Trial of BIBW 2992 (Afatinib) + Cetuximab in Non-Small Cell Lung Cancer
- Registration Number
- NCT01090011
- Lead Sponsor
- Boehringer Ingelheim
- Brief Summary
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.
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 171
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description combination arm BIBW 2992 patients to receive medium BIBW 2992 once daily plus biweekly cetuximab infusion at low, median and high dose level sequential arm BIBW 2992 patients to receive BIBW 2992 once daily, upon progression add biweekly cetuximab sequential arm Cetuximab patients to receive BIBW 2992 once daily, upon progression add biweekly cetuximab combination arm Cetuximab patients to receive medium BIBW 2992 once daily plus biweekly cetuximab infusion at low, median and high dose level
- Primary Outcome Measures
Name Time Method The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT). 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.
- Secondary Outcome Measures
Name Time Method 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 Frequency (%) of patients with drug-related serious adverse events
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 Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days
Duration of Objective Response (According to RECIST v1.1) up to 116 weeks Duration of objective response was measured from the time measurements criteria were met for CR/PR (whichever was first recorded) until the first date that recurrent or PD was objectively documented (taking as reference for PD the smallest measurements recorded since treatment started).
Duration of Disease Control (According to RECIST v1.1) up to 116 weeks Duration of disease control was defined as the time from the start of treatment to the time of progression or death (whichever occurred first), among patients with evidence SD, PR or CR.
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 Frequency (%) of patients with adverse events leading to treatment discontinuation
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 Minimum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmin,ss). Maximum measured concentration of Afatinib in plasma at steady state over 15 day dosing interval (Cmax,ss).
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 Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/F,ss)
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 mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days
Predose Plasma Concentrations of Afatinib for the Combination Arm Up to 57 days Predose plasma concentrations (Cpre,ss) of Afatinib at Course 1, Visit 2, 3, 4 and 5, at Course 2, Visit 1 and 2 and at Course 3, Visit 1.
Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) up to 116 weeks Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Disease control = CR + PR + SD.
Highest CTCAE Grade From first drug administration to 28 days after discontinuation of drug intake up to 915 days Safety of afatinib when administered together with cetuximab as indicated by intensity and incidence of adverse events, graded according to the U.S. National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) Version (v) 3.0
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 Area Under the Concentration-time Curve (AUC) of Afatinib in plasma at steady state over a uniform dosing interval tau (15 days) (AUCtau,ss) after oral administration of Afatinib and cetuximab combination therapy
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 Peak-trough fluctuation (PTF) of plasma afatinib for the combination arm. PTF = 100\*(Cmax-Cmin)/Caverage where Caverage = AUC/time, where time equals 24 hours.
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 Terminal half-life of Afatinib in plasma at steady state (t1/2,ss)
Progression-Free Survival (PFS) Time up to 116 weeks Progression-Free Survival was defined as the duration of time from start of treatment until the day of objective tumour progression confirmed by tumour imaging (PD according to RECIST 1.1) or death.
Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) up to 116 weeks Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD), At least a 20% increase in the sum of the longest diameter of target lesions or the appearance of new lesion(s); Stable Disease (SD), Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.
Objective tumor response = CR + PR.
Trial Locations
- Locations (6)
1200.71.1001 Boehringer Ingelheim Investigational Site
🇺🇸New York, New York, United States
1200.71.1004 Boehringer Ingelheim Investigational Site
🇺🇸Aurora, Colorado, United States
1200.71.2002 Boehringer Ingelheim Investigational Site
🇳🇱Amsterdam, Netherlands
1200.71.1003 Boehringer Ingelheim Investigational Site
🇺🇸New Haven, Connecticut, United States
1200.71.2001 Boehringer Ingelheim Investigational Site
🇳🇱Groningen, Netherlands
1200.71.1002 Boehringer Ingelheim Investigational Site
🇺🇸Nashville, Tennessee, United States