutic benefits compared to nab-paclitaxel monotherapy.

[0129] Furthermore, as shown in Figure 5, the duration of response (DoR) was also significantly improved in patients receiving nab-paclitaxel intermittently with liracorilant compared to nab-paclitaxel alone (data as of March 22, 2021). "PR" indicates a partial response, and "CR" indicates a complete response for each patient represented by an individual horizontal bar in the figure. The median DoR was 5.55 months in the intermittent group of the study, which was a significant improvement compared to 3.65 months in the comparison group (hazard ratio, HR 0.36; P-value = 0.006). Arrows in Figure 5 indicate patients whose response duration was still ongoing (patients were still in response at the end of the study period). In a subgroup excluding patients without refractory underlying disease and those who had previously received four or more lines of treatment, the DoR of intermittent liracoralant plus nab-paclitaxel compared to nab-paclitaxel alone was improved from 3.6 months to 5.6 months, with an HR of 0.26, a 95% CI of 0.11–0.62, a log-rank test P=0.0009, and a median DoR of 3.6 months. Therefore, these DoR results indicate that intermittent administration of liracoralant with nab-paclitaxel provided superior therapeutic benefit compared to nab-paclitaxel monotherapy.

[0130] As shown in Figure 6, presenting data for the final OS analysis (128 OS events) up to an additional predefined cutoff date of March 7, 2022, patients who received intermittent liracoralant along with nab-paclitaxel showed improved overall survival compared to patients who received nab-paclitaxel alone. Compared to 51% and 14% (respectively) of patients who received nab-paclitaxel alone, 59% of patients who received intermittent liracoralant along with nab-paclitaxel were still alive at 12 months, and 27% of these patients were still alive at 24 months. The hazard ratio (HR) calculated from the Kaplan-Meier curves shown in Figure 6 was 0.67 (95% CI [0.43, 1.03], P=0.066) for patients who received intermittent liracoralant along with nab-paclitaxel compared to patients who received nab-paclitaxel alone. Therefore, patients who received intermittent liracoralant and nab-paclitaxel had a 33% reduced risk of death compared to patients who received nab-paclitaxel alone. The median OS for patients receiving intermittent liracoralant was 13.9 months (95% CI [11.1, 18.4]) compared to patients receiving nab-paclitaxel alone (12.2 months (95% CI [7.7, 15.3]). The hazard ratio (HR) for continuous liracoralant + nab-paclitaxel (median OS of 11.3 months (95% CI [7.5, 16.4]) in the continuous liracoralant + nab-paclitaxel group) compared to nab-paclitaxel alone was 0.85 (95% CI [0.56, 1.29], P=0.447).

[0131] A subgroup analysis excluding patients with platinum-refractory underlying disease (7 from the intermittent lirachorilant + nab-paclitaxel group and 1 from the comparison group) and patients who had previously received four or more lines of therapy showed a statistically significant improvement in overall survival (OS) with intermittent lirachorilant + nab-paclitaxel compared to nab-paclitaxel monotherapy (95% CI [0.37, 0.91] P=0.010) at an HR of 0.52, representing a 48% reduction in mortality risk compared to patients receiving nab-paclitaxel monotherapy. These overall survival results demonstrate that intermittent administration of lirachorilant with nab-paclitaxel provided superior therapeutic benefits compared to nab-paclitaxel monotherapy. In addition to the improvements in PFS and DoR observed in the primary analysis, the OS analysis confirmed the survival benefit of intermittent relacoilant + nab-paclitaxel compared to nab-paclitaxel monotherapy, particularly in patients without platinum-refractory underlying disease.

[0132] Figure 7A shows a summary of the comparisons of progression-free survival (PFS), objective response rate (ORR), duration of response (DoR), and overall survival (OS) observed in the three patient groups during the study period, as of the initial cutoff date of March 22, 2021. Patients who did not respond to first-line platinum-based therapy before the study were considered to have "platinum-refractory primary disease," and these patients have a particularly poor prognosis. PFS, ORR, DoR, and OS were calculated for all 178 patients in this study ("Overall" column) and for the 167 patients who did not have "platinum-refractory primary disease" ("Exclusion of Platinum-Refractory Primary Disease" column). Both analyses showed that intermittent administration of liracorilant during the taxane chemotherapy cycle significantly improved PFS and DoR compared to taxane chemotherapy alone. OS was clearly improved in patients who received intermittent liracorilant compared to patients who received nab-paclitaxel alone. As shown in Figures 6 and 7B, the improvement in overall survival (OS) was statistically significant in the patient group excluding patients with platinum-refractory underlying diseases (see, for example, the HR in patients receiving intermittent lirachorilant compared to nab-paclitaxel monotherapy).

[0133] Therefore, as discussed above, and as shown in Figure 7A (presenting an initial analysis of data collected as of the initial cutoff date of March 22, 2021), women in the high-dose intermittent group showed a significantly improved progression-free survival (median PFS of 3.8 months versus 5.6 months, hazard ratio: 0.66; p-value: <0.05) and a statistically significant improvement in duration of response (DoR) (median DoR of 3.7 months versus 5.6 months, hazard ratio: 0.36; p-value: 0.006).

[0134] Figure 7B shows the summary of progression-free survival (PFS), duration of response (DoR), and overall survival (OS) data for a subgroup of patients without platinum-refractory primary disease who had previously received 1-3 lines of therapy. This subgroup showed greater improvements in PFS, DoR, and OS compared to nab-paclitaxel monotherapy. Patients with platinum-refractory primary disease and those who had previously received 4 or more lines of therapy had particularly poor prognoses and were generally excluded from clinical trials. Patients with platinum-refractory primary disease randomly represented a large proportion (n=1 vs. n=11) in the liracorilant intermittent dosing group compared to nab-paclitaxel monotherapy. The final OS analysis data cutoff date was March 7, 2022. Subsequent cutoff dates were determined by a predetermined criterion of reaching 120 OS "events" in the trial. The updated OS results (updated compared to the data presented in Figure 7A), as shown in Figure 6A, show that the median OS for patients treated with nab-paclitaxel and intermittent liracoralant was 13.9 months, compared to a median OS of 12.2 months for patients treated with nab-paclitaxel monotherapy. This represents a 33% reduction in the risk of death in patients treated with liracoralant plus intermittent nab-paclitaxel compared to patients treated with nab-paclitaxel monotherapy, indicating an improvement in OS (HR 0.67; P=0.066). As shown in Figure 7C, the results for a subgroup obtained by excluding patients with platinum-refractory underlying diseases and patients who had previously received four or more lines of therapy show a significant improvement in overall survival (OS), namely a 48% reduction in the risk of death in patients treated with lirachorilant plus intermittent nab-paclitaxel (without platinum-refractory underlying diseases) compared to patients treated with nab-paclitaxel monotherapy (HR 0.52; P=0.010).

[0135] Analysis of an additional subgroup of patients who had previously received / did not receive bevacizumab showed improvements in PFS, OS, and DoR with intermittent liracoralant + nab-paclitaxel compared to nab-paclitaxel monotherapy in patients who had previously received bevacizumab, although the objective response rate (ORR) was similar in all groups. (Of 178 women with recurrent platinum-resistant / refractory ovarian cancer, primary peritoneal cancer, fallopian tube cancer, or ovarian carcinosarcoma who had received four or fewer lines of prior chemotherapy, enrolled in the phase 2 open-label randomized trial of liracoralant + nab-paclitaxel versus nab-paclitaxel monotherapy (NCT03776812), 105 had previously received bevacizumab, and 73 had not.) 2 ) + intermittent lirachorilant (150 mg QD (once daily) on the day before, the day before, the day of, and the day after nab-paclitaxel) or nab-paclitaxel alone (100 mg / m²) 2 The data for patients in this subgroup who received either of the above are shown in the table below. The baseline characteristics of the two groups were generally balanced. Patients who had not previously received bevacizumab were balanced between North America and Europe, but 70% of patients who had previously received bevacizumab were in Europe. [Table 1]

[0136] In this subgroup analysis, patients who had previously received bevacizumab had better overall survival (OS) (hazard ratio 0.47; p-value 0.03; median 17.9 months vs. 12.6 months in the control group), progression-free survival (PFS) (hazard ratio 0.44; p-value 0.005; median 7.2 months vs. 3.7 months in the control group), and duration of recovery (DR) (hazard ratio 0.25; p-value 0.006; median 5.6 months vs. 3.4 months in the control group) compared with nab-paclitaxel alone. Overall risk reduction (ORR) was numerically highest in the intermittent liracorilant + nab-paclitaxel group, but similar across all groups. In patients who had not previously received bevacizumab, intermittent liracorilant + nab-paclitaxel treatment also resulted in a numerical improvement in PFS compared to nab-paclitaxel treatment alone.

[0137] Figure 7D shows aggregated data for progression-free survival (PFS), duration of response (DoR), and overall survival (OS) for further identified subgroups of patients: (a) patients without platinum-refractory underlying disease, (b) patients who had previously received 1-3 lines of therapy, and (c) patients whose previous therapy lines included previous bevacizumab treatment. In these subgroups, greater improvements in PFS, DoR, and OS were observed compared to those observed in other subgroup analyses (see, for example, Figure 7B for the group that did not require bevacizumab in the past). These results are also shown in charts, for example, Figures 4B and 6B.

[0138] These improvements in OS, PFS, and DoR are remarkable, and this liracoralant treatment regimen is considered to be the first to demonstrate a significant improvement in overall survival in patients with recurrent platinum-resistant ovarian cancer. The safety and tolerability of liracoralant plus nab-paclitaxel were comparable to those of nab-paclitaxel monotherapy.

[0139] Liracoralant treatment was safe and well-tolerated by patients in both the intermittent and continuous groups. Safety and tolerability were comparable between groups, with neutropenia being the most common adverse event (grade 3 or higher). The safety and tolerability of the three treatment regimens are shown in Figure 8 (data as of March 22, 2021). The intermittent group had fewer severe (grade ≥ 3) peripheral neuropathy compared to the comparison group. According to the study protocol, all patients treated with liracoralant in addition to nab-paclitaxel received prophylactic granulocyte colony-stimulating factor (GCSF) to reduce the risk of neutropenia, while patients treated with nab-paclitaxel monotherapy received G-CSF according to the standard practice of the principal investigator (treatment physician).

[0140] mRNA expression levels for selected targets were also measured in some patients. Such analyses also confirmed that several glucocorticoid receptor target genes were suppressed by treatment with liracorilant and nab-paclitaxel. A panel of 239 genes induced by the glucocorticoid prednisone was analyzed in whole blood samples obtained from some patients. Of these genes, 221 were suppressed in patients treated with liracorilant + nab-paclitaxel (change from baseline to day 15 of cycle 1), while these genes remained relatively unchanged with nab-paclitaxel alone (Figure 9B). For example, serum and glucocorticoid-regulated kinase (SGK1) mRNA expression, one of the classic glucocorticoid-responsive genes involved in cell survival, was measured. The left side of Figure 9C shows the change in SGK1 expression in whole blood samples from baseline to day 15 of cycle 1 (error bars represent median and interquartile range). As shown in Figure 9C, whole blood mRNA levels encoding SGK1 were reduced in patients treated with both lilacorant and nab-paclitaxel compared to whole blood samples from patients treated with nab-paclitaxel alone (P<0.0089). SGK1 expression was suppressed by lilacorant + nab-paclitaxel, but not in patients treated with nab-paclitaxel alone. Of the 239 genes previously shown to be GR target genes, 221 were suppressed after RELA + NP treatment. Significantly fewer GR target genes were suppressed by NP (P<0.00001). GR target genes that were suppressed by lilacolinant + nab-paclitaxel but not by nab-paclitaxel alone included SGK1 (P=0.0089), GSK3B (P=0.0045), and PIK3CG (P=0.0175).

[0141] In this study, 137 pre-treatment samples obtained from patient tumors were profiled for the expression of 444 genes. The left side of Figure 9D shows the expression (mRNA) levels of all genes in the samples as circles. The expression of NR3C1 (the gene encoding the glucocorticoid receptor) in each tumor is shown on the right side of Figure 9D. The median expression level for each of the 444 genes was determined first. The median NR3C1 fell within the 83rd percentile of the distribution of the 444 medians. Therefore, it was found that the expression of glucocorticoid receptor mRNA (NR3C1) was higher in ovarian cancer tumors compared to the mRNA expression of all genes in the patients (Figure 9D).

[0142] Figure 9B shows a comparison of mRNA levels encoding the glucocorticoid receptor in ovarian cancer patients treated with nab-paclitaxel monotherapy compared with liracorilant in ovarian cancer patients treated with nab-paclitaxel monotherapy. GR expression was observed in 96% of evaluable ovarian tumors in our Phase 2 trial. High GR expression was associated with poor response in the nab-paclitaxel monotherapy group. In contrast, high GR expression was associated with partial or complete response in both the liracorilant + nab-paclitaxel group. In patients with high GR, partial or complete response was twice as likely in the liracorilant + nab-paclitaxel group compared to the nab-paclitaxel monotherapy group.

[0143] In summary, this case presents the first randomized controlled phase 2 trial of lirachorilant plus nab-paclitaxel in patients with ovarian cancer and other cancers. The trial included platinum-resistant and platinum-refractory patients who had previously received up to five lines of therapy. Substantial benefit was observed in this heavily pre-treated population. Across the entire trial population, intermittent lirachorilant plus nab-paclitaxel showed a benefit compared to nab-paclitaxel monotherapy, including a trend toward improved PFS, DoR, and OS. In particular, subgroup analyses showed greater improvements in PFS, OS, and DoR with intermittent lirachorilant plus nab-paclitaxel in platinum-refractory, disease-free women who had previously received three or fewer lines of therapy, including bevacizumab. Patients treated with intermittent liracoralant plus nab-paclitaxel showed significantly improved PFS and DoR compared to patients treated with nab-paclitaxel monotherapy. Notably, patients treated with intermittent liracoralant had improved median overall survival compared to patients treated with nab-paclitaxel monotherapy, and this improvement in OS was significant in patients without platinum-refractory underlying disease. The safety profile of intermittent liracoralant plus nab-paclitaxel was comparable to that of nab-paclitaxel monotherapy. Therefore, these results indicate that intermittent administration of liracoralant with nab-paclitaxel surprisingly provided superior therapeutic benefits compared to nab-paclitaxel monotherapy.

[0144] Example 2: A planned Phase III clinical trial comparing intermittent lirachorilant with nab-paclitaxel to previous treatments. Given the promising results, which demonstrate extended overall survival (OS), extended progression-free survival (PFS), and extended duration of response (DR), and no significant changes in treatment safety or patient tolerance, the applicant presents a planned Phase III clinical trial to confirm and expand upon these positive clinical outcomes in this predictive embodiment.

[0145] As shown in Figure 10A, the clinical trial will enroll 360 patients with high-grade serous epithelial (grade 3), high-grade endometrioid, and ovarian, primary peritoneal, or fallopian tube cancers containing ≥30% endometrioid epithelial tumor components, whose disease has progressed within 6 months of the last dose of platinum-based therapy. Women who, after at least one treatment, have recurrent ovarian, primary peritoneal, or fallopian tube cancer, including high-grade serous epithelial ovarian, primary peritoneal, or fallopian tube cancer; high-grade endometrioid cancer; and ≥30% endometrioid epithelial tumor components, and who are resistant to platinum-based chemotherapy. These criteria are expected to exclude patients with platinum-refractory primary disease from the trial. Patients will be treated according to an experimental intermittent lilacolinant dosing protocol or one of four chemotherapy regimens selected by the physician. The primary endpoint measured was progression-free survival (PFS) as determined by blinded independent central review (BICR) based on RECIST v.1.1. Secondary efficacy endpoints included overall survival (OS), PFS based on RECIST v.1.1 as best combined response (BOR) (as determined by the principal investigator), duration of response (DoR) based on RECIST v.1.1, objective response rate (ORR), clinical benefit rate based on RECIST v.1.1, and combined response based on RECIST v.1.1 + GCIG (Gynecological Cancer InterGroup) criteria. Safety endpoints included patient safety, patient quality of life (QOL), Ca-125 (a protein marker monitored in ovarian cancer patients), pharmacodynamics, and pharmacokinetics. Patients received (A) nab-paclitaxel along with intermittent administration of liracorilant (150 mg orally) (80 mg / m²). 2 (B) Administration of either of the following (180 patients), where nab-paclitaxel is administered on days 1, 8, and 15 of a 28-day cycle, and lilacolinant is administered on days 1, 2, 7-9, 14-16, and 28, or (B) "Investigator's choice" by the treating physician, where the patient receives liposomal doxorubicin (40 mg / m²) on day 1 of a 28-day cycle.2 Intravenous (iv): Paclitaxel (80 mg / m²) administered on days 1, 8, 15, and 22 of a 28-day cycle. 2 iv) Nab-paclitaxel (100 mg / m²) on days 1, 8, and 15 of the 28-day cycle. 2 , iv); or 4 mg / m² on days 1, 8, and 15 of a 28-day cycle. 2 1.25 mg / m² on days 1-5 of each of the IV or 21-day cycles. 2 Patients are randomized in a 1:1 ratio to receive either topotecan (either IV, or IV), or to receive topotecan (chosen by the treating physician). Group (B) of this trial is a comparison group to the trial in which patients did not receive lirachorilant.

[0146] An example of such a clinical trial is shown in Figure 10B. Information provided by subgroup analyses disclosed herein indicates that a randomized, two-arm, open-label, multicenter phase 3 trial of intermittent lirachorilant plus nab-paclitaxel to nab-paclitaxel, titled ROSELLA, has been initiated and is ongoing (NCT05257408). In particular, the ROSELLA trial will enroll patients who have previously received bevacizumab. The trial is expected to enroll approximately 360 patients with high-grade serous carcinoma, epithelial carcinoma, ovarian cancer, primary peritoneal cancer, or fallopian tube cancer who have previously received 1 to 3 lines of systemic anticancer therapy, one of which must have been treated with bevacizumab. Patients may also show disease progression 6 months or less after the last dose of platinum-based therapy, but patients with platinum-refractory underlying disease will be excluded from the trial.

[0147] The results of the Phase 3 clinical trial are expected to include significant improvements in OS, PFS, DoR, and other measures of treatment in patients in group (A) compared to patients in group (B) who did not receive intermittent liracoralant. No significant differences in treatment safety or patient tolerance are expected between group (A) (liracoralant + nab-paclitaxel) and group (B) (nab-paclitaxel monotherapy).

[0148] While the aforementioned invention is described in some detail as an example and illustration to clarify the understanding, it will be readily apparent to those skilled in the art that certain changes and modifications can be made in light of the teachings of the present invention without departing from the spirit or scope of the appended claims.

[0149] All patents, patent publications, patent applications, and publications cited herein are incorporated herein by whole by reference, as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Furthermore, although the inventions described herein are described in some detail as examples and illustrations for clarity, it will be readily apparent to those skilled in the art that certain changes and modifications can be made in light of the teachings of the invention without departing from the spirit or scope of the appended claims.

Claims

1. A method of treating cancer, The treatment involves intermittently administering an effective dose of a glucocorticoid receptor modulator (GRM) to a patient with cancer, wherein the patient requires and is receiving cancer chemotherapy for the cancer, and the treatment includes administering a cancer chemotherapy agent according to a chemotherapy administration schedule, wherein the administration schedule requires that there be at least one day without administration of the cancer chemotherapy agent between days on which the cancer chemotherapy agent is administered to the patient. The aforementioned intermittent administration includes administering the GRM on the same day that the cancer chemotherapy agent is administered to the patient. A method for treating the aforementioned cancer.

2. The method according to claim 1, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, and peritoneal cancer.

3. The method according to claim 1, wherein the cancer is ovarian cancer.

4. The method according to claim 1, wherein the cancer chemotherapy agent is a taxane.

5. The method according to claim 4, wherein the cancer chemotherapy agent is a taxane selected from the group of taxanes consisting of paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel.

6. The method according to claim 5, wherein the cancer chemotherapy agent is a taxane containing paclitaxel.

7. The method according to claim 5, wherein the cancer chemotherapy agent is nab-paclitaxel.

8. The method according to any one of claims 1 to 7, wherein the GRM is also administered the day after the cancer chemotherapy agent is administered to the patient.

9. The method according to any one of claims 1 to 7, wherein the GRM is also administered on the day before the cancer chemotherapy agent is administered to the patient.

10. The method according to any one of claims 1 to 9, wherein the GRM is administered on the day before, on the day, and the day after the cancer chemotherapy agent is administered to the patient.

11. The method according to any one of claims 1 to 10, wherein there are four or more days between the days on which the GRM is administered to the patient on which the GRM is administered.

12. The method according to any one of claims 1 to 11, wherein the administration schedule for cancer chemotherapy includes administration of the cancer chemotherapy agent on day 1 and administration of the cancer chemotherapy agent again on the 7th day after day 1, and there is no administration of the cancer chemotherapy agent on the days between day 1 and the 7th day after day 1.

13. The method according to any one of claims 1 to 12, wherein the cancer chemotherapy agent is administered to the patient for three consecutive weeks in accordance with the administration schedule of the cancer chemotherapy.

14. The method according to claim 13, wherein the cancer chemotherapy agent is administered to the patient for three consecutive weeks in accordance with the administration schedule of the cancer chemotherapy, and is not administered in the week following the last week of the three consecutive weeks.

15. The method according to claim 13 or claim 14, wherein the cancer chemotherapy agent is administered to the patient for three consecutive weeks in accordance with the administration schedule of the cancer chemotherapy, and is not administered in the week following the last week of the three consecutive weeks, and the weekly administration regimen is then repeated for another three consecutive weeks.

16. The method according to any one of claims 1 to 15, wherein the glucocorticoid receptor modulator (GRM) is a non-steroidal GRM.

17. The method according to any one of claims 1 to 16, wherein the glucocorticoid receptor modulator (GRM) is a heteroarylketone condensed azadecalin GRM.

18. The method according to any one of claims 1 to 17, wherein the glucocorticoid receptor modulator (GRM) is a heteroarylketone condensed azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone ("Lilacorilant") having the following structure. 【Chemistry 1】

19. The method according to any one of claims 1 to 18, wherein the patient has been administered bevacizumab prior to receiving the GRM.

20. The use of pharmaceutical compositions for treating cancer, The cancer treatment comprises intermittently administering an effective dose of a glucocorticoid receptor modulator (GRM) to a patient having cancer, wherein the patient requires and is receiving cancer chemotherapy for the cancer, and the treatment comprises administering the cancer chemotherapy agent according to a cancer chemotherapy administration schedule, wherein the administration schedule requires that there be at least one day without administration of the cancer chemotherapy agent between days on which the cancer chemotherapy agent is administered to the patient. The aforementioned intermittent administration includes administering the GRM on the same day that the cancer chemotherapy agent is administered to the patient. Use of the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM.

21. The use according to claim 20, wherein the cancer is selected from the group consisting of ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, and peritoneal cancer.

22. The use according to claim 20, wherein the cancer is ovarian cancer.

23. The use according to claim 20, wherein the cancer chemotherapy agent is a taxane.

24. The use according to claim 23, wherein the cancer chemotherapy agent is a taxane selected from the group of taxanes consisting of paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, and ortataxel.

25. The use according to claim 24, wherein the cancer chemotherapy agent is a taxane containing paclitaxel.

26. The use according to claim 24, wherein the cancer chemotherapy agent is nab-paclitaxel.

27. The use according to any one of claims 20 to 26, wherein the GRM is also administered on the day following the administration of the cancer chemotherapy agent to the patient.

28. The use according to any one of claims 20 to 27, wherein the GRM is also administered on the day before the cancer chemotherapy agent is administered to the patient.

29. The use according to any one of claims 20 to 28, wherein the GRM is administered on the day before, on the day, and the day after the cancer chemotherapy agent is administered to the patient.

30. The use according to any one of claims 20 to 29, wherein there are four or more days between the days on which the GRM is administered to the patient on which the GRM is administered.

31. The use according to any one of claims 20 to 30, wherein the administration schedule for the cancer chemotherapy includes administration of the cancer chemotherapy agent on day 1 and administration of the cancer chemotherapy agent again on the 7th day after day 1, and there is no administration of the cancer chemotherapy agent on the days between day 1 and the 7th day after day 1.

32. The use according to any one of claims 20 to 31, wherein the cancer chemotherapy agent is administered to the patient for three consecutive weeks in accordance with the administration schedule of the cancer chemotherapy.

33. The use according to claim 32, wherein the cancer chemotherapy agent is administered to the patient for three consecutive weeks in accordance with the administration schedule of the cancer chemotherapy, and is not administered in the week following the last week of the three consecutive weeks.

34. The use according to claim 32 or 33, wherein the cancer chemotherapy agent is administered to the patient for three consecutive weeks in accordance with the administration schedule of the cancer chemotherapy, and is not administered in the week following the last week of the three consecutive weeks, and the weekly administration regimen is then repeated for another three consecutive weeks.

35. The use according to any one of claims 20 to 34, wherein the glucocorticoid receptor modulator (GRM) is a non-steroidal GRM.

36. The use according to any one of claims 20 to 35, wherein the GRM is heteroarylketone condensed azadecalin GRM.

37. The use according to any one of claims 20 to 36, wherein the GRM is a heteroarylketone condensed azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole-4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinoline-4a-yl)(4-(trifluoromethyl)pyridine-2-yl)methanone ("Lilacorilant") having the following structure. 【Chemistry 2】

38. The use according to any one of claims 20 to 37, wherein the patient has previously received bevacizumab.

Images