A Dose-finding Phase Ib Study Followed by a Randomized, Double-blind Phase II Study of Carboplatin and Paclitaxel With or Without Buparlisib in Patients With Previously Untreated Metastatic Non-small Cell Lung Cancer (NSCLC) of Squamous Histology
试验速览
- 阶段
- 1 期
- 状态
- 终止
- 入组人数
- 6
- 试验地点
- 3
- 主要终点
- Number of Total Dose-limiting Toxicity (DLT) During Dose Escalation to Determine Maximum Tolerated Dose (MTD)
研究概览
简要总结
The Phase Ib part of the study aimed to determine the maximum tolerated dose/recommended Phase II dose (MTD/RP2D) of once daily buparlisib in combination with every-three-week carboplatin and paclitaxel in patients with previously untreated metastatic squamous NSCLC.
The purpose of the Phase II portion of the study was to assess the treatment effect of adding buparlisib versus buparlisib-matching placebo to every-three-week carboplatin and paclitaxel on progression free survival (PFS) in patients with previously untreated metastatic squamous NSCLC.
详细描述
Based on the observation of DLTs and AEs, the safety profile of this investigational treatment was considered challenging requiring dose reductions/interruptions and even the evaluation of an alternative schedule of buparlisib administration. The study was early terminated, and the primary objective was not met. Therefore the phase ll portion of the study was never initiated.
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
- Triple (Participant, Care Provider, Investigator)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- Female
- 接受健康志愿者
- 否
入选标准
- •Patient has histologically and/or cytologically confirmed diagnosis of squamous NSCLC. Diagnosis of mixed squamous with a squamous component will be acceptable for enrollment.
- •Patient has archival or new tumor tissue for the analysis of PI3K biomarkers
- •Tumor is Stage IV at the time of signed informed consent (UICC/AJCC version 7)
- •Patient has measurable or non-measurable disease according to RECIST v1.1 criteria
- •For the Phase II portion, the patient must have measurable disease according to RECIST 1.1 criteria
- •Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 that the investigator believes is stable at the time of screening
- •Patient has adequate bone marrow and organ function
排除标准
- •Patient has received any prior systemic therapies for metastatic NSCLC. Study treatment in this clinical trial must be the patient's first systemic treatment for metastatic NSCLC. Patients are eligible if they received neo-adjuvant or adjuvant systemic therapy followed by a disease-free interval exceeding 12 months.
- •Patient has symptomatic CNS metastases
- •Patients with asymptomatic CNS metastases may participate in this trial. The patient must have completed any prior local treatment for CNS metastases ≥ 28 days prior to the start of study treatment (including radiotherapy and/or surgery, or ≥14 days for stereotactic radiosurgery).
- •Patient is currently receiving warfarin or other coumadin derived anticoagulant for treatment, prophylaxis or otherwise. Therapy with heparin, low molecular weight heparin (LMWH), or fondaparinux is allowed.
- •Patient is currently receiving treatment with drugs known to be strong inhibitors or inducers of isoenzyme CYP3A. The patient must have discontinued strong inducers for at least one week and must have discontinued strong inhibitors before the treatment is initiated. Switching to a different medication prior to randomization is allowed.
- •Patient has a medically documented history of or active major depressive episode, bipolar disorder (I or II), obsessive-compulsive disorder, schizophrenia, a history of suicidal attempt or ideation, or homicidal ideation (e.g. risk of doing harm to self or others) or patients with active severe personality disorders (defined according to DSM- IV) are not eligible. Note: for patients with psychotropic treatments ongoing at baseline, the dose and the schedule should not be modified within the previous 6 weeks prior to start of study drug
- •Patient has ≥ CTCAE grade 3 anxiety
- •Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL)
- •Patient who does not apply highly effective contraception during the study and through the duration as defined below after the final dose of study treatment.
研究组 & 干预措施
Buparlisib + Carboplatin + Paclitaxel
Carboplatin and paclitaxel plus buparlisib for up to 6 cycles, followed by blinded buparlisib maintenance
干预措施: Paclitaxel (Drug)
Buparlisib + Carboplatin + Paclitaxel
Carboplatin and paclitaxel plus buparlisib for up to 6 cycles, followed by blinded buparlisib maintenance
干预措施: Buparlisib (Drug)
Buparlisib + Carboplatin + Paclitaxel
Carboplatin and paclitaxel plus buparlisib for up to 6 cycles, followed by blinded buparlisib maintenance
干预措施: Carboplatin (Drug)
Placebo + Carboplatin + Paclitaxel
Carboplatin and paclitaxel plus buparlisib-matching placebo for up to 6 cycles, followed by blinded placebo maintenance
干预措施: Buparlisib placebo (Drug)
Placebo + Carboplatin + Paclitaxel
Carboplatin and paclitaxel plus buparlisib-matching placebo for up to 6 cycles, followed by blinded placebo maintenance
干预措施: Carboplatin (Drug)
Placebo + Carboplatin + Paclitaxel
Carboplatin and paclitaxel plus buparlisib-matching placebo for up to 6 cycles, followed by blinded placebo maintenance
干预措施: Paclitaxel (Drug)
结局指标
主要结局
Number of Total Dose-limiting Toxicity (DLT) During Dose Escalation to Determine Maximum Tolerated Dose (MTD)
时间窗: Cycle 1 (21 days)
Determine the MTD and/or RP2D of daily buparlisib in combination with paclitaxel and carboplatin in patients with advanced or metastatic squamous NSCLC.
Progression Free Survival (PFS) as measured using RECIST 1.1
时间窗: Randomization, every 6 weeks to the date of first document progression for up to 3 years
Progression-free survival is defined as the time from randomization to the date of the first documented progression or death from any cause. The Kaplan-Meier estimate of the PFS survival function was contructed.
次要结局
- Time to overall response(Every 6 weeks from randomization until first documented progression for up to 3 years)
- Time to deterioration by the Functional Assessment of EORTC QLQ- C-30 and lung cancer module (QLQ-LC-13)(Screening, Every 6 weeks until disease progression for up to 3 years)
- Duration of overall response(Every 6 weeks from randomization until first documented progression for up to 3 years)
- Number of Participants With Best Overall Response Rate (ORR) According to Response Evaluation Criteria in Solid Tumors (RECIST)(Every 6 weeks from randomization until first documented progression for up to 3 years)
- Overall Survival Time(Every 6 weeks from randomization until first documented progression for up to 3 years)
- Change From Baseline in Quality of Life Measured by the Functional Assessment of EORTC QLQ- C-30 and lung cancer module (QLQ-LC-13)(Screening, Every 6 weeks until disease progression for up to 3 years)
- The Overall Safety and Tolerability of buparlisib (BKM120)(Screening, Until 30 days after last dose)
- Characterize the PK of buparlisib under alternative dosing regimen when combined with paclitaxel and carboplatin in the target population(cycle 1 to 6 in Phase Ib portion)
- Buparlisib concentrations(Cycle 1 day 8 and 15, Cycle 2 day 1, Cycle 7-Cycle n, day 1)