Clinical trial NCT02711956: A Study of ZEN003694 in Combination With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer
Official title: A Phase 1b/2a Safety and Tolerability Study of ZEN003694 in Combination With Enzalutamide in Patients With Metastatic Castration-Resistant Prostate Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Metastatic Castration-Resistant Prostate Cancer
Keywords: Metastatic Castration-Resistant Prostate Cancer (mCRPC)
Phase 1b/2a
Prostate Cancer
Pharmacokinetics (PK)
ZEN003694
ZEN-3694
Metastatic Castrate-Resistant Prostate Cancer
BET inhibitor (BETi)
Bromodomain
Pharmacodynamics (PD)
Enzalutamide
XTANDI
MDV3100
Epigenetics
Lead sponsor: Zenith Epigenetics
Sponsor class: INDUSTRY
First posted: 2016-03-17
Enrollment: 75
Sex: MALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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

Primary outcomes:
measure: 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.
timeFrame: Cycle 1 (Day 1 thru Day 28)
measure: For Dose Escalation and Dose Confirmation: Incidence of Treatment-emergent Adverse Events (TEAE) and Treatment-related Serious Adverse Events (SAE)
timeFrame: Cycle 1 Day 1 to 30 days post last dose
Secondary outcomes:
measure: Evaluate Prostate-specific Antigen (PSA) Response Rate by PCWG2 Criteria
timeFrame: Screening up to 35 months
measure: Evaluate Radiographic Response Rate (Overall Response Rate) by PCWG2 Criteria
timeFrame: Screening up to 35 months
measure: Evaluate Overall Median Progression-free Survival by PCWG2 Criteria
timeFrame: Screening up to 35 months
measure: Evaluate Median Radiographic Progression-Free Survival by PCWG2 Criteria
timeFrame: Screening up to 35 months
measure: Measure the Pharmacokinetic (PK) Parameter: AUC(0-24h) of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide.
timeFrame: Cycle 1 Day 1: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose; Cycle 1 Day 2: pre-dose; Cycle 1 Day 15: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose
measure: Measure the Pharmacokinetic (PK) Parameter: Cmax of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide
timeFrame: Cycle 1 Day 1: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose; Cycle 1 Day 2: pre-dose; Cycle 1 Day 15: pre-dose, 0.25, 0.5, 1, 2, 4, 6 and 8 hours post-dose
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: University of California Los Angeles Medical Center
state: California
city: San Francisco
country: United States
facility: University of California San Francisco Medical Center
state: California
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Farmington Hills
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: New York
country: United States
facility: Weill Cornell Medicine - New York Presbyterian
state: New York
city: Portland
country: United States
facility: Oregon Health & Science University
state: Oregon
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance
state: Washington
Study officials:
References: