CN117956997A

CN117956997A - Intermittent administration of glucocorticoid receptor modulators for the treatment of ovarian and other cancers

Info

Publication number: CN117956997A
Application number: CN202280062636.1A
Authority: CN
Inventors: S·舍普赫德; J·K·贝拉诺夫
Original assignee: Corcept Therapeutics Inc
Current assignee: Corcept Therapeutics Inc
Priority date: 2021-09-16
Filing date: 2022-09-02
Publication date: 2024-04-30

Abstract

Methods and compositions for treating cancer (e.g., ovarian, fallopian tube, uterine, cervical, vaginal, vulvar, or peritoneal cancer) are disclosed. The methods include intermittent administration of a Glucocorticoid Receptor Modulator (GRM), such as a non-steroidal GRM (e.g., relocatable), to a patient, which may be orally administered with a cancer chemotherapeutic agent. Patients may have received bevacizumab treatment prior to receiving such intermittent GRM plus chemotherapy treatment. GRM may be given as follows: at least one day apart without administration of GRM; administration at a schedule related to a cancer chemotherapy schedule (e.g., a weekly chemotherapy regimen); administration on the day, day before or day after chemotherapy administration; administered by a combination thereof; and/or on other days. The overall survival, progression free survival, duration of remission and other benefits of ovarian cancer patients receiving intermittent administration of relocatable and albumin-binding-paclitaxel are improved compared to patients receiving albumin-binding-paclitaxel but not relocatable.

Description

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

Cross Reference to Related Applications

The present application claims U.S. provisional patent application No. 63/244,825 filed on 9/16 of 2021; U.S. provisional patent application Ser. No. 63/324,873, filed on 3/29 of 2022; U.S. provisional patent application Ser. No. 63/345,682, filed 5/25 at 2022; and international application PCT/US2021/050617 filed on 9/16 of 2021, the entire contents of all of which are incorporated herein by reference.

Background

Glucocorticoid receptor ("GR") is present in almost all body tissues. Cortisol is an endogenous hormone that acts through GR, affects many biological systems, and may play a role in the progression of cancer. For example, cortisol and GR mediated signaling can affect inflammation and can affect the immune system. However, it is not clear whether this effect is to promote or inhibit cancer growth. Although many tumor types express GR and GR is highly expressed in some tumors (e.g., ovarian cancer tumors), the impact of modulating GR-mediated signaling on cancer progression and cancer treatment is not yet clear.

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, as well as peritoneal cancer, are important components of female cancer (men rarely suffer from peritoneal cancer). These and other cancers may be hormone sensitive cancers.

Such cancers are usually diagnosed only in advanced stages. Treatment options are limited and these cancer patients have poor prospects. Conventional treatment options for such cancers include surgery and chemotherapy (such patients rarely use radiation therapy (also known as "radiotherapy")). Although in some cases such cancers may be resectable at diagnosis, most patients with these cancers receive chemotherapy (such as platinum-based chemotherapy). Chemotherapeutic agents generally rely on an onset of extensive damage to DNA and instability of chromosomal structure, which may reduce cancer cell proliferation, promote or induce apoptosis of tumor cells, and may ultimately lead to destruction of cancer cells.

For example, ovarian cancer can be a devastating disease. Although most ovarian cancer patients initially respond to chemotherapy (typically platinum-based chemotherapy), the rate of cancer recurrence is high, with the vast majority of ovarian cancer patients relapsing (Kemp et al, int J work's Health 5:45-51 (2013): about 80% relapsing in 18 months; luvero et al, crit Rev Oncol/Hematol 140:28-38 (2019)). Unfortunately, the rate of chemo-remission for these relapsing patients may be low and may only provide a short progression-free survival (Luvero et al, THERAP ADV MED Oncol 6 (5): 229-239 (2014)). The total survival of less than one year after recurrence is normal for recurrent ovarian cancer.

For platinum-resistant ovarian cancer patients, further treatment is limited; only a small fraction of patients respond to standard chemotherapy (Luvero et al, 2014). Further treatment options include surgery, chemotherapy, molecular targeted drugs (anti-angiogenic and PARP inhibitors) and radiation therapy. (alone or in combination). Paclitaxel, liposomal doxorubicin, topotecan, as a single agent or in combination with bevacizumab, or gemcitabine plus carboplatin combination, has been approved for recurrent patients receiving the initial treatment of recurrent platinum-resistant ovarian cancer and is the most commonly used therapy in this case (Luvero, 2014; pujade-Lauraine, et al J Clin Oncol 37:2437-2448 (2019)). In patients who received fewer than two prior treatment regimens, no refractory disease, and no history of ileus within six months of treatment, chemotherapy plus bevacizumab showed the best effect (Pujade-Lauraine et al, J Clin Oncol 32:1302-1308 (2014)). For platinum-resistant ovarian cancer patients or patients with refractory disease, the standard of care is limited to continuous use of chemotherapy that has not been previously administered. However, the efficacy of these further chemotherapy regimens is generally poor.

There is also a great unmet need for effective, well-tolerated treatments for ovarian, cervical, vaginal, vulvar, fallopian tube, uterine and other female genital and tissue tumors, and peritoneal cancers. There remains an unmet need for an effective, well-tolerated treatment for platinum-resistant ovarian cancer females.

Disclosure of Invention

Disclosed herein are novel methods of treating cancer, and novel uses of Glucocorticoid Receptor Modulator (GRM) compounds, such as non-steroidal GRMs, including heteroaryl-ketone fused azanaphthalene compounds, for treating cancer.

Applicants disclose a method of 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 in need of and receiving cancer chemotherapy treatment for the cancer; cancer chemotherapy treatment includes administration of a cancer chemotherapeutic agent according to a cancer chemotherapy administration schedule that includes at least one day between days of administration of the cancer chemotherapeutic agent without administration of the cancer chemotherapeutic agent. As disclosed herein, intermittent GRM administration includes at least a first round of GRM administration and a second round of GRM administration, wherein there is no GRM administration for at least one day between the first round and the second round of administration. The first round of GRM administration may be one day; or two consecutive days; or three consecutive days; or GRM administration for more consecutive days. The second round of GRM administration may be one day; or two consecutive days; or three consecutive days; or GRM administration for more consecutive days. The number of days given in the first and second rounds need not be the same.

Intermittent GRM administration to a patient concurrently receiving cancer chemotherapy may include administration of GRM on a day coordinated with the schedule of administration of cancer chemotherapy. A round of GRM administration may be administered on a day associated with the patient's cancer chemotherapy administration schedule, or may be administered on a day determined by the patient's cancer chemotherapy administration schedule. For example, a round of GRM administration can be administered to a patient prior to, at the time of (e.g., the same day as) or after the patient receives a dose of a chemotherapeutic agent.

In embodiments, a round of GRM administration may begin or complete one or more days prior to administration of the chemotherapeutic agent to the patient. In embodiments, a round of GRM administration may begin or complete on the day of administration of the chemotherapeutic agent to the patient. In embodiments, a round of GRM administration may begin or complete one or more days after administration of the chemotherapeutic agent to the patient.

Applicant further discloses the use of GRM for treating cancer according to the methods disclosed herein. For example, such uses include intermittent administration of GRM to a cancer patient who is receiving treatment with a cancer chemotherapeutic agent according to a dosing schedule that requires at least one day without administration of the cancer chemotherapeutic agent to the patient between two days of patient receiving treatment with the cancer chemotherapeutic agent. Intermittent GRM administration to a patient concurrently receiving cancer chemotherapy may include administration of GRM on a day coordinated with the schedule of administration of cancer chemotherapy. In embodiments, intermittent GRM administration includes administration of GRM on the same day as administration of the cancer chemotherapeutic agent to the patient. Intermittent GRM administration may include administration of GRM on one or more days where no cancer chemotherapeutic agent is administered to the patient. Intermittent GRM administration may include administration of GRM on the same day as administration of the cancer chemotherapeutic agent to the patient, as well as one or more days when no cancer chemotherapeutic agent is administered to the patient.

In embodiments, the GRM is a non-steroidal GRM. In aspects of the methods and uses disclosed herein, the non-steroidal GRM is a compound comprising a heteroaryl ketone fused azadecalin structure; in an embodiment, the GRM is a heteroaryl ketone fused azadecalin structure disclosed in U.S. patent 8,859,774 (the entire contents of which are incorporated herein by reference). The heteroaryl ketone fused azadecalin GRM may be relocatable ((R) - (1- (4-fluorophenyl) -6- ((1-methyl-1H-pyrazol-4-yl) sulfonyl) -4,4a,5,6,7, 8-hexahydro-1H-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone ("relocatable", having the structure:

Ruilakolan is also known as CORT125134; it is disclosed in example 18 of U.S. patent 8,859,774.

As used herein, cancer chemotherapeutic agents include all antineoplastic agents, such as chemically toxic compounds and formulations that are generally toxic to cancer cells (and also generally to non-cancer cells), antiproliferative agents, antimetastatic agents, and include antibodies, checkpoint inhibitors, and other drugs and treatments that inhibit, prevent, or reverse cancer growth or spread in cancer patients, alone or in combination with other drugs. The cancer chemotherapeutic agent may be a taxane, such as paclitaxel or albumin binding-paclitaxel.

Cancers that may be treated by the novel methods disclosed herein include cancers of the female reproductive organs and tissues and peritoneal cancers. Such cancers include, for example, ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, and peritoneal cancer. In embodiments, the novel methods are directed to ovarian cancer, including platinum-resistant ovarian cancer. In embodiments, the novel methods are directed to cervical cancer. In embodiments, the novel methods are directed to uterine cancer. In embodiments, the novel methods are directed to fallopian tube cancer. In embodiments, the novel methods for treating cancer are directed to peritoneal cancer.

The novel and unexpected methods and uses disclosed herein are believed to provide improved and effective treatment for cancer patients suffering from peritoneal cancer or female genital organ and tissue cancers, including, for example, ovarian, fallopian tube, uterine, cervical, vaginal, and vulvar cancers. Results from the clinical studies disclosed herein (see, e.g., studies of combination of relocatable and albumin binding-paclitaxel for treatment of patients with recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer), NCT 03776812) demonstrate that these methods (including the combined administration of taxane chemotherapy and GR modulator relocatable to patients with female genital organ cancer and primary peritoneal cancer) provide greater benefits than taxane chemotherapy alone. For example, intermittent administration of relocatable and albumin-bound paclitaxel may yield clinically significant benefits without increasing the side effect burden compared to albumin-bound paclitaxel monotherapy. These benefits include improvement of Progression Free Survival (PFS), a risk ratio (HR) of 0.66 (p=0.038; median PFS of 5.6 months to 3.8 months); duration of remission (DoR) improvement, HR of 0.36 (p=0.006; doR median of 5.6 months vs 3.7 months); total survival (OS) was improved compared to albumin binding-paclitaxel monotherapy with HR of 0.67 (p=0.066; median OS13.9 months vs 12.2 months).

As noted above, there is a great, unmet need for effective, well-tolerated treatments for cancer, including platinum-resistant cancers (such as ovarian, cervical, vaginal, vulvar, fallopian tube, uterine and other female genital and tissue tumors, and peritoneal cancers). The methods and uses of the invention are believed to provide improved treatment of cancers such as peritoneal cancer and female genital and tissue cancers.

Brief description of the drawings

FIG. 1 is a schematic representation of the phase 2 clinical trial protocol of example 1. 178 patients with platinum-resistant or platinum-refractory ovarian cancer, primary peritoneal cancer or fallopian tube cancer were treated with 1:1:1 (100 milligrams per square meter (mg/m ²); 60 patients (comparative group (COMPARATOR) "), CONTINUOUS administration of Ruilakolan with albumin-binding-paclitaxel (80 mg/m ²; 58 patients;" CONTINUOUS group (CONTINUOUS) "), or intermittent Ruilakolan administration with albumin-binding-paclitaxel (80 mg/m ²; 60 patients;" intermittent group (INTERMITTENT) "). Patients receiving CONTINUOUS Ruilakolan received 100mg of Ruilakolan (mg/day) (up to 150 mg/day as appropriate) patients receiving intermittent Ruilakolan received 150mg of Ruilakolan a day before, on the day and on the day after administration of albumin-binding-paclitaxel, if the patients progressed during platinum-based therapy, or no treatment interval after platinum-based therapy was less than 6 months (i.e., the patients relapsed, so the platinum-based therapy was further required within 6 months after the completion of the previous round of platinum-based therapy), were considered to be platinum-resistant if the last platinum-based therapy of the patients developed during platinum-based therapy was more than 1 month (one month after the platinum-based therapy was considered to be a platinum-resistant patient

Figure 2 shows the characteristics of each of the three groups of enrolled patients in the study. All but one patient received taxane treatment prior to study participation ("one patient in the intermittent" group did not receive taxane treatment prior).

Figure 3 lists the patient's treatment at the time of the primary (mid-term) analysis (data cut off at 2021, day 3, 22).

Figure 4A presents the Progression Free Survival (PFS) times for three groups of patients by data collected by the initial expiration date of month 22 of 2021. PFS was significantly improved (risk ratio (HR) of 0.66, log rank test p=0.038; no adjustment for multiplexing) in patients receiving albumin-binding-paclitaxel and intermittent relocatable treatment compared to albumin-binding-paclitaxel alone. Wherein the median PFS is 5.6 months 1.8 months longer than 3.8 months of the albumin binding-paclitaxel monotherapy group. Each event is the patient experiencing disease progression (according to RECIST v 1.1) or death, whichever occurs first. For the exclusion of primary refractory disease patients and the exclusion of a subset of patients who had previously received more than 3 previous treatment lines, intermittent relocatable + albumin binding-paclitaxel improved PFS compared to albumin binding-paclitaxel alone, HR 0.58, 95% ci 0.37-0.91, log rank test p=0.0162; median PFS was 5.6 months to 3.8 months.

Fig. 4B presents Progression Free Survival (PFS) times analyzed for a subset of patients without primary platinum refractory disease who have received 1 to 3 previous treatment lines for their cancers, wherein the previous treatment includes previous bevacizumab.

Figure 5 shows the duration of remission (DoR) for each of three groups of patients by data collected by the initial expiration date of month 3, 22 of 2021. Although Objective Remission Rates (ORR) were similar for all three groups (intermittent group: n=20 (35.7%); continuous group: n=19 (35.2%); comparative group: n=19 (35.8%)) the duration of remission was significantly prolonged for patients receiving intermittent relocatable combined albumin-paclitaxel treatment compared to albumin-paclitaxel alone (p=0.006; hr is 0.36). For a subset of patients with the exclusion of primary refractory disease and patients who had previously received more than 3 prior treatment lines, intermittent relocatable + albumin binding-paclitaxel improved DoR compared to albumin binding-paclitaxel alone, HR 0.26, 95% ci 0.11-0.62, log rank test p=0.0009; the median DoR was 5.6 to 3.6 months.

Fig. 6A shows the total survival (OS) time for each of the three patient groups from data collected by the later expiration date (predetermined by reaching at least 120 OS events) of day 3, month 7 of 2022. These data demonstrate an improvement in OS in the patient groups receiving intermittent relocatable and albumin-binding paclitaxel treatments compared to the patient groups receiving albumin-binding paclitaxel treatment alone, a risk ratio (HR) of intermittent relocatable + albumin-binding paclitaxel treatment of 0.67 (p=0.066) and a HR of persistent relocatable + albumin-binding paclitaxel treatment of 0.85 (p=0.447) compared to the albumin-binding paclitaxel treatment alone. Thus, the risk of mortality was reduced by 33% in intermittent rella-conad patients compared to control patients. The median OS of patients receiving intermittent rella-cola was 13.9 months, while the median OS of patients receiving albumin-bound-paclitaxel but not receiving rella-cola was 12.2 months. Each event indicated death of one patient. See also fig. 7B and 7C.

Fig. 6B shows the total survival (OS) time analyzed for a subset of patients without primary platinum refractory disease who had previously received 1 to 3 previous lines of treatment for cancer, wherein the previous treatment included prior bevacizumab.

Fig. 7A lists a comparative table of Progression Free Survival (PFS), objective Remission Rate (ORR), duration of remission (DoR), and total survival (OS) observed in three groups of patients during the study. Note that this figure shows PFS, ORR, doR and OS data for an earlier expiration date by 2021, month 3, and 22. Further overall survival results continue to be collected after this initial expiration date (see fig. 6 and 7B above). Patients that did not respond to first-line platinum-based therapy prior to the study were considered "primary platinum refractory" patients; the prognosis of these patients is particularly poor. PFS, ORR, doR and OS for all 178 patients in the study were calculated (overall "column), as well as 167 patients who were not" primary platinum refractory "patients (primary platinum refractory excision" column)). Both analyses showed that intermittent administration of relocatable during the taxane administration period significantly improved PFS and DoR compared to the taxane alone.

Figure 7B lists Progression Free Survival (PFS), duration of remission (DoR), and total survival (OS) data for a subset of patients without primary platinum refractory disease and who have received 1-3 prior treatment lines. In this subgroup, a significant improvement in PFS, doR and OS compared to albumin binding-paclitaxel monotherapy was observed. The date of expiration of the final OS analysis was 2022, 3 months and 7 days.

Fig. 7C shows OS data in a subgroup of day 3, month 7 of expiration 2022, which excludes primary platinum refractory patients and patients who had previously received four or more previous treatment lines. Excluding primary platinum refractory patients and women who had previously received four or more prior treatment lines, women who received intermittent treatment with relocatable had a 48% reduction in risk of mortality (risk ratio: 0.52; p-value: 0.010) compared to women who received albumin-binding-paclitaxel treatment alone. Their median OS was 13.9 months, while women receiving albumin-binding-paclitaxel monotherapy were 12.2 months.

Figure 7D lists Progression Free Survival (PFS), duration of remission (DoR), and total survival (OS) data for a subset of patients who were free of primary platinum refractory disease and had received 1-3 prior treatment lines, including prior bevacizumab treatment. In this subgroup, greater improvements were observed for PFS, doR, and OS than were observed in the other subgroup analyses (e.g., comparing the group in fig. 7B that did not require prior use of bevacizumab).

Figure 8 lists the number of certain clinical symptoms observed in three groups of patients during the study for comparison. The safety and tolerability of the melagatran and albumin binding-paclitaxel treatment was comparable to that of albumin binding-paclitaxel treatment alone.

FIG. 9A presents a comparison of mRNA levels encoding Glucocorticoid Receptor (GR) in ovarian cancer patients receiving albumin-binding-paclitaxel alone versus ovarian cancer patients receiving both Ruilakolan and albumin-binding-paclitaxel. In our phase 2 study, GR expression was observed in 96% of the evaluable ovarian tumors. In the group treated with albumin binding-paclitaxel alone, high expression of GR was associated with adverse reactions. In contrast, high expression of GR was associated with partial or complete remission of both groups of rella-cola + albumin binding-paclitaxel (upper panel). For high GR patients, the partial or complete remission rate was doubled compared to the albumin-binding-paclitaxel alone treatment group (bottom panel).

FIG. 9B shows the results of "GR-induced genes" (defined as 239 genes induced by a single dose of prednisone, measured in whole blood from another healthy volunteer study). In patients receiving both rella-kolan (continuous or intermittent administration) and albumin-binding-paclitaxel (triangle) treatment, 221 genes of the 239 GR-induced genes were inhibited in mRNA expression from day 1 to day 15 of cycle 1. Of the 239 genes previously shown to be GR target genes, 221 were inhibited following the relocatable + albumin binding-paclitaxel treatment. The number of GR target genes inhibited by albumin binding-paclitaxel alone was significantly reduced (P < 0.00001).

Fig. 9C shows three GR target genes that are inhibited by rela+np, not NP alone, including SGK1 (p=0.0089), PIK3CG (p=0.0045), and GSK3B (p=0.0175).

Fig. 9D presents measurements of mRNA levels in 137 pre-treatment tumor samples, including tumors in patients treated with albumin-binding-paclitaxel alone and tumors in patients treated with albumin-binding-paclitaxel and rilagulosa. First, the median of each of 444 genes was determined (left). NR3C1 mRNA was highly expressed in all tumors tested; the median of NR3C1 falls at the 83 rd percentile of all gene distributions.

Fig. 10A is a schematic of the planned clinical trial regimen of example 2. The targets included 360 patients with high grade serous epithelial cancers (grade 3), high grade (grade 3) endometrioid cancers, carcinoma sarcomas with an endometrioid epithelial tumor content of 30% or more, ovarian cancer, primary peritoneal or fallopian tube cancer, and progression 6 months or less after the last dose of platinum-based treatment. Women who have recurrent ovarian, primary peritoneal, or fallopian tube cancer after at least one treatment and are resistant to platinum-based chemotherapy, include the following histological subtypes:

high grade (grade 3) serous epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer;

High grade (grade 3) endometrial cancer; and carcinoma sarcoma with endometrial epithelium tumor content more than or equal to 30%. These criteria are expected to exclude primary platinum refractory patients from the study. The primary endpoint to be measured was Progression Free Survival (PFS) by blind independent center evaluation (BICR) according to RECIST v.1.1. The secondary efficacy endpoint will include total survival (OS); PFS (by researchers) according to RECIST v.1.1. for optimal overall relief (BOR); duration of remission (DoR) according to RECIST v.1.1; clinical benefit rate according to RECIST v.1.1; and the integrated response safety endpoints derived from RECIST v.1.1 and GCIG (international group for gynaecological cancers (Gynecological Cancer InterGroup)) criteria include patient safety, patient quality of life (QOL), ca-125, pharmacodynamics, and pharmacokinetics. The patient will be 1:1 is randomly divided into a) receiving intermittent administration of rella-directed to (oral 150 mg) and albumin binding-paclitaxel (80 mg/m ², 180 patients), wherein albumin binding-paclitaxel is administered on days 1, 8 and 15 of the 28 day cycle, and rella-directed on days 1, 2 and 7-9, 14-16 and 28; or B) "the choice of the researcher", i.e. the patient intravenous administration of liposomal doxorubicin (40 mg/m ²) on day 1 of the 28 day cycle according to the advice of the attending physician; paclitaxel (80 mg/m ²) was intravenously injected on days 1, 8, 15, and 22 of the 28 day cycle; intravenous albumin binding-paclitaxel (100 mg/m ²) on days 1, 8 and 15 of the 28 day cycle; or topotecan (4 mg/m ²) on days 1, 8 and 15 of the 28 day cycle or topotecan (1.25 mg/m ²) on days 1-5 of each 21 day cycle.

Fig. 10B is a schematic of a randomized, control, double arm, open-label, multicenter phase 3 study of intermittent rella-kalant + albumin binding-paclitaxel and albumin binding-paclitaxel, named ROSELLA (NCT 05257408), which has been initiated and is in progress.

Detailed Description

Applicants have unexpectedly found that intermittent administration of Glucocorticoid Receptor Modulators (GRMs) in combination with cancer chemotherapy provides greater benefits to cancer patients than chemotherapy alone. Intermittent GRM with taxane administration provides greater benefit to cancer patients than taxane treatment alone. For example, applicants have unexpectedly found that intermittent administration of the non-steroidal drug GRM rella-cola in combination with taxane chemotherapy (e.g., albumin binding-paclitaxel) can provide longer duration of remission and progression free survival for cancer patients than taxane therapy alone. For example, as disclosed herein, intermittent administration of relocatable may provide a cancer patient with greater benefit than similar albumin-binding-paclitaxel therapies without administration of relocatable on the day before, the day after, and the day after weekly administration of albumin-binding-paclitaxel (as shown in the examples herein, for three consecutive weeks in a four week cycle, and over multiple cycles). Such greater benefits include improving progression free survival of ovarian, fallopian tube, peritoneal and other cancer patients, improving duration of remission, and other benefits.

The current unexpected results differ from the previous results, indicating that continuous administration of the combination of relocatable and albumin binding-paclitaxel may provide benefits. Phase 1 studies of relocatable + albumin binding-paclitaxel demonstrated clinical activity in patients with metastatic PDAC, ovarian cancer and other solid tumors. The combination therapy of relocatable plus albumin binding-paclitaxel has a longer duration of benefit than the previous albumin binding-paclitaxel monotherapy, resulting in a durable control of the disease in ovarian, fallopian tube and primary peritoneal cancer patients (Munster et al 2019). Applicants disclose herein that intermittent administration of GRM with taxane chemotherapy, as opposed to continuous administration of GRM with taxane chemotherapy, surprisingly provides additional benefits compared to the absence of GRM.

The methods and uses disclosed herein comprise intermittently administering to a subject an effective amount of GRM effective to treat cancer in the subject. In embodiments, the GRM is a Selective Glucocorticoid Receptor Modulator (SGRM). In embodiments, the methods disclosed herein comprise intermittently administering to a subject an effective amount of a non-steroidal GRM (where "non-steroidal" means GRM does not comprise a steroid structure) to effectively treat cancer in the subject.

In an embodiment, the GRM is a non-steroidal compound comprising a heteroaryl-ketone fused azadecalin structure, wherein the heteroaryl-ketone fused azadecalin structure is as described and disclosed in U.S. patent 8,859,774. In an embodiment, the GRM is a heteroaryl-ketone fused azanaphthalene compound disclosed in U.S. patent 8,859,774. Pharmaceutical compositions for use as disclosed herein may contain a non-steroidal GRM compound comprising a heteroaryl-ketone fused azadecalin structure. In an embodiment, the GRM is a heteroaryl-ketone fused azanaphthalene compound (R) - (1- (4-fluorophenyl) -6- ((1-methyl-1H-pyrazol-4-yl) sulfonyl) -4,4a,5,6,7, 8-hexahydro-1H-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone ("relocatable") having the structure:

The relocatable is disclosed in example 18 of us patent 8,859,774; which is also known as CORT125134. Ruilakolan is a GRM that does not significantly affect progesterone, mineralocorticoids, androgens or estrogen receptors. Thus, rella-cola is SGRM. In embodiments, the relocatable is administered orally.

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

In embodiments of the methods and uses disclosed herein, intermittent administration includes administering an effective amount of GRM (such as a non-steroidal GRM, e.g., rella-colan) for two consecutive days, waiting for a period of time ("interval"), and then administering an effective amount of GRM again for two consecutive days; the interval may be, for example, one week, two weeks, three weeks, four weeks, or more. The interval may be two or several days, or may be a number of days not equal to an integer number of weeks. In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of GRM (such as a non-steroidal GRM, e.g., relocatable) for three consecutive days, waiting for an interval period, and then administering an effective amount of GRM again for three consecutive days; the interval may be, for example, one week, two weeks, three weeks, four weeks, or more. In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of GRM (such as a non-steroidal GRM, e.g., rella-cola) weekly, or biweekly, or monthly, or twice monthly, or three times monthly. In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of GRM (such as a non-steroidal GRM, e.g., relocatable) every other day.

For example, intermittent administration of GRM (e.g., heteroaryl-ketone fused azadecalin GRM) may include administration on the day of administration of a cancer chemotherapeutic agent to a patient. Intermittent administration of GRM (such as heteroaryl-ketone fused azadecalin GRM) may further include administration the day prior to administration of the cancer chemotherapeutic agent to the patient; or the day after administration of the cancer chemotherapeutic agent to the patient; and may include administering the non-steroidal GRM on the day before, on the day after, and on the day after the administration of the cancer chemotherapeutic agent to the patient. Intermittent administration of heteroaryl-ketone fused azadecalin GRM may include at least 4 days between administration of heteroaryl-ketone fused azadecalin GRM, wherein heteroaryl-ketone fused azadecalin GRM is not administered.

The novel methods and uses disclosed herein may be used to treat cancer patients who are also receiving cancer chemotherapy. In embodiments of the methods disclosed herein, intermittent administration of a GRM (such as a non-steroidal GRM, e.g., relocatable) may be timed according to the schedule of administration of a cancer chemotherapeutic agent to a patient. For example, GRM may be administered one day before, on the same day as, or on the same day after the administration of a cancer chemotherapeutic agent to a patient. GRM may be administered on two or more of the day prior to, the day of, or the day after administration of the cancer chemotherapeutic agent to the patient. In embodiments of the methods and uses disclosed herein, intermittent GRM administration includes administering an effective amount of GRM (such as a non-steroidal GRM, e.g., rella-cola) to the patient on the day before, on the day after, and on the day after administration of the cancer chemotherapeutic agent. The cancer chemotherapeutic agent may be, for example, a taxane (such as paclitaxel or albumin binding-paclitaxel).

In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of GRM (such as a non-steroidal GRM, e.g., relocatable) the day prior to administration of the cancer chemotherapeutic agent to the patient; the cancer chemotherapeutic agent may be, for example, a taxane (such as paclitaxel or albumin binding-paclitaxel). In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of GRM (such as a non-steroidal GRM, e.g., rella-colan) on the day of administration of a cancer chemotherapeutic agent to a patient; the cancer chemotherapeutic agent may be, for example, a taxane (such as paclitaxel or albumin binding-paclitaxel). In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of GRM (such as a non-steroidal GRM, e.g., relocatable) the day after administration of the cancer chemotherapeutic agent to the patient; the cancer chemotherapeutic agent may be, for example, a taxane (such as paclitaxel or albumin binding-paclitaxel).

The novel methods and uses disclosed herein include intermittent administration of GRM (such as non-steroidal GRM), useful for treating patients suffering from ovarian, fallopian tube, uterine, cervical, vaginal, vulvar, peritoneal or other cancer. Such intermittent administration of an effective amount of GRM (such as a non-steroidal GRM, e.g., rella-cola) in combination with cancer chemotherapy is effective in treating cancer. Pharmaceutical compositions for use as disclosed herein may contain a non-steroidal GRM compound (such as, for example, rella-coland) comprising a heteroaryl-ketone fused azadecalin structure.

GRM (such as non-steroidal GRM) may be administered orally. In embodiments, the relocatable is administered orally. In some cases, the GRM (such as a non-steroidal GRM) is administered by injection, infusion, or other means.

In some cases, an effective amount of GRM is a dose of 1 to 100 mg/kg/day, wherein the GRM is administered with at least one chemotherapeutic agent. In some embodiments, the dose of GRM is 1,2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 30, 40, 5060, 70, 80, 90, or 100 mg/kg/day. In some cases, GRMs are administered according to an intermittent dosing regimen for at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, or 80 weeks.

As used herein, a cancer chemotherapeutic agent (also referred to as a chemotherapeutic agent) may be any chemotherapeutic agent suitable for treating cancer, such as any chemotherapeutic agent suitable for treating 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 chemically toxic compound, an antiproliferative agent, an antimetastatic agent, and may be an antibody or other drug or treatment that may inhibit, prevent or reverse the growth or spread of cancer, alone or in combination with other drugs. In embodiments of the methods and uses disclosed herein, the cancer chemotherapeutic agent may be a taxane. The taxane may be, for example, paclitaxel, albumin-bound paclitaxel, docetaxel, lyocell, telmisartan, cabazitaxel, or octreotide. In embodiments, the chemotherapeutic agent is a taxane containing paclitaxel (e.g., albumin binding-paclitaxel).

Accordingly, applicants disclose herein a method of treating cancer comprising: intermittently administering an effective amount of GRM to a patient having a cancer, wherein the patient is in need of and receiving a cancer chemotherapy treatment for the cancer, the treatment comprising administering a cancer chemotherapeutic agent according to a dosing schedule of cancer chemotherapy that requires at least one day between days of administration of the cancer chemotherapeutic agent to the patient without administration of the cancer chemotherapeutic agent, wherein the intermittent administration comprises administering the GRM on the same day as the administration of the cancer chemotherapeutic agent to the patient, thereby treating the cancer. In embodiments, the GRM is a non-steroidal GRM (such as a heteroaryl-ketone fused azadecalin GRM, e.g., rella-colan).

In embodiments of the methods disclosed herein, GRM is also administered the day after administration of the cancer chemotherapeutic agent to the patient. In embodiments of the methods disclosed herein, the GRM is also administered the day prior to the administration of the cancer chemotherapeutic agent to the patient. In embodiments of the methods disclosed herein, the GRM is administered the day before, the day after, and the day after the administration of the cancer chemotherapeutic agent to the patient. In embodiments, the GRM is a non-steroidal GRM (such as a heteroaryl-ketone fused azadecalin GRM, e.g., rella-colan).

Applicants also disclose herein the use of GRMs, such as non-steroidal GRMs, such as heteroaryl-ketone fused azadecalin GRMs (e.g., relocatable), in any of the methods disclosed herein for treating cancer. The use includes the use of such GRM in the manufacture of a medicament for treating cancer according to the methods disclosed herein. In embodiments of the methods and uses disclosed herein, the schedule of cancer chemotherapy administration includes administration of the cancer chemotherapeutic agent on a first day and again on a subsequent day after (i.e., not on a second day after) at least one day between the first days, and no administration of the cancer chemotherapeutic agent on one or more days between the first day and the subsequent day. For example, in embodiments of the methods and uses disclosed herein, the schedule of cancer chemotherapy administration includes administration of the cancer chemotherapeutic on a first day and again on a 7 th day after the first day, without administration of the cancer chemotherapeutic on a day between the first day and the 7 th day after the first day.

In other embodiments of the methods disclosed herein, the cancer chemotherapeutic agent is administered to the patient three consecutive weeks according to the cancer chemotherapy dosing schedule. In still further embodiments of the methods disclosed herein, the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy dosing schedule, and then not administered to the patient one week after the three consecutive weeks. In embodiments, the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy dosing schedule, then not administered to the patient for one week after the last of the three consecutive weeks, then the weekly dosing regimen is repeated for three more consecutive weeks.

The applicant further discloses the use of a pharmaceutical composition for the treatment of cancer, wherein the cancer treatment comprises intermittent administration of an effective amount of GRM (such as heteroaryl-ketone fused azadecalin GRM) to a patient suffering from cancer, wherein the patient is in need of, and is receiving, a cancer chemotherapy treatment for the cancer, the treatment comprising administration of a cancer chemotherapeutic agent according to a cancer chemotherapy administration schedule requiring at least one day between days of administration of the cancer chemotherapeutic agent to the patient without administration of the cancer chemotherapeutic agent, wherein the intermittent administration comprises administration of the GRM on the same day as the administration of the cancer chemotherapeutic agent to the patient, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and GRM (such as heteroaryl-ketone fused azadecalin GRM, e.g. relocatable).

In embodiments of the uses 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 embodiments, the cancer is ovarian cancer. In embodiments, the cancer is fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer or peritoneal cancer. In embodiments, the cancer is platinum-resistant ovarian cancer. In embodiments, the cancer is platinum-resistant fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer, or peritoneal cancer. In embodiments of the uses disclosed herein, the cancer chemotherapeutic agent may be a taxane. In embodiments of use, the taxane may be, for example, paclitaxel, albumin binding-paclitaxel, docetaxel, lyocell, tesetaxel, cabazitaxel, or ostazol. In embodiments, the chemotherapeutic agent is a taxane containing paclitaxel (e.g., albumin binding-paclitaxel).

In embodiments of the uses disclosed herein, GRM (such as non-steroidal GRM, e.g., heteroaryl-ketone fused azadecalin GRM) is also administered the day after administration of the cancer chemotherapeutic agent to the patient. In embodiments of the uses disclosed herein, the heteroaryl-ketone fused azadecalin GRM is also administered the day prior to administration of the cancer chemotherapeutic agent to the patient. In embodiments of the uses disclosed herein, the heteroaryl-ketone fused azadecalin GRM is administered the day before, the day after, and the day after the administration of the cancer chemotherapeutic agent to the patient.

In embodiments of the uses disclosed herein, the cancer chemotherapeutic administration schedule includes administration of the cancer chemotherapeutic agent on a first day and re-administration on a 7 th day after the first day, without administration of the cancer chemotherapeutic agent on a day between the first day and the 7 th day after the first day.

In other embodiments of the uses disclosed herein, the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to the cancer chemotherapy dosing schedule. In still further embodiments of the uses disclosed herein, the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy dosing schedule, and then not administered to the patient for one week after the last week of the three consecutive weeks. In embodiments of the uses disclosed herein, the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy dosing schedule, then not administered to the patient one week after the last week of the three consecutive weeks, then the weekly dosing schedule is repeated for three more consecutive weeks.

B. Definition of the definition

As used herein, the term "tumor" and the term "cancer" are used interchangeably and refer to abnormal growth of tissue caused by excessive cell division. "malignant" tumors may invade surrounding tissue (such tumor invasion is referred to as "locally advanced"). The malignant tumor that leaves the primary organ is a malignant tumor that has metastasized.

As used herein, the term "first line" refers to a therapy that is first administered to a patient after diagnosis (e.g., cancer). Other common terms of "first line" therapy include induction therapy, primary therapy, and primary therapy.

As used herein, the terms "total survival" and "total survival" (OS) refer to the number or percentage of patients in a treatment group that remain alive at a particular period or selected point in time after initiation of treatment.

As used herein, the term "progression free survival" (PFS) refers to the length of time that the cancer does not worsen (does not "progress", e.g., the tumor size does not increase significantly, or does not metastasize) during and after initiation of treatment. Progression free survival is an indicator of the efficacy of a treatment.

As used herein, the terms "remission" and "remission rate" refer to improvements associated with treatment, or a slowing or cessation of disease progression. For example, patients exhibiting an improvement (such as a reduction in symptom severity, a slowing or stopping of tumor growth, an improvement in quality of life, or other improvement) during or after treatment are considered to be responsive to treatment.

As used herein, the terms "objective relief" and "objective relief rate" (ORR) refer to measurable relief, i.e., a measurable improvement associated with treatment. ORR is defined as the proportion of patients whose tumor size decreases by a predetermined amount in the shortest time period; please refer to the solid tumor remission assessment standard ("RECIST") guide version 1.1 (available over the world wide web, website: ctep. Cancer. Gov/protocolDevelopment/docs/RECIST _guide. Pdf).

As used herein, the term "duration of remission" (DoR) refers to the length of time a patient experiences improvement in connection with treatment.

As used herein, the terms "partial response" and "partial remission" (PR) refer to a reduction in the sum of diameters (SOD) of target lesions by at least 30% as referenced to baseline SOD in response to treatment.

As used herein, the terms "complete response" and "complete remission" (CR) refer to the disappearance of all signs of cancer in response to treatment-no detectable tumor evidence. CR is typically measured by imaging studies (e.g., CT scan) or histopathological evaluation (e.g., bone marrow biopsy or breast cancer resection specimen).

As used herein, the term "recurrence" refers to a recurrence of cancer, or to the recurrence or increase of symptoms of cancer after a period of time in response to treatment.

As used herein, the term "platinum resistance" refers to cancer that recurs or progresses over a period of time after successful treatment (e.g., partial or complete remission) with platinum-containing chemotherapy (e.g., cisplatin or carboplatin). For example, ovarian cancer that recurs within 6 months after platinum-containing chemotherapy is considered platinum-resistant ovarian cancer.

As used herein, the term "platinum refractory" refers to cancers that are not responsive to treatment with anti-cancer drugs that contain metallic platinum (such as cisplatin and carboplatin). Immediate progression or recurrence of the disease following the early platinum-based treatment indicates treatment failure. A "primary platinum refractory" patient does not respond to the first treatment of platinum-based cancer therapy; other patients may initially respond to platinum-based cancer therapies, but fail to respond to further platinum-based cancer therapies after cancer recurrence. Platinum refractory patients are a subgroup of platinum resistant patients.

As used herein, the term "risk ratio" (HR) refers to a comparison indicator of patient remission (e.g., survival) at any point in time for a group of patients receiving a particular treatment versus patient remission (e.g., survival) for a control group receiving another treatment or placebo. Patient survival may be measured, for example, progression free survival, total survival, or other survival measures. A risk ratio of 1 means that there was no difference in survival between the two groups. A risk ratio greater than 1 or less than 1 means that the survival rate of one of the groups is better. For example, if HR is calculated as a comparison of the total survival in the experimental group to the total survival in the control group, HR < 1 indicates a longer total survival in the experimental group. More generally, a risk ratio refers to a comparison of the frequency of occurrence of a particular event in one group with the frequency of occurrence in another group over time.

As used herein, the term "ascites" refers to abnormal fluid accumulation typically in the abdomen.

The terms "cancer chemotherapeutic agent," "cancer therapeutic agent," "cancer chemotherapeutic agent," and "chemotherapeutic agent" as used herein refer to any and all antineoplastic agents, compounds, and compositions useful in the treatment of cancer. In addition to the chemically toxic compounds and formulations used herein that are generally toxic to cancer cells (and also generally non-cancer cells), cancer chemotherapeutic agents and treatments using such agents may include antibody treatments, toxic or antibiotic compounds and formulations that are generally toxic to cancer cells (also generally non-cancer cells), antiproliferative agents (reducing cancer cell growth or replication), antimetastatic agents (reducing metastasis), and other agents and treatments that can inhibit, prevent, or reverse cancer growth or spread in a cancer patient. The cancer chemotherapeutic agent may be used alone or in combination with other cancer chemotherapeutics or other agents.

Cancer chemotherapeutic 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, albumin binding-paclitaxel, docetaxel, lyocell, temataxel, cabazitaxel, and ostatic), vinca alkaloids (e.g., vinca alkaloids), anthracyclines (e.g., doxorubicin), epipodophyllotoxins (epipodophyllotoxins) (e.g., etoposide), cisplatin, methotrexate, actinomycin D, dolastatin 10 (dolastatin), trimethoprim (trimetrexate), metoproline (metoprine), daunorubicin (daunorubicin), teniposide, alkylating agents (e.g., chlorambucil (chlorambucil)), 5-fluorouracil, camptothecins, and cisplatin, and anti-inflammatory agents (such as colchicine).

As used herein, the term "taxane" refers to a class of diterpenoid compounds having a taxane core. Many taxanes are useful as cancer chemotherapeutics, which are commonly used as mitotic inhibitors and anti-microtubule agents. The taxane includes paclitaxel (e.g., TAXOL; bristol-Myers Squibb Oncology, prlington, N.J.), albumin binding-TAXOL"Abx"; albumin engineered nanoparticle formulations, also known as albumin binding-paclitaxel (united states pharmaceutical partner (American Pharmaceutical Partners)), sham berg, inoyi,/>(Docetaxel, docetaxel (doxetaxel); celecoxib-anwante), lyocell, tesetaxel, cabazitaxel, and ostazol.

As used herein, the term "bevacizumab" refers to an antibody drug that binds to the protein Vascular Endothelial Growth Factor (VEGF). Bevacizumab alone or in combination with other drugs is used to treat a variety of cancer types including, for example, ovarian cancer, cervical cancer, colorectal cancer, lung cancer and other cancers. Bevacizumab is believed to treat cancer by inhibiting the growth of new blood vessels. Bevacizumab is marketed under the brands Avastin, ai Fashi (Mvasi) and Ji Labei f (Zirabev).

As used herein, the terms "PARP inhibitor" and "poly (ADP-ribose) polymerase inhibitor" refer to substances that inhibit or block poly (ADP-ribose) polymerase (PARP). PARP inhibitors may be used in combination with other cancer chemotherapeutic agents. PARP is considered an important cellular tool for repairing DNA damage; one of the purposes of many cancer chemotherapeutics is to destroy the DNA of cancer cells. PARP inhibitors are believed to treat cancer by inhibiting DNA repair in cancer cells treated with cancer chemotherapeutic agents.

As used herein, the terms "adverse event" and "adverse effect" refer to an unexpected medical problem experienced by a patient during treatment with a drug or other therapy, including during treatment with an experimental therapy (e.g., in a clinical trial). Adverse events may be mild, moderate or severe and may be caused by factors other than the drug or treatment 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.

As used herein, the terms "safety" and "safety" with respect to a clinical trial refer to the risk, number, or number of adverse events in the clinical trial, typically a clinical trial that compares the effect of a test treatment to the effect of a standard treatment. A new drug, new therapy, or new treatment is judged to be "safe" if the number of adverse events associated with the patient receiving the test treatment is less than or similar to the number of adverse events associated with the standard treatment, or the severity of the adverse events observed is similar (similar means that the number of adverse events is not significantly greater than the number of adverse events associated with the standard therapy).

As used herein, the terms "patient" and "subject" refer to a person who is or will be receiving or has been receiving treatment for a disease or disorder.

As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of an agent effective to treat, eliminate, or slow at least one symptom of a treated disease. In some cases, a "therapeutically effective amount" or "effective amount" may refer to an amount of a functional substance or pharmaceutical composition that is capable of exhibiting a detectable therapeutic or inhibitory effect. The effect may be detected by any assay known in the art. An effective amount may be an amount effective to elicit an anti-tumor response. For the purposes of this disclosure, an effective amount of GRM or an effective amount of a chemotherapeutic agent is an amount that, when combined with the chemotherapeutic agent or GRM, respectively, will produce the desired beneficial clinical outcome associated with cancer improvement. Such a desired beneficial clinical outcome may be, for example, a slowing or stopping of tumor growth; tumor size or tumor burden is reduced; improvement of symptoms or complications, or reduction of the number of adverse events (such as neutropenia, anemia, alleviation of neuropathy or fatigue); improvement of quality of life; or other improvements.

As used herein, the terms "administer," "administered," or "administered" provide a compound or composition (e.g., those described herein) to a subject or patient. Oral administration may be buccal (where the compound or composition remains in the mouth, e.g., under the tongue, and is absorbed there) by injection, i.e., by needle, microneedle, pressure syringe, or other means of piercing the skin or forcing the compound or composition through the skin of the subject.

The terms "measure", "measuring level", "measuring the level", etc., refer to determining, detecting, or quantifying the amount, level, or concentration of a target analyte. The target analyte may be, for example, mRNA or hormone (e.g., cortisol or ACTH), or other target analytes in a sample obtained from a subject. The sample may be, for example, a blood sample. The level may be measured from a portion of the sample. For example, analyte levels may be measured in the plasma portion of a blood sample; can be measured in the serum portion of the blood sample; or in an embodiment, may be measured in whole blood.

As used herein, the term "sample" refers to a biological sample obtained from a human subject. Such samples are typically removed from the subject and, after acquisition, completely separated from the subject (i.e., in vitro samples). The sample may be any cell, tissue or liquid sample obtained from a human subject. The sample may be, for example, a blood sample, a saliva sample, a urine sample, or other sample obtained from a patient. The sample may be subjected to various treatments, storage or processing procedures prior to analysis according to the methods described herein. In general, the term "sample" or "samples" is not limited by its source, origin, purchasing means, processing, storage or analysis means, or any modification. Thus, in embodiments, the sample is an in vitro sample and may be analyzed using in vitro methods. The methods disclosed herein are in vitro methods when used with samples obtained and removed from a human subject.

As used herein, the term "AUC" refers to the area under the concentration-time curve and is used as a measure of the level of a drug in a subject to whom the drug is administered. Drug levels in samples obtained from a patient (such as whole blood, plasma, or serum samples; urine samples; saliva samples; or other samples) may be measured.

As used herein, the term "C _{Maximum value}" refers to the maximum concentration of a drug observed in a subject to which the drug is administered or in a sample obtained from the subject. For example, it may be in whole blood, plasma or serum samples; a urine sample; a saliva sample; or other samples for measurement of C _{Maximum value}.

As used herein, the term "exposure" refers to the amount of a drug that, upon administration to a patient, can produce activity systemically. Drug exposure may differ from dose because not all drugs administered to a patient may have a clinical effect (e.g., some drugs may be expelled, metabolized, or otherwise unavailable). Exposure can be measured by AUC or C _{Maximum value}, both of which provide an objective measure of drug in a patient.

As used herein, the term "combination therapy" refers to the administration of at least two agents to a patient to treat a disease. The two agents may be administered simultaneously, or may be administered sequentially in any order throughout or part of the course of treatment. The at least two agents may be administered on the same or different dosing schedules. In some cases, one agent is administered on a predetermined schedule, while the other agent is administered intermittently. In some cases, both agents are administered intermittently.

As used herein, the terms "simultaneous administration," "concurrent administration," "combination therapy," and the like refer to administration of at least two agents to a subject to treat a disease or disorder. The two agents may be administered simultaneously, or may be administered sequentially in any order throughout or part of the course of treatment. The at least two agents may be administered on the same or different dosing schedules. Such agents may include, for example, rella-cola and another drug, which may be, for example, a drug for treating cancer, or another therapeutic agent. In some cases, one agent is administered intermittently. In some cases, both agents are administered intermittently. In some cases, the first agent may be administered once a week for one, two or three weeks, and the second agent may be administered on one or more of the preceding, the day, and the following day of administration of the first agent.

As used herein, the term "compound" is used to refer to a molecular moiety having a unique, identifiable chemical structure. The molecular moiety ("compound") may exist as a free species in which it is not associated with other molecules. The compound may also exist as part of a larger aggregate in which it is associated with one or more other molecules, but retains its chemical characteristics. Solvates in which a molecular moiety having a defined chemical structure ("compound") is associated with a molecule of a solvent are examples of such related forms. Hydrates are solvates in which the associated solvent is water. Reference to a "compound" refers to the molecular moiety (of the described and structured) itself, whether in free or associated form.

As used herein, the term "pharmaceutically acceptable carrier" is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, use of such medium or agent in the composition is contemplated. Supplementary active compounds may also be incorporated into the compositions.

As used herein, the terms "steroid" and "steroids of various types" and the phrase "steroid skeleton" refer to a steroid skeleton containing seventeen carbon atoms to bond into four fused ring compounds having the structure:

formula 1: a steroid skeleton. Cortisol contains a steroidal skeleton, is a steroid, and is a steroid hormone.

As used herein, the phrase "non-steroidal skeleton" in the context of GRM refers to GRM that has no structural homology or is not modified with cortisol or other compounds containing a steroidal skeleton. Non-steroidal compounds lack a steroidal backbone.

As used herein, the term "glucocorticoid" (GC) includes any compound known in the art that binds to and activates the glucocorticoid receptor. Thus, GC is a glucocorticoid receptor agonist; other terms of GC include corticosteroids, steroids, and glucocorticosteroids. By "glucocorticoid" is meant a steroid hormone or steroid molecule that binds to the glucocorticoid receptor. In humans and many other mammals, the predominant GC is cortisol; however, corticosterone exerts this effect, for example in rodents. Other GCs include, for example, dexamethasone, prednisone, prednisolone, triamcinolone, hydrocortisone (hydrocortisone), beclomethasone (beclamethasone), and other natural and synthetic compounds. Glucocorticoids are generally characterized by having 21 carbon atoms, an α, β -unsaturated ketone in ring a, an α -ketol group attached to ring D. They differ in the degree of oxidation and hydroxylation of C-11, C-17 and C-19 (Rawn, "biosynthesis and transport of membrane lipids," formation of cholesterol derivatives (Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives),"Biochemistry,Daisy et al (ed.), 1989, page 567).

The term "glucocorticoid receptor" (GR) as used herein refers to a type II GR, which is an intracellular receptor that specifically binds cortisol and/or cortisol analogs such as dexamethasone (see, e.g., turner and Muller, j.mol. Endocrinol.200535 (2): 283-292). The glucocorticoid receptor is also known as the cortisol receptor. The term includes isomers of GR, recombinant GR and mutant GR. The gene encoding GR is called NR3C1.

The term "glucocorticoid receptor modulator" (GRM) refers to any compound that modulates the binding of GC to GR. For example, GRM (such as dexamethasone) as an agonist can increase the activity of Tyrosine Aminotransferase (TAT) in HepG2 cells (human hepatoma cell line; ECACC, UK). GRM, such as mifepristone, as an antagonist, is able to reduce the activity of Tyrosine Aminotransferase (TAT) in HepG2 cells. TAT activity can be detected as described in the literature: ali et al, j.med.chem.,2004, 47, 2441-2452.

As used herein, the term "selective glucocorticoid receptor modulator" (SGRM) refers to any composition or compound that modulates GC binding to GR, or modulates any biological response associated with GR and agonist binding. By "selective", the drug preferentially binds to GR over other nuclear receptors such as Progesterone Receptor (PRO), mineralocorticoid Receptor (MR), or Androgen Receptor (AR). Preferably, the selective glucocorticoid receptor modulator binds GR with an affinity that is 10-fold higher (1/10 of the K _d value) than its affinity for MR, AR or PRO. The relocatable is SGRM.

"Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits the binding of GC to GR. Thus, GR antagonists can be identified by measuring the ability of a compound to inhibit the binding of dexamethasone to GR. TAT activity can be detected as described in the literature: ali et al, j.med.chem.,2004, 47, 2441-2452.GRA is a compound with IC ₅₀ (half maximal inhibitory concentration) less than 10 micromolar. See example 1 of U.S. patent 8,859,774, incorporated herein by reference in its entirety. GRA is GRM.

The compound comprising a heteroaryl-ketone fused azadecalin structure (which may also be referred to as a heteroaryl-ketone fused azadecalin backbone) may be a non-steroidal compound, may be a GRM compound, and may be an SGRM compound. Exemplary heteroaryl-ketone fused azanaphthalene compounds are described in U.S. patent 8,859,774. In an embodiment, heteroaryl-ketone fused azadecalin GRM for use in the methods and uses disclosed herein is the compound (R) - (1- (4-fluorophenyl) -6- ((1-methyl-1H-pyrazol-4-yl) sulfonyl) -4,4a,5,6,7, 8-hexahydro-1H-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone (example 18 of U.S. patent 8,859,774), also known as "relocalan" and "CORT125134", having the following structure:

The term "composition" as used herein is intended to encompass products comprising the specified ingredients, such as the compounds, tautomeric forms thereof, derivatives thereof, analogs thereof, stereoisomers thereof, polymorphs thereof, deuterated species thereof, pharmaceutically acceptable salts, esters, ethers, metabolites, isomer mixtures thereof, pharmaceutically acceptable solvates thereof and specified amounts of the pharmaceutically acceptable composition, as well as any products produced directly or indirectly from the combination of the specified amounts of the specified ingredients. For pharmaceutical compositions, the term is intended to encompass a product comprising the active ingredient and inert ingredients comprising the carrier, as well as any product formed directly or indirectly from any two or more ingredients in combination, complexation or aggregation, or decomposition of one or more of the ingredients, or other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention are intended to encompass any composition made by mixing a compound of the present invention with a pharmaceutically acceptable carrier therefor.

In some embodiments, the term "consisting essentially of … …" refers to a composition in which the only active ingredient in the formulation is the indicated active ingredient, but may also include other compounds which are useful in stabilizing, preserving the formulation, etc., but which are not directly related to the therapeutic effect of the indicated active ingredient. In some embodiments, the term "consisting essentially of … …" may refer to a composition comprising an active ingredient and a component that facilitates the release of the active ingredient. For example, the composition may comprise one or more components that provide for sustained release of the active ingredient to the subject over time. In some embodiments, the term "consisting of … …" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier or excipient.

"Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to substances that facilitate administration of an active agent to and absorption by a subject, and may be included in the compositions of the present invention without causing significant adverse toxicological effects to the patient. These terms as used herein are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically acceptable excipients include: water, naCl, physiological saline, ringer's lactate solution, ordinary sucrose, ordinary glucose, binders, fillers, disintegrants, encapsulating agents, plasticizers, lubricants, coating agents, sweeteners, flavoring agents, colorants, and the like. Those of ordinary skill in the art will appreciate that other pharmaceutically acceptable excipients may be used in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional medium or agent is incompatible with the active compound, use of such medium or agent in the composition is contemplated. Supplementary active compounds may also be incorporated into the compositions. Those of ordinary skill in the art will appreciate that other pharmaceutically acceptable excipients may be used in the present invention.

Methods for identifying or characterizing GRM compounds are known in the art. GRM binds to and modulates GR activity. For example, GRM can antagonize GR activity by inhibiting the binding of GR to other agents that activate GR; such modulation can be detected by observing GR mediated activity. Compounds that exhibit the desired binding affinity for GR are tested for activity in inhibiting GR mediated activity. The compounds are typically subjected to a tyrosine aminotransferase assay (TAT assay) which evaluates the ability of the test compounds to inhibit dexamethasone-induced tyrosine aminotransferase activity. GR modulators suitable for use in the methods disclosed herein have less than 10 micromolar IC ₅₀ (half maximal inhibitory concentration). Other assays may also be used, including but not limited to the assays described below, to confirm GR modulating activity of the compounds.

Cell-based assays involving whole cells or cell components containing glucocorticoid receptor can also be used to detect binding of test compounds or modulation of glucocorticoid receptor activity. Exemplary cell types that can be used in the methods of the invention include, for example, any mammalian cell, including leukocytes, such as neutrophils, monocytes, macrophages, eosinophils, basophils, mast cells and lymphocytes, such as T cells and B cells, leukemia cells, burkitt's lymphoma cells, tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, cardiomyocytes, muscle cells, breast tumor cells, ovarian cancer, cervical cancer, glioblastoma, hepatocytes, kidney cells and neuronal cells, and fungal cells, including yeast. The cells may be primary cells or tumor cells or other types of immortalized cell lines. Of course, the glucocorticoid receptor may be expressed in cells that do not express the endogenous form of the glucocorticoid receptor.

In some embodiments, a decrease in signal transduction triggered by glucocorticoid receptor activation can be used to identify a glucocorticoid receptor modulator. The signaling activity of glucocorticoid receptor can be determined in a number of ways. For example, downstream molecular events may be monitored to determine signal transduction activity. Downstream events include activities or manifestations that occur as a result of stimulation of glucocorticoid receptors. Exemplary downstream events useful in functional assessment of transcriptional activation and antagonism in unaltered cells include upregulation of various Glucocorticoid Response Element (GRE) -dependent genes (PEPCK, tyrosine aminotransferase, aromatase). Furthermore, the expression of osteocalcin (which is down-regulated by glucocorticoids) in a specific type of cell that is susceptible to GR activation, such as osteoblasts, can be used; primary hepatocytes showing glucocorticoid-mediated up-regulation of PEPCK and glucose-6-phosphate (G-6-Pase). GRE-mediated gene expression in transfected cell lines using well-known GRE-regulated sequences, such as the mouse mammary tumor virus promoter (MMTV) transfected upstream of a reporter construct, has been shown. Examples of useful reporter constructs include luciferase (luc), alkaline phosphatase (ALP) and Chloramphenicol Acetyl Transferase (CAT). Functional assessment of transcriptional inhibition may be performed in cell lines such as monocytes or human skin fibroblasts. Useful functional assays include measuring IL-1 beta stimulated IL-6 expression; downregulation of collagenase, cyclooxygenase-2 and various chemokines (MCP-1, RANTES); LPS-stimulated cytokine release (e.g., tnfα); or those of gene expression regulated by NFkB or AP-1 transcription factors in transfected cell lines.

Compounds tested by the whole cell assay were also tested in the cytotoxicity assay. Cytotoxicity assays were used to determine to what extent the sensory effect was due to non-glucocorticoid receptor binding cellular effects. In an exemplary embodiment, the cytotoxicity assay comprises contacting a constitutively active cell with a test compound. Any decrease in cell viability is indicative of a cytotoxic effect.

A further illustrative example of the many assays that can be used to identify compositions for use in the methods of the invention are assays based on glucocorticoid activity in vivo. For example, assays that evaluate the ability of putative GR modulators to inhibit 3H-thymidine uptake in DNA in glucocorticoid-stimulated cells may be used. Alternatively, it is postulated that GR modulators may compete with 3H-dexamethasone for binding to hepatoma tissue culture GR (see, e.g., choi et al Steroids 57:313-318, 1992). As another example, the ability of putative GR modulators to repress nuclear binding of the 3H-dexamethasone-GR complex may be utilized (Alexandrova et al, J.Steroid biochem. Mol. Biol.41:723-725, 1992). To further identify putative GR modulators, kinetic assays that can distinguish between glucocorticoid agonists and modulators by receptor binding kinetics may also be used (described in Jones, biochem J.204:721-729, 1982).

In another illustrative example Daune, molecular.pharm.13: 948-955, 1977; and the assay described in U.S. patent 4,386,085 can be used to identify anti-glucocorticoid activity. Briefly, thymocytes from adrenal resected rats were incubated in nutrient medium containing dexamethasone and varying concentrations of test compound (putative GR modulator). ³ H-uridine was added to the cell culture medium, which was further incubated, followed by detection of the extent of incorporation of the radiolabel into the polynucleotide. Glucocorticoid agonists reduce the amount of ³ H-uridine incorporated. Thus, GR agonists will counter this effect.

Pharmaceutical composition and administration

In an embodiment, the invention provides a method of treating cancer comprising intermittently administering a pharmaceutical composition comprising a pharmaceutically acceptable excipient and a heteroaryl-ketone fused azadecalin GRM (such as rella-cola) along with a cancer chemotherapy regimen. In embodiments, pharmaceutical compositions comprising rella-cola include those disclosed in U.S. patent publication No. 2020/0197372, the entire contents of which are incorporated herein by reference.

Any suitable GRM dose may be used in the methods and uses disclosed herein. The GRM can be administered at a dosage of at least about 10 milligrams (mg)/day, about 25 mg/day, about 40mg/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, the GRM is administered as at least one dose on the day of administration to the cancer patient. In embodiments, GRM may be administered 1,2, 3,4, 5, 6, 7,8, 9, 10 or more doses on the day of administration to a cancer patient. In embodiments, GRM is administered at1, 2, 3,4, 5, 6, 7,8, 9, 10 or more doses on the day of oral administration to a cancer patient.

Pharmaceutical compositions comprising heteroaryl-ketone fused azadecalin GR modulators are formulated in an acceptable carrier, which may then be placed in an appropriate container and labeled for use in treating cancer, e.g., when administered with a regimen comprising a cancer chemotherapeutic agent. For administration of heteroaryl-ketone fused azadecalin GRMs, such labels should include, for example, relevant instructions for the amount, frequency, and method of administration.

The duration of treatment of cancer with heteroaryl-ketone fused azadecalin GRM and a cancer chemotherapeutic agent can vary depending on the severity of the patient's condition and the patient's response. In some embodiments, GRM may be administered with a cancer chemotherapy regimen for 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 several days or one week when the patient does not receive GRM, at least one week when the patient does not receive cancer therapy, or at least one week when the patient does not receive GRM or cancer therapy.

For example, a cancer chemotherapy regimen may be one in which the patient receives 1,2, 3 or more cycles of chemotherapy, wherein the cycle of chemotherapy may include three consecutive weeks of administration of a chemotherapeutic agent on a weekly day, followed by one (or more) weeks of no chemotherapeutic agent. Administration of GRM concurrently with the use of such a cancer chemotherapy regimen may include administration of GRM to the patient on the day that the patient receives the chemotherapeutic agent. Administration of GRM with such a cancer chemotherapy regimen may include administration of GRM to the patient on the day the patient receives the chemotherapeutic agent, as well as on the previous day, or on the subsequent day, or on both the previous and subsequent days.

Administration of the therapeutic compound or agent of this embodiment to a patient requires compliance with the general regimen of administration of the compound (if necessary) taking into account the toxicity of the therapy. Surgical intervention may also be applied in combination with the therapy.

The method may be combined with other therapeutic modalities such as surgery, radiation therapy, targeted therapy, immunotherapy, the use of growth factor inhibitors or anti-angiogenic agents.

Examples

The following examples are provided for illustration only and are not limiting. Those skilled in the art will readily recognize that various non-critical parameters may be changed or modified to produce substantially similar results.

EXAMPLE 1 intermittent administration of Ruilakolan with Albumin-paclitaxel improves progression-free and overall survival in platinum-resistant ovarian cancer patients

Unless otherwise indicated, the data and analyses provided herein were all from a preliminary analysis (based on 154 Progression Free Survival (PFS) events and 76 total survival (OS) events) recorded by day 22 of 3 months 2021 (medium or initial analysis). After at least 120 OS events were achieved (by 2022, 3, 7 days), further OS analysis was performed (as scheduled). A subgroup analysis was also performed, with 7 primary platinum refractory patients being excluded from the group with intermittent administration of relocatable and albumin binding-paclitaxel, and 1 primary platinum refractory patient being excluded from the comparative group (albumin binding-paclitaxel only).

In one clinical trial, the effect of administration of GRM added in cancer chemotherapy was studied. While daily administration of GRM can continue to antagonize GR-mediated chemotherapy-resistant pathways, intermittent administration of larger doses of GRM during the most severe periods of chemotherapy exposure may result in greater GR antagonism. To determine if different GRM dosing regimens will have different effects on the outcome of the treatment, and if so, to determine which regimen may provide greater benefit, some patients received continuous administration of rilacan while others received intermittent administration of rilacan.

A 3-arm, randomized, open-label, control phase 2 study was performed in which the clinical outcome of patients receiving albumin-binding-paclitaxel was compared to the clinical outcome of patients receiving relocatable and albumin-binding-paclitaxel. The results of this study are presented in this example, which demonstrates that intermittent administration of relocatable in combination with albumin binding-paclitaxel can improve Progression Free Survival (PFS) in cancer patients. Such patients include patients with recurrent platinum-resistant ovarian cancer and other cancers (including fallopian tube cancer, high grade serous or endometrioid epithelial ovarian cancer, or ovarian carcinoma sarcoma, and primary peritoneal cancer patients). Patients are classified as refractory to platinum (i.e., patients who do not respond to platinum-based therapy or relapse within 1 month after platinum-based therapy) or resistant to platinum (i.e., patients who relapse within 6 months of platinum-based therapy). Patients who participated in the study received at least one treatment line, but developed cancer progression [ relapse ] within 6 months after the last platinum-based treatment (i.e., no platinum interval no more than 6 months [ platinum resistance ]), or developed disease progression during or immediately after the platinum-based treatment (i.e., platinum refractory). Patients with primary platinum resistance (progression occurring within 6 months after the last dose of first-line platinum-containing chemotherapy) were eligible for participation in the study.

This study recruited cancer patients, including patients with ovarian cancer, fallopian tube cancer, peritoneal cancer, and other cancers, to compare the two methods of administration of albumin-binding paclitaxel monotherapy with the combination therapy of relocatable and albumin-binding paclitaxel. A schematic 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 treated with 1:1:1 (x) was randomized to receive albumin-binding-paclitaxel monotherapy (albumin-paclitaxel monotherapy; 60 patients, referred to as "comparison group"), continuous administration of relocatable with albumin-paclitaxel (58 patients, referred to as "continuous" group), or intermittent administration of relocatable with albumin-binding-paclitaxel (60 patients, referred to as "intermittent" group). All patients in these groups received a 28 day chemotherapy cycle in which albumin binding-paclitaxel was administered on days 1, 8 and 15.

The patients in the control group received 100 milligrams per square meter (mg/m ²) of albumin-bound-paclitaxel and no rella-colic. The results of the comparison group are used as a basis for comparison with other groups. The consecutive group of patients received once daily doses of rella-directed (initially 100 milligrams (mg/day), depending on the patient's response to the initial 100 milligrams of dose, the dose would be increased gradually to 125mg for patients that seem to be able to tolerate higher doses, once daily, as appropriate, to 150 mg/day, while also receiving 80mg/m ² albumin-binding-paclitaxel on days 1, 8 and 15 of the 28 day cycle (dose escalation control is as follows: if no intolerable 2-or any 3-or 4-way toxicity occurs on the first cycle, the dose of rella-directed would need to be reduced or stopped from day 1 of the 2 nd cycle, the dose of rella-directed would be increased gradually to 125mg for patients that would be able to tolerate the dose of rella-directed to 125mg, once daily, if no intolerable 2-or any 3-or 4-way toxicity occurs on the 2 nd cycle, the dose of rella-directed to albumin-binding-paclitaxel would need to be reduced or stopped from day 1 of the 3 rd cycle, the dose would need to be increased gradually from day 1 of the first cycle, the dose would be increased gradually to 150mg of the first cycle, if no progressive dose was not increased gradually on day 1 nd cycle.

Intermittent group patients received 80mg/m ² albumin-binding-paclitaxel on days 1, 8 and 15 of the 28 day cycle and 150mg of relocatable once daily on the day before, on the day and on the day after albumin-binding-paclitaxel administration (except that no relocatable was administered to the patients on the day before the first albumin-binding-paclitaxel administration). That is, the intermittent group of patients received a dose of 150mg of rella-cola on days 1 and 2, once a day; once daily on days 7, 8 and 9; once daily on days 14, 15 and 16; and re-administering on day 28 of the monthly cycle, wherein albumin binding-paclitaxel is administered on days 1, 8, and 15 of the monthly cycle.

Independent comparisons were made between the intermittent study group and the comparative study group, and between the continuous study group and the comparative study group. The primary endpoint of this study was progression free survival as determined according to the solid tumor remission assessment criteria (RECIST) guidelines version 1.1 (URL accessible via the world Wide Web: http:// ctep. Cancer. Gov/protocolDevelopment/docs/RECIST _guide. Pdf). Secondary endpoints included objective remission rate, duration of remission, total survival, safety of albumin binding-paclitaxel and relocatable co-administration. All efficacy targets and corresponding endpoints, remission assessments and disease progression listed below were assessed according to RECIST v 1.1.

As described above, patients participating in the present study had previously received multi-line therapy (median 3 lines, up to 5 lines), including previous taxane, previous bevacizumab, and previous PARP inhibitor therapy. Many ovarian cancer patients in this study are platinum resistant (and more than 35% are platinum refractory). Primary platinum refractory patients were in too high a proportion in the intermittent group. All but one patient had been treated with a taxane, more than half of the patients had previously been treated with bevacizumab, and slightly more than one third of the patients had previously been treated with PARP inhibitors. Fig. 2 provides further information about patient characteristics and patient response to treatment for study participation, including total number of patients (right-most column), and the status of each of the three groups: intermittent administration of relocatable; continuous administration of relocatable; albumin binding-paclitaxel administration alone (comparison group) (data were as short as 2021, month 3, 22). The stratification factor is the presence of recurrence and ascites within 6 months of the last taxane treatment. Some patients may obtain molecular profiling results. The proportion of patients with BRCA 1 or 2 mutations in this subset is shown at the bottom of the table of fig. 2.

The exposure and peak concentration of albumin binding-paclitaxel and relocatable were measured. Overall, there was a large difference in the exposure to relocatable and albumin binding-paclitaxel, consistent with the pharmacokinetic profile of the two compounds and the outpatient nature of the study design. The overall range of albumin binding-paclitaxel exposure largely overlaps in all three groups. Evaluation of the exposure to relocatable and albumin binding-paclitaxel (measured by AUC and C _{Maximum value}) with the safety endpoint showed that the exposure overlapped to a large extent with or without adverse events.

Figure 3 provides patient treatment information for participation in the study by day 22 of 3 of 2021. For example, figure 3 shows the percentage of patients who stopped study treatment at some point in time during the course of the study, whether albumin-bound-paclitaxel alone (comparative group) or with rella-and albumin-bound-paclitaxel (whether intermittent or continuous rella-and). As expected, most abortions are 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 stopped study treatment, figure 3 provides the number and percentage of patients who stopped treatment due to disease progression, adverse events, death, or other reasons.

Figure 4 shows the Progression Free Survival (PFS) time of three groups of patients up to month 3 and 22 of 2021. Notably, patients receiving albumin-paclitaxel combined intermittent rella-cola therapy had an improved PFS risk ratio (HR) compared to patients receiving albumin-paclitaxel alone: HR was 0.66 (95% CI: 0.44-0.98). Median PFS in patients receiving albumin-binding-paclitaxel and intermittent rella-cola ("intermittent group") treatment was 5.6 months longer than median PFS in patients treated with albumin-binding-paclitaxel alone ("comparative group") for 1.8 months. Although the number of platinum refractory patients in all study groups was very balanced, there were more primary platinum refractory patients in the intermittent group. Analysis of a primary platinum refractory patient with a particularly poor prognosis showed that the risk ratio for PFS was improved (0.64 vs 0.66) and that the intermittent treatment regimen had a stronger trend to improve overall survival, with a risk ratio of 0.55 and a p value of 0.056. A subset of patients without primary platinum refractory disease and who received 1-3 prior treatment lines ("phase 3 population") included 137 patients, 46 of whom received albumin-binding-paclitaxel (80 mg/m ²) +intermittent rella-kolan (150 mg once a day before, on and after albumin-binding-paclitaxel administration), and 50 received only albumin-binding-paclitaxel (100 mg/m ²). Albumin binding-paclitaxel was administered on days 1, 8 and 15 of each 28-day cycle. For a subset of patients with the exclusion of primary refractory disease and patients who had previously received more than 3 prior treatment lines, intermittent relocatable + albumin binding-paclitaxel improved PFS compared to albumin binding-paclitaxel alone, HR 0.58, 95% ci 0.37-0.91, log rank test p=0.0162; median PFS was 5.6 months to 3.8 months.

The median PFS of women in the continuous group was 1.5 months longer than that of the control group; the PFS also showed a numerical improvement compared to albumin binding-paclitaxel alone, with a risk ratio of 0.83, but not statistically significant at the P < 0.05 level. Thus, these PFS results demonstrate that intermittent administration of relocatable and albumin-bound paclitaxel provides greater therapeutic benefits than administration of albumin-bound paclitaxel alone.

Furthermore, as shown in fig. 5, the duration of patient remission (DoR) was also significantly improved in patients receiving intermittent relocatable in combination with albumin-paclitaxel compared to albumin-paclitaxel alone (data cut off by 2021, day 3, month 22). For patients represented by individual horizontal bars in the graph, "PR" represents partial relief and "CR" represents complete relief. The median DoR in the intermittent group in the study was 5.55 months, a significant improvement over the 3.65 months in the control group (risk ratio HR 0.36; p value=0.006). The arrows in fig. 5 represent patients with prolonged duration of remission (patients still respond at the end of the study period). For a subset of patients with no primary refractory disease and patients who had been previously treated with more than 3 previous treatment lines, intermittent relocatable + albumin binding-paclitaxel improved DoR compared to albumin binding-paclitaxel alone, HR 0.26, 95% ci 0.11-0.62, log rank test p=0.0009; the median DoR was 5.6 and 3.6 months. Thus, these DoR results demonstrate that intermittent administration of relocatable and albumin-bound paclitaxel provides greater therapeutic benefits than administration of albumin-bound paclitaxel alone.

As shown in fig. 6, showing final OS analysis data (128 OS events) at a preset expiration date of 3 months and 7 days of 2022, the patient group receiving intermittent relocatable and albumin-binding paclitaxel treatment showed an improvement in total survival compared to the patient group receiving albumin-binding-paclitaxel treatment alone. Of patients receiving intermittent rella-and albumin-binding paclitaxel treatment, 59% survived 12 months, 27% survived 24 months, while of patients receiving albumin-binding paclitaxel alone, this percentage was 51% and 14%, respectively. The intermittent relocatable to albumin binding-paclitaxel treated patients calculated from the kaplan-meyer curve shown in fig. 6 had a risk ratio (HR) of 0.67 (95% ci [0.43,1.03], p=0.066) compared to patients treated with albumin binding-paclitaxel alone. Thus, the risk of mortality in patients receiving intermittent relocatable and albumin-bound paclitaxel is reduced by 33% compared to patients receiving albumin-bound paclitaxel alone. Patients receiving intermittent Ruilakolan treatment had a median OS of 13.9 months (95% CI [11.1, 18.4 ]), whereas patients receiving albumin-binding-paclitaxel treatment alone had a median OS of 12.2 months (95% CI [7.7, 15.3 ]). Continuous Ruilakolan+Albumin binding-paclitaxel control received only Albumin binding-paclitaxel with HR of 0.85 (95% CI [0.56,1.29], P=0.447) (median OS of continuous Ruilakolan+Albumin binding-paclitaxel group 11.3 (95% CI [7.5, 16.4 ]) months).

One rule out subgroup analysis of primary platinum refractory patients (7 from intermittent relocatable plus albumin-bound paclitaxel group, 1 from comparison group) and patients who had previously received 4 or more previous treatment lines, the results of which showed statistically significant improvement in OS with 0.52 HR (95% ci [0.37,0.91], p=0.010) compared to albumin-bound paclitaxel alone, indicating a 48% reduction in risk of mortality compared to patients who received albumin-bound paclitaxel alone. These overall survival results indicate that intermittent administration of relocatable with albumin-bound paclitaxel provides greater therapeutic benefit than administration of albumin-bound paclitaxel alone. In addition to the improvements in PFS and DoR observed in the primary assays, OS assays also demonstrated that intermittent rella-kalant + albumin-binding-paclitaxel had survival benefits compared to albumin-binding-paclitaxel alone, especially for non-primary platinum refractory patients.

Fig. 7A lists a comparative table of Progression Free Survival (PFS), objective Remission Rate (ORR), duration of remission (DoR), and total survival (OS) observed in three groups of patients at an initial expiration date of day 22 of 3 of 2021 during the study. Patients that did not respond to first-line platinum-based therapy prior to the study were considered "primary platinum refractory" patients; the prognosis of these patients is particularly poor. PFS, ORR, doR and OS for all 178 patients in the study were calculated (overall "column), as well as 167 patients who were not" primary platinum refractory "patients (primary platinum refractory excision" column)). Both analyses showed that intermittent administration of relocatable over the course of taxane therapy significantly improved PFS and DoR compared to taxane therapy alone. Patients receiving intermittent relocatable had significantly improved OS compared to patients receiving albumin-binding-paclitaxel alone; as shown in fig. 6 and 7B, the improvement in OS was statistically significant in the patient group excluding primary platinum refractory patients (e.g., HR in patients receiving intermittent relocatable treatment compared to patients receiving albumin-paclitaxel alone).

Thus, as described above, as shown in FIG. 7A (initial analysis of data up to day 22 of 3, 2021, initial expiration date), the progression free survival of the high dose intermittent treatment group women was significantly improved (median PFS:5.6 months versus 3.8 months, risk ratio: 0.66; P value: < 0.05) relative to the comparative group, and the duration of remission (DoR) was also statistically significantly improved (median DoR:5.6 months versus 3.7 months, risk ratio: 0.36; P value: 0.006) relative to the comparative group.

Figure 7B lists Progression Free Survival (PFS), duration of remission (DoR), and total survival (OS) data for a subset of patients without primary platinum refractory disease and who have received 1-3 prior treatment lines. In this subgroup, a significant improvement in PFS, doR and OS compared to albumin binding-paclitaxel monotherapy was observed. Patients with primary platinum refractory disease and patients who received more than 3 prior treatment lines have particularly poor prognosis, and are usually excluded from clinical trials. The random proportion of primary platinum refractory disease patients in the intermittent rella-administrable group was higher (n=11 to n=1) compared to albumin-binding-paclitaxel monotherapy. The date of expiration of the final OS analysis was 2022, 3 months and 7 days. This later expiration date is determined based on predetermined criteria for reaching 120 OS "events" in the study. The updated OS results (updated compared to the data shown in fig. 7A), which is also shown in fig. 6A, show that the median OS for patients receiving albumin-binding-paclitaxel and intermittent relocatable treatment was 13.9 months, while the median OS for patients receiving albumin-binding-paclitaxel alone was 12.2 months. Intermittent administration of melagatran-binding-paclitaxel resulted in an improvement in OS (HR 0.67; p=0.066) and a 33% reduction in mortality risk compared to patients treated with albumin-binding-paclitaxel alone. As shown in fig. 7C, which shows the subgroup results obtained by excluding primary platinum refractory patients and patients who had previously received four or more previous treatment lines, patients receiving intermittent administration of relocatable albumin-binding-paclitaxel treatment had a significantly improved OS-mortality risk reduced by 48% (HR 0.52; p=0.010) compared to patients treated with albumin-binding-paclitaxel alone.

Analysis of the other subgroups (patients previously receiving/not receiving bevacizumab) found that intermittent relocatable + albumin binding-paclitaxel PFS, OS and DoR improved in patients previously receiving bevacizumab compared to patients treated with albumin binding-paclitaxel alone, while Objective Remission Rates (ORR) were similar for all groups. 178 women with recurrent, platinum-resistant/refractory ovarian cancer, primary peritoneal, fallopian tube or ovarian cancer sarcoma and receiving +.4 prior treatment line chemotherapies participated in this phase 2, open-label, randomized study of Ruilakolan + albumin binding-paclitaxel versus albumin binding-paclitaxel alone (NCT 03776812), with 105 patients previously receiving bevacizumab treatment and 73 patients not previously receiving bevacizumab treatment. The following table sets forth data for this subset of patients receiving albumin binding-paclitaxel (80 mg/m ²) +intermittent rella-cola (150 milligrams each time (once a day) one day before, one day and one day after administration of albumin binding-paclitaxel)) or treatment with albumin binding-paclitaxel (100 mg/m ²) alone. The baseline characteristics of the two groups are substantially balanced. Patients who have not previously received bevacizumab treatment are balanced throughout north america and europe, with 70% of patients who have previously received bevacizumab treatment coming from europe.

Watch (watch)

/>

¹ Initial analysis data expiration date: 2021, 3, 22; is applied to PFS and DoR.

² The P value is the nominal value, and no multiplex adjustment is applied.

³ The expiration date of the final (OS) analysis was 2022, 3, 7.

* Comparison of intermittent Ruilakolan+Albumin binding-paclitaxel and Albumin binding-paclitaxel alone

"RELA" refers to Ruilakolan; "NP" refers to albumin binding-paclitaxel, "mo" refers to month, and "NR" refers to unreachable.

In this subgroup analysis, patients previously treated with bevacizumab had better OS (risk ratio 0.47; p-value 0.03; median 17.9 months versus 12.6 months), PFS (risk ratio 0.44; p-value 0.005; median 7.2 months versus 3.7 months) and DoR (risk ratio 0.25; p-value 0.006; median 5.6 months versus 3.4 months) than the albumin-binding-paclitaxel alone (control). Although ORR is highest in the intermittent rella-kalant + albumin binding-paclitaxel group, ORR is similar between all groups. Intermittent relocatable + albumin binding-paclitaxel treatment also resulted in improved PFS values compared to albumin binding-paclitaxel treatment alone for patients not previously using bevacizumab.

Fig. 7D lists Progression Free Survival (PFS), duration of remission (DoR), and total survival (OS) data for the following patient subgroups further specified: a) no primary platinum refractory disease, b) 1-3 previous treatment lines have been received, and c) previous treatment lines include previous bevacizumab treatment. In this subgroup, greater improvements were observed for PFS, doR, and OS than were observed in the other subgroup analyses (e.g., comparing the group in fig. 7B that did not require prior use of bevacizumab). For example, the graphs shown in FIGS. 4B and 6B also illustrate these results.

This improvement in OS, PFS and DoR is very significant, which is believed to be the first treatment regimen for recurrent platinum resistance with a significant improvement in the overall survival of patients with recurrent platinum resistant ovarian cancer. The safety and tolerability of the melagatran albumin binding-paclitaxel therapy is comparable to that of albumin binding-paclitaxel monotherapy.

Whether in intermittent or continuous groups, the Ruilakolan treatment is safe and well tolerated by the patient. Safety and tolerability were comparable between groups, with neutropenia being the most common grade 3 or more adverse event. The safety and tolerability of the three treatment regimens are shown in figure 8 (data cut off at 2021, month 3, 22). The incidence of severe (. Gtoreq.3 grade) peripheral neuropathy was lower in the intermittent group than in the comparative group. According to the study protocol, all patients receiving melagatran and albumin-bound paclitaxel received prophylactic Granulocyte Colony Stimulating Factor (GCSF), a treatment that reduced the risk of neutropenia, whereas patients receiving albumin-bound paclitaxel monotherapy were given G-CSF according to standard practices of clinical researchers (therapists).

MRNA expression levels of selected targets in some patients were also measured. Such assays also demonstrate that some glucocorticoid receptor target genes are inhibited by the treatment with rella-cola and albumin binding-paclitaxel. A set of 239 genes induced by the glucocorticoid prednisone was analyzed in whole blood samples obtained from some patients. In patients receiving rella-kalant + albumin binding-paclitaxel 221 of these genes were inhibited (change from baseline to 15 days of cycle 1), whereas these genes were relatively unchanged when albumin binding-paclitaxel was used alone (fig. 9B). For example, mRNA expression of one of the classical glucocorticoid response genes, serum involved in cell survival and glucocorticoid regulated kinase (SGK 1) was measured. The left side of fig. 9C shows SGKl expression changes (error bars expressed in median and quartile range) from baseline to day 15 of cycle 1 in whole blood samples. As shown in FIG. 9C, the level of SGK 1-encoding mRNA in whole blood samples of patients receiving both Ruilakolan and Albumin-paclitaxel was reduced (P < 0.0089) compared to SGK1 mRNA in whole blood samples of patients receiving Albumin-paclitaxel alone. Ruilakolan+albumin binding-paclitaxel inhibited SGK1 expression, whereas SGK1 gene expression was not inhibited in patients receiving albumin binding-paclitaxel alone. Of 239 genes previously shown as GR target genes, 221 were inhibited following rela+np treatment. The number of GR target genes inhibited by NP was significantly reduced (P < 0.00001). GR target genes that are inhibited by relocatable+albumin binding-paclitaxel but not by albumin binding-paclitaxel alone include SGK1 (p=0.0089), GSK3B (p=0.0045), and PIK3CG (p=0.0175).

In this study, 137 pretreatment samples obtained from patient tumors were subjected to profiling analysis of 444 gene expression. The expression (mRNA) levels of all genes in the sample are indicated by circles in the left part of FIG. 9D. The right part of FIG. 9D shows the expression of NR3C1 (the gene encoding the glucocorticoid receptor) in each tumor. The median expression level of each of the 444 genes was first determined. The median of NR3C1 falls at the 83 th percentile of the 444 median distributions. Thus, the glucocorticoid receptor encoding mRNA (NR 3C 1) was found to be expressed higher in ovarian cancer tumors compared to mRNA expression of all genes in patients (fig. 9D).

Figure 9B presents a comparison of mRNA levels encoding glucocorticoid receptor in ovarian cancer patients receiving albumin-binding paclitaxel alone versus ovarian cancer patients receiving both relocatable and albumin-binding paclitaxel. In our phase 2 study, GR expression was observed in 96% of the evaluable ovarian tumors. In the group treated with albumin binding-paclitaxel alone, high expression of GR was associated with adverse reactions. In contrast, high expression of GR is associated with partial or complete remission of both groups of rella-cola + albumin binding-paclitaxel. For high GR patients, the partial or complete remission rate of the relocatable+albumin binding-paclitaxel treatment group was doubled compared to the albumin binding-paclitaxel alone treatment group.

In summary, this example describes a first example of a relocatable + albumin binding-paclitaxel randomized control phase 2 trial performed in ovarian cancer and other cancer patients. Subjects included platinum-resistant and refractory patients who had previously received up to 5 prior treatment lines. In these populations receiving a significant number of pretreatments, significant benefits were observed. The benefits of intermittent relocatable + albumin binding-paclitaxel treatment, including improved PFS and DoR, and a trend to improve OS, were observed in the entire study population compared to albumin binding-paclitaxel monotherapy. In a subgroup analysis, a greater improvement in PFS, OS and DoR was observed for intermittent rella-kalant + albumin binding-paclitaxel, especially in female patients without primary platinum refractory disease and who previously received +.3 prior treatment lines (including prior bevacizumab). PFS and DoR were significantly improved in patients treated with intermittent relocatable + albumin binding-paclitaxel compared to patients treated with albumin binding-paclitaxel alone. Notably, the median overall survival of patients receiving intermittent relocatable was improved compared to patients receiving albumin-binding-paclitaxel alone; this OS improvement was very significant for the non-primary platinum refractory patient group. The safety of intermittent rella-kalant + albumin binding-paclitaxel was comparable to that of albumin binding-paclitaxel alone. Thus, these results demonstrate that intermittent administration of relocatable with albumin-binding paclitaxel unexpectedly provides greater therapeutic benefit than administration of albumin-binding paclitaxel alone.

Example 2 planned phase III clinical trial comparing intermittent Ruilakolan to Albumin binding-paclitaxel to previous treatment methods

In view of the promising results indicating an extended total survival (OS), an extended Progression Free Survival (PFS), an extended duration of remission (DoR), without significant changes in safety and patient tolerance to treatment, applicants have proposed a planned phase III clinical study to confirm and extend the positive clinical outcome of this predictive example.

As shown in fig. 10A, the clinical trial recruited 360 patients with high grade serous epithelial cancer (grade 3), high grade (grade 3) endometrial-like cancer, carcinoma sarcoma with an endometrial-like epithelial tumor composition of 30% or more, ovarian cancer, primary peritoneal cancer, or fallopian tube cancer, and the last dose of platinum-based treatment with disease progression 6 months or less. Women who have recurrent ovarian, primary peritoneal, or fallopian tube cancer after at least one treatment and are resistant to platinum-based chemotherapy, include the following histological subtypes: high grade (grade 3) serous epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer; high grade (grade 3) endometrial cancer; and carcinoma sarcoma with endometrium-like epithelial tumor content of 30% or more. These criteria are expected to exclude primary platinum refractory patients from the study. The patient is treated according to an experimental intermittent rella-cola administration regimen or according to one of four chemotherapy regimens selected by the physician. The primary endpoint of the measurement was Progression Free Survival (PFS) by blind independent center evaluation (BICR) according to RECIST v.1.1. Secondary efficacy endpoints include total survival (OS); according to RECIST v.1.1. PFS (performed by researchers), best Overall Relief (BOR); duration of remission (DoR) according to RECIST v.1.1; objective Remission Rate (ORR); clinical benefit rate according to RECIST v.1.1; and a comprehensive response according to RECIST v.1.1 and GCIG (international group for gynaecological cancers). Safety endpoints include patient safety, patient quality of life (QOL), ca-125 (a protein marker monitored in ovarian cancer patients), pharmacodynamics, and pharmacokinetics. The patient will be 1:1 is randomly divided into a) receiving intermittent administration of rella-directed to (oral 150 mg) and albumin binding-paclitaxel (80 mg/m ², 180 patients), wherein albumin binding-paclitaxel is administered on days 1, 8 and 15 of the 28 day cycle, and rella-directed on days 1,2 and 7-9, 14-16 and 28; or B) "the choice of the researcher", i.e. the patient, according to the direction of the attending physician, intravenous liposomal doxorubicin (40 mg/m ²) on day 1 of the 28 day cycle; paclitaxel (80 mg/m ²) was intravenously injected on days 1, 8, 15, and 22 of the 28 day cycle; intravenous albumin binding-paclitaxel (100 mg/m ²) on days 1, 8 and 15 of the 28 day cycle; or the physician may choose to intravenously administer topotecan (4 mg/m ²) on days 1, 8, and 15 of the 28 day cycle or to intravenously administer topotecan (1.25 mg/m ²) on days 1-5 of each 21 day cycle. Group B of the study is a comparative group of the study in which patients did not receive relocatable.

An example of such a clinical trial is shown in fig. 10B. According to the subgroup analysis disclosed herein, a random, control, double arm, open-label, multicenter phase 3 study of intermittent rella-kalant + albumin binding-paclitaxel and albumin binding-paclitaxel named ROSELLA has been initiated and is in progress (NCT 05257408). Specifically, the ROSELLA trial will recruit patients who had previously received bevacizumab. This study is expected to recruit about 360 patients with high grade serous, epithelial, ovarian, primary peritoneal or fallopian tube cancer who received systemic anti-cancer treatment with 1 to 3 previous treatment lines, one of which must be bevacizumab treatment. Furthermore, patients will develop disease progression less than or equal to 6 months after receiving the last dose of platinum-based therapy; however, primary platinum refractory patients will be excluded from the study.

The results of phase 3 clinical studies are expected to include significant improvements in OS, PFS, doR and other therapeutic metrics for group a) patients compared to group B patients who did not receive intermittent relocatable. No significant differences in safety and patient tolerance to treatment were expected for group a) (rella-kalant + albumin binding-paclitaxel) and group B) (albumin binding-paclitaxel alone).

Although the invention has been described in detail by way of illustration and example for the purpose of illustration, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

All patents, patent publications, patent applications, and publications cited in this specification are herein incorporated by reference in their entirety as if each individual publication or patent application were specifically and individually indicated to be incorporated by reference. Furthermore, although the invention has been described in detail by way of illustration and example for purposes of illustration, it will be readily apparent to those of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims.

Claims

1. A method of treating cancer, comprising:

Intermittently administering an effective amount of a Glucocorticoid Receptor Modulator (GRM) to a patient having a cancer, wherein the patient is in need of and is receiving a cancer chemotherapy treatment for the cancer, the treatment comprising administering the cancer chemotherapeutic according to a schedule of administration of the cancer chemotherapy that requires at least one day between days of administration of the cancer chemotherapeutic to the patient without administration of the cancer chemotherapeutic,

Wherein said intermittent administration comprises administering said GRM on the same day as said cancer chemotherapeutic is administered to the patient,

Thereby treating the cancer.

2. The method of 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 of claim 1, wherein the cancer is ovarian cancer.

4. The method of claim 1, wherein the cancer chemotherapeutic agent is a taxane.

5. The method of claim 4, wherein the cancer chemotherapeutic agent is a taxane selected from the group consisting of taxanes: paclitaxel, albumin binding-paclitaxel, docetaxel, lyocell, tesetaxel, cabazitaxel, and ostazol.

6. The method of claim 5, wherein the cancer chemotherapeutic agent is a taxane containing paclitaxel.

7. The method of claim 5, wherein the cancer chemotherapeutic agent is albumin binding-paclitaxel.

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

9. The method of any one of claims 1-7, wherein the GRM is also administered the day prior to the administration of the cancer chemotherapeutic agent to the patient.

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

11. The method of any one of claims 1 to 10, wherein the GRM is not administered for at least 4 days between days of administration of the GRM to the patient.

12. The method of any one of claims 1 to 11, wherein the cancer chemotherapy administration schedule comprises administration of the cancer chemotherapeutic on a first day and again on day 7 after the first day, without administration of the cancer chemotherapeutic on a day between the first day and a seventh day after the first day.

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

14. The method of claim 13, wherein the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy administration schedule, and then not administered to the patient one week after the last week of the three consecutive weeks.

15. The method of claim 13 or 14, wherein the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy administration schedule, then not administered to the patient one week after the last week of the three consecutive weeks, then repeating the weekly administration regimen for three more consecutive weeks.

16. The method of any one of claims 1 to 15, wherein the Glucocorticoid Receptor Modulator (GRM) is a non-steroidal GRM.

17. The method of any one of claims 1 to 16, wherein the Glucocorticoid Receptor Modulator (GRM) is a heteroaryl-ketone fused azadecalin GRM.

18. The method of any one of claims 1 to 17, wherein the Glucocorticoid Receptor Modulator (GRM) is a heteroaryl-ketone fused azanaphthalene compound (R) - (1- (4-fluorophenyl) -6- ((1-methyl-1H-pyrazol-4-yl) sulfonyl) -4,4a,5,6,7, 8-hexahydro-1H-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone ("relocalan") having the structure:

19. The method of any one of claims 1 to 18, wherein the patient receives administration of the GRM after administration of bevacizumab.

20. Use of a pharmaceutical composition for treating cancer, wherein the cancer treatment comprises intermittent administration of an effective amount of a Glucocorticoid Receptor Modulator (GRM) to a patient having cancer, wherein the patient is in need of and receiving a cancer chemotherapy treatment for the cancer, the treatment comprising administration of the cancer chemotherapeutic according to a schedule of administration of the cancer chemotherapy that requires at least one day between days of administration of the cancer chemotherapeutic to the patient without administration of the cancer chemotherapeutic,

The pharmaceutical composition comprises a pharmaceutically acceptable excipient and GRM.

21. The use of 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 of claim 20, wherein the cancer is ovarian cancer.

23. The use of claim 20, wherein the cancer chemotherapeutic agent is a taxane.

24. The use of claim 23, wherein the cancer chemotherapeutic agent is a taxane selected from the group consisting of: paclitaxel, albumin binding-paclitaxel, docetaxel, lyocell, tesetaxel, cabazitaxel, and ostazol.

25. The use of claim 24, wherein the cancer chemotherapeutic agent is a taxane containing paclitaxel.

26. The use of claim 24, wherein the cancer chemotherapeutic agent is albumin binding-paclitaxel.

27. The use of any one of claims 20 to 26, wherein the GRM is also administered the day after administration of the cancer chemotherapeutic agent to a patient.

28. The use of any one of claims 20 to 27, wherein the GRM is also administered the day prior to the administration of the cancer chemotherapeutic agent to the patient.

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

30. The use of any one of claims 20 to 29, wherein the GRM is not administered for at least 4 days between days of administration of the GRM to a patient.

31. The use of any one of claims 20 to 30, wherein the schedule of cancer chemotherapy administration comprises administration of the cancer chemotherapeutic on a first day and again on day 7 after the first day, without administration of the cancer chemotherapeutic on a day between the first day and a seventh day after the first day.

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

33. The use of claim 32, wherein the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy administration schedule, and then not administered to the patient one week after the last week of the three consecutive weeks.

34. The use of claim 32 or 33, wherein the cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to a cancer chemotherapy administration schedule, then not administered to the patient one week after the last week of the three consecutive weeks, then the weekly administration regimen is repeated for three more consecutive weeks.

35. The use of any one of claims 20 to 34, wherein the Glucocorticoid Receptor Modulator (GRM) is a non-steroidal GRM.

36. The use of any one of claims 20 to 35, wherein the GRM is a heteroaryl-ketone fused azadecalin GRM.

37. The use of any one of claims 20 to 36, wherein the GRM is a heteroaryl-ketone fused azanaphthalene compound (R) - (1- (4-fluorophenyl) -6- ((1-methyl-1H-pyrazol-4-yl) sulfonyl) -4,4a,5,6,7, 8-hexahydro-1H-pyrazolo [3,4-g ] isoquinolin-4 a-yl) (4- (trifluoromethyl) pyridin-2-yl) methanone ("relocatable") having the structure:

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