Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Subjects With Castration Resistant Prostate Cancer Who Have Not Received Chemotherapy

• ClinicalTrials.gov Identifier: NCT04179864
• Recruitment Status: Recruiting
• First Posted: November 27, 2019
• Last Update Posted: July 1, 2021
• Sponsor: Epizyme, Inc.
• Information provided by (Responsible Party): Epizyme, Inc.

Tracking Information

• First Submitted Date: November 14, 2019
• First Posted Date: November 27, 2019
• Last Update Posted Date: July 1, 2021
• Actual Study Start Date: September 26, 2019
• Estimated Primary Completion Date: March 1, 2022 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 24, 2021)

• Ph 1b: Determine the safety and tolerability of each of the combinations [ Time Frame: Assessed at end of Cycle 1 (each cycle is 28 days) ]
  Assess safety and tolerability of Tazemetostat in combination with enzalutamide or with abiraterone/prednisone by reviewing incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1Safety and tolerability of Tazemetostat in combination with enzalutamide or with abiraterone/prednisone
• Ph 1b: Select the recommended phase 2 doses (RP2D) of tazemetostat for each combination [ Time Frame: 1 cycle/28 days ]
  Based on pharmacokinetic (PK) and pharmacodynamic parameters as well as efficacy and the overall tolerability of each of the combinations (tazemetost with enzalutamide or tazemetostat with abiraterone/prednisone)
• Ph 2: Determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone by assessing change in radiographic progression free survival [ Time Frame: Day 1 of Cycles 3, 5, 7, 10, and 13, and every 12 weeks after Cycle 13 for 1 year (each cycle is 28 days) ]
  Assessed by change radiographic progression free survival (rPFS) according to Prostate Cancer Clinical Trials Working Group 3 (PCWG3) criteria for progression in bone or in soft tissue

Original Primary Outcome Measures (submitted: November 25, 2019)

• Ph 1b: Determine the safety and tolerability of each of the combinations by reviewing dose limiting toxicities. [ Time Frame: The incidence and severity of treatment-emergent adverse events (AEs) qualifying as protocol-defined DLTs in Cycle 1 (28 days) ]
  Safety and tolerability of Tazemetostat in combination with enzalutamide or with abiraterone/prednisone
• Ph 1b: Select the recommended phase 2 doses (RP2D) for each combination [ Time Frame: 1 cycle/28 days ]
  Based on pharmacokinetic (PK) and pharmacodynamic parameters as well as efficacy and the overall tolerability of each of the combinations

Current Secondary Outcome Measures (submitted: May 24, 2021)

• Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - PSA Change [ Time Frame: Assessed at Day 1 of every cycle for an average of one year (each cycle is 28 days) ]
  Confirmed prostate-specific antigen (PSA) responses will be defined as ≥50% reductions in PSA from baseline to lowest post baseline PSA result
• Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - PSA Change [ Time Frame: Assessed at Day 1 of every cycle for an average of one year (each cycle is 28 days) ]
  PSA progression is defined as a ≥25% increase from baseline to the day of PSA progression per PCWG3 criteria
• Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - First Skeletal-Related Event (SRE) [ Time Frame: During screening and every 9 weeks if clinically indicated at baseline, average of one year. ]
  Time from randomization to first SRE will be assessed.
• Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - ORR [ Time Frame: Assessed at Day 1 of every cycle for an average of one year (each cycle is 28 days) ]
  Assess objective response rate (ORR) per PCWG3 criteria and RECIST 1.1 guidelines
• Determine benefit of combining tazemetostat with enzalutamide or abiraterone/prednisone (phase 1b) and benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone (phase 2) - DCR [ Time Frame: Assessed at 6 months on treatment ]
  Assess disease control rate (DCR), no radiographic progression per PCWG3 criteria and no unequivocal clinical progression or death
• Evaluate the safety and tolerability of the combination of study drugs by assessing PK data [ Time Frame: Phase 1b PK of Tazemetostat will be assessed on Day 1 of Cycles 1 and 2. Phase 2 PK of Tazemetostat will be assessed on Day 1 of Cycles 2, 3, 5 and 10. (each cycle is 28 days) ]
  Assess the PK of tazemetostat from collection of blood draws
• Evaluate the safety and tolerability of the combination of study drugs by assessing PK data [ Time Frame: Phase 1b PK of enzalutamide will be assessed on Day 1 of Cycles 1 and 2. Phase 2 PK enzalutamide will be assessed on Day 1 of Cycles 2, 3, 5 and 10. (each cycle is 28 days) ]
  Assess the PK of enzalutamide from collection of blood draws
• Evaluate the safety and tolerability of the combination of study drugs by assessing PK data [ Time Frame: Phase 1b PK of abiraterone/prednisone will be assessed on Day 1 of Cycles 1 and 2. (each cycle is 28 days) ]
  Assess the PK of abiraterone/prednisone from collection of blood draws
• Assess the rate of reducing circulating tumor cells (CTC) [ Time Frame: Assessed at screening, on Day 1 of Cycles 1, 2, 3, 4, 5, 7, 10 and 13 (each cycle is 28 days) and post-treatment (30 days after last dose) ]
  Assess the rate of reducing circulating tumor cells (CTC) from a state of having a detectable number of CTCs to having an undetectable number of CTCs
• Assess CTC response rate [ Time Frame: Assessed at screening, Day 1 of Cycles 1, 2, 3, 4, 5, 7, 10, 13 (each cycles is 28 days), and post-treatment (30 days after last dose) ]
  Assess CTC response rate as defined by a ≥30% reduction in CTC number from baseline.
• PHASE 2 ONLY: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, quality of life (QoL) will be assessed. [ Time Frame: Assessed at screening, Day 1 of Cycles 3, 5, 7, 10, 13 (each cycle is 28 days), and post-treatment (30 days after last dose) ]
  Quality of Life (QoL) as assessed by changes from baseline in FACT-P Functional Well-being Subscale (FWB)
• PHASE 2 ONLY: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, quality of life (QoL) will be assessed. [ Time Frame: Assessed at screening, Day 1 of Cycles 3, 5, 7, 10, 13 (each cycle is 28 days), and post-treatment (30 days after last dose) ]
  Quality of Life (QoL) as assessed by changes from baseline in Brief Pain Inventory (BPI) short form
• PHASE 2 ONLY: To determine the benefit of combining tazemetostat with enzalutamide when compared to enzalutamide alone, quality of life (QoL) will be assessed. [ Time Frame: Assessed at screening, Day 1 of Cycles 3, 5, 7, 10, 13 (each cycle is 28 days), and post-treatment (30 days after last dose) ]
  Quality of Life (QoL) as assessed by changes from baseline in EQ-5D-5L visual analogue scale.

Original Secondary Outcome Measures (submitted: November 25, 2019)

• PSA ≥50% Response Rate [ Time Frame: Assessed every cycle for an average of one year. ]
  Confirmed PSA responses will be defined as ≥50% reductions in PSA from baseline to lowest post baseline PSA result, with a consecutive assessment
• Time to PSA Progression [ Time Frame: Assessed every cycle for an average of one year. ]
  PSA progression is defined as a ≥25% increase and an absolute increase of ≥ 2 μg/L (2 ng/mL) above the nadir (or baseline value for subjects who did not have a decline in PSA value at week 17)
• Time to First Skeletal-Related Event (SRE) [ Time Frame: During screening and every 9 weeks if clinically indicated at baseline, average of one year. ]
  Time from randomization to first SRE will be assessed. An SRE is defined as radiation therapy or surgery to bone, pathologic bone fracture, spinal cord compression, or change of antineoplastic therapy to treat bone pain
• ORR and Best Overall Soft Tissue Response [ Time Frame: Assessed at screening and every 9 weeks for the first 6 months then every 12 weeks thereafter, average of one year. ]
  ORR is defined per PCWG3 criteria and mRECIST 1.1 guidelines
• Disease Control Rate [ Time Frame: At screening to 6 months on study therapy ]
  No radiographic progression per PCWG3, unequivocal clinical progression, or death
• Time to Initiation of Subsequent Antineoplastic Cytotoxic Chemotherapy [ Time Frame: Duration of the study, an average of one year. ]
  A log-rank test will be used to compare time to initiation of subsequent antineoplastic cytotoxic chemotherapy between tazemetostat in combination with enzalutamide or abiraterone/prednisone, and enzalutamide or abiraterone/prednisone treatment alone, respectively
• Further evaluate the incidence of treatment-emergent adverse events for safety and tolerability of each of the combinations [ Time Frame: From randomization until radiographic progression, for up to one year. ]
  Combinations tazemetostat with enzalutamide or tazemetostat with abiraterone/prednisone
• Assess pharmacokinetic of tazemetostat, enzalutamide and abiraterone by area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUC0-last). [ Time Frame: Assessed on cycle 1 on days 1, 2 and 21; and cycle 2, day 1 (each cycle is 28 days). ]
  Assess the PK of tazemetostat when administered in combination with enzalutamide and abiraterone/prednisone and the PK of enzalutamide and abiraterone when administered in combination with tazemetostat.
• Assess pharmacokinetic of tazemetostat, enzalutamide and abiraterone by maximum plasma concentration (Cmax). [ Time Frame: Assessed on cycle 1 on days 1, 2 and 21; and cycle 2, day 1 (each cycle is 28 days). ]
  Assess the PK of tazemetostat when administered in combination with enzalutamide and abiraterone/prednisone and the PK of enzalutamide and abiraterone when administered in combination with tazemetostat
• Assess pharmacokinetic of tazemetostat, enzalutamide and abiraterone by under Cmax: maximum plasma concentration. [ Time Frame: Assessed on cycle 1 on days 1, 2 and 21; and cycle 2, day 1 (each cycle is 28 days). ]
  Assess the PK of tazemetostat when administered in combination with enzalutamide and abiraterone/prednisone and the PK of enzalutamide and abiraterone when administered in combination with tazemetostat
• Assess circulating tumor cells conversion rate [ Time Frame: Assessed every cycle for duration of the study, an average of one year. ]
  In subjects who enter the study with unfavorable CTCs (5 or more cells per 7.5 mL of blood), conversion to favorable status is defined as 4 or fewer cells per 7.5 mL of blood. The CTC conversion rate is the proportion of subjects who convert to a favorable status (per PCWG3 criteria).
• Assess CTC 30% response rate [ Time Frame: Assessed every cycle for duration of the study, an average of one year. ]
  CTC 30% response is defined as a ≥30% reduction in number of CTCs per 7.5 mL of blood from baseline in subjects who enter the study with unfavorable CTCs.

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

Descriptive Information

• Brief Title: Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Subjects With Castration Resistant Prostate Cancer Who Have Not Received Chemotherapy
• Official Title: A Phase 1b/2 Open-Label Study Evaluating Tazemetostat in Combination With Enzalutamide or Abiraterone/Prednisone in Chemotherapy Naive Subjects With Metastatic Castration-Resistant Prostate Cancer
• Brief Summary: A phase 1b/2 study to examine taz in combination with enz or abi/pred in patients with metastic castration resistant prostate cancer
• Detailed Description: This is a global, multi-center, open-label, randomized phase 1b, active-controlled safety and efficacy study of oral administration of tazemetostat in combination with enzalutamide or abiraterone/prednisone (phase 1b) versus enzalutamide or abiraterone/prednisone alone in asymptomatic or mildly symptomatic subjects with progressive, metastatic castration-resistant prostate cancer (mCRPC) who have progressed on either abiraterone acetate, enzalutamide, or apalutamide or who are second generation anti-androgen treatment naive, and who have not received chemotherapy for mCRPC. This study is designed to determine the recommended phase 2 doses (RP2D) of tazemetostat in combination with either enzalutamide or abiraterone/prednisone, based on safety, tolerability, pharmacokinetic, pharmacodynamic, and efficacy profiles.
• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Metastatic Prostate Cancer

Intervention

• Drug: Tazemetostat
  Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
  Other Names:

  • EPZ-6438
  • E7438
• Drug: Abiraterone/prednisone
  1,000 mg (two 500 mg tablets or four 250 mg tablets) orally once daily in combination with prednisone 5 mg administered orally twice daily.
  Other Name: Zytiga
• Drug: Enzalutamide
  enzalutamide 160 mg (four 40 mg capsules) orally once daily
  Other Name: Xtandi

Study Arms

• Experimental: Phase 1b: Tazemetostat in Combination with Abiraterone/Prednisone
  In Phase 1b, Abiraterone/prednisone will be administered on cycle 1 day 1 and Tazemetostat on cycle 1 day 2
  Interventions:

  • Drug: Tazemetostat
  • Drug: Abiraterone/prednisone
• Experimental: Phase 1b: Tazemetostat in Combination with Enzalutamide
  In Phase 1b, Enzalutamide will be administered on cycle 1 day 1 and Tazemetostat on cycle 1 day 2
  Interventions:

  • Drug: Tazemetostat
  • Drug: Enzalutamide
• Experimental: Phase 2: Tazemetostat in Combination with Enzalutamide
  In Phase 2, Enzalutamide and Tazemetostat will be administered on cycle 1 day 1
  Interventions:

  • Drug: Tazemetostat
  • Drug: Enzalutamide
• Active Comparator: Phase 2: Enzalutamide only
  In Phase 2, Enzalutamide will be administered on cycle 1 day 1
  Intervention: Drug: Enzalutamide

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: March 8, 2021): 104
• Original Estimated Enrollment (submitted: November 25, 2019): 48
• Estimated Study Completion Date: August 1, 2022
• Estimated Primary Completion Date: March 1, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Age at the time of consent ≥ 18 years.
2. Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
3. Life expectancy of > 3 months.
4. Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.

5. Progressive disease in the setting of medical or surgical castration (ie, castration- resistant prostate cancer [CRPC]) by PCWG3 criteria for study entry.

   • Evidence of disease progression by rising PSA or
   • Soft tissue progression per RECIST 1.1 or
   • Evidence of disease progression by observation of 2 new bone lesions since the initiation of last systemic therapy.

6. Metastatic prostate cancer disease, documented by the following imaging

   • Bone lesions on bone scan (per PCWG3) or by soft tissue disease (per RECIST 1.1) by CT/MRI imaging Must have undergone bilateral orchiectomy or be willing to continue GnRH analogue or antagonist.

7. Prior treatment with a second-generation androgen inhibitor as follows:

   • For phase 1b, EITHER Previously untreated with or progressed on a second generation androgen inhibitor (abiraterone, enzalutamide, or apalutamide) OR progressed on a second generation inhibitor (inhibitor (abiraterone, enzalutamide, or apalutamide)
   • For phase 2 randomized component (i.e, enzalutamide- containing treatment arms) of the study, previously progressed on abiraterone.

Exclusion Criteria:

1. Known symptomatic brain metastases

2. Treatment with any of the following for prostate cancer within the indicated timeframe prior to day 1 of starting study treatment:

   • First generation: AR antagonists (eg, bicalutamide, nilutamide, flutamide) within 4 weeks.
   • 5-alpha-reductase inhibitors, ketoconazole, estrogens (including diethylstilbesterol), or progesterones within 2 weeks.
   • Chemotherapy (except as permitted in inclusion criteria #10) within 3 weeks.
   • Prior radionuclide therapy within 4 weeks.
   • Another interventional product or standard agent in a clinical study within 28 days prior to the first planned dose of Tazemetostat
   • For phase 2 subjects to be randomized to one of the enzalutamide treatment arms only, prior treatment with the second-generation androgen inhibitor enzalutamide
3. Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment
4. Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.

Sex/Gender

• Sexes Eligible for Study: Male

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Shefali Agarwal, MD; 617-229-7575; clinicaltrials@epizyme.com

Contact: Daniel Powers, DO; 978-289-8488

• Listed Location Countries: Belgium, Spain, United States

Administrative Information

• NCT Number: NCT04179864
• Other Study ID Numbers: EZH-1101
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Responsible Party: Epizyme, Inc.
• Study Sponsor: Epizyme, Inc.
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Epizyme, Inc.
• Verification Date: June 2021