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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
102
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
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.
enzalutamide 160 mg (four 40 mg capsules) orally once daily
Genesis Healthcare Partners
San Diego, California, United States
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
Dana Farber Cancer Institute
Boston, Massachusetts, United States
Beth Israel Deaconess Medical Center
Boston, Massachusetts, United States
Comprehensive Cancer Centers of Nevada - Central Valley
Las Vegas, Nevada, 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
Montefiore Einstein Center for Cancer Care
The Bronx, New York, United States
...and 14 more locations
Phase 1b: Number of Participants With Treatment-Emergent Non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs)
An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily had a causal relationship with this study drug. An SAE was an AE which occurred during any study phase and at any dose of study drug, that fulfilled 1 or more of following: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability or incapacity, was a congenital abnormality or birth defect, or was an important medical event that might jeopardize the participant or might require medical intervention to prevent one of the outcomes listed above. TEAEs were AEs that started or worsened in severity on or after the date of the first dose of study drug through 30 after the end of study drug, or prior to initiation of another investigational agent or cytotoxic chemotherapy. The treatment-emergent non-serious AEs are presented with a frequency threshold of 5%.
Time frame: From first dose of study drug (Day 1) up to either 30 days after last dose of study drug or until the initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks
Phase 1b: Recommended Phase 2 Dose (RP2D) of Tazemetostat
RP2D was based on pharmacokinetics (PK) parameters, pharmacodynamics (PD) parameters as well as efficacy and the overall tolerability of each combination (tazemetost with enzalutamide or tazemetostat with abiraterone/prednisone).
Time frame: From Day 1 up to Day 28 of Cycle 1 (each cycle was 28 days)
Phase 2: Radiographic Progression-Free Survival (rPFS)
rPFS was defined as the time from date of randomization (phase 2)/date of first dose of study drug (phase 1b) to the first objective evidence of radiographic progression using response evaluation criteria in solid tumors version 1.1 (RECIST 1.1) (soft tissue) and prostate cancer clinical trials working group 3 (PCWG3) (bone), or death from any cause, whichever occurred first. The radiographic PD for soft tissue lesion was determined based on computed tomography (CT) or magnetic resonance imaging (MRI) per RECIST 1.1 criteria and no confirmatory scan was required for soft tissue PD; for bone lesion was determined by 2 or more new bone lesions on bone scan per PCWG3 criteria (i.e., the appearance of 2 or more new bone lesions on bone scan) and the 2 scans (i.e., the confirmatory scan is required for bone disease progression) should be at least 6 weeks apart from each other.
Time frame: Assessments performed at screening (within 4 weeks of randomization) and every 8 weeks for first 6 months and then every 12 weeks thereafter, until death, PD, unacceptable toxicity, consent withdrawal, or termination of study. Approximately 200 weeks
Phase 1b and 2: Percentage of Participants With Confirmed Prostate-Specific Antigen >=50% (PSA50) Response
Blood samples were collected for evaluation of PSA. Confirmed PSA50 response was defined as \>=50% decline of PSA from baseline at any time on study for participants with a baseline PSA \>=1.0 microgram per liter (mcg/L) (nanogram/milliliter \[ng/mL\]) per PCWG3 criteria. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization.
Time frame: From Cycle 1 Day 1 (Baseline) up to either 30 days after last dose of study drug or until initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively
Phase 1b and 2: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with complete response (CR) or partial response (PR). CR was defined as disappearance of all target lesions, any pathological lymph nodes (LN) must be \<10 millimeter (mm) in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters.
Time frame: Tumor assessments performed at screening (within 4 weeks of randomization) and every 8 weeks for first 6 months and then every 12 weeks thereafter, until death, PD, unacceptable toxicity, consent withdrawal, or termination of study.Approximately 259 weeks
Phase 1b and 2: Best Overall Response (BOR)
BOR was defined as percentage of participants with CR, PR, stable disease (SD), PD, or not evaluable (NE). CR was defined as disappearance of all target lesions, any pathological LN must be \<10 mm in the short axis. PR was defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the baseline sum of the diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD was defined as at least a 20% increase in the sum of the diameters of target lesions, taking as a reference, the smallest sum of diameters recorded since the drug started. In addition, the sum had an absolute increase from nadir of 5 mm. NE was defined as which cannot be classified by 1 of the above preceding definitions. Percentages are rounded off to the tenth decimal place.
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Time frame: Tumor assessments performed at screening (within 4 weeks of randomization) and every 8 weeks for first 6 months and then every 12 weeks thereafter, until death, PD, unacceptable toxicity, consent withdrawal, or termination of study.Approximately 259 weeks
Phase 1b and 2: Disease Control Rate (DCR) at 6 Months
DCR at 6 months (24 weeks) was defined as percentage of participants with measurable soft tissue disease at baseline who had BOR of CR or PR and remaining on study without progression at 23 weeks or with a duration of SD for at least 23 weeks after of randomization (phase 2)/first dose (phase 1b) using overall imaging-based response assessed by RECIST 1.1 (soft tissue) and PCWG-3 criteria (bone). BOR: percentage of participants with CR, PR, SD, PD, or NE. CR: disappearance of all target lesions, any pathological LN must be \<10 mm in the short axis. PR: at least a 30% decrease in sum of diameters of target lesions, taking as a reference, baseline sum of diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. PD: at least a 20% increase in sum of diameters of target lesions, taking as a reference, smallest sum of diameters recorded since the drug started. In addition, sum had an absolute increase from nadir of 5 mm.
Time frame: Baseline and at 6 months (24 weeks)
Phase 1b and 2: Time to First Skeletal-Related Event (SRE) Per Prostate Cancer Clinical Trials Working Group 3 Criteria
Time to first SRE per PCWG3 criteria was defined as the time from the date of randomization (phase II)/date of the first dose of study drug (phase Ib) to the date of first SRE. An SRE was defined as radiation therapy or surgery to bone, pathologic bone fracture, or spinal cord compression.
Time frame: From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks
Phase 1b and 2: Time to Initiation of the Next Systemic Treatment (TTNT) for Prostate Cancer
TTNT was defined as the time from the date of randomization (phase II)/date of the first dose of the study drug (phase Ib) to the date of the first documented administration of systemic treatment for prostate cancer.
Time frame: From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks
Phase 1b and 2: Time to Prostate-Specific Antigen Progression (TTPP)
TTPP was defined as the duration from the date of randomization (phase II)/date of first dose of study drug (phase Ib) to the date of first PSA progression per PCWG3 criteria. PSA progression was defined as a \>=25% increase and an absolute increase of \>=2 mcg/L (2 ng/mL) above the nadir (or baseline value for participants who did not have a decline in PSA value beyond 12 weeks). Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization.
Time frame: From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks
Phase 1b and 2: Percentage of Participants With Reduction in Circulating Tumor Cells (CTC)
Blood samples were collected for evaluation of CTC. Reduction in CTC was defined as participants from a state of having a detectable number of CTCs to having an undetectable number of CTCs. Percentage of participants with detectable CTC at baseline and non-detectable CTC are presented. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization. Percentage of participants with detectable CTC at baseline and non-detectable CTC at any post-baseline time point up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively are presented.
Time frame: From Cycle 1 Day 1 (Baseline) up to either 30 days after last dose of study drug or until initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively
Phase 1b and 2: Percentage of Participants With Circulating Tumor Cells Response
Blood samples were collected for evaluation of CTC. CTC response was defined as a \>=30% reduction in CTC number from baseline in participants who entered the study. Baseline was defined as: Phase 1b: last value recorded for a variable prior to or on the date the participant received the first dose of study drug; Phase 2: last value recorded for a variable prior to or on the date of randomization.
Time frame: From Cycle 1 Day 1 (Baseline) up to either 30 days after last dose of study drug or until initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 149 weeks and 191 weeks for Phase 1b and Phase 2 respectively
Phase 2: Number of Participants With Treatment-Emergent Non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events
An AE was any untoward medical occurrence in a participant or clinical investigation participant administered a medicinal product and which did not necessarily had a causal relationship with this study drug. An SAE was an AE which occurred during any study phase and at any dose of the study drug, that fulfilled 1 or more of following: resulted in death, was life-threatening, required hospitalization or prolongation of existing hospitalization, resulted in disability or incapacity, was a congenital abnormality or birth defect, or was an important medical event that might jeopardize the participant or might require medical intervention to prevent one of the outcomes listed above. TEAEs were AEs that started or worsened in severity on or after the date of the first dose of study drug through 30 after end of study drug, or prior to initiation of another investigational agent or cytotoxic chemotherapy. The treatment-emergent non-serious AEs are presented with a frequency threshold of 5%.
Time frame: From first dose of study drug (Day 1) up to either 30 days after last dose of study drug or until the initiation of subsequent anticancer therapy or end of treatment visit. Assessed up to 191 weeks
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Tazemetostat
Blood samples were collected at specified timepoints for the assessment of AUC0-last of tazemetostat.
Time frame: Cycle 1 Days 2 and 21 (each cycle was 28 days)
Phase 1b: Maximum Plasma Concentration (Cmax) of Tazemetostat
Blood samples were collected at specified timepoints for the assessment of Cmax of tazemetostat.
Time frame: Cycle 1 Days 2 and 21 (each cycle was 28 days)
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 8 Hours Post-Dose (AUC0-8) of Tazemetostat
Blood samples were collected at specified timepoints for the assessment of AUC0-8 of tazemetostat.
Time frame: Up to 8 hours post-dose on Cycle 1 Days 2 and 21 (each cycle was 28 days)
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 12 Hours Post-Dose (AUC0-12) of Tazemetostat
Blood samples were collected at specified timepoints for the assessment of AUC0-12 of tazemetostat.
Time frame: Up to 12 hours post-dose on Cycle 1 Days 2 and 21 (each cycle was 28 days)
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose (AUC0-24) of Enzalutamide
Blood samples were collected at specified timepoints for the assessment of AUC0-24 of enzalutamide.
Time frame: Up to 24 hours post-dose on Cycle 1 Days 1, 2 and 21 (each cycle was 28 days)
Phase 2: Maximum Plasma Concentration of Enzalutamide
For Phase 2, PK blood samples for assessment of Cmax of enzalutamide were pre-specified to be collected at different time points by treatment arm. In the Phase 2: Tazemetostat 1200 mg + Enzalutamide arm, samples were collected at Cycle 1 Days 2 and 21 only. In the Phase 2: Enzalutamide arm, samples were collected at Cycle 1 Day 1 only. No PK samples were collected at other time points for these arms.
Time frame: Cycle 1 Days 2 and 21 for Phase 2: Tazemetostat 1200 mg + Enzalutamide arm and Cycle 1 Day 1 for Phase 2: Enzalutamide arm (each cycle was 28 days)
Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Enzalutamide
For Phase 2, PK blood samples for assessment of AUC0-last of enzalutamide were pre-specified to be collected at different time points by treatment arm. In the Phase 2: Tazemetostat 1200 mg + Enzalutamide arm, samples were collected at Cycle 1 Days 2 and 21 only. In the Phase 2: Enzalutamide arm, samples were collected at Cycle 1 Day 1 only. No PK samples were collected at other time points for these arms.
Time frame: Cycle 1 Days 2 and 21 for Phase 2: Tazemetostat 1200 mg + Enzalutamide arm and Cycle 1 Day 1 for Phase 2: Enzalutamide arm (each cycle was 28 days)
Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose of Enzalutamide
For Phase 2, PK blood samples for assessment of enzalutamide AUC0-24 were pre-specified to be collected at different time points by treatment arm. In the Phase 2: Tazemetostat 1200 mg + Enzalutamide arm, samples were collected at Cycle 1 Days 2 and 21 only. In the Phase 2: Enzalutamide arm, samples were collected at Cycle 1 Day 1 only. No PK samples were collected at other time points for these arms.
Time frame: Up to 24 hours post-dose on Cycle 1 Days 2 and 21 for Phase 2: Tazemetostat 1200 mg + Enzalutamide arm and up to 24 hours post-dose on Cycle 1 Day 1 for Phase 2: Enzalutamide arm (each cycle was 28 days)
Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Prostrate (FACT-P): Functional Well-being Subscale (FWB) and Prostate Cancer Subscale (PCS) Scores
FACT-P questionnaire included subscales:physical well-being(PWB) (Questions \[Q\] GP1 to GP7),social/family well-being subscale(SWB) (Q GS1 to GS7),emotional well-being subscale(EWB) (Q GE1 to GE6),functional well-being subscale(FWB) (Q GF1 to GF7) and prostate cancer subscale(PCS) (Q C2, C6, P1 to P8, BL2 and BL5). Each question had 5 responses, 0: "not at all", 1: "a little bit", 2: "somewhat", 3: "quite a bit" and 4: "very much". Scores ranged from 0 ("not at all") to 4 ("very much") for positively phrased questions. Negatively phrased questions had a reverse scoring, from 0 ("very much") to 4 ("not at all"). Q that were reversed (via subtraction of the response from 4) were: GP1-7, GE1, GE3-6, C2, P1-3, P6-P8 and BL2. Total FACT-P score was sum of scores of all sub-scales (PWB, SWB, EWB, FWB and PCS). Higher scores: better quality of life. Baseline: last value recorded for a variable prior to or on date of randomization. Change from baseline in FWB and PCS scores is presented.
Time frame: Baseline (Day 1), Cycle (C) 3 Day 57, C 5 Day 113, C 7 Day 169, C 10 Day 253, C 13 Day 337, C 14 Day 421, C 15 Day 505, C 16 Day 589, C 17 Day 673, C 18 Day 757, C 19 Day 841, C 20 Day 925, C 21 Day 1009, C 22 Day 1093, C 23 Day 1177 and C 24 Day 1261
Phase 2: Time to Definitive Deterioration (TDD) in Prostate Symptoms as Assessed by the Functional Assessment of Cancer Therapy-Prostrate: Prostate Cancer Subscale Score
TTD was defined as the interval from date of randomization until date of first clinically meaningful deterioration (3 points or more decline for subscale score, 10 points or more decline for total score) that was confirmed at subsequent visit at least 3 weeks apart with no improvement in between visits or death (by any cause) in absence of a clinically meaningful deterioration, regardless of whether participant discontinued study drug(s) prior to deterioration. PCS included Q C2, C6, P1 to P8, BL2 and BL5. Each question had 5 responses,0: "not at all",1: "a little bit",2: "somewhat",3: "quite a bit" and 4: "very much". Scores ranged from 0 ("not at all") to 4 ("very much") for positively phrased questions. Negatively phrased questions had a reverse scoring, from 0 ("very much") to 4 ("not at all"). Total FACT-P: sum of scores of all sub-scales(PWB, SWB, EWB, FWB and PCS). Higher scores: better quality of life. TDD in prostate symptoms as assessed by FACT-P: PCS score is presented.
Time frame: Baseline (Day 1) up to Cycle 24 Day 1261