A Study of Tazemetostat With Enzalutamide or Abiraterone/Prednisone in Participants With Advanced Prostate Cancer
- Conditions
- Interventions
- Registration Number
- NCT04179864
- Lead Sponsor
- Epizyme, Inc.
- 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-r...
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- TERMINATED
- Sex
- Male
- Target Recruitment
- 102
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Age at the time of consent ≥ 18 years.
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Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
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Life expectancy of > 3 months.
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Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.
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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.
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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.
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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.
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Known symptomatic brain metastases
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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.
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Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment
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Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Phase 1b: Tazemetostat in Combination with Abiraterone/Prednisone 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 Phase 1b: Tazemetostat in Combination with Abiraterone/Prednisone Tazemetostat 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 Phase 1b: Tazemetostat in Combination with Enzalutamide Tazemetostat 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 Phase 1b: Tazemetostat in Combination with Enzalutamide 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 Phase 2: Tazemetostat in Combination with Enzalutamide 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. Phase 2: Enzalutamide only Enzalutamide In Phase 2, Enzalutamide will be administered on cycle 1 day 1 Phase 2: Tazemetostat in Combination with Enzalutamide Tazemetostat 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.
- Primary Outcome Measures
Name Time Method Ph 1b: Select the recommended phase 2 doses (RP2D) of tazemetostat for each combination 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 1b: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) 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 2: Change in radiographic progression free survival (rPFS) 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
- Secondary Outcome Measures
Name Time Method Phase 1b and 2: Time to PSA progression (TTPP) 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: AUC0-last: area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration. 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. 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 2: Change in Functional Assessment of Cancer Therapy - Prostate (FACT-P) From baseline to end of study, an average of one year Assessed by Well-being Subscale (FWB) and Prostate Cancer Subscale (PCS) scores
Phase 1b and 2: Percentage of participants with a ≥50% decline of Prostate Specific-Antigen (PSA50). 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 Phase 2: Percentage of Participants with Treatment Emergent Adverse Event (TEAEs) 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: Objective response rate (ORR) and best overall response (BOR) in soft tissue At 6 months on treatment. According to Response Evaluation Criteria in Solid Tumors 1.1 (RECIST 1.1) guidelines.
Phase 1b and 2: Time to first skeletal-related event (SRE) During screening and every 9 weeks if clinically indicated at baseline, average of one year Phase 1b and 2: CTC response rate 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 2: Cmax: maximum plasma concentration. From baseline to end of study, an average of one year Cmax is defined as the maximum observed concentration of drug.
Phase 2: Time to definitive deterioration (TDD) in functional status and in prostate symptoms From baseline to end of study, an average of one year Assessed by the FACT-P FWB and PCS scores.
Phase 1b and 2: Disease control rate (DCR) 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 initiation of the next systemic treatment for prostate cancer (TTNT) 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: Reduction in circulating tumor cells (CTC) 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
Trial Locations
- Locations (24)
Dana Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
🇺🇸Boston, Massachusetts, United States
Genesis Healthcare Partners
🇺🇸San Diego, California, United States
Comprehensive Cancer Centers of Nevada - Central Valley
🇺🇸Las Vegas, Nevada, United States
SCRI - Tennessee Oncology Chattanooga
🇺🇸Chattanooga, Tennessee, United States
Academisch Ziekenhuis Groeninge Campus Kennedylaan
🇧🇪Kortrijk, West Vlaanderen, Belgium
XCancer - Tennesee Cancer Specialists
🇺🇸Knoxville, Tennessee, United States
SCRI - Tennessee Oncology Nashville
🇺🇸Nashville, Tennessee, United States
Hospital del Mar Parc de Salut Mar
🇪🇸Barcelona, Spain
The Urology Center Of Colorado
🇺🇸Denver, Colorado, United States
Hematology Oncology Associates of the Treasure Coast
🇺🇸Port Saint Lucie, Florida, United States
XCancer - Northwest Oncology and Hematology
🇺🇸Rolling Meadows, Illinois, United States
Montefiore Einstein Center for Cancer Care
🇺🇸Bronx, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸New York, New York, United States
Associated Medical Professionals of NY, PLLC - Urology
🇺🇸Syracuse, New York, United States
University of Pittsburgh Medical Center - Hillman Cancer Center
🇺🇸Pittsburgh, Pennsylvania, United States
Urology Associates P.C.
🇺🇸Hendersonville, Tennessee, United States
Hospital de la Santa Creu i. Sant Pau
🇪🇸Barcelona, Spain
Urology San Antonio
🇺🇸San Antonio, Texas, United States
Hospital Universitario de Jerez de la Frontera
🇪🇸Jerez De La Frontera, Cadiz, Spain
Hospital Clinico San Carlos
🇪🇸Madrid, Spain
Hospital Universitario 12 de Octubre
🇪🇸Madrid, Spain
Hospital Universitario La Paz
🇪🇸Madrid, Spain
Clinica Universidad de Navarra
🇪🇸Pamplona, Spain