Study to Evaluate CORT125281 in Combination With Enzalutamide in Patients With mCRPC

CORT125281 is a selective glucocorticoid receptor (GR) antagonist. In this study, CORT125281
will be administered orally in combination with enzalutamide to patients with metastatic
castration-resistant prostate cancer (mCRPC) to evaluate the safety, tolerability,
pharmacokinetics, pharmacodynamics, and preliminary efficacy of the regimen. The study
consists of two phases: a dose-escalation phase and an expansion phase. The dose escalation
phase is designed to determine DLTs, MTD/biologically active doses and the RD of CORT125281
plus enzalutamide in patients with mCRPC. Once the recommended dose has been determined, the
following expansion cohorts will be enrolled and treated with CORT125281 plus enzalutamide at
the recommended dose level.

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

2. Patients who have progressed during treatment with enzalutamide or other
second-generation AR inhibitors.

The effect of food on CORT125281 PK will be assessed in a portion of the patients enrolled in
the Expansion Phase. The expansion cohorts will be enrolled in parallel.

In each phase of the study, routine assessments of safety and tolerability will be performed
using adverse event (AE) monitoring, measurement of vital signs, recording 12 lead
electrocardiogram (ECG), physical examination and clinical laboratory safety tests, and
samples will be collected to determine standard PK parameters for CORT125281, enzalutamide,
and their major metabolites. PD, quality of life evaluations and preliminary evaluations of
anti-tumor activity of CORT125281 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 metastatic adenocarcinoma of the prostate without
histological neuroendocrine differentiation or small cell features

- 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

- Progressive disease by 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 most recent
prior therapy.

- 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.

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

- Adequate baseline organ function within 14 days prior to the first dose of
enzalutamide and/or CORT125281

- 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 ACTH (cosyntropin) stimulation test

- If a patient engages in sexual intercourse with a woman of childbearing potential, a
condom and another form of birth control must be used during and for 100 days after
completing treatment with CORT125281 or enzalutamide. 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.

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

- Cohort A: Patients must have progressed during treatment with abiraterone

- Cohort B: 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
160 mg once daily (QD). These patients will continue enzalutamide without interruption
during the screening period (no wash-out period required).

Major Exclusion Criteria:

- Received chemotherapy, non-palliative radiotherapy, immunotherapy, or any
investigational cancer therapies within 21 days prior to the first dose of CORT125281,
or treatment with such therapies is planned during protocol treatment. Concomitant
anticancer therapy is not permitted during the enzalutamide Lead-in Period during dose
escalation.

- More than two prior cytotoxic chemotherapy regimens for the treatment of mCRPC

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

- Dose Escalation Phase

- Progressed during treatment with enzalutamide prior to Cycle 1 Day -28 (only
applies to patients receiving enzalutamide Lead-in) or

- Received prior 2nd generation anti-androgen and require urgent disease response
or stabilization

- Expansion Phase Cohort A:

- Received prior treatment with enzalutamide, or

- Received prior 2nd generation anti-androgen and require urgent disease response or
stabilization

- Expansion Phase Cohort B: Require urgent disease response or stabilization

- Ongoing or anticipated therapy with hormone therapy (other than LHRH antagonist),
including any dose of megestrol acetate (Megace), finasteride (Proscar), dutasteride
(Avodart) or received abiraterone within 28 days prior to the first dose of CORT125281

- 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 (e.g., saw palmetto, PC-SPES, PC-
HOPE, St. John's wort, selenium supplements, grape seed extract, etc.) within 28 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
CORT125281, or requirement for chronic or frequently used systemic glucocorticoids for
medical conditions (e.g., 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