Study of Drug 1 (Enzalutamide) Plus Drug 2 (Relacorilant) for Patients With Prostate Cancer

The study is an open-label Phase 1 study of the combination of relacorilant with enzalutamide in patients with metastatic castration resistant prostate cancer (mCRPC). Patients will be enrolled in 6 patient cohorts with a 6+3 design and a 28 day DLT period. Doses of relacorilant, enzalutamide will be adjusted based on safety and pharmacokinetics (PK). Once a safe dose with appropriate drug levels (PK) has been established, the cohort will be expanded to a total of 12 patients to refine safety and PK at the recommended phase II dose (RP2D).

Inclusion criteria

• Histologically or cytologically confirmed prostate cancer with documented metastatic disease
• Evidence of castrate testosterone level <50ng/dl (or surgical castration)
• Evidence of disease progression:

• 2 or more new lesions on bone scan or
• Progressive disease on CT/MRI according to Response Evaluation Criteria in Solid Tumors 1.1 criteria or
• Rising Prostate Specific Antigen (PSA): PSA evidence for progressive prostate cancer consists of a minimum PSA level of at least 2 ng/ml, which has subsequently risen on at least 2 successive occasions, at least 2 weeks apart.
• Prior treatment with at least one line of potent androgen receptor signaling inhibitor (e.g. abiraterone, enzalutamide, apalutamide) in either castration-sensitive or castration-resistant setting.
• Any prior therapy for castrate disease is acceptable except prior GR antagonist treatment (e.g. mifepristone or relacorilant).
• Any other radiotherapy or radionuclide require 28-day washout prior to first dose of study drug.
• Denosumab or zoledronic acid are allowed.
• ECOG performance status ≤ 2.
• Patients must have normal hepatic function as defined below:

• Total bilirubin </=1.5 x the upper limit of normal
• AST(SGOT)/ALT(SGPT) </=2.5 X institutional upper limit of normal
• Albumin >/=3.0 g/dL
• Patients must have normal bone marrow function as defined below:

• Platelet count (plt) >/= 80,000 /microliter
• Hemoglobin (Hgb) >/= 9 g/dL
• Absolute neutrophil count (ANC) >/= 1500
• Patients must have normal renal function as defined below:

• GFR >/= 30 mL/min
• Ability to understand and the willingness to sign a written informed consent document.
• Patients with active Diabetes Mellitus on glucose lowering medications are eligible provided they agree to and are able to self-monitor daily blood glucose levels due to potential risk of lowering glucose levels on relacorilant.
• Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (one of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration. Two acceptable methods of birth control thus include the following:

• Condom (barrier method of contraception); AND
• One of the following is required:

• Established use of oral, or injected or implanted hormonal method of contraception by the female partner;
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner;
• Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository by the female partner;
• Tubal ligation in the female partner;
• Vasectomy or other procedure resulting in infertility (e.g., bilateral orchiectomy), for more than 6 months.

Exclusion criteria

• Therapy with other hormonal therapy, including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart), or any herbal product known to decrease PSA levels (e.g., saw palmetto and PC-SPES), or any systemic corticosteroid within 2 weeks prior to first dose of study drug.

a.Patients who have been on systemic corticosteroids with prednisone equivalent of 10mg or greater for greater than 3 months immediately prior to participation in this study must have documented ability to tolerate cessation of corticosteroids prior to enrollment.

• Inability to swallow capsules or known gastrointestinal malabsorption.
• Evidence of visceral disease on imaging in a patient who is an appropriate candidate for cytotoxic chemotherapy (docetaxel or cabazitaxel).
• History of other malignancies, with the exception of: adequately treated non-melanoma skin cancer, adequately treated superficial bladder cancer, stage 1 or 2 malignancies who are without evidence of disease, or other cancers curatively treated with no evidence of disease for > 5 years from enrollment.
• Blood pressure that is not controlled despite > 2 oral agents (SBP >160 and DBP >90 documented during the screening period with no subsequent blood pressure readings >160/100).
• History of seizure disorder or active use of anticonvulsants. Medications used to treat neuropathic pain such as gabapentin or pregabalin are allowed.
• Documented history of or current brain metastases due to seizure risk
• Serious intercurrent infections or non-malignant medical illnesses that are uncontrolled.
• Active psychiatric illness/social situations that would limit compliance with protocol requirements.
• NYHA class II, NYHA class III, or IV congestive heart failure (any symptomatic heart failure).
• Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 (See Section 9.12below for list of strong inhibitor or inducers) due to concerning possible drug-drug interactions
• Presence of concurrent medical conditions requiring systemic glucocorticoids for immunosuppression (e.g. Autoimmune diseases, organ transplantation) that is active and has required glucocorticoids in the last 6 months.