TulmiSTAR-01: A Two-part, Phase I Dose Escalation and Expansion Followed by a Randomized, Open-label Multicenter, Phase II Study to Assess the Safety and Efficacy of the Combination of Tulmimetostat (DZR123) and JSB462 (Luxdegalutamide) vs Standard of Care in Patients With Progressive Metastatic Castrate Resistant Prostate Cancer
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 入组人数
- 188
- 试验地点
- 41
- 主要终点
- Part 1a: Dose-limiting toxicities (DLTs)
研究概览
简要总结
This is a two-part, Phase I/II, open-label, global, multicenter study assessing the safety and efficacy of the combination of tulmimetostat (DZR123) and JSB462 (luxdegalutamide) versus standard of care in participants with progressive metastatic castrate resistant prostate cancer (mCRPC).
详细描述
The Phase 1 study, comprised of Parts 1a and 1b, aims to assess the safety and tolerability of the combination of tulmimetostat and JSB462:
- Part 1a is the parallel dose escalation that aims to determine the recommended dose(s) of tulmimetostat and JSB462, in combination, for further exploration.
- Part 1b is the dose expansion/optimization that aims to determine the recommended dose of the combination for Phase II.
The purpose of the Phase II study (Part 2) is to compare the combination of tulmimetostat with JSB462 in terms of the biochemical response as assessed by PSA50 compared to the standard of care (SoC) in adult men with progressive, taxane-naive mCRPC.
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
- •Participant is an adult man ≥ 18 years of age.
- •Participant must have histologically and/or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine or small cell features (current or prior biopsy of the prostate and/or metastatic site).
- •Participant must have ≥ 1 metastatic lesion that is present on screening/baseline CT, MRI, or bone scan imaging obtained ≤ 28 days prior to start of treatment (Part 1a dose escalation) or randomization (Part 1b dose expansion and Part 2).
- •Participant must have progressive mCRPC.
- •Participant must have a castrate level of serum/plasma testosterone (< 50 ng/dL or < 1.7 nmol/L).
- •Prior ARPI therapy:
- •Part 1a and 1b only: must have progressed on at least one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).
- •Part 2 only: must have progressed on one prior second generation ARPI (abiraterone, enzalutamide, darolutamide, or apalutamide).
- •Prior chemotherapy:
- •Part 1a dose escalation only: may have received ≤ 2 prior lines of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting.
- •Part 1b dose expansion/optimization only: may have received up to one prior line of chemotherapy in CRPC setting. Note: Prior chemotherapy is permitted in the HSPC setting.
- •Part 2 only: Participants must be taxane-naïve in mCRPC setting; prior chemotherapy permitted in HSPC setting only
排除标准
- •Previous treatment with any PRC2 inhibitor, including but not limited to EZH2 inhibitors, EZH2/1 inhibitors, or embryonic ectoderm development (EED) inhibitors.
- •Previous treatment with a protein degrader compound that targets the AR.
- •Known hypersensitivity or contraindication to any of the study treatment components or its excipients or to drugs of similar chemical classes.
- •Treatment with any investigational agent within 28 days (or 5 half-lives, whichever is longer) prior to study entry.
- •Previous treatment with radioligand therapy in the mCRPC setting, except in Part 1a where participants may have received RLT in mCRPC setting.
- •Participants with evidence of mCRPC or biochemical recurrence / PSA only disease or asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy and with normal PSA for ≥ 1 year prior to study entry.
- •Participants with a history of CNS metastases must have received therapy (surgery, radiotherapy, gamma knife) and be neurologically stable, asymptomatic, and not receiving corticosteroids for the purpose of maintaining neurologic integrity. Those with leptomeningeal disease are eligible if those areas have been treated, are stable, and no neurological impairment is present. For those with parenchymal CNS metastasis (or a history of CNS metastasis), baseline and subsequent radiological imaging must include evaluation of the brain with MRI (preferred) or CT with contrast.
- •Other protocol-defined inclusion/exclusion criteria may apply.
研究组 & 干预措施
Part 1a: Cohort DL2B
Tulmimetostat DL2 QD + JSB462 Dose 2 QD
干预措施: JSB462 Dose 2 QD (Drug)
Part 1a: Cohort DL1A
Tulmimetostat DL1 QD + JSB462 Dose 1 QD
干预措施: JSB462 Dose 1 QD (Drug)
Part 1a: Cohort DL2B
Tulmimetostat DL2 QD + JSB462 Dose 2 QD
干预措施: Tulmimetostat DL2 QD (Drug)
Part 1a: Cohort DL3B
Tulmimetostat DL3 QD + JSB462 Dose 2 QD
干预措施: Tulmimetostat DL3 QD (Drug)
Part 1a: Cohort DL1A
Tulmimetostat DL1 QD + JSB462 Dose 1 QD
干预措施: Tulmimetostat DL1 QD (Drug)
Part 1a: Cohort DL3B
Tulmimetostat DL3 QD + JSB462 Dose 2 QD
干预措施: JSB462 Dose 2 QD (Drug)
Part 1b : Arm A
Tulmimetostat Dose 1 QD + JSB462 QD
干预措施: Tulmimetostat Doses 1 or 2 QD (Drug)
Part 1b : Arm A
Tulmimetostat Dose 1 QD + JSB462 QD
干预措施: JSB462 QD (Drug)
Part 1a: Cohort DL3A
Tulmimetostat DL3 QD + JSB462 Dose 1 QD
干预措施: JSB462 Dose 1 QD (Drug)
Part 1b: Arm B
Tulmimetostat Dose 2 QD + JSB462 QD
干预措施: Tulmimetostat Doses 1 or 2 QD (Drug)
Part 1a: Cohort DL1B
Tulmimetostat DL1 QD + JSB462 Dose 2 QD
干预措施: JSB462 Dose 2 QD (Drug)
Part 1a: Cohort DL3A
Tulmimetostat DL3 QD + JSB462 Dose 1 QD
干预措施: Tulmimetostat DL3 QD (Drug)
Part 1a: Cohort DL2A
Tulmimetostat DL2 QD + JSB462 Dose 1 QD
干预措施: Tulmimetostat DL2 QD (Drug)
Part 1a: Cohort DL1B
Tulmimetostat DL1 QD + JSB462 Dose 2 QD
干预措施: Tulmimetostat DL1 QD (Drug)
Part 1b: Arm B
Tulmimetostat Dose 2 QD + JSB462 QD
干预措施: JSB462 QD (Drug)
Part 2: Arm 1
Tulmimetostat RP2D QD + JSB462 QD
干预措施: JSB462 QD (Drug)
Part 2: Arm 1
Tulmimetostat RP2D QD + JSB462 QD
干预措施: Tulmimetostat RP2D QD (Drug)
Part 2: Arm 2
Standard of Care at the discretion of the investigator
干预措施: Standard of Care (SoC) (Drug)
Part 1a: Cohort DL2A
Tulmimetostat DL2 QD + JSB462 Dose 1 QD
干预措施: JSB462 Dose 1 QD (Drug)
结局指标
主要结局
Part 1a: Dose-limiting toxicities (DLTs)
时间窗: Up to 28 days
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness/injury, or concomitant medications that occurs within the first 28 days of treatment with tulmimetostat and JSB462 and meets any of the criteria specified in the protocol. The National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 5.0 will be used for all grading. For the purpose of dose-escalation decisions, DLTs will be considered and included in the Bayesian Logistic Regression Model (BLRM).
Part 1a and Part 1b: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)
时间窗: From date of randomization till 30 days safety fup, assessed up to approximately 14 months
The analysis of adverse events will include categorization by type, frequency, and severity, as graded by the NCI CTCAE version 5.0.
Part 1a and Part 1b: Number of Participants with dose adjustments
时间窗: From date of randomization till 30 days safety fup, assessed up to approximately 14 months
The number of participants with dose adjustments (reductions, interruption, or permanent discontinuation) will be summarized by treatment arm.
Part 1a and Part 1b: Dose Intensity
时间窗: From date of randomization till 30 days safety fup, assessed up to approximately 14 months
Dose intensity (computed as the ratio of actual cumulative dose received and actual duration of exposure) and the relative dose intensity (computed as the ratio of dose intensity and planned dose intensity) will be summarized by means of descriptive statistics
Part 1a and Part 1b: Duration of exposure to each study drug
时间窗: From date of randomization till 30 days safety fup, assessed up to approximately 14 months
The duration of exposure (in months) to Tulmimetostat and JSB462 (Part 1a and Part 1b) will be summarized by means of descriptive statistics
Part 1b and Part 2: prostate-specific antigen 50 (PSA50) at Month 6
时间窗: Month 6
PSA50 is defined as a PSA reduction of at least 50% from baseline at 6 months confirmed by a second PSA measurement ≥ 3 weeks later.
次要结局
- Part 1a and Part 1b: Plasma concentrations of tulmimetostat and JSB462(Cycle 1-2: Day 1 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.)
- Part 2: Plasma concentrations of tulmimetostat and JSB462(Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.)
- Part 1a and Part 1b: AUC of tulmimetostat and JSB462(Cycle 1-2: Day 1 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.)
- Part 2: AUC of tulmimetostat and JSB462(Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.)
- Part 1a and Part 1b: Cmax of tulmimetostat and JSB462(Cycle 1-2: Day 1 (predose/0 hour, 1 hour, 2 hours, 4 hours, 6 hours and 8 hours; Tulmimetostat only: 30 minutes and 3 hours). Cycle 1: Day 2 (24 hours), Days 8 and 15 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.)
- Part 2: Cmax of tulmimetostat and JSB462(Cycle 1 and 2: Day 1 (predose/0 hour and 2 hours). Cycles 3-5: Day 1 (predose/0 hour). 1 cycle = 28 days.)
- Part 1b and Part 2: prostate-specific antigen 50 (PSA50) at 3, 9, and 12 months(Month 3, Month 9, Month 12)
- Part 1b and Part 2: radiographic progression free survival (rPFS)(From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to approximately 15 months)
- Part 1b and Part 2: overall survival (OS)(From date of randomization until date of death from any cause, assessed up to approximately 15 months)
- Part 1b and Part 2: objective response (OR)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months)
- Part 1b and Part 2: best overall response (BOR)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months)
- Part 1b and Part 2: duration of response (DOR)(From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to approximately 15 months)
- Part 1b and Part 2: time to first symptomatic skeletal event (TTSSE)(From randomization until the first occurrence of a new symptomatic bone fracture, spinal cord compression, tumor-related orthopedic surgery, radiation therapy for bone pain, or death, assessed up to 15 months.)
- Part 2: Incidence rate of Adverse Events (AEs) and Serious Adverse Events (SAEs)(From date of randomization till 30 days safety fup, assessed up to approximately 15 months)
- Part 2: Number of Participants with dose adjustments(From date of randomization till 30 days safety fup, assessed up to approximately 15 months)
- Part 2: Dose Intensity(From date of randomization till 30 days safety fup, assessed up to approximately 15 months)
- Part 2: Duration of exposure to each study drug(From date of randomization till 30 days safety fup, assessed up to approximately 15 months)