IDE196 (Darovasertib) in Combination With Crizotinib Versus Investigator's Choice of Treatment as First-line Therapy in HLA-A2 Negative Metastatic Uveal Melanoma (DAR-UM-2)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 420
- 试验地点
- 136
- 主要终点
- Phase 2a: To determine the optimal dose of IDE196 + Crizotinib combination for Phase 2B and Phase 3 by evaluating the following:
研究概览
简要总结
This is a Phase 2/3, multi-arm, multi-stage, open-label study of human leukocyte antigen (HLA)-A*02:01 negative participants with metastatic uveal melanoma (MUM) who will be randomized to receive either IDE196 + crizotinib or investigator's choice of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine).
详细描述
This study is designed as a multi-stage Phase 2 study within a Phase 3 study to evaluate the safety, tolerability, pharmacokinetics, dose-exposure relationship, and anti-tumor activity of IDE196 in combination with crizotinib compared to the comparator arm of investigator's choice of treatment (pembrolizumab, ipilimumab + nivolumab, or dacarbazine).
The Phase 2a dose optimization stage will evaluate two doses of IDE196 in combination with crizotinib compared to the comparator arm. Participants will be randomized to the three treatment arms. At the point of optimal IDE196 + crizotinib dose selection, the other dose arm will be dropped with discontinuation of enrollment to that arm. Participants receiving the IDE196 dose (in combination with crizotinib) that is not selected, will be offered the choice to remain on the same dose or change to the chosen optimal dose.
The optimal dose will be chosen to complete the Phase 2b portion. The Phase 2b part of the study will continue to enroll the chosen combination dose of IDE196 + crizotinib compared with the comparator arm. Participants will be randomized to the two treatment arms.
The Phase 3 part of the study will continue to enroll the chosen combination dose of IDE196 + crizotinib compared with the comparator arm. Participants will be randomized to the two treatment arms to evaluate the primary endpoint of overall survival (OS).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Histological or cytological confirmed Metastatic Uveal Melanoma
- •HLA-A*02:01 negative
- •No prior systemic therapy in the metastatic or advanced setting regional or liver-directed therapy. Ablations or surgical resection of oligometastatic disease, and neoadjuvant or adjuvant therapy is allowed
- •Measurable disease per RECIST 1.1
- •Able to be safely administered and absorb study therapy
- •ECOG performance status 0 or 1
- •Life expectancy of ≥3 months
- •Adequate organ function
排除标准
- •Previous treatment with a PKC inhibitor (including prior treatment with IDE196), an inhibitor directly targeting MET, or an inhibitor directly targeting GNAQ/11
- •Concurrent malignant disease
- •AEs from prior anti-cancer therapy that have not resolved to Grade ≤1
- •Symptomatic or untreated central nervous system (CNS) metastases, or CNS metastases that require corticosteroids
- •High risk of syncope or falls
- •Known AIDS related illness
- •Active adrenal insufficiency, active colitis, or active inflammatory bowel disease
- •History of interstitial lung disease, active pneumonitis, or history of pneumonitis requiring steroids
- •Active infection requiring systemic antibiotic therapy or active Hepatitis B/C
- •Major surgery, radiotherapy, or use of hematopoietic colony-stimulating factors (CSF) within 2 weeks prior to start of study drug
- •Females who are pregnant or breastfeeding
- •History of severe hypersensitivity reactions (eg, anaphylaxis) to other biologic drugs or monoclonal antibodies
- •Contraindication for treatment with investigator's choice therapies as per applicable labelling
- •History of stroke within the last 6 months of the first dose of study drug
- •Impaired Cardiac function or clinically significant cardiac diseases, including angina pectoris or acute myocardial infarction <= 6 months prior to start of study treatment
- •Has any other condition that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the opinion of the investigator, would make the participant inappropriate for entry into the study, including institutionalization on the basis of an official or court order
研究组 & 干预措施
Phase 2a Dose Optimization of IDE196 + crizotinib
Multiple doses of IDE196 will be tested in combination with fixed dose of crizotinib to identify the optimal combination dose.
干预措施: IDE196 (Drug)
Phase 2a Dose Optimization of IDE196 + crizotinib
Multiple doses of IDE196 will be tested in combination with fixed dose of crizotinib to identify the optimal combination dose.
干预措施: Crizotinib (Drug)
Phase 2b / 3 Chosen Combination dose of IDE196 + crizotinib
Chosen combination dose of IDE196 + crizotinib will be tested in additional participants.
干预措施: IDE196 (Drug)
Phase 2b / 3 Chosen Combination dose of IDE196 + crizotinib
Chosen combination dose of IDE196 + crizotinib will be tested in additional participants.
干预措施: Crizotinib (Drug)
Phase 2a / 2b / 3 Comparator Arm
Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
干预措施: Pembrolizumab (Drug)
Phase 2a / 2b / 3 Comparator Arm
Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
干预措施: Ipilimumab (Drug)
Phase 2a / 2b / 3 Comparator Arm
Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
干预措施: Nivolumab (Drug)
Phase 2a / 2b / 3 Comparator Arm
Participants will receive investigator's choice of Pembrolizumab, Ipilimumab + Nivolumab, or Dacarbazine.
干预措施: Dacarbazine (Drug)
结局指标
主要结局
Phase 2a: To determine the optimal dose of IDE196 + Crizotinib combination for Phase 2B and Phase 3 by evaluating the following:
时间窗: Approximately 5 months
dose exposure response (safety and efficacy) relationship, plasma concentration profiles and pharmacokinetic (PK) parameters, treatment-emergent Adverse Events (TEAEs), laboratory abnormalities, electrocardiogram (ECG), and vital sign changes and study treatment discontinuation due to AEs.
Phase 2 Progression-Free Survival (PFS)
时间窗: Approximately 2 years
by blinded independent central review (BICR) of IDE196 + Crizotinib compared to investigator's choice of treatment per RECIST v1.1
Phase 3 Overall Survival (OS) of IDE196 + Crizotinib compared to investigator's choice of treatment.
时间窗: Approximately 4 years
OS from randomization to date of death due to any cause
次要结局
- Change from baseline over time and between treatment arms in(Approximately 2 years)
- Safety of IDE196 + Crizotinib: Incidence of Adverse Events(Approximately 2 years)
- Objective Response Rate (ORR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatment(Approximately 2 years)
- Duration of Response (DOR) per BICR and Investigator assessment of IDE196 + Crizotinib compared to investigator's choice of treatment(Approximately 2 years)
- Phase 2a: Dose-exposure-response of IDE196 as measured by correlating the concentration of IDE196 in plasma with safety and efficacy.(Approximately 5 months)
- Phase 2a: Dose-exposure-response of Crizotinib measured by correlating the concentration of Crizotinib in plasma with safety and efficacy.(Approximately 5 months)
- Phase 2b + 3: Progression-Free Survival (PFS) per Investigator Assessment of IDE196 + Crizotinib compared to investigator's choice of treatment .(Approximately 2 years)
- Change from baseline over time and between treatment arms in Global health status and quality of life will be assessed using the EORTC QLQ-C30 questionnaire.(Approximately 2 years)
- Best Objective Response (BOR) per BICR and Investigator Assessment of IDE196 + Crizotinib compared to Investigator's choice of treatment(Approximately 2 years)
- Disease Control Rate (DCR) per BICR and Investigator Assessment of IDE196 + Crizotinib compared to investigator's choice of treatment.(Approximately 2 years)
- Time to response as assessed by Investigator and BICR(Approximately 2 years)