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

• ClinicalTrials.gov Identifier: NCT02711956
• Recruitment Status: Completed
• First Posted: March 17, 2016
• Results First Posted: August 10, 2021
• Last Update Posted: November 30, 2021
• Sponsor: Zenith Epigenetics
• Information provided by (Responsible Party): Zenith Epigenetics

Tracking Information

• First Submitted Date: March 14, 2016
• First Posted Date: March 17, 2016
• Results First Submitted Date: June 18, 2021
• Results First Posted Date: August 10, 2021
• Last Update Posted Date: November 30, 2021
• Actual Study Start Date: December 2016
• Actual Primary Completion Date: November 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: July 15, 2021)

• 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. [ Time Frame: Cycle 1 (Day 1 thru Day 28) ]
  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.
• For Dose Escalation and Dose Confirmation: Incidence of Treatment-emergent Adverse Events (TEAE) and Treatment-related Serious Adverse Events (SAE) [ Time Frame: Cycle 1 Day 1 to 30 days post last dose ]
  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.

Original Primary Outcome Measures (submitted: March 14, 2016)

• For dose escalation only: Incidence of dose-limiting toxicities (DLT) [ Time Frame: Cycle 1 (Day 1 thru Day 28) ]
  A DLT is a treatment-related, clinically significant adverse event or laboratory abnormality occurring during the first cycle of treatment (Day 1 thru Day 28).
• For dose escalation and dose confirmation: Incidence of treatment-related adverse events (AE) and treatment-related serious adverse events (SAE) [ Time Frame: Up to 18 months ]

Current Secondary Outcome Measures (submitted: July 15, 2021)

• Evaluate Prostate-specific Antigen (PSA) Response Rate by PCWG2 Criteria [ Time Frame: Screening up to 35 months ]
  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.
• Evaluate Radiographic Response Rate (Overall Response Rate) by PCWG2 Criteria [ Time Frame: Screening up to 35 months ]
  Tumor response will be evaluated using the PCWG2 criteria. Patients with measurable disease will be evaluated for clinical benefit as determined by tumor response using RECIST v1.1. Patients with non-measurable bone disease will be evaluated for progression based on the presence of any new lesions by bone scans. Radiographic tumor evaluation will be performed at screening and every 3 cycles or more frequently as determined by the investigator. Using the tumor response that is determined by the investigator, best overall response will be determined using RECIST v1.1. Best overall response is defined as the best response recorded from the start of treatment until disease progression or study exit. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
• Evaluate Overall Median Progression-free Survival by PCWG2 Criteria [ Time Frame: Screening up to 35 months ]
  Overall progression free survival (PFS) is determined using the PCWG2 criteria. Overall PFS is measured from screening until the time that disease progression (radiographic progressive disease or clinical deterioration) or death is documented, whichever occurs first. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
• Evaluate Median Radiographic Progression-Free Survival by PCWG2 Criteria [ Time Frame: Screening up to 35 months ]
  Radiographic progression-free survival (rPFS) is determined using the PCWG2 criteria to assess both soft-tissue and bone assessments. The rPFS is measured from screening until the time the first radiographic scan shows disease progression, or until the time of death, whichever occurs first. If radiographic disease progression is identified at the first on-treatment radiographic assessment at Cycle 3 Day 1 (8 weeks), radiographic progression must be confirmed by a second assessment 6 or more weeks later. Patients who do not progress radiographically or did not die prior to study exit are censored on the date of their last dose of ZEN003694. Arms will be combined to analyze efficacy in Cohort A and Cohort B.
• Measure the Pharmacokinetic (PK) Parameter: AUC(0-24h) of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide. [ Time Frame: 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 ]
  AUC(0-24h) is defined as the area under the curve (plasma concentration of drug over a 24-hour time period).
• Measure the Pharmacokinetic (PK) Parameter: Cmax of ZEN003694 and ZEN003791 (Active Metabolite) Administered in Combination With Enzalutamide [ Time Frame: 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 ]
  Cmax is defined as the maximum or peak plasma concentration of drug.

Original Secondary Outcome Measures (submitted: March 14, 2016)

• Measure the pharmacokinetic (PK) parameter: AUC of ZEN003694 administered in combination with enzalutamide [ Time Frame: 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; Cycle 2 Day 1: pre-dose ]
  AUC is defined as the area under the curve (plasma concentration of drug over time).
• Measure the pharmacokinetic (PK) parameter: Cmax of ZEN003694 administered in combination with enzalutamide [ Time Frame: 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; Cycle 2 Day 1: pre-dose ]
  Cmax is defined as the maximum or peak plasma concentration of drug.
• Measure the pharmacokinetic (PK) parameter: Cmin of ZEN003694 administered in combination with enzalutamide [ Time Frame: 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; Cycle 2 Day 1: pre-dose ]
  Cmin is defined as the minimum or trough plasma concentration of drug.
• Measure the pharmacokinetic (PK) parameter: Tmax of ZEN003694 administered in combination with enzalutamide [ Time Frame: 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; Cycle 2 Day 1: pre-dose ]
  Tmax is defined as the time from dosing to the maximum plasma concentration.
• Measure the pharmacokinetic (PK) parameter: t1/2 of ZEN003694 administered in combination with enzalutamide [ Time Frame: 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; Cycle 2 Day 1: pre-dose ]
  t1/2 is defined as the half-life of drug.
• Evaluate prostate-specific antigen (PSA) response rate by PCWG2 criteria [ Time Frame: From screening up to 18 months ]
• Evaluate radiographic response rate by PCWG2 criteria [ Time Frame: From screening up to 18 months ]
• Evaluate median progression-free survival by PCWG2 criteria [ Time Frame: From screening up to 18 months ]
• Evaluate circulating tumor cell (CTC) response rate during dose confirmation phase only [ Time Frame: From screening up to 12 months ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: 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
• 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.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Castration-Resistant Prostate Cancer

Intervention

• Drug: ZEN003694
• Drug: Enzalutamide
  Other Names:

  • XTANDI
  • MDV3100

Study Arms

Experimental: DE and DC - ZEN003694 in Combination with Enzalutamide

Dose Escalation (DE) and Dose Confirmation (DC): ZEN003694 will be administered orally once daily with enzalutamide in 28-day cycles, enrolling mCRPC patients.

Two patient populations will be enrolled in DE and DC. Cohort A: Patients with prior progression on enzalutamide or apalutamide by PCWG2 criteria who were receiving a stable dose of enzalutamide at the time of study entry. Cohort B: Patients who were enzalutamide-naïve with prior progression on abiraterone by Prostate Cancer Working Group 2 (PCWG2) criteria.

Interventions:

• Drug: ZEN003694
• Drug: Enzalutamide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 1, 2020): 75
• Original Estimated Enrollment (submitted: March 14, 2016): 58
• Actual Study Completion Date: November 2019
• Actual Primary Completion Date: November 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02711956
• Other Study ID Numbers: ZEN003694-002
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Zenith Epigenetics
• Original Responsible Party: Same as current
• Current Study Sponsor: Zenith Epigenetics
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Zenith Epigenetics
• Verification Date: November 2021