Study to Evaluate Exicorilant (CORT125281) in Combination With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 1/2a Dose-Escalation and Expansion Study to Evaluate the Safety, Tolerability, and Pharmacokinetics of CORT125281 With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer

This study consists of a dose escalation study with an expansion phase to evaluate the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD), and preliminary efficacy of exicorilant (CORT125281) in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) to identify a recommended dose (RD) for Phase 2 studies.

Exicorilant is a selective glucocorticoid receptor (GR) antagonist. In this study, exicorilant will be administered orally in combination with enzalutamide to patients with mCRPC to evaluate the safety, tolerability, PK, PD, and preliminary efficacy of the regimen. The study consists of 2 phases: a dose-determination phase and an expansion phase. The dose determination phase is designed to determine dose-limiting toxicities and the RD of exicorilant plus enzalutamide in patients with mCRPC. Once the recommended dosing regimen has been determined, the following expansion cohorts will be enrolled and treated with exicorilant plus enzalutamide at the RD level.

Abiraterone-Resistant Cohort: Patients who have progressed during treatment with abiraterone, and have received no other androgen receptor (AR)-blocking therapies.

AR Antagonist-Resistant Cohort: Patients who have progressed during treatment with enzalutamide or other second-generation AR inhibitors.

The effect of food on exicorilant PK will be assessed in a portion of the patients enrolled in the Expansion Phase. The 2 expansion cohorts will be enrolled in parallel.

In each phase of the study, routine assessments of safety and tolerability will be performed and samples will be collected to determine standard PK parameters for exicorilant, enzalutamide, and their major metabolites. PD, quality of life evaluations and preliminary evaluations of antitumor activity of exicorilant with enzalutamide will be performed throughout the study.

Major Inclusion Criteria:

• Able to understand the purpose and risks of the study; willing and able to adhere to scheduled visits, treatment plans, laboratory tests, and other study evaluations and procedures, and provide written informed consent

• Males ≥18 years of age at the time of signing consent

• Histologically confirmed adenocarcinoma of the prostate with metastatic disease

• Dose-Determination Phase Segment 1 and Expansion Phase: Progressive disease as defined by prostate-specific antigen (PSA) or imaging after most recent prior therapy. PSA ≥1 ng/mL, if a confirmed rise in PSA is the only indication of progression. Progression by PSA requires rising PSA over a previous reference value by at least 2 measurements obtained ≥1 week apart. PSA measurements can be collected during or after the most recent prior therapy.

• Dose-Determination Phase Segment 2: Currently receiving enzalutamide with a rising PSA as follows:

  1. Rising PSA: 25% increase over nadir and an absolute value of >1 ng/mL by at least 2 measurements obtained ≥1 week apart. PSA measurements can be collected during or after the most recent prior therapy.
  2. Patients must have received enzalutamide for a minimum of 12 weeks and have been on stable doses of enzalutamide ≥80 mg once daily for at least 4 weeks prior to Cycle 1 Day 1. Patients will continue enzalutamide without interruption during the Screening Period (no wash-out period). This will be the enzalutamide starting dose for combination with exicorilant beginning on Cycle 1 Day 1.
  3. M0 disease is allowed

• Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy as follows:

  1. Abiraterone-Resistant Cohort: Patients must have progressed during treatment with abiraterone
  2. Androgen Receptor Antagonist-Resistant Cohort: Patients must have progressed during treatment with enzalutamide or second-generation AR-blocking therapies. Patients progressing on enzalutamide immediately prior to enrolling in this study must be on stable doses of enzalutamide. These patients will continue enzalutamide without interruption during the Screening Period (no wash-out period required).

• Baseline tumor assessment performed within 28 days prior to the first dose of study treatment (exicorilant and/or on-study enzalutamide, whichever is earliest).

• Prior surgical or chemical castration with serum testosterone <1.7 nmol/L (50 ng/dL). If the method of castration is use of a luteinizing hormone-releasing hormone (LHRH) analogue, there must be a plan to maintain effective LHRH analogue treatment for the duration of the trial.

• Consent to have all protocol-required pharmacodynamic biomarker samples, including the pretreatment and on treatment paired tumor biopsies (mandatory for a subset of patients)

• Consent to provide mandatory pharmacogenomic blood sample (Dose-Determination Segment 1 only)

• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1

• Adequate baseline organ function within 14 days prior to the first dose of study treatment (on-study enzalutamide and/or exicorilant, whichever is earliest)

• Patients receiving systemic corticosteroids greater than 2-weeks in duration within 3 months of study entry or with clinical evidence of adrenal insufficiency must have evidence of adequate adrenal function based upon morning plasma cortisol concentration or adrenocorticotrophic hormone (ACTH, cosyntropin) stimulation test

• If a patient engages in sexual intercourse with a woman of childbearing potential, a condom with spermicide and another form of birth control must be used during and for 100 days after the final dose of study treatment (exicorilant or enzalutamide, whichever is latest). A condom is required during and for 100 days after completing treatment with enzalutamide if a patient is engaged in sexual activity with a pregnant woman. Patients must also agree to avoid sperm donation during the study and for at least 100 days after the final treatment administration.

Major Exclusion Criteria:

• Received chemotherapy, non-palliative radiotherapy, immunotherapy, or any investigational cancer therapies within 21 days prior to the first dose of exicorilant, or treatment with such therapies is planned during protocol treatment. Concomitant anticancer therapy is not permitted during the enzalutamide Lead-In Period during Dose-Determination Phase Segment 1.

• More than 2 prior cytotoxic chemotherapy regimens for the treatment of mCRPC

• Dose Determination Phase and Expansion Phases will exclude patients for the following:

  • Dose-Determination Phase (Segment 1 only):

    • Progressed during treatment with enzalutamide prior to Cycle 1 Day -28 (only applies to patients receiving enzalutamide Lead-In) or
    • Received prior second-generation anti-androgen and require urgent disease response or stabilization

  • Expansion Phase Abi-Resistant Cohort:

    • Received prior treatment with enzalutamide, or
    • Received prior second-generation anti-androgen and require urgent disease response or stabilization

  • Expansion Phase ARant-Resistant Cohort: Require urgent disease response or stabilization

• Ongoing or anticipated therapy with hormone therapy (other than LHRH analogue), including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride (Avodart) or received abiraterone within 28 days prior to the first dose of exicorilant

• Contraindication or precaution for enzalutamide

• Parenchymal brain metastases

• Any clinically significant uncontrolled condition that may increase the risk to the study patient or that the Investigator considers places the patient at unacceptable risk

• Received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity within 21 days of study treatment initiation or plans to initiate treatment with these products/alternative therapies during the entire duration of the study

• Received systemic glucocorticoids within 21 days prior to the first dose of exicorilant, or requirement for chronic or frequently used systemic or inhaled glucocorticoids for medical conditions (eg, rheumatoid arthritis, immunosuppression after organ transplantation). Short courses (≤5 days) for non-cancer related reasons are allowed if clinically required (such as prophylaxis for CT)

• Concurrent therapy with strong inhibitors or inducers of CYP3A4 or CYP2C8 or with sensitive substrates of CYP3A4, CYP2C9, or CYP2C19.