A Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Participants With Advanced Prostate Cancer (CELLO-1)

• ClinicalTrials.gov Identifier: NCT04179864
• Recruitment Status: Active, not recruiting
• First Posted: November 27, 2019
• Last Update Posted: April 29, 2024
• Sponsor: Epizyme, Inc.
• Information provided by (Responsible Party): Ipsen ( Epizyme, Inc. )

Tracking Information

• First Submitted Date: November 14, 2019
• First Posted Date: November 27, 2019
• Last Update Posted Date: April 29, 2024
• Actual Study Start Date: November 18, 2019
• Estimated Primary Completion Date: June 28, 2024 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 9, 2023)

• Ph 1b: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) [ Time Frame: At end of Cycle 1 (each cycle is 28 days) ]
  An Adverse event (AE) is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
• 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: Change in radiographic progression free survival (rPFS) [ 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 9, 2023)

• Phase 1b and 2: Percentage of participants with a ≥50% decline of Prostate Specific-Antigen (PSA50). [ Time Frame: From baseline at any time on study, an average of one year ]
  For participants with a baseline PSA ≥2.0 ug/L (ng/mL) per PCWG3 criteria
• Phase 1b and 2: Objective response rate (ORR) and best overall response (BOR) in soft tissue [ Time Frame: At 6 months on treatment. ]
  According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) guidelines.
• Phase 1b and 2: Disease control rate (DCR) [ Time Frame: At 6 months on treatment. ]
  Assessed by radiographic progression per PCWG3 criteria, with no unequivocal clinical progression or death
• Phase 1b and 2: Time to first skeletal-related event (SRE) [ Time Frame: During screening and every 9 weeks if clinically indicated at baseline, average of one year ]
• Phase 1b and 2: Time to initiation of the next systemic treatment for prostate cancer (TTNT) [ Time Frame: From baseline to end of study, an average of one year ]
  TTNT is defined as the time from the date of randomization to date of first documented administration of the next systemic treatment for prostate cancer.
• Phase 1b and 2: Time to PSA progression (TTPP) [ Time Frame: From baseline to the day of PSA progression, an average one one year. ]
  Defined as the duration per PCWG3 criteria in months.
• Phase 1b and 2: Reduction in circulating tumor cells (CTC) [ Time Frame: From screening to 30 days after last dose ]
  From a state of having a detectable number of CTCs to having an undetectable number of CTCs
• Phase 1b and 2: CTC response rate [ Time Frame: From baseline to end of study, an average of one year ]
  Defined as the percentage of participants with a ≥30% reduction in CTC number
• Phase 1b and Phase 2: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) [ Time Frame: From baseline to end of study, an average of one year ]
  An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention.
• Phase 1b and 2: AUC0-last: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. [ Time Frame: From baseline to end of study, an average of one year ]
  AUClast is defined as the concentration of drug from time zero to the last observable concentration.
• Phase 1b and 2:AUC0-24: area under the plasma concentration-time curve from time 0 to the time of 24 hours. [ Time Frame: From baseline to end of study, an average of one year ]
  AUC_0-24 is defined as the concentration of drug over time from time zero to 24 hours.
• Phase 1b and 2: Cmax: maximum plasma concentration. [ Time Frame: From baseline to end of study, an average of one year ]
  Cmax is defined as the maximum observed concentration of drug.
• Phase 2: Change in Functional Assessment of Cancer Therapy - Prostate (FACT-P) [ Time Frame: From baseline to end of study, an average of one year ]
  Assessed by Well-being Subscale (FWB) and Prostate Cancer Subscale (PCS) scores
• Phase 2: Time to definitive deterioration (TDD) in functional status and in prostate symptoms [ Time Frame: From baseline to end of study, an average of one year ]
  Assessed by the FACT-P FWB and PCS scores.

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: A Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Participants With Advanced Prostate Cancer
• Official Title: CELLO-1: 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

This is a global, multi-center, open-label, randomized phase 1b/2, 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.

• Detailed Description: Not Provided
• 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
• Metastatic Castration-resistant 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
  • IPN60200
• 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 in combination with tazemetostat in cycle 1 (28 days) to establish the recommended dose of tazemetostat in this combination; participants may continue treatment in additional 28-day cycles, as tolerated, until progression or unacceptable toxicity
  Interventions:

  • Drug: Tazemetostat
  • Drug: Abiraterone/prednisone
• Experimental: Phase 1b: Tazemetostat in Combination with Enzalutamide
  In Phase 1b, enzalutamide will be administered in combination with tazemetostat in cycle 1 (28 days) to establish the recommended dose of tazemetostat in this combination; participants may continue treatment in additional 28-day cycles, as tolerated, until progression or unacceptable toxicity
  Interventions:

  • Drug: Tazemetostat
  • Drug: Enzalutamide
• Experimental: Phase 2: Tazemetostat in Combination with Enzalutamide

  Participants will receive the newly established recommended phase 2 dose, orally twice daily when given in combination with enzalutamide) as determined in phase 1b part of the study) or enzalutamide alone.

  All participants will receive treatment in 28-day cycles.

  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: Active, not recruiting
• Actual Enrollment (submitted: March 4, 2024): 102
• Original Estimated Enrollment (submitted: November 25, 2019): 48
• Estimated Study Completion Date: June 28, 2024
• Estimated Primary Completion Date: June 28, 2024 (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 antagonist including enzalutamide, apalutamide, darolutamide, and proxalutamide, etc.
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 information is only displayed when the study is recruiting subjects
• Listed Location Countries: Belgium, Spain, United States

Administrative Information

• NCT Number: NCT04179864
• Other Study ID Numbers: EZH-1101; 2019-003649-14 ( EudraCT Number )
• 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

• Plan to Share IPD: Yes

Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.

• Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
• Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).
• URL: http://vivli.org/members/ourmembers/

• Current Responsible Party: Ipsen ( Epizyme, Inc. )
• Original Responsible Party: Same as current
• Current Study Sponsor: Epizyme, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Ipsen Medical Director; Ipsen

• PRS Account: Ipsen
• Verification Date: April 2024