| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic castration-resistant prostate cancer. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Metastatic castration-resistant prostate cancer. |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10076506 |
| E.1.2 | Term | Castration-resistant prostate cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective is to determine the maximum tolerated dose (MTD) and/or biologically active doses of CORT125281 in combination with enzalutamide to identify the recommended dose (RD) for Phase 2 studies. |
|
| E.2.2 | Secondary objectives of the trial |
• Evaluate the safety and tolerability of CORT125281 in combination with enzalutamide
• Characterize the preliminary efficacy of CORT125281 in combination with enzalutamide by determining the objective response rate (ORR), proportion of patients with a reduction in prostate-specific antigen (PSA) level by >50%, time to a symptomatic skeletal event (SSE), radiographic progression-free survival (rPFS) including the proportion of patients who are progression-free at 4, 6, and 12 months, duration of response, and overall survival
• Assess time to PSA progression and clinical progression, including the proportion of patients who are progression free at 4, 6, and 12 months
• Determine the pharmacokinetic (PK) profile of CORT125281 and enzalutamide, when co-administered
• Determine the effect of food on the PK of CORT125281 |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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 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:
- 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.
- Patients must have received enzalutamide for a minimum of 12 weeks and be on stable doses of enzalutamide ≥80 mg QD 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 CORT125281 beginning on Cycle 1 Day 1.
- M0 disease is allowed.
• Expansion Phase: Patients must have progressed while receiving an androgen-directed therapy,
as follows:
- Abi-Resistant Cohort: Patients must have progressed during treatment with abiraterone.
- ARant-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).
• 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 PD biomarker samples. The pre-treatment and on -treatment paired tumor biopsies will be mandatory for a subset of patients.
• Consent to provide mandatory pharmacogenomic blood sample (Dose-Determination Phase 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 (enzalutamide and/or CORT125281, whichever is earlier).
• 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 with
spermicide and another form of birth control must be used during and for 100 days after the final dose of study treatment (CORT125281 or enzalutamide, whichever is later). 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.
|
|
| E.4 | Principal 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-Determination Phase Segment 1.
• More than two prior cytotoxic chemotherapy regimens for the treatment of mCRPC
• The Dose Determination and Expansion Phases will exclude patients for the following:
o 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 2nd generation anti-androgen and require urgent disease response or stabilization
Expansion Phase Abi-Resistant Cohort:
Received prior treatment with enzalutamide, or
Received prior 2nd generation anti-androgen and require urgent disease response or stabilization
o 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 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 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 CORT125281, or requirement for chronic or frequently used systemic or inhaled 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Radiographic disease progression, SSE, and overall survival. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Follow-up phase: every 4 months until 2 years from the date that the last patient enrolls in the study. |
|
| E.5.2 | Secondary end point(s) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| The end of study is defined as the date of last contact (visit, telephone, e-mail) with any study patient. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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