A Two-Part, Phase 1b/2, Multicenter, Open-Label, Dose Escalation and Double-Blind, Randomized, Placebo-Controlled, Dose Expansion Study of the Safety, Efficacy and Pharmacokinetics of Navtemadlin Plus Pembrolizumab as Maintenance Therapy in Subjects With Locally Advanced and Metastatic Non-Small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 撤回
- 主要终点
- Phase 2- To assess the treatment effect of navtemadlin plus pembrolizumab treatment on PFS compared with the treatment effect of navtemadlin placebo plus pembrolizumab treatment.
研究概览
简要总结
This study evaluates Navtemadlin (KRT-232) in combination with Pembrolizumab as a maintenance therapy in patients with locally advanced and metastatic non small cell lung cancer.
详细描述
This is a 2 part, phase 1b/2, maintenance study for patients who have achieved a partial response (PR) or complete response (CR) after completion of up to 4 cycles of a combination platinum-based chemotherapy plus CPI regimen.
Phase 1b is a 3+3 dose escalation design that will be used to determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D) of navtemadlin in combination with pembrolizumab. A Safety Review Committee (SRC) will review the safety data during the dose escalation to decide on dose escalation and/or exploration of intermediate doses.
Phase 2 will evaluate the efficacy and safety of the RP2D of navtemadlin plus pembrolizumab compared to navtemadlin placebo plus pembrolizumab. Each Arm will have approximately 40 subjects enrolled for a total of approximately 80 subjects. Eligible subjects will be randomized 1:1. This part of the study has a randomized, controlled, double-blind design. A stratified, permuted-block randomization scheme will be used for treatment allocation.
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
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
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
- •Histologically or cytologically confirmed diagnosis of NSCLC documented as TP53WT
- •Locally advanced or metastatic disease; must have completed up to 4 cycles of platinum-based chemo plus CPI and achieved a CR or PR per RECIST V1.1
- •Adequate hematologic, hepatic and renal function (within 14 days)
排除标准
- •Symptomatic or uncontrolled central nervous system (CNS) metastases
- •Prior treatment with a MDM2 inhibitor
- •Grade 2 or higher QTc prolongation (>480 msec per NCI-CTCAE criteria version 5.0)
- •History of bleeding diathesis; major hemorrhage or intracranial hemorrhage within 24 weeks
- •History of major organ transplant
- •Active pneumonitis or known history of interstitial lung disease, drug-related pneumonitis, or radiation pneumonitis
- •Prior radiotherapy, cytoreductive therapy, cytokine therapy or any investigational therapy within 28 days
- •Medical condition, serious intercurrent illness, psychiatric condition or other circumstance that, in the Investigator's judgment could jeopardize the subject's safety, or that could interfere with study objectives
研究组 & 干预措施
Navtemadlin in combination with pembrolizumab
Navtemadlin will be administered orally, once daily (QD), on days 1-7 in a 21-day cycle.
Pembrolizumab will be administered intravenously on Day 1 of a 21-day cycle.
干预措施: Navtemadlin (Drug)
Navtemadlin in combination with pembrolizumab
Navtemadlin will be administered orally, once daily (QD), on days 1-7 in a 21-day cycle.
Pembrolizumab will be administered intravenously on Day 1 of a 21-day cycle.
干预措施: Pembrolizumab (Drug)
Navtemadlin placebo in combination with pembrolizumab
Navtemadlin placebo will be administered orally, once daily (QD), on days 1-7 in a 21-day cycle.
Pembrolizumab will be administered intravenously on Day 1 of a 21-day cycle.
干预措施: Navtemadlin Placebo (Drug)
Navtemadlin placebo in combination with pembrolizumab
Navtemadlin placebo will be administered orally, once daily (QD), on days 1-7 in a 21-day cycle.
Pembrolizumab will be administered intravenously on Day 1 of a 21-day cycle.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Phase 2- To assess the treatment effect of navtemadlin plus pembrolizumab treatment on PFS compared with the treatment effect of navtemadlin placebo plus pembrolizumab treatment.
时间窗: 64 Months
PFS is defined as the time from randomization date to disease progression (assessed by the Independent Review Committee \[IRC\] per RECIST v1.1) or death, whichever occurs first
Phase 1b- To determine the recommended Phase 2 dose (RP2D)
时间窗: 21 days
The Safety Review Committee will determine the RP2D based on safety data of the combination of navtemadlin and pembrolizumab.
次要结局
- Phase 1b- To characterize the pharmacokinetic (PK) profile of navtemadlin(1 day)
- Phase 1b- To assess the treatment effect on progression-free survival (PFS)(64 Months)
- Phase 2- To assess the treatment effect of navtemadlin plus pembrolizumab treatment on PFS compared with the treatment effect of navtemadlin placebo plus pembrolizumab treatment.(64 Months)