Phase I/II, Multicenter, Open-label, Clinical and Pharmacokinetic Study of Lurbinectedin (PM01183) in Combination With Pembrolizumab in Patients With Relapsed Small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 发起方
- 入组人数
- 28
- 试验地点
- 5
- 主要终点
- Phase I: Maximum tolerated dose (MTD) and recommended phase II dose (RD) of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC.
研究概览
简要总结
This is a prospective, open-label, uncontrolled and multicenter phase I/II study of PM01183 in combination with pembrolizumab in patients with relapsed small cell lung cancer (SCLC).
The study will be divided into two stages:
- A dose-ranging phase I stage with escalating doses of PM01183 in combination with a fixed dose of pembrolizumab, followed by:
- A non-randomized phase II stage as an expansion study at the recommended dose (RD) determined during the phase I stage.
The phase I stage will focus on the selection of the RD based on safety/tolerability, while the phase II stage will assess the overall response rate (ORR) and clinical response.
详细描述
• During the phase I stage, patients will start receiving pembrolizumab at a fixed dose of 200 mg as a 30-min intravenous (IV) infusion followed by PM01183 at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). A cycle is defined as an interval of 3 weeks.
PM01183 dose will be escalated from the starting dose in successive cohorts of patients, with a pre-established fixed dose increase (in mg/m2) of approximately 30%.
Dose escalation will follow a classical 3+3 design, according to the observed tolerance and safety. All evaluable patients within a dose level will be followed for at least one cycle (i.e., 3 weeks) before dose escalation may proceed. The maximum tolerated dose (MTD) will be the lowest dose level explored during dose escalation at which one third or more of evaluable patients experience a dose-limiting toxicity (DLT) in Cycle 1.
Dose escalation will be terminated once the MTD or the last dose level (i.e., DL2) is reached, whichever occurs first, except if all DLTs occurring at a given dose level are related to neutropenia. If this is the case, dose escalation may be resumed, starting at the lowest dose level at which exclusively neutropenia-related DLTs were observed, and will follow the same original schedule but with mandatory primary granulocyte colony-stimulating factor (G-CSF) prophylaxis.
An expansion cohort to complete a minimum of 6 evaluable patients will be recruited at the immediate lower dose level from the MTD, or at DL2 if the MTD is not defined yet. This level will be confirmed as the RD if less than one third of the first 6 evaluable patients experience DLT during Cycle 1. Intermediate dose levels could be tested upon agreement of the Scientific Steering Committee members, as defined in Section 8.4, if deemed appropriate. This will also be discussed with Pharma Mar and MSD.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- 未提供
排除标准
- 未提供
研究组 & 干预措施
Experimental: lurbinectedin (PM01183) + pembrolizumab
During the phase I stage, patients will start receiving pembrolizumab at a fixed dose of 200 mg as a 30-min intravenous (IV) infusion followed by lurbinectedin at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). Lurbinectedin dose will be escalated from the starting dose in successive cohorts of patients, with a pre-established fixed dose increase (in mg/m2) of approximately 30%.
During the phase II stage, patients will receive pembrolizumab at a fixed dose of 200 mg as a 30-min IV infusion followed by lurbinectedin as a 1-h IV infusion on Day 1 Q3W at the redommended dose (RD) determined during the phase I stage. A cycle is defined as an interval of 3 weeks. No dose escalation will be allowed during the phase II stage.
干预措施: Lurbinectedin (Drug)
Experimental: lurbinectedin (PM01183) + pembrolizumab
During the phase I stage, patients will start receiving pembrolizumab at a fixed dose of 200 mg as a 30-min intravenous (IV) infusion followed by lurbinectedin at a starting dose of 2.4 mg/m2 as a 1-h IV infusion on Day 1, both every 3 weeks (Q3W). Lurbinectedin dose will be escalated from the starting dose in successive cohorts of patients, with a pre-established fixed dose increase (in mg/m2) of approximately 30%.
During the phase II stage, patients will receive pembrolizumab at a fixed dose of 200 mg as a 30-min IV infusion followed by lurbinectedin as a 1-h IV infusion on Day 1 Q3W at the redommended dose (RD) determined during the phase I stage. A cycle is defined as an interval of 3 weeks. No dose escalation will be allowed during the phase II stage.
干预措施: Pembrolizumab (Drug)
结局指标
主要结局
Phase I: Maximum tolerated dose (MTD) and recommended phase II dose (RD) of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC.
时间窗: 12 months
The MTD will be the lowest dose level explored during dose escalation at which more than one third of evaluable patients develop a DLT in Cycle 1. The RD will be the highest dose level explored at which less than one third of evaluable patients develop a DLT during Cycle 1.
Phase II: Efficacy of lurbinectedin in combination with pembrolizumab in terms of overall response rate (ORR), according to RECIST 1.1, in patients with relapsed SCLC.
时间窗: 38 months
ORR is defined as the percentage of evaluable patients with a confirmed response, either complete (CR) or partial (PR). The ORR will be assessed using the RECIST 1.1 on a set of measurable lesions identified at baseline as target lesions or as non-target lesions (if any), and followed until PD by an appropriate method.
次要结局
- Phase I: MTD and RD of lurbinectedin in combination with pembrolizumab with mandatory primary prophylaxis with G-CSF in patients with relapsed SCLC (if DLTs of this combination are exclusively related to neutropenia).(12 months)
- Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Duration of response (DOR).(38 months)
- Both stages: Pharmacogenetic (PGt) analysis.(38 months)
- Phase I: Preliminary information on the clinical antitumor activity of the combination.(28 months)
- Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Clinical benefit ≥3 months.(38 months)
- Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Overall survival (OS).(38 months)
- Phase II: Antitumor activity of this combination as per RECIST 1.1 (and iRECIST 1.1, whenever applicable) in terms of Progression-free survival (PFS).(38 months)
- Both Stages: Safety profile and feasibility of lurbinectedin in combination with pembrolizumab in patients with relapsed SCLC.(38 months)
- Both stages: Characterize the plasma pharmacokinetics (PK) of lurbinectedin in this combination and to detect major drug-drug PK interactions.(38 months)
- Both stages: Pharmacogenomic (PGx) analysis in tumor samples of patients exposed to lurbinectedin and pembrolizumab in order to assess potential markers of response and/or resistance.(38 months)
研究者
Antonio Calles Blanco
Physician Thoracic Oncology, Head & Neck and Sarcoma Unit Early Drug Development and Phase I Unit
Blanco, Dr Antonio Calles MD