A Study of ZEN003694 in Combination With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer

Phase 2CompletedNCT02711956

Zenith Epigenetics75 enrolled

Overview

This is an open label, non-randomized, Phase 1b/2a, dose escalation and dose confirmation study of ZEN003694 in combination with enzalutamide in patients with mCRPC.

Study Type

INTERVENTIONAL

Allocation

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Metastatic Castration-Resistant Prostate Cancer

Interventions

ZEN003694DRUG

EnzalutamideDRUG

Eligibility

Sex: MALEMin age: 18 Years

Medical Language ↔ Plain English

Inclusion Criteria: 1. Males age ≥ 18 years 2. Metastatic, castrate resistant, histologically confirmed prostate cancer; surgically castrated or continuous medical castration for ≥ 8 weeks prior to screening 3. Serum testosterone \< 50 ng/dL determined within 4 weeks of first administration of study drug 4. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 5. Adequate laboratory parameters \[absolute neutrophil (ANC), platelets, asparate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, creatinine and coagulation parameters\] at screening 6. Dose Escalation Cohort DE-A: Prior progression on enzalutamide or apalutamide at any time by PCWG2 criteria and receiving a stable dose of enzalutamide at the start of study treatment. 7. Dose Escalation Cohort DE-B: Enzalutamide-naïve and apalutamide-naïve patients following prior progression on abiraterone by PCWG2 criteria and receiving a stable dose of enzalutamide at the start of study treatment. 8. Dose Confirmation Cohort A (DC-A) only: Currently receiving enzalutamide as most recent systemic therapy for mCRPC and have experienced PSA progression by PCWG2 criteria in the absence of radiographic and/or clinical progression. Patients may or may not have experienced prior progression on abiraterone. 9. Dose Confirmation Cohort B (DC-B) only: Enzalutamide-naïve patients following prior progression on abiraterone by PCWG2 criteria and within 12 weeks of discontinuing abiraterone. Exclusion Criteria: 1. Any history of brain metastases or prior seizure or conditions predisposing to seizure activity 2. Have previously received an investigational BET inhibitor (including previous participation in this study or Study ZEN003694-001) 3. Have received prior systemic anti-cancer therapy (including abiraterone) or investigational therapy within 2 weeks or five half-lives, whichever is shorter, prior to the first administration of study drug 4. Failure to recover to Grade 1 or lower toxicity related to prior systemic therapy (excluding alopecia and neuropathy) prior to study entry 5. Radiation therapy within 2 weeks of the first administration of study drug 6. Have received prior chemotherapy in the metastatic castration-resistant setting (prior chemotherapy in the hormone-sensitive setting is allowed provided last dose was at least 6 months prior to study entry) 7. Have received prior investigational anti-androgen therapy, including ARN-509 8. Currently receiving medications known to be strong inhibitors of CYP2C8, strong inducers (except enzalutamide) or inhibitors of CYP3A4 and substrates of CYP3A4, CYP2C9 and CYP2C19 with a narrow therapeutic window. Strong inducers, inhibitors and substrates must be discontinued at least 7 days prior to the first administration of study drug. 9. Not a candidate for enzalutamide treatment, in the opinion of the Investigator

Locations (8)

University of California Los Angeles Medical Center

Los Angeles, California, United States

University of California San Francisco Medical Center

San Francisco, California, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Karmanos Cancer Institute

Outcomes

Primary Outcomes

For Dose Escalation: Incidence of Dose-limiting Toxicities (DLT) to Determine the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of ZEN003694 in Combination With Enzalutamide.

Determination of DLT was made during the first 28 days of treatment in the dose escalation phase. A DLT is defined as a clinically significant AE or laboratory abnormality that is considered possibly, probably, or definitely related to study drug. The MTD reflects the highest dose of ZEN003694 in combination with enzalutamide that did not cause a DLT in more than 1 of 6 patients. The RP2D is the recommended dose of ZEN003694 in combination with enzalutamide as determined in the dose confirmation phase of the study.

Time frame: Cycle 1 (Day 1 thru Day 28)

For Dose Escalation and Dose Confirmation: Incidence of Treatment-emergent Adverse Events (TEAE) and Treatment-related Serious Adverse Events (SAE)

Treatment-emergent adverse events (TEAEs) were defined as any adverse events (AEs) that begin or worsen on or after the start of study drug through 30 days after the last dose of study drug. The severity of AEs was graded based on the National Cancer Institute's Common Terminology for Adverse Events (V4.03). A serious adverse event (SAE) was any AE that was: fatal; life-threatening; required in-patient hospitalization or prolonged an existing hospitalization; disabling or incapacitating; a congenital anomaly or birth defect; or any other important medical event.

Time frame: Cycle 1 Day 1 to 30 days post last dose

Secondary Outcomes

Evaluate Prostate-specific Antigen (PSA) Response Rate by PCWG2 Criteria

The PSA response rate will be evaluated using PCWG2 criteria and defined as the proportion of patients with a PSA decline of at least 50%. Any change from baseline is confirmed by a second measurement at least 3 weeks later. PSA Response Rate will be evaluated using PCWG2 criteria and defined as following: Percentage change from baseline in PSA to 12 weeks post ZEN003694 dose. Only evaluate for patients with at least 12 weeks of treatment, the PSA assessment at 12 weeks (84 days +/-3 days) will be used; Maximum percent decrease in PSA from baseline that occurs at any point after treatment. Evaluable for all patients with post-baseline PSA. Arms will be combined to analyze efficacy in Cohort A and Cohort B.

Data from ClinicalTrials.gov

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