Study of Relacorilant in Combination With Nab-Paclitaxel for Patients With Recurrent Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer

Relacorilant is a small molecule antagonist of the glucocorticoid receptor (GR). The goals of this study are to evaluate the efficacy of relacorilant either administered daily (continuous) or on the day prior, the day of, and the day after chemotherapy (intermittent) in combination with nab-paclitaxel in the treatment of platinum-resistant ovarian, fallopian tube, or primary peritoneal cancers compared with nab-paclitaxel alone. The safety, pharmacokinetics (PK), and pharmacodynamic profile of relacorilant in combination with nab-paclitaxel will also be assessed.

Eligible patients will be randomized 1:1:1 to one of the following three treatment arms. Patient randomization will be stratified by treatment-free interval from most recent taxane (relapsed within 6 months vs >6 months) and presence of ascites (yes vs no).

• Arm A (Continuous relacorilant): Relacorilant starting at 100 mg, administered orally, once daily every day in combination with nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.
• Arm B (Intermittent relacorilant): Relacorilant 150 mg, administered orally, on the day before (excluding Cycle 1, Day -1), the day of, and the day after nab-paclitaxel, in combination with nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.
• Arm C (Comparator): Nab-paclitaxel on Days 1, 8, and 15 of each 28-day cycle.

Patients will remain on study treatment until reaching a protocol-defined event of disease progression (PD), experiencing unmanageable toxicity, or until other treatment discontinuation criteria are met. All patients will be followed for progression, subsequent therapies, and survival in the long-term follow-up phase. Patients in Arm C who experience unequivocal PD per RECIST v1.1 will be given the opportunity to receive relacorilant in combination with nab-paclitaxel after discussion with the Medical Monitor (Crossover patients).

Inclusion criteria

• Signed and dated Investigational Review Board/Independent Ethics Committee-approved informed consent form (ICF) prior to study-specific screening procedures.
• Female patients aged ≥18 years old at time of consent
• Histologic diagnosis of high grade serous or endometrioid epithelial ovarian, primary peritoneal, or fallopian tube cancer or ovarian carcinosarcoma. Clear cell, mucinous and borderline histologic subtypes are excluded.
• Received at least 1 line of therapy with evidence of cancer progression within 6 months after the last dose of platinum-based therapy (ie, having a platinum-free interval of ≤6 months [platinum resistant]), or progressive disease during or immediately after primary platinum-therapy, (ie, platinum refractory). Patients with primary platinum resistance (progression within 6 months of the last dose of first-line platinum-containing chemotherapy) are considered eligible.

Notes: For the calculation of the platinum-free interval, cancer progression must be defined by clear evidence of progression, such as radiographic progression per RECIST v1.1. Calculating the platinum-free interval on the basis of increased Cancer Antigen (CA-125) is not allowed.

• Measurable or non-measurable disease by RECIST v1.1:

• Previously irradiated lesions are not allowed as measurable disease, unless there is documented evidence of progression in the lesions.
• To be eligible with non-measurable disease, patients must have evaluable disease with CA 125 at least twice the upper limit of reference range (of CA-125 ≥70 U/mL), along with radiographically evaluable disease by computerized tomography (CT)/magnetic resonance imaging (MRI).
• Availability and consent to provide tumor tissue for biomarker assays (archival or recent biopsy).
• No more than 4 prior chemotherapeutic or myelosuppressive regimens (not including maintenance therapy such as single-agent bevacizumab or poly (ADP-ribose) polymerase [PARP] inhibitors). Patients with platinum-refractory cancer cannot have had more than 2 prior lines of treatment for refractory disease.
• Appropriate to treat with nab-paclitaxel, in the opinion of the Investigator.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Adequate organ and bone marrow function meeting the following criteria at the Screening Visit:

• Absolute neutrophil count (ANC) ≥1,500 cells/mm^3.
• Platelet count ≥100,000/mm^3.
• Hemoglobin ≥9 g/dL.
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) (or ≤5 × ULN in the context of liver metastasis).
• Total bilirubin ≤1.5 × ULN.
• Creatinine clearance ≥45 mL/min/1.73 m^2 (measured or estimated).
• Albumin ≥3 g/dL (≥30 g/L) .
• If patient has undergone surgery of the gastrointestinal or hepatobiliary tract, adequate absorption as evidenced by: albumin ≥3.0 g/dL, controlled pancreatic insufficiency (if present), and lack of malabsorption.
• Able to swallow and retain oral medication and does not have uncontrolled emesis.
• Able to comply with protocol requirements.
• Negative pregnancy test for patients of childbearing potential. Patients of childbearing potential must use appropriate precautions to avoid pregnancy, defined as of non-childbearing potential (ie, postmenopausal or permanently sterilized) or using highly effective contraception with low user-dependency, for at least 3 months after the last dose of relacorilant, or per the duration indicated in the product label for nab-paclitaxel, whichever is latest. A woman is postmenopausal if it is more than 12 months since her last menstruation, without an alternative medical cause. Accepted methods of permanent sterilization methods are hysterectomy, bilateral salpingectomy, and/or bilateral oophorectomy. Accepted methods of highly effective contraception with low-user-dependency are:

• An intrauterine device (IUD), provided that the subject has tolerated its use for at least 3 months before the first dose of study medication and undertakes not to have it removed for 1 month after the last dose.
• Abstinence from heterosexual intercourse, when it is in line with the subject's preferred and usual lifestyle. Periodic abstinence and withdrawal are NOT acceptable.
• Vasectomized partner provided that the partner is the sole sexual partner of the trial participant and that the vasectomized partner has received medical assessment of the surgical success.
• Oral hormonal contraceptives are NOT permitted.

Exclusion criteria

• Clinically relevant toxicity from prior systemic anticancer therapies or radiotherapy that in the opinion of the Investigator has not resolved to Grade 1 or less prior to randomization.
• Any major surgery within 4 weeks prior to randomization. If subject received major surgery including (curative or palliative surgery), they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
• Treatment with the following prior to randomization:

• Concurrent treatment with other anticancer therapy including other chemotherapy, immunotherapy, radiotherapy, chemoembolization, targeted therapy, an investigational agent or the non-approved use of a drug or device within 28 days before the first dose of study drug.
• Hormonal anticancer therapies within 7 days of the first dose of study drug.
• Systemic, inhaled, or prescription strength topical corticosteroids within 21 days of the first dose of study drug. Short courses (≤5 days) for non-cancer-related reasons are allowed if clinically required (such as prophylaxis for CT).
• Received radiation to more than 25% of marrow-bearing areas.
• Toxicities of prior therapies (except alopecia) that have not resolved to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0 ≤Grade 1.
• Requirement for treatment with chronic or frequently used oral corticosteroids for medical conditions or illnesses (eg, rheumatoid arthritis, immunosuppression after organ transplantation).
• History of severe hypersensitivity or severe reaction to either study drug.
• Peripheral neuropathy from any cause >Grade 1.
• Pregnant or lactating patients or patients expecting to conceive children within the projected duration of the trial, starting with the Screening Visit through at least 3 months after the last dose of relacorilant, or per the duration indicated in the product label for nab-paclitaxel, whichever is latest.
• Human immunodeficiency virus or current chronic/active infection with hepatitis C virus or hepatitis B virus, including:

• Patients with chronic or active hepatitis B as diagnosed by serologic tests are excluded from the study. In equivocal cases, hepatitis B or C polymerase chain reaction may be performed and must be negative for enrollment.
• Patient has a clinically significant uncontrolled condition(s) or which in the opinion of the Investigator may confound the results of the trial or interfere with the patient's participation, including but not limited to:

• Unstable angina pectoris, angioplasty, cardiac stenting, or myocardial infarction 6 months before study entry.
• Uncontrolled hypertension (sustained systolic blood pressure >150 mmHg or diastolic pressure >100 mmHg despite optimal management). Patients will be considered eligible if hypertension is treated and controlled during Screening.
• Active infection that requires parenteral antibiotics.
• Bowel obstruction or gastric outlet obstruction.
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• Untreated parenchymal central nervous system metastases.
• Any other concurrent cancer or a history of another invasive malignancy within the last 3 years that has a likelihood of recurrence of >30% within the next 5 years. Adequately treated non-melanoma skin cancers or non-muscle invasive urothelial cancer or other tumors curatively treated with no evidence of disease are permissible.
• Are taking a concomitant medication that is a strong CYP3A inhibitor or inducer, or that is a substrate of CYP3A with a narrow therapeutic window.
• Concurrent treatment with mifepristone or other glucocorticoid receptor (GR) antagonists.
• Concurrent treatment on other investigational treatment studies for the treatment of ovarian, fallopian tube, or primary peritoneal cancer.
• Has received a live vaccine within 30 days of planned start of study therapy. Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.