Metastatic Castration-resistant Prostate Cancer, Metastatic Prostate Cancer
Conditions
Keywords
metastatic castration resistant prostate cancer, tazemetostat, EPZ-6438, E7438, enzalutamide, abiraterone, Prednisone, Zytiga, Xtandi
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.
Interventions
DRUGTazemetostat
Tazemetostat (EPZ-6438) is a selective small-molecule inhibitor of the histone-lysine methyltransferase EZH2 gene
DRUGAbiraterone/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.
DRUGEnzalutamide
enzalutamide 160 mg (four 40 mg capsules) orally once daily
Sponsors
Epizyme, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Treatment-Emergent Non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs) | 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 | 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%. |
| Phase 1b: Recommended Phase 2 Dose (RP2D) of Tazemetostat | From Day 1 up to Day 28 of Cycle 1 (each cycle was 28 days) | 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). |
| Phase 2: Radiographic Progression-Free Survival (rPFS) | 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 | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b and 2: Percentage of Participants With Confirmed Prostate-Specific Antigen >=50% (PSA50) Response | 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 | 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. |
| Phase 1b and 2: Objective Response Rate (ORR) | 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 | 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. |
| Phase 1b and 2: Best Overall Response (BOR) | 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 | 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. |
| Phase 1b and 2: Disease Control Rate (DCR) at 6 Months | Baseline and at 6 months (24 weeks) | 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. |
| Phase 1b and 2: Time to First Skeletal-Related Event (SRE) Per Prostate Cancer Clinical Trials Working Group 3 Criteria | From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks | 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. |
| Phase 1b and 2: Time to Initiation of the Next Systemic Treatment (TTNT) for Prostate Cancer | From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks | 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. |
| Phase 1b and 2: Time to Prostate-Specific Antigen Progression (TTPP) | From first dose of study drug (Phase 1b) and randomization (Phase 2) (Day 1) up to approximately 259 weeks | 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. |
| Phase 1b and 2: Percentage of Participants With Reduction in Circulating Tumor Cells (CTC) | 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 | 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. |
| Phase 1b and 2: Percentage of Participants With Circulating Tumor Cells Response | 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 | 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. |
| Phase 2: Number of Participants With Treatment-Emergent Non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events | 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 | 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%. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration (AUC0-last) of Tazemetostat | Cycle 1 Days 2 and 21 (each cycle was 28 days) | Blood samples were collected at specified timepoints for the assessment of AUC0-last of tazemetostat. |
| Phase 1b: Maximum Plasma Concentration (Cmax) of Tazemetostat | Cycle 1 Days 2 and 21 (each cycle was 28 days) | Blood samples were collected at specified timepoints for the assessment of Cmax of tazemetostat. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 8 Hours Post-Dose (AUC0-8) of Tazemetostat | Up to 8 hours post-dose on Cycle 1 Days 2 and 21 (each cycle was 28 days) | Blood samples were collected at specified timepoints for the assessment of AUC0-8 of tazemetostat. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 12 Hours Post-Dose (AUC0-12) of Tazemetostat | Up to 12 hours post-dose on Cycle 1 Days 2 and 21 (each cycle was 28 days) | Blood samples were collected at specified timepoints for the assessment of AUC0-12 of tazemetostat. |
| Phase 1b: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose (AUC0-24) of Enzalutamide | Up to 24 hours post-dose on Cycle 1 Days 1, 2 and 21 (each cycle was 28 days) | Blood samples were collected at specified timepoints for the assessment of AUC0-24 of enzalutamide. |
| Phase 2: Maximum Plasma Concentration of Enzalutamide | 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) | 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. |
| Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of the Last Quantifiable Concentration of Enzalutamide | 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) | 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. |
| Phase 2: Area Under the Plasma Concentration-Time Curve From Time 0 to the Time of 24 Hours Post-Dose of Enzalutamide | 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) | 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. |
| 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 | 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 | 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. |
| Phase 2: Time to Definitive Deterioration (TDD) in Prostate Symptoms as Assessed by the Functional Assessment of Cancer Therapy-Prostrate: Prostate Cancer Subscale Score | Baseline (Day 1) up to Cycle 24 Day 1261 | 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. |
Countries
Belgium, Spain, United States
Contacts
STUDY_DIRECTORIpsen Medical Director
Ipsen
Participant flow
Recruitment details
This Phase 1b/2, 2-part, open-label study was conducted at 21 sites in asymptomatic or mildly symptomatic participants with progressive, metastatic castration resistant prostate cancer (mCRPC).
Pre-assignment details
The study consisted of 2 parts: Phase 1b (dose-escalation) and Phase 2 (randomized). The study was terminated early as Sponsor decided to discontinue the development of tazemetostat in mCRPC and the primary endpoint was not met for this study. There were no safety concerns.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized <65 years | 0 Participants |
| Age, Customized >=65 years | 29 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 9 Participants |
| Race (NIH/OMB) White | 2 Participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk | EG009 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 2 | 2 / 3 | 2 / 3 | 3 / 3 | 0 / 3 | 1 / 1 | 2 / 3 | 3 / 3 | 7 / 41 | 18 / 40 |
| other Total, other adverse events | 2 / 2 | 3 / 3 | 3 / 3 | 3 / 3 | 3 / 3 | 1 / 1 | 3 / 3 | 3 / 3 | 41 / 41 | 39 / 40 |
| serious Total, serious adverse events | 0 / 2 | 1 / 3 | 0 / 3 | 0 / 3 | 2 / 3 | 0 / 1 | 1 / 3 | 1 / 3 | 13 / 41 | 10 / 40 |
Outcome results
None listed