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
- 2 期
- 状态
- 招募中
- 入组人数
- 14
- 试验地点
- 3
- 主要终点
- • Part 1a: Dose-limiting toxicities (DLTs) • Part 1a and Part 1b: Safety: Type, frequency and severity of AEs per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and notable values in laboratory, vital signs, and electrocardiogram (ECGs). Tolerability: Dose interruptions, dose reductions, drug discontinuations, dose intensity, and duration of exposure to each study drug
研究概览
简要总结
Phase I • Part 1a: To determine the recommended dose(s) for expansion (RDE) of tulmimetostat and JSB462 in combination • Part 1a and Part 1b: To characterize the safety and tolerability of tulmimetostat in combination with JSB462 • Part 1b: To determine the recommended Phase II dose (RP2D) of tulmimetostat and JSB462 in combination • Part 1b: To assess the biochemical response rate (BCR) as detected by PSA50 at Month 6 in participants treated with tulmimetostat and JSB462 at the RDEs Phase II - Part 2 • To compare the BCR as assessed by PSA50 at Month 6 of the combination of tulmimetostat and JSB462 with the standard of care treatment (SoC)
入排标准
- 年龄范围
- 18 years 至 65+ years（65+ Years, 18-64 Years）
- 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. Documented progressive mCRPC will be based on at least 1 of the following criteria: • Serum/plasma PSA progression defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng/mL; 1.0 ng/mL is the minimal starting value if confirmed rise in PSA is the only indication of progression • Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)] • Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher et al 2016))
- •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.
研究组 & 干预措施
-
Participants receiving -
干预措施: - (Drug)
结局指标
主要结局
• Part 1a: Dose-limiting toxicities (DLTs) • Part 1a and Part 1b: Safety: Type, frequency and severity of AEs per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and notable values in laboratory, vital signs, and electrocardiogram (ECGs). Tolerability: Dose interruptions, dose reductions, drug discontinuations, dose intensity, and duration of exposure to each study drug
• Part 1a: Dose-limiting toxicities (DLTs) • Part 1a and Part 1b: Safety: Type, frequency and severity of AEs per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and notable values in laboratory, vital signs, and electrocardiogram (ECGs). Tolerability: Dose interruptions, dose reductions, drug discontinuations, dose intensity, and duration of exposure to each study drug
Part 1b and Part 2: PSA50 at Month 6, defined as the PSA reduction of at least 50% from baseline at 6 months confirmed by a second PSA measurement ≥ 3 weeks later.
Part 1b and Part 2: PSA50 at Month 6, defined as the PSA reduction of at least 50% from baseline at 6 months confirmed by a second PSA measurement ≥ 3 weeks later.
次要结局
- Plasma concentrations of tulmimetostat and JSB462 (Phase I and Phase II), and derived PK parameters including AUC and Cmax (Phase I only)
- Radiographic progression free survival (rPFS) defined as time between randomization and the first occurrence of disease progression as per PCWG3-modified RECIST v1.1 or death due to any cause;
- Overall survival (OS) is defined as the time between randomization to date of death due to any cause
- Objective response (OR) is defined as a confirmed complete response (CR) or partial response (PR) per PCWG3-modified RECIST 1.1 as assessed by the investigator
- Best overall response (BOR) is defined as the best response per Prostate Cancer Working Group 3 (PCWG3)-modified RECIST 1.1 as assessed by the Investigator
- Duration of response (DOR) is defined as time between first documented CR/PR and disease progression or death due to any cause per PCWG3-modified RECIST 1.1 as assessed by the investigator
- Part 1b and Part 2: Time to first symptomatic skeletal event (TTSSE ) defined as time from randomization to the first new symptomatic pathological bone fracture, spinal cord compression, tumor-related orthopedic surgical intervention, requirement for radiation therapy to relieve bone pain or death from any cause, whichever occurs first.
- Safety: Type, frequency and severity of adverse events (AEs) per Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, and notable values in laboratory, vital signs, and ECGs.
- Tolerability: Dose interruptions, dose reductions, drug discontinuations, dose intensity, and duration of exposure to each study drug
- PSA50 at 3, 9 and 12 months, radiographic progression free survival (rPFS), overall survival (OS), objective response (OR), best overall response (BOR) and duration of response (DOR)
研究者
Novartis Pharma Arzneimittel GmbH
Scientific
Novartis Pharma AG