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
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 102
- 试验地点
- 24
- 主要终点
- Phase 1b: Number of Participants With Treatment-Emergent Non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •Age at the time of consent ≥ 18 years.
- •Eastern Cooperative Oncology Group (ECOG) performance status 0 to 1 (Appendix
- •Life expectancy of > 3 months.
- •Histologically or cytologically confirmed adenocarcinoma of the prostate. Small cell or neuroendocrine tumors of the prostate are also permitted.
- •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.
- •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.
- •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.
排除标准
- •Known symptomatic brain metastases
- •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.
- •Severe concurrent disease, infection, or comorbidity that, in the judgment of the Investigator, would make the subject inappropriate for enrollment
- •Has had prior exposure to tazemetostat or other inhibitor(s) of enhancer of zeste homologue-2.
研究组 & 干预措施
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
干预措施: Tazemetostat (Drug)
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
干预措施: Abiraterone/prednisone (Drug)
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
干预措施: Tazemetostat (Drug)
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
干预措施: Enzalutamide (Drug)
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.
干预措施: Tazemetostat (Drug)
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.
干预措施: Enzalutamide (Drug)
Phase 2: Enzalutamide only
In Phase 2, Enzalutamide will be administered on cycle 1 day 1
干预措施: Enzalutamide (Drug)
结局指标
主要结局
Phase 1b: Number of Participants With Treatment-Emergent Non-Serious Adverse Events and Treatment-Emergent Serious Adverse Events (TESAEs)
时间窗: 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
时间窗: 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)
时间窗: 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.
次要结局
- 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))
- 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))
- 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)
- 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)
- 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)
- Phase 1b and 2: Disease Control Rate (DCR) at 6 Months(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(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(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)(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)(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(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(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(Cycle 1 Days 2 and 21 (each cycle was 28 days))
- Phase 1b: Maximum Plasma Concentration (Cmax) of Tazemetostat(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(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(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(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(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(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(Baseline (Day 1) up to Cycle 24 Day 1261)