A Phase Ib Open-label Clinical Trial of Continuous Once Daily Oral Treatment Using BIBW 2992 Plus Cetuximab (Erbitux®) in Patients With Non-small Cell Lung Cancer With Progression Following Prior Erlotinib (Tarceva®) or Gefitinib (Iressa®)
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 171
- 试验地点
- 6
- 主要终点
- The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).
研究概览
简要总结
The primary objective of this trial is to determine the maximum tolerated dose (MTD) and recommended Phase II doses for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib or gefitinib.
Overall safety, pharmacokinetics and anti-tumor activity for the combination of BIBW 2992 and cetuximab in patients with non-small cell lung cancer and acquired resistance to erlotinib, gefitinib or BIBW 2992 will be evaluated as secondary objectives.
Initially a standard, 3+3 dose escalation will be performed to determine the MTD of BIBW 2992 when administered together with cetuximab in patients with advanced non small cell lung cancer and acquired resistance to erlotinib or gefitinib.
Subsequently, the preliminary efficacy and safety of the identified MTD of cetuximab administered with BIBW 2992 will be explored in a combo arm via a further expansion of MTD cohort up to a total of 140 EGFR mutation positive NSCLC with acquired resistance to erlotinib/gefitinib.
Furthermore, the safety and preliminary anti-tumor activity of the combination therapy in EGFR mutant NSCLC patients who developed acquired resistance (AR) to BIBW 2992, will be assessed in a sequential arm. The sequential arm will use a two-stage design with an early stopping rule after 12 patients with acquired resistance to BIBW 2992 have received up to 5 courses of BIBW 2992 plus cetuximab. If no responses are seen in 12 patients during 5 courses of combination therapy, accrual in the sequential arm will stop. If 1 or more responses are observed, the sequential arm will expand up to about 40 patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Parallel
- 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
combination arm
patients to receive medium BIBW 2992 once daily plus biweekly cetuximab infusion at low, median and high dose level
干预措施: Cetuximab (Drug)
combination arm
patients to receive medium BIBW 2992 once daily plus biweekly cetuximab infusion at low, median and high dose level
干预措施: BIBW 2992 (Drug)
sequential arm
patients to receive BIBW 2992 once daily, upon progression add biweekly cetuximab
干预措施: Cetuximab (Drug)
sequential arm
patients to receive BIBW 2992 once daily, upon progression add biweekly cetuximab
干预措施: BIBW 2992 (Drug)
结局指标
主要结局
The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).
时间窗: from day 1 treatment until progression or undue toxicity, up to 28 days
A DLT was defined as an AE or laboratory abnormality that a) related to the study regimen; b) or met any of the following criteria: * CTCAE Grade 2 or higher decrease in cardiac left ventricular function * CTCAE Grade 2 diarrhea lasting for 7 or more days, despite appropriate use of standard anti-diarrheal therapy * CTCAE Grade ≥3 diarrhea despite appropriate use of standard anti-diarrheal therapy for at least 2 days * CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-emetics for at least 3 days * CTCAE Grade ≥3 rash despite standard medical management * CTCAE Grade ≥3 fatigue lasting for more than 7 days * CTCAE Grade 4 hypomagnesaemia or Grade 3 hypomagnesaemia with clinical significant sequelae * All other toxicities of CTCAE Grade ≥3 (except alopecia, and allergic reaction) leading to an interruption of afatinib and/or cetuximab for more than 14 days until recovery to baseline or Grade 1, whichever was higher.
次要结局
- Frequency (%) of Patients With Adverse Events Leading to Dose Reduction(From first drug administration to 28 days after discontinuation of drug intake up to 915 days)
- Frequency (%) of Patients With Related Serious Adverse Events(From first drug administration to 28 days after discontinuation of drug intake up to 915 days)
- Vz/F,ss(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- Duration of Objective Response (According to RECIST v1.1)(up to 116 weeks)
- Duration of Disease Control (According to RECIST v1.1)(up to 116 weeks)
- Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation(From first drug administration to 28 days after discontinuation of drug intake up to 915 days)
- Concentration of Afatinib in Plasma for the Combination Arm(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- CL/F,ss,15(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters(From first drug administration to 28 days after discontinuation of drug intake up to 915 days)
- MRTpo,ss(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- Predose Plasma Concentrations of Afatinib for the Combination Arm(Up to 57 days)
- Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)(up to 116 weeks)
- Progression-Free Survival (PFS) Time(up to 116 weeks)
- Highest CTCAE Grade(From first drug administration to 28 days after discontinuation of drug intake up to 915 days)
- Frequency (%) of Patients With Adverse Events Leading to Death(From first drug administration to 28 days after discontinuation of drug intake up to 915 days)
- Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- Peak-trough Fluctuation (PTF)(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- t1/2,ss(Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55)
- Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)(up to 116 weeks)