TWI794984B - Intermittent dosing of glucocorticoid receptor modulators for the treatment of ovarian and other cancers - Google Patents

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), which may be orally administered, along with a cancer chemotherapy agent to the patient. The GRM may be a non-steroidal compound, may have a heteroaryl ketone fused azadecalin structure, and may be relacorilant. Intermittent GRM administration includes GRM administration at intervals separated by at least one day without GRM administration, and includes regimens wherein the GRM is administered according to a schedule linked to the cancer chemotherapy schedule. The GRM may be administered the day of, or the day before, or the day after, chemotherapy administration, or combinations thereof, and/or on other days. For example, for a weekly chemotherapy regimen, the GRM may be administered the day before, the day of, and the day after such cancer chemotherapy agent administration.

Description

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

The present invention discloses methods and compositions for treating cancer such as ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer or peritoneal cancer. The methods comprise intermittently administering to a patient an orally administrable glucocorticoid receptor modulator (GRM), together with a cancer chemotherapeutic agent. The GRM can be a non-steroidal compound, can have a heteroaryl ketone-fused azadecalin structure, and can be relacorilant.

Glucocorticoid receptors ("GR") are present in nearly all body tissues. Cortisol, an endogenous hormone acting 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 unclear whether such effects promote or inhibit cancer growth. Although many tumor types express GR, and GR is highly expressed in some tumors (such as ovarian cancer tumors), the effect of modulating GR-mediated signaling pathways on cancer progression and cancer therapy is unclear, and GR-mediated signaling The importance of delivery pathways in cancer progression and cancer therapy has not been resolved.

Cancers such as ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer and vulvar cancer, and other cancers of female reproductive organs and tissues, and peritoneal cancers that affect women (peritoneal cancer rarely affects men) significant part. These and other cancers can be hormone sensitive.

Such cancers are often only diagnosed at an advanced stage. Treatment options are limited and the outlook for patients with these cancers is poor. Conventional treatment options for this type of cancer include surgery and chemotherapy (radiation therapy (also known as "radiotherapy") is rarely used in such patients). Although in some cases such cancers may be resectable at the time of diagnosis, most patients with these cancers are treated with chemotherapy, such as platinum-based chemotherapy. Chemotherapeutic agents generally rely on causing widespread damage to DNA and destabilization of chromosomal structure, which can reduce cancer cell proliferation, promote or induce tumor cell apoptosis, and can ultimately lead to the destruction of cancer cells.

For example, ovarian cancer can be a devastating disease. Although most ovarian cancer patients initially respond to chemotherapy (often platinum-based chemotherapy), the cancer has a high recurrence rate, with the majority of ovarian cancer patients relapsing (Kemp et al., 2013; about 80% within 18 months internal recurrence; Luvero 2019)). Unfortunately, chemotherapy response rates in such relapsed patients can be poor and may provide only short progression-free survival (Luvero et al., 2014). Overall survival after recurrence of less than one year is the norm for recurrent ovarian cancer.

Further therapy is limited to patients with platinum-resistant ovarian cancer; only a small proportion of such patients respond to standard chemotherapy treatment (Luvero et al., 2014). Further treatment options include surgery, chemotherapy, molecularly targeted agents (anti-angiogenic and PARP inhibitors), and radiation. (alone or in combination). Paclitaxel, liposomal doxorubicin, topotecan (as single agent or in combination with bevacizumab) for relapsed patients receiving primary therapy for recurrent platinum-resistant ovarian cancer combination), or the combination of gemcitabine and carboplatin is approved and is the most commonly used therapy in this setting (Luvero 2014, Pujade-Lauraine 2019). Chemotherapy plus bevacizumab has shown optimal results in patients who received fewer than two prior regimens, did not have refractory disease, and had no history of intestinal obstruction within six months of treatment (Pujade-Lauraine 2014). For patients with platinum-resistant ovarian cancer or those with refractory disease, the standard of care is limited to the continuous use of chemotherapy not previously administered. However, the results of such further chemotherapy options are generally poor.

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

Disclosed herein are novel methods for the treatment of cancer, and the use of glucocorticoid receptor modulator (GRM) compounds, such as non-steroidal GRMs, including heteroaryl-keto-fused azadecalin compounds, in the treatment of cancer Novel use.

Applicants disclose methods of treating cancer comprising intermittent administration of GRMs to cancer patients undergoing cancer chemotherapy. GRM can be administered orally. The methods include intermittently administering an effective amount of GRM to a patient suffering from cancer who needs and receives cancer chemotherapy treatment for the cancer; the cancer chemotherapy treatment includes administering a cancer chemotherapy agent according to a cancer chemotherapy administration schedule, the cancer chemotherapy The dosing schedule includes no administration of the cancer chemotherapeutic agent for at least one day between days of administration of the cancer chemotherapeutic agent. As disclosed herein, intermittent GRM administration comprises at least a first round of GRM administration and a second round of GRM administration, wherein the first and second rounds are separated by at least one day of no GRM administration. The first round of GRM administration can be administered on one day; or on two consecutive days; or on three consecutive days; or on more consecutive days. The second round of GRM administration can be administered on one day; or on two consecutive days; or on three consecutive days; or on more consecutive days. The first and second rounds do not necessarily have the same number of days.

Intermittent GRM administration to patients also receiving cancer chemotherapy can include administering the GRM on days coordinated with the administration schedule of the cancer chemotherapy. A round of GRM administration can be administered on a day that correlates with, or can be administered on, a day determined by the patient's cancer chemotherapy dosing schedule. For example, a round of GRM administration can be administered to the patient before, while (eg, on the same day), or after the patient receives a dose of a chemotherapeutic agent.

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

Applicants further disclose the use of GRMs for the treatment of cancer according to the methods disclosed herein. For example, such uses include the intermittent administration of GRM to a cancer patient administered a cancer chemotherapeutic agent over multiple days between days on which the cancer chemotherapeutic agent is administered to the patient on a dosing schedule that requires at least one day that the patient is not administered the cancer chemotherapeutic agent . Intermittent GRM administration to patients also receiving cancer chemotherapy can include administering the GRM on days coordinated with the administration schedule of the cancer chemotherapy. In an embodiment, intermittent GRM administration comprises administering the GRM on the same day that the patient is administered the cancer chemotherapeutic agent. Intermittent GRM administration can include administering the GRM on one or more days when the cancer chemotherapeutic agent is not being administered to the patient. Intermittent GRM administration can include administering the GRM on the same day that the patient is administered the cancer chemotherapeutic agent and on one or more days that the patient is not administered the cancer chemotherapeutic agent.

。瑞拉可蘭亦稱為CORT125134；其揭示為U.S. 8,859,774之實例18。 In an embodiment, 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; is incorporated herein by reference in its entirety) in the heteroaryl ketone-fused azadecalin structure. Heteroaryl-keto-fused azadecalin GRM can be rilacoran, which is (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole -4-yl)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(tri Fluoromethyl)pyridin-2-yl)methanone ("Ryraclan"), which has the following structure:

. Rilacoran is also known as CORT125134; it is disclosed as Example 18 of US 8,859,774.

Cancer chemotherapeutic agents include chemotoxic compounds and formulations that are generally toxic to cancer cells (and often non-cancer cells as well), anti-proliferative agents, anti-metastatic agents, antibodies, and agents that inhibit, stop or reverse the growth or Diffusion of other agents and treatments. The cancer chemotherapeutic agent may be a taxane such as paclitaxel or nab-paclitaxel.

Cancers treatable 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 relate to ovarian cancer, including platinum-resistant ovarian cancer. In embodiments, the novel methods relate to cervical cancer. In embodiments, the novel methods relate to uterine cancer. In embodiments, the novel methods relate to fallopian tube cancer. In an embodiment, the novel method for treating cancer relates to peritoneal cancer.

Novel and surprising methods of treatment and uses disclosed herein are believed to be for patients with peritoneal cancer or cancers of the female reproductive organs and tissues including, for example, ovarian, fallopian tube, uterine, cervix, vagina, and vulvar cancers improved and effective treatment for cancer patients. For example, Applicants disclose herein that cancer patients with platinum-resistant ovarian or other cancers treated with nanoparticulate nab-paclitaxel chemotherapy alone, and treated with continuous, daily rilakoran Treatment of cancer patients with platinum-resistant ovarian or other cancers who received nab-paclitaxel chemotherapy concomitantly with platinum-resistant nab-paclitaxel chemotherapy treated intermittently with nab-paclitaxel Cancer patients with ovarian cancer and other cancers experience increased disease progression-free survival and improved duration of response.

As mentioned above, for cancers (including platinum-resistant cancers such as ovarian cancer, cervical cancer, vaginal cancer, vulvar cancer, fallopian tube cancer, uterine cancer and other tumors of female reproductive organs and tissues) and for peritoneal cancer There is a great previously unmet need for effective, well-tolerated treatments. The present methods and uses are believed to provide improved treatment of cancers such as peritoneal cancer and cancers of the female reproductive organs and tissues.

Applicants have surprisingly found that intermittent administration of a glucocorticoid receptor modulator (GRM) in combination with cancer chemotherapy provides cancer patients with greater benefit than chemotherapy alone or than continuous administration of GRM and chemotherapy. Intermittent GRM administration plus taxane provides greater benefit to cancer patients than taxane therapy alone and provides greater benefit to cancer patients than taxane therapy with continuous GRM administration. For example, Applicants have surprisingly found that intermittent administration of the non-steroidal GRM rilacoran and taxane compared to treatment with taxane alone, or compared to continuous administration of rilacoran and taxane Combinations of alkane chemotherapy (such as nanoparticulate nab-paclitaxel) provided 28 greater benefits (such as increased progression-free survival) for cancer patients. For example, as disclosed herein, rilacoclan was administered intermittently the day before, the day of, and the day after weekly administration of nanoparticulate nab-paclitaxel (as demonstrated in the Examples herein, for three consecutive weeks in a four-week cycle). and over multiple cycles thereof) provides greater benefit to cancer patients than similar nanoparticulate nab-paclitaxel treatment without risaclan. Such greater benefits include providing improved progression-free survival, improved duration of response, and other benefits in patients with ovarian, fallopian tube, peritoneal, and other cancers.

This surprising result differs from previous results, indicating that continued administration of rilacoran in combination with nanoparticulate nab-paclitaxel may provide benefit. A phase 1 study of risaclan + nab-paclitaxel demonstrated clinical activity in patients with metastatic PDAC, ovarian cancer, and other solid tumors. Combination of rilacoran + nab-paclitaxel provided longer duration of benefit compared with prior nab-paclitaxel monotherapy, resulting in ovarian cancer, fallopian tube cancer, and primary sustainable disease control in patients with recurrent peritoneal carcinoma (Munster et al., 2019). Applicants disclose herein that intermittent GRM administration with taxane chemotherapy surprisingly provides additional benefit.

The methods and uses disclosed herein comprise intermittently administering to a subject a GRM in an amount effective to treat cancer in the subject. In an embodiment, the GRM is a selective glucocorticoid receptor modulator (SGRM). In embodiments, the methods disclosed herein comprise intermittently administering to a subject a non-steroidal GRM in an amount effective to treat cancer in the subject (wherein "non-steroidal" means that the GRM does not contain a steroidal structure).

。 瑞拉可蘭揭示於美國專利8,859,774之實例18中；其亦稱為CORT125134。瑞拉可蘭係不會顯著影響黃體酮、礦物皮質激素、雄激素或雌激素受體之GRM。因此，瑞拉可蘭係SGRM。在實施例中，瑞拉可蘭係經口服投與。 In embodiments, GRM is a non-steroidal compound comprising a heteroaryl ketone-fused azadecalin structure as described and disclosed in U.S. Patent No. 8,859,774 . In an embodiment, the GRM is a heteroaryl ketone-fused azadecalin compound disclosed in US Pat. No. 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, GRM is a heteroaryl ketone fused azadecalin compound (R)-(1-(4-fluorophenyl)-6-((1-methyl-1H-pyrazole-4- base)sulfonyl)-4,4a,5,6,7,8-hexahydro-1H-pyrazolo[3,4-g]isoquinolin-4a-yl)(4-(trifluoromethyl ) pyridin-2-yl)methanone ("Rilaclan"), which has the following structure:

. Rilacoran is disclosed in Example 18 of US Patent 8,859,774; it is also known as CORT125134. Rilacoran did not significantly affect the GRM of progesterone, mineralocorticoid, androgen, or estrogen receptors. Therefore, Rila Kelan is an SGRM. In an embodiment, rilakoran is administered orally.

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

In embodiments of the methods and uses disclosed herein, intermittent administration comprises administering an effective amount of a GRM, such as a non-steroidal GRM, e.g., rilacoran, on two consecutive days, waiting for a period of time ("interval"), and then continuously An effective amount of GRM is re-administered on two days; the interval can be, for example, one week, two weeks, three weeks, four weeks or longer. The interval may be two days 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, the intermittent administration comprises administering an effective amount of a GRM, such as a non-steroidal GRM, e.g., relackolan, on three consecutive days, waiting an interval, and then administering the effective amount again on three consecutive days GRM; the interval can be, for example, one week, two weeks, three weeks, four weeks or longer. In embodiments of the methods disclosed herein, the intermittent administration comprises administering an effective amount of GRM once a week, or once every two weeks, or once a month, or twice a month, or three times a month, Such as non-steroidal GRMs such as Rilacoran. In embodiments of the methods disclosed herein, intermittent administration comprises administering on alternate days an effective amount of a GRM, such as a non-steroidal GRM, eg, rilacoclan.

For example, intermittent administration of a GRM such as a heteroaryl-keto-fused azadecalin GRM can include administration on days when a cancer chemotherapeutic agent is administered to the patient. Intermittent administration of a GRM, such as a heteroaryl-keto-fused azadecalin GRM, can further include administration the day before the patient is administered the cancer chemotherapeutic agent; or the day after the patient is administered the cancer chemotherapeutic agent administering; and may comprise administering the non-steroidal GRM the day before, on the day, and the day after administering the cancer chemotherapeutic agent to the patient. Intermittent administration of the heteroaryl-keto-fused azadecalin GRM can comprise administration of the heteroaryl-keto-fused azadecalin GRM separated by at least 4 days, wherein the heteroaryl-ketone is not administered Fused azadecalin GRM.

The novel methods and uses disclosed herein can be used to treat cancer patients who are also receiving cancer chemotherapy. In embodiments of the methods disclosed herein, the intermittent administration of a GRM, such as a non-steroidal GRM, eg, relaccolan, can be timed according to the schedule for administering cancer chemotherapeutic agents to the patient. For example, the GRM can be administered the day before, the day, or the day after the cancer chemotherapeutic agent is administered to the patient. The GRM can be administered on the basis of two or more of the day before, the day, or the day after the patient is administered the cancer chemotherapeutic agent. In embodiments of the methods and uses disclosed herein, intermittent GRM administration comprises administering an effective amount of a GRM, such as a non-steroidal GRM, e. orchid. The cancer chemotherapeutic agent may be, for example, a taxane, such as paclitaxel or nab-paclitaxel.

In embodiments of the methods disclosed herein, the intermittent administration comprises administering an effective amount of a GRM, such as a non-steroidal GRM, e.g., relakolan, the day before the patient is administered a cancer chemotherapeutic agent; the cancer chemotherapeutic agent may be For example taxanes such as paclitaxel or nanoparticulate nab-paclitaxel. In embodiments of the methods disclosed herein, intermittent administration comprises administering an effective amount of a GRM, such as a non-steroidal GRM, e.g., relackolan, on the day the patient is administered the cancer chemotherapeutic agent; the cancer chemotherapeutic agent may be, for example, Taxanes such as paclitaxel or nanoparticulate nab-paclitaxel. In embodiments of the methods disclosed herein, the intermittent administration comprises administering an effective amount of a GRM, such as a non-steroidal GRM, e.g., relakolan, one day after administration of the cancer chemotherapeutic agent to the patient; the cancer chemotherapeutic agent may be For example taxanes such as paclitaxel or nanoparticulate nab-paclitaxel.

Novel methods and uses disclosed herein involving intermittent administration of GRMs, such as non-steroidal GRMs, can be used to treat patients suffering from ovarian, fallopian tube, uterine, cervical, vaginal, vulvar, peritoneal, or other cancers . Combination of such intermittent administration of an effective amount of a GRM such as a non-steroidal GRM, for example relackolan, with cancer chemotherapy is effective in treating cancer. Pharmaceutical compositions for use as disclosed herein may contain a non-steroidal GRM compound comprising a heteroaryl ketone-fused azadecalin structure, such as, for example, rilacoran.

GRMs, such as non-steroidal GRMs, can be administered orally. In an embodiment, rilacoran is administered orally. In some instances, GRMs, such as non-steroidal GRMs, are administered by injection, infusion, or by other means.

In some instances, the effective amount of a GRM is a dose of between 1 and 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, 50, 60, 70, 80, 90, or 100 mg/kg /sky. In some instances, the GRM is administered according to an intermittent administration regimen for at least 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, 12 weeks , 13 weeks, 14 weeks, 15 weeks, 16 weeks, 17 weeks, 18 weeks, 19 weeks, 20 weeks, 25 weeks, 30 weeks, 35 weeks, 40 weeks, 45 weeks, 50 weeks, 55 weeks, 60 weeks, 65 weeks weeks, 70 weeks, 75 weeks or 80 weeks.

The chemotherapeutic agent may be any chemotherapeutic agent suitable for the treatment of cancer, for example any chemotherapeutic agent suitable for the treatment of ovarian, fallopian tube, uterine, cervical, vaginal, vulvar or peritoneal cancer. Chemotherapeutic agents can be, for example, chemotoxic compounds, antiproliferative agents, antimetastatic agents, antibodies, or other agents or treatments that inhibit, stop, or reverse the growth or spread of cancer. In embodiments of the methods and uses disclosed herein, the cancer chemotherapeutic agent may be a taxane. The taxane can be, for example, paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tesetaxel, cabazitaxel, or otata Race (ortataxel). In an embodiment, the cancer chemotherapeutic agent is a taxane containing paclitaxel (eg, nanoparticulate nab-paclitaxel).

Therefore, the applicant herein discloses a method of treating cancer, the method comprising: intermittently administering an effective amount of GRM to a patient suffering from cancer, wherein the patient needs and is receiving cancer chemotherapy for the cancer, the treatment comprising according to Administering a cancer chemotherapeutic agent on a cancer chemotherapeutic dosing schedule that requires no administration of a cancer chemotherapeutic agent for at least one day between days when the cancer chemotherapeutic agent is administered to the patient, wherein the intermittent administration includes administration of the cancer chemotherapeutic agent to the patient The GRM is administered on the same day as the chemotherapeutic agent, thereby treating the cancer. In an embodiment, the GRM is a non-steroidal GRM, such as a heteroaryl-keto-fused azadecalin GRM, eg, relaccolan.

In embodiments of the methods disclosed herein, the GRM is also administered the day after the cancer chemotherapeutic agent is administered to the patient. In embodiments of the methods disclosed herein, the GRM is also administered the day before the cancer chemotherapeutic agent is administered to the patient. In embodiments of the methods disclosed herein, the GRM is administered the day before, the day, and the day after the cancer chemotherapeutic agent is administered to the patient. In an embodiment, the GRM is a non-steroidal GRM, such as a heteroaryl-keto-fused azadecalin GRM, eg, relaccolan.

Applicants also disclose herein a GRM, such as a non-steroidal GRM, such as a heteroaryl-keto-fused azadecalin GRM (e.g., rilacoran) in any of the methods disclosed herein for use in the treatment of cancer use. Such uses include the use of such GRMs in the manufacture of medicaments for the treatment of cancer according to the methods disclosed herein. In embodiments of the methods and uses disclosed herein, the cancer chemotherapy dosing schedule includes administering the cancer chemotherapy agent on the first day, and subsequent days after the first day after an interval of at least one day (i.e., not The second day after the first day) the cancer chemotherapeutic agent is administered again, and the cancer chemotherapeutic agent is not administered 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 cancer chemotherapy dosing schedule includes the cancer chemotherapy agent on the first day, and the cancer chemotherapy agent is administered again on a day seven days after the first day, and the cancer chemotherapy agent is administered again on the first day. The cancer chemotherapeutic agent is not administered on days between one day and the day seven days after the first day.

In other embodiments of the methods disclosed herein, the cancer chemotherapy agent is administered to the patient for three consecutive weeks according to the cancer chemotherapy dosing schedule. In yet other embodiments of the methods disclosed herein, the cancer chemotherapeutic agent is administered to the patient according to the cancer chemotherapy dosing schedule for three consecutive weeks, and then not administered one week after the three consecutive weeks. In an embodiment, the cancer chemotherapy agent is administered to the patient according to the cancer chemotherapy dosing schedule for three consecutive weeks, and then the week after the last week of the three consecutive weeks is not administered, and 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-keto-fused azadecalin GRM, to a patient suffering from cancer, wherein the patient needs and is receiving cancer chemotherapy treatment for the cancer that includes administration of a cancer chemotherapy agent according to a cancer chemotherapy dosing schedule that requires at least one day without administration of the cancer chemotherapy agent between the days when the cancer chemotherapy agent is administered to the patient A cancer chemotherapeutic agent, wherein the intermittent administration comprises administering the GRM on the same day that the patient is administered the cancer chemotherapeutic agent, the pharmaceutical composition comprising a pharmaceutically acceptable excipient and a GRM (such as a heteroaryl-ketone Azadecalin GRMs, such as Rilacoran).

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 an embodiment, the cancer is ovarian cancer. In an embodiment, the cancer is fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer, vulvar cancer or peritoneal cancer. In an embodiment, the cancer is platinum resistant ovarian cancer. In an embodiment, the cancer is platinum resistant fallopian tube, uterus, cervix, vagina, vulva or peritoneum. In an embodiment of the uses disclosed herein, the cancer chemotherapeutic agent may be a taxane. In an embodiment of the use, the taxane can be, for example, paclitaxel, nab-paclitaxel, docetaxel, larotaxel, tercetaxel, cabazitaxel, or otatataxel. In an embodiment, the cancer chemotherapeutic agent is a taxane containing paclitaxel (eg, nanoparticulate nab-paclitaxel).

In embodiments of the uses disclosed herein, a GRM such as a non-steroidal GRM, eg, a heteroaryl-keto-fused azadecalin GRM, is also administered one day after administration of the cancer chemotherapeutic agent to the patient. In an embodiment of the uses disclosed herein, the heteroaryl-keto-fused azadecalin GRM is also administered the day before the cancer chemotherapeutic agent is administered to the patient. In embodiments of the uses disclosed herein, the heteroaryl-keto-fused azadecalin GRM is administered the day before, the day, and the day after administration of the cancer chemotherapeutic agent to the patient.

In an embodiment of the uses disclosed herein, the cancer chemotherapy dosing schedule includes the cancer chemotherapy agent on Day 1, and again administering the cancer chemotherapy agent on a day that is seven days after the first day, between Days 1 to 10. The cancer chemotherapeutic agent is not administered on days between the days seven days after the first day.

In other embodiments of the uses disclosed herein, the cancer chemotherapy agent is administered to the patient for three consecutive weeks according to the cancer chemotherapy dosing schedule. In yet other embodiments of the uses disclosed herein, the cancer chemotherapeutic agent is administered to the patient according to the cancer chemotherapy dosing schedule for three consecutive weeks, and then not administered one week after the last week of the three consecutive weeks. In an embodiment of the uses disclosed herein, the cancer chemotherapeutic agent is administered to the patient according to the cancer chemotherapy dosing schedule for three consecutive weeks, and then the week following the last week of the three consecutive weeks is not administered, and then another three consecutive weeks This weekly dosing regimen is repeated. B. Definition

As used herein, the term "tumor" and the term "cancer" are used interchangeably and both refer to abnormal growth of tissue resulting from excessive cell division. A tumor that invades surrounding tissue and/or can metastasize is called "malignant."

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

As used herein, the terms "overall survival" and "overall survival rate" refer to the number or percentage of patients in a treatment group who are alive for a specified period of time after initiation of treatment or are alive at a selected point in time.

As used herein, the term "progression-free survival" ("PFS") refers to the length of time during and after the initiation of treatment during which the cancer does not get worse (does not "progress", e.g., the size of the tumor does not significantly increase grow or not transfer). Disease progression free survival is an indication of how effective the treatment is.

As used herein, the terms "response" and "response rate" refer to improvement associated with treatment, or slowing or cessation of disease progression. For example, a patient who exhibits an improvement during or after treatment, such as a decrease in severity of symptoms, slowing or cessation of tumor growth, improved quality of life, or other improvement, is said to respond to treatment.

As used herein, the terms "objective response" and "objective response rate" (ORR) refer to a measurable response, ie, a measurable improvement associated with treatment. ORR is defined as the proportion of patients whose tumor size is reduced by a predetermined amount for a minimum period of time; see the Response Evaluation Criteria in Solid Tumors ("RECIST") Guidelines, Version 1.1 (available via the World Wide Web at URL: ctep .cancer.gov/protocolDevelopment/docs/recist_guideline.pdf).

As used herein, the term "duration of response" refers to the length of time a patient experiences improvement associated with treatment.

As used herein, the terms "partial response" and "partial response" (PR) refer to at least a 30% reduction in the sum of diameters (SOD) of target lesions, taking as reference the baseline SOD that responded 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 evidence of tumor. CR is generally determined by imaging studies (eg, CT scan) or by histopathological evaluation (eg, bone marrow biopsy or breast cancer resection samples).

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

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

As used herein, the term "platinum refractory" refers to cancers that do not respond to treatment with anticancer drugs that contain the metal platinum, such as cisplatin and carboplatin. Disease progression or relapse shortly after prior platinum-based therapy is indicative of non-response to treatment. "Primary platinum-refractory" patients who do not respond to the first treatment with a platinum-based cancer therapy; other patients may initially respond to a platinum-based cancer therapy but fail to respond to other platinum-based cancer therapies when the cancer recurs reaction. Platinum refractory patients are a subgroup of platinum resistant patients.

As used herein, the term "hazard ratio" (HR) refers to the period of patient survival at any point in time in the group of patients given a particular treatment compared to the period of patient survival in a control group given another treatment or a placebo measure. Patient survival can be determined, for example, as disease progression-free survival or other measures of survival. A hazard ratio of 1 means that there is no difference in survival between the two groups. A hazard ratio greater than 1 or less than 1 means that survival is better in one of the groups. More generally, hazard ratio refers to a measure that determines how often a particular event occurs in one group compared to another group over time.

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

As used herein, the terms "cancer chemotherapeutic", "cancer chemotherapeutic agent", "cancer therapeutic", "cancer chemotherapeutic agent" and "chemotherapeutic agent" refer to Compounds and compositions for treating cancer. Cancer chemotherapeutic agents and treatments with such agents include antibody therapy, toxic or antitoxic compounds and formulations that are generally toxic to cancer cells (and often non-cancer cells), anti-proliferative agents (reducing cancer cell growth or replication), anti- Agents that metastasize (reduce metastasis), and other agents and treatments that inhibit, stop or reverse the growth or spread of cancer in cancer patients.

Cancer chemotherapeutic agents include, but are not limited to, doxorubicin, vincristine, cyclophosphamide, fluorouracils such as 5-fluorouracil (5-FU), topotecan, interferons, platinum derivatives, Taxanes (such as paclitaxel, nanoparticulate nab-paclitaxel, docetaxel, ralotaxel, tercetaxel, cabazitaxel, and otatataxel), vinca alkaloids (such as vinblastine), anthracyclines (such as doxorubicin), epipodophyllotoxins (such as etoposide), cisplatin, methotrexate, actinomycin D, Dolastatin 10, colchicine, trimetrexate, metoprine, daunorubicin, teniposide, alkyl Antioxidants (such as chlorambucil), 5-fluorouracil, camptothecin and cisplatin, etc.

As used herein, the term "taxane" refers to a class of diterpene compounds having a taxene core. Many taxanes are useful as cancer chemotherapeutics, typically as mitotic inhibitors and antimicrotubule agents. Taxanes include paclitaxel (e.g., TAXOL (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ)), nanoparticle albumin-bound paclitaxel ( ^ABRAXANE® , "Abx"; an albumin-engineered nanoparticle formulation of paclitaxel , also known as nanoparticle nab-paclitaxel (American Pharmaceutical Partners, Schaumberg, Ill.)), TAXOTERE ^® (docetaxel, doxetaxel; Sanofi-Aventis), larotaxel, Tetrataxel Citax, Cabazitaxel and Ottataxa.

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

As used herein, the terms "PARP inhibitor" and "poly(ADP-ribose) polymerase inhibitor" refer to substances that inhibit or block the enzyme poly(ADP-ribose) polymerase (PARP). PARP inhibitors can be used in combination with other cancer chemotherapeutic agents. PARP is believed to be an important cellular tool for repairing DNA damage; one purpose of many cancer chemotherapy agents is to damage 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 unanticipated medical problems experienced by a patient during treatment with a drug or other therapy, including, for example, during treatment by an experimental treatment in a clinical trial. Adverse events can be mild, moderate, or severe, and can be caused by something other than the drug or therapy being given. Adverse events that can 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" in reference to clinical trials refer to the risk, amount or number of adverse events in a clinical trial (usually a clinical trial that compares the effects of a test treatment with the effects of a standard treatment). A new drug, treatment, or treatment that results in a reduced or similar number of adverse events, or observed adverse events of similar severity, compared with standard care in patients receiving the test treatment will be judged "safe" (where similar Meaning that the number of adverse events was significantly less than the number of adverse events associated with standard treatment).

As used herein, the terms "patient" and "individual" refer to a human being who is or will be or has been treated for a disease or condition.

As used herein, the term "effective amount" or "therapeutic amount" refers to an amount of an agent effective to treat, eliminate or alleviate at least one symptom of the disease being treated. In some instances, a "therapeutically effective amount" or "effective amount" may refer to the amount of a functional agent or pharmaceutical composition that can be used to exhibit a detectable therapeutic or inhibitory effect. This effect can be detected by any assay known in the art. An effective amount can be an amount effective to elicit an anti-tumor response. For the purposes of the present disclosure, an effective amount of a GRM or an effective amount of a chemotherapeutic agent is an amount that, when combined with a chemotherapeutic agent or a GRM, respectively, will produce the desired beneficial clinical outcome associated with amelioration of the cancer. Such desired beneficial clinical results can be, for example, slowing or cessation of tumor growth; reduction in tumor size or tumor burden; improvement in symptoms or comorbidities, or reduction in the number of adverse events, such as, for example, neutropenia, anemia , neuropathy, or fatigue; improvement in quality of life; or other improvement.

As used herein, the term "administer, administering, administered or administration" refers to providing a compound or composition (eg, as described herein) to an individual or patient. Administration can be by oral administration, ie, the subject receives the compound or composition by mouth, as a pill, capsule, liquid, or in other form suitable for oral administration. Oral administration can be buccal (where the compound or composition is held in the mouth, eg, under the tongue, where it is absorbed). Administration can be by injection, ie, delivery of a compound or composition via a needle, microneedle, pressure syringe, or other means that punctures the skin or forcibly transports the compound or composition through the skin of an individual. Injection can be intravenous (ie, into a vein); intraarterial (ie, into an artery); intraperitoneal (ie, into the peritoneum); intramuscular (ie, into a muscle); other routes of injection. Routes of administration can also include rectal, vaginal, transdermal, pulmonary (e.g., by inhalation), subcutaneous (e.g., by injection, or by absorption into the skin from an implant containing the compound or composition), or by other means.

The terms "determining", "measuring levels", "measuring the level" and similar terms refer to determining, detecting or quantifying the amount, level or concentration of a target analyte. A target analyte can be, for example, mRNA, or a hormone such as Cortisol or ACTH, or other target analyte in a sample obtained from an individual. A sample can be, for example, a blood sample. The content can be determined from a portion of the sample. For example, analyte levels can be determined in the plasma portion of a blood sample; in the serum portion of a blood sample; or, in embodiments, in whole blood.

As used herein, the term "sample" refers to a biological sample obtainable from a human individual. Such samples are typically removed from the individual and, when obtained, become completely separate from the individual (ie, are in vitro samples). A sample can be any cell, tissue or fluid sample obtained from a human individual. A sample can be, for example, a blood sample, saliva sample, urine sample, or other sample obtained from a patient. Samples may be subjected to various handling, storage or processing procedures prior to analysis according to the methods described herein. In general, the term "sample" or "samples" is not intended to be limited by its origin, origin, manner of acquisition, handling, processing, storage or analysis or any modification. Thus, in embodiments, the sample is an in vitro sample and can be analyzed using in vitro methods. The methods disclosed herein are in vitro methods when used with and removed from a sample obtained from a human individual.

As used herein, the term "AUC" means the area under the concentration-time curve and is used as a measure for determining the amount of drug in an individual to whom the drug has been administered. Drug levels can be determined in samples obtained from a patient, such as whole blood, plasma, or serum samples; urine samples; saliva samples; or other samples.

As used herein, the term " _Cmax " means the maximum observed concentration of a drug in an individual who has been administered the drug or in a sample obtained from an individual who has been administered the drug. C _max can be determined, for example, in a whole blood, plasma, or serum sample; a urine sample; a saliva sample; or in other samples.

As used herein, the term "exposure" refers to the amount of a drug that is systemically available that produces activity after administration of the drug to a patient. Drug exposure may not be the same as dose because not all drugs administered to a patient are available for clinical effect (eg, some drugs may be excreted, or metabolized, or otherwise unavailable). Exposure can be determined by AUC or by _Cmax , both of which provide an objective measure of a 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 sequentially in any order during all or part of the treatment period. The at least two agents can be administered following the same or different dosing regimens. In some instances, one agent is administered following a scheduled regimen while the other agent is administered intermittently. In some instances, both agents are administered intermittently.

As used herein, the terms "co-administration", "simultaneous administration", "administration in combination", "combination therapy" and similar terms refer to the administration of at least two agents to an individual for the treatment of a disease or condition. The two agents may be administered simultaneously or sequentially in any order during all or part of the treatment period. The at least two agents can be administered following the same or different dosing regimens. Such agents may include, for example, relackolan and another drug, which may be, for example, a drug useful in the treatment of cancer, or another therapeutic agent. In some instances, one agent is administered intermittently. In some instances, both agents are administered intermittently. In some instances, the first agent may be administered once a week for one, two, or three weeks, and the second agent may be administered one or more of the day before, the day, and the day after the first agent is administered .

As used herein, the term "compound" is used to denote a molecular moiety having a unique, identifiable chemical structure. Molecular moieties ("compounds") may exist as free species in which they are not associated with other molecules. A compound may also exist as part of a larger aggregate where it associates with other molecules but retains its chemical identity. A solvate (in which a molecular moiety ("compound") having a defined chemical structure ("compound") and molecules of a solvent) is an example of such an association. Hydrates are solvates in which the associating solvent is water. The recitation of "compound" refers to the molecular moiety (having the recited structure) itself, whether it exists 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 analog. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active compounds, it is contemplated for use in the composition. Supplementary active compounds can also be incorporated into the compositions.

。皮質醇含有類固醇主鏈，係一種類固醇化合物，且係一種類固醇激素。 As used herein, the terms "steroids and steroids" and the phrase "steroid backbone" refer to compounds containing a steroid backbone of seventeen carbon atoms joined by four fused rings, the structure of which is:

. Cortisol has a steroid backbone, is a steroid compound, and is a steroid hormone.

As used herein, the phrase "non-steroidal backbone" in the context of GRM means that it does not share structural homology with or is not a modification of Cortisol or other compounds containing a steroidal backbone. 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 for GC include corticosteroid, corticosteroid, steroid, and glucocorticoid steroid. "Glucocorticoid steroid" refers to a steroid hormone or steroid molecule that binds to the glucocorticoid receptor. In humans and many other mammals, the main GC is Cortisol; however, in carious animals, for example, corticosterone plays this role. Other GCs include, for example, dexamethasone, prednisolone, triamcinolone, hydrocortisone, beclamethasone, and other natural and synthetic compounds. Glucocorticoid steroids are generally characterized by having 21 carbon atoms, an α,β-unsaturated ketone in ring A and an α-ketool group attached to ring D. The difference lies in the degree of oxidation or hydroxylation at C-11, C-17 and C-19 (Rawn, "Biosynthesis and Transport of Membrane Lipids and Formation of Cholesterol Derivatives", Biochemistry, Daisy et al. (Ed.), 1989, page 567).

As used herein, the term "glucocorticoid receptor" ("GR") refers to type II GR, a family of intracellular receptors that specifically bind to cortisol and/or cortisol analogs such as dexamethasone ( See, eg Turner & Muller, J. Mol. Endocrinol. 1 October 2005, 35 283-292). Glucocorticoid receptors are also known as cortisol receptors. The term includes isoforms 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, a GRM such as dexamethasone used as an agonist increases the activity of tyrosine transaminase (TAT) in HepG2 cells (human liver hepatocellular carcinoma cell line; ECACC, UK). GRMs such as mifepristone used as antagonists reduce the activity of tyrosine transaminase (TAT) in HepG2 cells. TAT activity can be determined as described in A. 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 binding to an agonist. With regard to "selectivity", the drug binds preferentially to the GR rather than to other nuclear receptors such as the progesterone receptor (PRO), mineralocorticoid receptor (MR) or androgen receptor (AR). Preferably, the selective glucocorticoid receptor modulator binds GR with an affinity 1Ox (1/10 of the _Kd value) greater than its affinity for MR, AR or PRO. Rila Kelan is SGRM.

"Glucocorticoid receptor antagonist" (GRA) refers to any compound that inhibits the binding of GC to GR. Accordingly, GR antagonists can be identified by assaying the ability of a compound to inhibit the binding of dexamethasone to the GR. TAT activity can be determined as described in A. Ali et al., J. Med. Chem., 2004, 47, 2441-2452. GRA is a compound with an _IC50 (half maximal inhibitory concentration) of less than 10 micromolar. See Example 1 of US Patent 8,859,774, the entire contents of which are incorporated herein by reference in their entirety. GRA is GRM.

。 Compounds comprising a heteroaryl-keto-fused azadecalin structure (which may also be referred to as a heteroaryl-keto-fused azadecalin backbone) may be non-steroidal compounds, may be GRM compounds, and may be For SGRM compounds. Exemplary heteroaryl-keto-fused azadecalin compounds are described in US Patent 8,859,774. In an embodiment, the heteroaryl-keto-fused azadecalin GRM used 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]isoquinoline- 4a-yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (Example 18 of US 8,859,774), also known as "Rilakoran" and "CORT125134", has the following structure:

.

As used herein, the term "composition" is intended to cover compositions comprising specified amounts of specified ingredients (such as the compounds, their tautomeric forms, their derivatives, their analogs, their stereoisomers, their polymorphs, their Deuterated substances, their pharmaceutically acceptable salts, esters, ethers, metabolites, mixtures of isomers, their pharmaceutically acceptable solvates and pharmaceutically acceptable compositions) and products due to specified amounts of Any product resulting directly or indirectly from the combination of specified ingredients. The term in relation to pharmaceutical compositions is intended to cover products comprising the active ingredient and inert ingredients constituting the carrier, as well as the combination, complex or aggregation of any two or more of these ingredients, or the result of one or more of these ingredients dissociation of , or any product resulting directly or indirectly from other types of reactions or interactions of one or more of these components. Accordingly, the pharmaceutical compositions of the present invention are intended to encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier thereof.

In some embodiments, the term "consisting essentially of" means that the formulation consists of the sole active ingredient being the indicated active ingredient, however, may include such formulations for stabilization, preservation, etc., but not directly involved in all Other compounds indicative of the therapeutic effect of the 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 contain one or more ingredients that provide for prolonged release of the active ingredient to the individual over time. In some embodiments, the term "composition" refers to a composition comprising an active ingredient and a pharmaceutically acceptable carrier or excipient.

"Pharmaceutically acceptable excipient" and "pharmaceutically acceptable carrier" refer to agents that facilitate administration of an active agent to an individual and are absorbed by the individual and can be included in the compositions of the present invention without causing significant adverse toxicology to the patient. The substance of the effect. As used herein, these terms are intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, antioxidants, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Non-limiting examples of pharmaceutically acceptable excipients include water, NaCl, saline solution, lactated Ringer's, normal sucrose, normal dextrose, binders, fillers, disintegrants, capsules Encapsulating agents, plasticizers, lubricants, coatings, sweeteners, flavoring and coloring agents, and the like. Those of ordinary skill will know that other pharmaceutical excipients can be used in the present invention. The use of such media and agents for pharmaceutically active substances is well known in the art. Unless any conventional media or agent is incompatible with the active compounds, it is contemplated for use in the composition. Supplementary active compounds can also be incorporated into the compositions. Those of ordinary skill will know that other pharmaceutical excipients can be used in the present invention.

Methods for identifying or characterizing GRM compounds are known in the art. GRM binds to GR and regulates the activity of GR. For example, GRM can antagonize GR activity by inhibiting GR binding to other agents that activate GR; such modulation can be detected by observing GR-mediated activity. Compounds that have demonstrated a desired binding affinity for GR can be tested for activity in inhibiting GR-mediated activity. These compounds are typically subjected to the tyrosine transaminase assay (TAT assay), which evaluates the ability of the test compound to inhibit dexamethasone-induced tyrosine transaminase activity. See Example 1. GR modulators suitable for the methods disclosed herein have an _IC50 (half maximal inhibitory concentration) of less than 10 micromolar. Other assays, including, but not limited to, those described below, can also be used to confirm the GR modulating activity of these compounds.

Cell-based assays involving whole cells or cell fractions containing glucocorticoid receptors can also be used to determine the binding or activity modulation of test compounds to glucocorticoid receptors. Exemplary cell types that can be used in accordance with 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 (Burkitt's lymphoma cells), tumor cells (including mouse mammary tumor virus cells), endothelial cells, fibroblasts, heart cells, muscle cells, breast cancer cells (breast tumor cell), ovarian cancer (ovarian cancer carcinomas), cervical cancer, glioblastoma, liver cells, kidney cells and neuronal cells, and fungal cells (including yeast). The cells can be primary cells or tumor cells or other types of immortal cell lines. Of course, the glucocorticoid receptor can be expressed in cells that do not express the endogenous form of the glucocorticoid receptor.

In some embodiments, the reduction in signaling triggered by glucocorticoid receptor activation is used to identify modulators of the glucocorticoid receptor. The signaling activity of the glucocorticoid receptor can be determined in a number of ways. For example, downstream molecular events can be monitored to determine signaling activity. Downstream events include such activity or expression that occurs due to stimulation of glucocorticoid receptors. Exemplary downstream events useful for functional assessment of transcriptional activation and antagonism in unchanged cells include upregulation of a number of glucocorticoid response element (GRE) dependent genes (PEPCK, tyrosine transaminase, aromatase). In addition, specific cell types that are susceptible to GR activation can be used, such as osteocalcin expression in osteoblasts, which is downregulated by glucocorticoids; primary hepatocytes, which display PEPCK and glucose-6-phosphatase (G-6 -Pase) mediated up-regulation by glucocorticoids. GRE-mediated gene expression has also been demonstrated in cell lines transfected with well-known GRE regulatory sequences such as mouse mammary tumor virus promoter (MMTV) transfection upstream of reporter gene constructs. Examples of useful reporter constructs include luciferase (luc), alkaline phosphatase (ALP), and chloramphenicol acetyltransferase (CAT). Functional assessment of transcriptional repression can be performed in cell lines such as monocytes or human dermal fibroblasts. Useful functional assays include measurement of IL-1β-stimulated IL-6 expression; downregulation of collagenase, cyclooxygenase-2, and various chemokines (MCP-1, RANTES); LPS-stimulated release of cytokines such as TNFα or assay of gene expression regulated by NFkB or AP-1 transcription factors in transfected cell lines.

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

A further illustration of the many assays that can be used to identify compositions for use in the methods of the invention are based on assays of glucocorticoid activity in vivo. For example, assays that assess the ability of putative GR modulators to inhibit uptake of 3H-thymidine into DNA in cells stimulated by glucocorticoids can be used. Alternatively, putative GR modulators can be accomplished with H-dexamethasone to bind to liver cancer tissue culture GR (see, eg, Choi et al., Steroids 57:313-318, 1992). As another example, the ability of putative GR modulators to block nuclear binding of the H-dexamethasone-GR complex can be used (Alexandrova et al., J. Steroid Biochem. Mol. Biol. 41:723-725, 1992). To further identify putative GR modulators, kinetic assays capable of discriminating between glucocorticoid agonists and modulators via receptor binding kinetics (e.g., Jones, Biochem J. 204:721-729, 1982) can also be used. mentioned).

In another illustrative example, the assay described by Daune, Molec. Pharm. 13:948-955, 1977; and US Pat. No. 4,386,085 can be used to identify antiglucocorticoid activity. Briefly, thymocytes from adrenalectomized rats were cultured with varying concentrations of test compounds (putative GR modulators) in nutrient medium containing dexamethasone. ³ H-uridine is added to the cell culture, the cell culture is further grown, and the extent of radiolabel incorporation into the polynucleotide is determined. Glucocorticoid agonists reduce the amount of ³ H-uridine incorporated. Therefore, GR antagonists will counteract this effect. Pharmaceutical composition and administration

In an embodiment, the invention provides methods for treating cancer comprising intermittent administration of a GRM comprising a pharmaceutically acceptable excipient and a heteroaryl-keto-fused azadecalin (such as rilacocl Blue) pharmaceutical composition, and cancer chemotherapy regimen. In embodiments, pharmaceutical compositions comprising rillakolan include pharmaceutical compositions disclosed in US Patent Publication 2020/0197372, which is hereby incorporated by reference in its entirety.

Any suitable GRM dosage can be used in the methods and uses disclosed herein. The dose of GRM administered can be at least about 10 milligrams (mg)/day, about 25 mg/day, about 40 mg/day, about 50 mg/day, about 60 mg/day, about 70 mg/day, about 80 mg/day, about 100 mg/day, about 110 mg/day, about 120 mg/day, about 130 mg/day, about 140 mg/day, about 150 mg/day, about 160 mg/day, about 170 mg /day, about 180 mg/day, about 190 mg/day, about 200 mg/day, about 225 mg/day, about 250 mg/day or more. In some embodiments, the GRM is administered in at least one dose on the day it is administered to the cancer patient. In embodiments, the GRM may be administered in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses on the days it is administered to the cancer patient. In embodiments, the GRM is administered orally in 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more doses on the days it is administered to the cancer patient.

After a pharmaceutical composition comprising a heteroaryl-keto-fused azadecalin GR modulator has been formulated in an acceptable carrier, it can be placed in a suitable container and labeled for the treatment of cancer, for example when When administered in conjunction with a regimen that includes a cancer chemotherapeutic agent. For administration of the heteroaryl-keto-fused azadecalin GRM, such labeling would include, for example, instructions regarding the amount, frequency, and method of administration.

The duration of treatment of cancer with heteroaryl-keto-fused azadecalin GRMs and cancer chemotherapeutic agents may vary depending on the severity of the condition in the patient and the patient's response. In some embodiments, GRM can be administered with a cancer chemotherapy regimen for a period of about 1 week to about 104 weeks (2 years), or about 4 weeks to about 80 weeks, or about 3 weeks to about 60 weeks. For example, such periods can include at least a few days or a week in which the patient does not receive a GRM, at least a week in which the patient does not receive a cancer therapeutic, or at least a week in which the patient does not receive a GRM or a cancer therapeutic.

For example, a cancer chemotherapy regimen can be one in which a patient receives 1, 2, 3, or more cycles of chemotherapy, where the cycle of chemotherapy can include administration of a chemotherapeutic agent one day a week for three consecutive weeks, followed by one (or more) weeks without Chemotherapy agents are administered. Administering the GRMs with such cancer chemotherapy regimens can include administering the GRMs to the patient on the days that the patient receives the chemotherapeutic agent. Administering the GRM with such a cancer chemotherapy regimen can include administering the GRM to the patient on the day the patient receives the chemotherapeutic agent and on the day before or after, or the day before and the day after, the day that the patient receives the chemotherapeutic agent.

Administration of therapeutic compounds or agents to patients will follow the usual regimen for administering such compounds, taking into account the toxicity, if any, of the therapy. Surgical intervention can also be administered in combination with the therapy.

The method can be combined with other therapeutic approaches such as surgery, radiation, targeted therapy, immunotherapy, use of growth factor inhibitors, or anti-angiogenic factors.

Although the foregoing invention has been described in some detail for purposes of clear understanding by way of illustration and example, in view of the teachings of the present invention, those of ordinary skill will readily understand that the present invention can be modified without departing from the spirit or scope of the appended claims. Inventions subject to certain changes and modifications. example

The following examples are provided by way of illustration only and not limitation. A skilled artisan will readily appreciate a variety of non-critical parameters that can be varied or modified to produce substantially similar results. Example 1. Intermittent administration of rilacoran plus nanoparticulate nab-paclitaxel improves progression-free survival in patients with platinum-resistant ovarian cancer

The effect of adding GRM administration to cancer chemotherapy treatment was studied in a clinical trial. While daily GRM administration can provide continuous antagonism of GR-mediated chemoresistance pathways, higher doses of GRM administered intermittently can produce higher GR antagonism around the time of maximal chemotherapy exposure. To determine whether different GRM dosing regimens may have different effects on treatment outcomes, and if so, to determine which regimen may provide superior benefit, some patients were treated with continuous rilacolan administration, and others with Intermittent administration of rilakoran.

A 3-arm, randomized, open-label, controlled phase 2 study in which clinical findings from patients receiving nab-paclitaxel were compared with those from patients receiving nab-paclitaxel plus nab-paclitaxel Comparison of such clinical findings. This example presents results from the study showing that intermittent administration of rilacoclan in combination with administration of nab-paclitaxel improves progression-free survival (PFS) in cancer patients. Such patients include those with recurrent platinum-resistant ovarian cancer and other cancers, including those with fallopian tube, high-grade serous or endometrioid epithelial ovarian cancer, or ovarian carcinosarcoma, and those with primary peritoneal cancer patients). Patients were classified as platinum refractory (those who did not respond to platinum-based therapy or who relapsed within one month of treatment with platinum-based therapy) or platinum-resistant (those who relapsed within 6 months of platinum-based therapy their patients). Patients enrolled in this study have received at least first-line therapy with evidence of cancer progression [ relapse ] within 6 months of the last dose of platinum-based therapy (i.e., have a platinum-free interval of ≤ 6 months [ platinum resistance ] ) Or disease progression during or shortly after platinum-based therapy (i.e., platinum-refractory ). Patients with primary platinum resistance (progressed within 6 months of the last dose of first-line platinum-containing chemotherapy) were eligible for this study.

Cancer patients, including those with ovarian, fallopian tube, peritoneal, and other cancers, were enrolled in this study to combine nab-paclitaxel monotherapy with relacolan and nab-paclitaxel Comparison of Two Administration Methods of Paclitaxel Treatment. A schematic diagram of the clinical trial protocol is presented in FIG. 1 . 178 patients with platinum-resistant or refractory ovarian, primary peritoneal, or fallopian tube cancer were randomized 1:1:1 to receive nanoparticle nab-paclitaxel alone (nanoparticle nab-bound paclitaxel). paclitaxel monotherapy; 60 patients, referred to as the "comparison" group), continuous administration of rilacolan plus nanoparticulate nab-paclitaxel (58 patients, referred to as the "continuous" group), or rilacolan Intermittent administration of Kelan plus nanoparticulate nab-paclitaxel (60 patients, referred to as the "intermittent" group). All patients in these groups were treated with a 28-day chemotherapy cycle with nanoparticle nab-paclitaxel administered on days 1, 8, and 15.

Patients in the comparator group received 100 milligrams per square meter (mg/m ² ) nanoparticulate nab-paclitaxel and no risaclan. The results of the comparison group were used as the basis for comparisons with other groups. Patients in the continuation group received a once-daily dose of rilacoran (initially 100 mg/day (mg/day), with a patient-discretionary dose increase to 150 mg/day allowed on or after Cycle 2, and these patients Appears to be able to tolerate higher doses based on its response to the initial 100 mg dose), while also receiving 80 mg/ ^m2 nanoparticulate nab-paclitaxel on days 1, 8, and 15 of a 28-day cycle . (Dose escalation is administered as follows: dose reduction or omission of either risaclan or nab-paclitaxel is required if there is no intolerable grade 2 or any grade 3 or 4 toxicity during the first cycle , the dose of rilaklan will be increased to 125 mg once daily starting from day 1 of cycle 2. For patients who increase the dose of rilaklan to 125 mg, if there is no intolerable If Grade 2 or any Grade 3 or 4 toxicity requires dose reduction or omission of either rilacoclan or nab-paclitaxel, starting on Day 1 of Cycle 3, the rilacoclan dose will be Increase to 150 mg once daily. If the dose is not increased during Cycle 1 or 2, the dose should not be increased in future cycles.

Patients in the intermittent group received 80 mg/m ^nab -paclitaxel on days 1, 8, and 15 of the 28-day cycle, and before nab-paclitaxel administration A once-daily dose of 150 mg rilacoclan was received one day, the same day, and the day after (except that no risaclan was administered to the patient the day before the first nab-paclitaxel administration). That is, patients in the intermittent group were administered once daily on days 1 and 2; once daily on days 7, 8, and 9; and daily on days 14, 15, and 16. once; and again on day 28 of a monthly cycle in which nanoparticulate nab-paclitaxel is administered on days 1, 8, and 15 of the monthly cycle at a dose of 150 mg orchid.

Independent comparisons were made between the intermittent versus (versus/vs.) comparison study group and the continuous versus comparison group. The primary endpoint of this study was progression-free survival, as determined by the Response Evaluation Criteria in Solid Tumors ("RECIST") version 1.1 guidelines (available via the World Wide Web at the following URL: http:// ctep.cancer.gov/protocolDevelopment/docs/recist_guideline.pdf) determination. Secondary endpoints included objective response rate, duration of response, overall survival, and safety for the combination administration of nanoparticulate nab-paclitaxel and rilakoran. All efficacy objectives listed below and corresponding endpoints, assessment of response and disease progression were assessed according to RECIST v1.1.

As noted above, patients enrolled in this study had received multiple lines of prior therapy (median 3 and up to 5 lines), including prior taxane, prior bevacizumab, and prior PARP inhibitor therapy. Many ovarian cancer patients in this study were platinum-resistant (and more than 35% were platinum-refractory). In the intermittent group, predominantly platinum-refractory patients were overrepresented. All but one patient had previously received a taxane, more than half had previously received bevacizumab, and slightly more than one-third had previously received a PARP inhibitor. For the total number of patients (far right column) and each of the three groups between intermittent dosing of rilacoclan; continuous dosing of rilacoclan; and administration of nanoparticulate nab-paclitaxel alone (comparison group), the relevant Further information on the characteristics of the patients enrolled in this study and the response of the patients to the treatments administered to them is provided in FIG. 2 . Stratification factors were recurrence within 6 months based on most recent taxane and presence of ascites. Molecular profiling results were available for some patients. The scores for patients in this subgroup with BRCA 1 or 2 mutations are presented at the bottom of the table in FIG. 2 .

Exposure and peak concentrations of both nanoparticulate nab-paclitaxel and rilacoran were determined. Overall, there was greater variability in exposure to rilacoran and nab-paclitaxel, consistent with the out-patient nature of the pharmacokinetic profile of the two compounds and the study design. The total extent of nanoparticulate nab-paclitaxel exposure overlapped to a large extent in all three groups. Assessment of relative safety endpoints of riscolan and nab-paclitaxel exposure (as determined by AUC and _Cmax ) revealed a large degree of overlapping exposure in the presence or absence of adverse events.

Figure 3 presents information on the disposition of patients enrolled in the study. For example, Figure 3 shows the percentage of patients who discontinued study treatment at some time point during the study, either with nab-paclitaxel alone (comparison) or with relacolan plus nab-paclitaxel Paclitaxel (whether intermittent or continuous) treatment. As expected, most discontinuations were due to disease progression and only about 10% were due to adverse events. In addition to the number and percentage of patients in each group who discontinued study treatment, Figure 3 also provides the number and percentage of those patients who discontinued treatment due to disease progression, due to adverse events, due to death, or due to other reasons.

Figure 4 presents the progression-free survival (PFS) time of the three groups of patients. Patients receiving nab-paclitaxel and intermittent rilacoran ("intermittent") had a median PFS of 5.6 months, which was greater than that of nab-paclitaxel alone ("comparison"). ”) treated patients had a median PFS of 1.8 months longer. This difference in PFS was significant at the P<0.05 level. Significantly, the hazard ratio (HR) for PFS was lower for patients receiving nab-paclitaxel plus intermittent rilacoran compared with PFS for patients receiving nab-paclitaxel alone. Improvement: HR is 0.66, at the level of P<0.05, HR is also significant. Although the number of platinum-refractory patients was balanced across all study groups, there were more primary platinum-refractory patients in the intermittent group. Analysis excluding primary platinum-refractory patients with a particularly poor prognosis showed a hazard ratio improvement in PFS (0.64 vs. 0.66) and a strong tendency for improvement in overall survival with intermittent regimens, with a hazard ratio of 0.55 and a P -value of 0.056.

Median PFS for women in the continuation group was 1.5 months longer than in the comparison group; this PFS also showed improvement compared with nab-paclitaxel alone, with a hazard ratio of 0.83 but no difference at P<0.05. Statistically significant. Therefore, these PFS results show that intermittent administration of rilacoclan plus nab-paclitaxel provides superior therapeutic benefit compared to nanoparticle nab-paclitaxel alone; Intermittent administration of rillacolan plus nanoparticulate nab-paclitaxel provided superior therapeutic benefit compared to plus nanoparticulate nab-paclitaxel.

In addition, as shown in Figure 5, the duration of patient response (DoR) was also significantly greater in patients receiving intermittent Rilacoran plus nab-paclitaxel compared to nab-paclitaxel alone improve. For patients presented as individual horizontal bars in this figure, "PR" indicates a partial response, and "CR" indicates a complete response. In the intermittent arm of the present study, the median DoR was 5.55 months, which was significantly improved compared to 3.65 months in the comparator arm (hazard ratio, HR, 0.36; P -value=0.006). Arrows in Figure 5 indicate those patients whose duration of response continued (patients still showed response at the end of the study period). Thus, these DoR results show that intermittent administration of rilacoclan plus nanoparticulate nab-paclitaxel compared to nanoparticulate nab-paclitaxel alone and compared to continuous Nab-paclitaxel provides excellent therapeutic benefit.

As illustrated in Figure 6, the group of patients receiving intermittent riscolan in combination with nab-paclitaxel showed a tendency to improve overall survival compared to the group of patients receiving nab-paclitaxel alone. As shown in Figure 5 showing the DoR, many patients continued to benefit from the therapy, and it is believed that this trend toward improved overall survival may continue; these patients will continue to be monitored and further analyzes of the intermittent groups and Overall survival and other patient responses in the continuous group compared with nanoparticle nab-paclitaxel monotherapy group. Therefore, this trend in the overall survival results further suggests that Rilacklan administration compared to nab-paclitaxel alone and compared to continuous administration of rilacoclan plus administration of nanoparticle nab-paclitaxel Intermittent administration of blue plus nanoparticle nab-paclitaxel provided excellent therapeutic benefit.

Figure 7 tabulates the progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and overall survival (OS) observed in the three groups of patients during the study. Patients who had not responded to first-line platinum-based therapy prior to this study were considered "primary platinum-refractory" patients; these patients had a particularly poor prognosis. PFS, ORR, DoR, and OS were calculated for all 178 patients in this study (column "Total") and for 167 patients who were not "primary platinum refractory" (column "excluding primary platinum refractory") ). Two analyses, showed that intermittent administration of rivaclan during the cycle of taxane chemotherapy administration significantly improved PFS and DoR compared with taxane chemotherapy alone, and also provided Greater good. The data indicated that OS tended to improve in patients receiving intermittent rilaccolan administration compared to the other groups; this was especially clearly shown on the hazard ratio (HR) data.

Relacolan treatment was safe and well tolerated by patients for both the intermittent and continuous groups. Safety and tolerability were comparable between groups, with neutropenia being the most common grade ≥3 adverse event. The safety and tolerability of the three treatment regimens are illustrated in FIG. 8 . Severe (grade ≥ 3) peripheral neuropathy was less common in the intermittent group than in the comparator group. According to the study protocol, all patients receiving risaclan and nab-paclitaxel received prophylactic granulocyte colony-stimulating factor (GCSF), a treatment used to reduce the risk of neutropenia, while those receiving Patients on nab-paclitaxel monotherapy were administered G-CSF according to the standard practice of clinical investigators.

In some patients, mRNA expression levels of selected targets were also determined. Such analyzes also confirmed that treatment with rilakorant and nab-paclitaxel inhibited some glucocorticoid receptor target genes. A panel of 239 genes induced by the glucocorticoid presole was analyzed in whole blood samples obtained from some patients. 221 of these genes were suppressed (change from baseline to cycle 1, day 15) in patients receiving risaclan + nab-paclitaxel, whereas nab-paclitaxel alone For paclitaxel conjugated, there were no changes in these genes. For example, the mRNA expression of one of the canonical glucocorticoid-responsive genes, serum and glucocorticoid-regulated kinase (SGK1 ), which is involved in cell survival, is determined. The left side of Figure 9 shows the change in SGK1 expression in whole blood samples from baseline to cycle 1 day 15 (error bars represent median and interquartile range). As shown in Figure 9, compared with the levels of SGK1 mRNA in whole blood samples from patients receiving nab-paclitaxel alone, the levels of SGK1 mRNA in patients who Among them, the content of mRNA encoding SGK1 in whole blood decreased (P<0.013). Relackolan + nab-paclitaxel suppressed SGK1 expression, whereas SGK1 gene expression was not suppressed in patients treated with nab-paclitaxel alone.

To determine whether high expression of GR-encoding mRNA affects treatment including rilacoran, 137 pre-treatment samples obtained from tumors from patients in this study were characterized. The expression (mRNA) content of all genes in the sample is shown in circles on the right part of FIG. 9 . The median expression content of each of the 444 genes was first determined. The NR3C1 median falls within the 83rd percentile of the distribution of 444 median values. Thus, the expression of glucocorticoid receptor encoding mRNA (NR3C1 ) was found to be high in ovarian cancer tumors compared to the mRNA expression of all genes in patients (shown as triangles in the right part of FIG. 9 ).

In conclusion, this example presents the first randomized, controlled, phase 2 trial of rilacoran + nab-paclitaxel in patients with ovarian and other cancers. Platinum-resistant and refractory patients with up to 5 prior line therapies were included in the study. Substantial benefit was observed in this heavily pretreated population. Patients treated with intermittent rilaccolan + nab-paclitaxel had significantly improved time to PFS and significantly improved DoR compared to patients receiving nab-paclitaxel alone. In addition, overall survival tended to be improved in patients receiving intermittent rilaccolan compared with patients receiving nanoparticulate nab-paclitaxel alone. The safety profile of intermittent rilacoran + nab-paclitaxel was comparable to that of nab-paclitaxel alone. Thus, these results show that intermittent administration of rilacoclan plus nanoparticle nab-paclitaxel is more effective than nanoparticulate nab-paclitaxel alone and compared to continuous administration of rilacoclan plus nanoparticle nab-paclitaxel. Nab-paclitaxel provides excellent therapeutic benefit.

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. . In addition, although the foregoing invention has been described in some detail for purposes of clear understanding by way of illustration and example, in view of the teachings of the present invention, those of ordinary skill will readily appreciate that, without departing from the spirit or scope of the appended claims, Certain variations and modifications of the present invention are as follows.

Figure 1 is a schematic diagram of the clinical trial protocol of the example. 178 patients with platinum-resistant or platinum-refractory ovarian, primary peritoneal, or fallopian tube cancer were randomized 1:1:1 to receive nanoparticulate nab-paclitaxel (100 mg/m2 (mg /m ² ); 60 patients), continuous administration of rilacoclan plus nanoparticle nab-paclitaxel (80 mg/m ² ; 58 patients), or intermittent administration of rilaccolan plus nanoparticle albumin-bound paclitaxel paclitaxel (80 mg/m ² ; 60 patients). Patients receiving continuous rilacoclan received 100 mg rilacoclan/day (mg/day) (with discretionary escalation of the rilacoclan dose up to 150 mg/day allowed). Patients receiving intermittent rilacoclan received 150 mg rilacoclan the day before, on the day, and the day after nab-paclitaxel administration. If the patient's disease progressed during platinum-based therapy, or if the treatment-free interval after platinum-based therapy was less than 6 months (i.e., the patient relapsed and therefore required less than 6 months after completion of the previous round of platinum-based therapy). months for further platinum-based therapy), patients were considered platinum-resistant. Patients were considered "platinum refractory" if their disease progressed during or within 1 month of the last platinum-based therapy. (Platinum-refractory patients are a subgroup of platinum-resistant patients.)

Figure 2 presents the characteristics of the patients enrolled in each of the three groups of patients in this study. All but one patient had received taxane therapy prior to enrollment in the study (one patient in the "intermittent" arm had not received prior taxane therapy).

Figure 3 presents a list of patient dispositions at the end of the study.

Figure 4 presents the progression-free survival (PFS) time of the three groups of patients. Compared with nab-paclitaxel alone, patients receiving nab-paclitaxel and intermittent rilaccolan experienced significantly improved PFS with a hazard ratio of 0.66. The hazard ratio was significant at the P<0.05 level. The median PFS was 5.6 months, 1.8 months longer than in the nab-paclitaxel monotherapy arm, which was 3.8 months longer. Each event was a patient who experienced disease progression (per RECIST) or died.

Figure 5 illustrates the duration of response in each of the three groups of patients. Duration of response was significantly improved in patients who received intermittent rilakoran plus nab-paclitaxel compared with nab-paclitaxel alone (P=0.006; HR, 0.36), however, all three The objective response rate (ORR) of the groups was similar (intermittent: n=20 (35.7%); continuous: n=19 (35.2%); comparative: n=19 (35.8%))

Figure 6 illustrates the overall survival time for each of the three patient groups. These data demonstrate that overall survival tends to be improved in the group of patients receiving intermittent rilaccolan in combination with nab-paclitaxel compared to the group of patients receiving nab-paclitaxel alone. Each event indicated the death of one patient.

Figure 7 tabulates the progression-free survival (PFS), objective response rate (ORR), duration of response (DoR) and overall survival (OS) observed in the three groups of patients during the study. Patients who had not responded to first-line platinum-based therapy prior to this study were considered "primary platinum-refractory" patients; these patients had a particularly poor prognosis. PFS, ORR, DoR, and OS were calculated for all 178 patients in this study (column "Total") and for 167 patients who were not "primary platinum refractory" (column "excluding primary platinum refractory") ). Two analyses, showed that intermittent administration of rivaclan during the cycle of taxane chemotherapy administration significantly improved PFS and DoR compared with taxane chemotherapy alone, and also provided Greater good.

Figure 8 tabulates the number of certain clinical conditions observed in the three groups of patients during the study. The safety and tolerability of treatment with risaclan and nab-paclitaxel was comparable to the safety and tolerability of treatment with nab-paclitaxel alone.

Figure 9 presents the determination of the levels of mRNA encoding serum and glucocorticoid-regulated kinase (SGK1 ) and mRNA encoding glucocorticoid receptor (NR3C1 ). These levels are determined in whole blood. The left side of the panel presents a comparison between NR3C1 mRNA expression in ovarian tumors (triangles) and the mRNA expression of all genes assayed in ovarian tumors (circles). mRNA was measured in 137 pre-treatment tumor samples, including tumors from patients treated with nab-paclitaxel alone and tumors from patients treated with nab-paclitaxel and relacolan performance content. Median values for each of the 444 genes were first determined. NR3C1 mRNA was highly expressed in all tumors tested (NR3C1 median falls in the 83rd percentile of the distribution of all genes). The right side of the panel shows the results for "GR-induced genes" (defined as 239 genes induced by a single dose of prednisone, as measured in whole blood from an independent healthy volunteer study). From day 1 to day 15 of cycle 1, these 239 GR - mRNA expression was suppressed in 221 of the induced genes. The graph shows the results for the SGK1 gene (an example of a GR-inducible gene). SGK1 mRNA levels were suppressed (negative median fold change from baseline to cycle 1 day 15) in patients receiving both risaclan and nab-paclitaxel, whereas those receiving nanoparticulate nab-paclitaxel alone SGK1 mRNA levels (circles) measured in nab-paclitaxel patients were essentially unchanged from baseline, and there was a statistically significant difference between the two groups (P=0.013).

Claims (15)

A use of a pharmaceutical composition in the preparation of a medicament, wherein the medicament is used for treating cancers selected from cancers of female reproductive organs and tissues and peritoneal cancers, and the treatment of the cancers includes intermittently administering effective doses of heteroaromatics to patients suffering from cancers A base-keto-fused azadecalin glucocorticoid receptor modulator (GRM), wherein the patient needs and is receiving cancer chemotherapy treatment for the cancer, which treatment includes administering 80 mg/m according to the cancer chemotherapy administration schedule ² , the taxane cancer chemotherapy agent, the administration schedule requires that the taxane cancer chemotherapy agent is not administered for at least one day between the days when the taxane cancer chemotherapy agent is administered to the patient, wherein the intermittent administration includes The GRM is administered on the same day when the taxane cancer chemotherapeutic agent is administered to the patient, and the pharmaceutical composition comprises a pharmaceutically acceptable excipient and the GRM. As the use of Claim 1, wherein the cancer of the female reproductive organs and tissues is selected from the group consisting of ovarian cancer, fallopian tube cancer, uterine cancer, cervical cancer, vaginal cancer and vulvar cancer. The use according to claim 1, wherein the cancer is ovarian cancer. As the use of claim 1, wherein the taxane cancer chemotherapeutic agent is selected from paclitaxel, nanoparticle albumin-bound paclitaxel, docetaxel, larotaxel, tercetaxel, cabazitaxel and otata The taxane group composed of race. Such as the use of claim 4, wherein the taxane cancer chemotherapy agent is paclitaxel containing paclitaxel alkyl. The use according to claim 4, wherein the taxane cancer chemotherapeutic agent is nanoparticle albumin-bound paclitaxel. The use according to any one of claims 1 to 6, wherein the GRM is also administered on the day after the cancer chemotherapy agent is administered to the patient. The use according to any one of claims 1 to 6, wherein the GRM is also administered the day before the patient is administered the cancer chemotherapy agent. The use according to any one of claims 1 to 6, wherein the GRM is administered on the day before, on the day, and on the day after the patient is administered the cancer chemotherapy agent. The use according to any one of claims 1 to 6, wherein the GRM is not administered for at least 4 days between the day when the GRM is administered to the patient. The use according to any one of claims 1 to 6, wherein the cancer chemotherapy administration schedule comprises administering the taxane cancer chemotherapy agent on the first day, and administering the taxane again on a day seven days after the first day. For the taxane cancer chemotherapy agent, the taxane cancer chemotherapy agent is not administered for several days between the first day and the day seven days after the first day. The use of any one of claims 1 to 6, wherein the taxane cancer chemotherapy agent is based on The cancer chemotherapy dosing schedule is administered to the patient for three consecutive weeks. The use according to claim 12, wherein the taxane cancer chemotherapeutic agent is administered to the patient for three consecutive weeks according to the cancer chemotherapy administration schedule, and then not administered one week after the last week of the three consecutive weeks. The use according to claim 12, wherein the taxane cancer chemotherapy agent is administered to the patient for three consecutive weeks according to the cancer chemotherapy administration schedule, and then the week after the last week of the three consecutive weeks is not administered, and then This weekly dosing regimen was repeated for three consecutive weeks. As the use of any one of claims 1 to 6, wherein the GRM is a heteroaryl ketone condensed azadecalin 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]isoquinoline-4a- yl)(4-(trifluoromethyl)pyridin-2-yl)methanone (“Rilakoran”), which has the following structure:

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