Trial of BIBW 2992 (Afatinib) + Cetuximab in Non-Small Cell Lung Cancer

Study Overview
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Brief Summary
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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.

Official Title
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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®)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Cetuximab
* Drug: Cetuximab
* Drug: BIBW 2992
* Drug: BIBW 2992


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment Either or both of the following: 1) A tumor which harbors an Epidermal Growth Factor Receptor (EGFR) -mutation known to be associated with drug sensitivity (i.e., G719X, exon 19 deletion, L858R, L861Q) from previous tumor biopsy or surgery. A tumor which harbors exon 20 insertion or de novo T790M mutation is eligible for the treatment in the sequential arm 2) Objective clinical benefit from treatment with an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR TKI) as defined by either Documented partial or complete response (Response Evaluation Criteria in Solid Tumors, RECIST), or Stable disease >=6 months as defined by RECIST in absence of radiographic progression after initiation of gefitinib or erlotinib; or stable disease/PR/CR >=12 weeks as defined by RECIST after initiation of BIBW 2992 3. Systemic progression of disease (RECIST v1.1) while on continuous treatment with erlotinib or gefitinib or BIBW 2992 within the last 30 days. Patients whose disease progresses only in the central nervous system (CNS) are not eligible 4. No intervening systemic therapy between cessation of gefitinib or erlotinib or BIBW 2992 and initiation of the treatment in the study 5. Adequate tumor-derived material such as fresh or archived tumor tissue or pleural fluid from malignant pleural effusion after disease progression on erlotinib/gefitinib/BIBW 2992 prior to the study entry must be made available for EGFR mutation analyses 6. Patients aged 18 years or older 7. Life expectancy of at least three (3) months 8. Eastern Cooperative Oncology Group (ECOG) performance score 0-2 9. Written informed consent that is consistent with ICH-GCP guidelines Exclusion criteria: Prior treatment with EGFR targeting antibodies; prior severe infusion reaction to a monoclonal antibody Adverse events due to major surgery (at least 28 days after) or minor surgery not recovered to CTC grade 1 or less. Surgical wounds must be healing without clinical evidence of infection prior to study treatment to be eligible. Radiotherapy less than two weeks prior to the start of the study treatment Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (except erlotinib/gefitinib/BIBW 2992) <=30 days before study treatment Less than three days from prior treatment with gefitinib or erlotinib. Patients with adverse events related to gefitinib or erlotinib must recover to CTC AE grade 1 or less to be eligible. No need to stop BIBW 2992 before start of the study treatment for patient who progressed on BIBW 2992 from a separate clinical trial/treatment setting Brain metastases, which are symptomatic. Patients with treated, asymptomatic brain metastases are eligible if there has been no change in brain disease status for at least four (4) weeks, no history of cerebral oedema or bleeding in the past four (4) weeks. Anticonvulsant therapy will be allowed if patient is stable on anticonvulsant treatment. Other malignancies diagnosed within the past five (5) years (other than non melanomatous skin cancer, ductal carcinoma in situ and in situ cervical cancer) Known pre-existing interstitial lung disease Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohns disease, malabsorption, or Common Toxicity Criteria for Adverse Events (CTCAE) grade >2 diarrhea of any etiology Women of childbearing potential (WOCBP), or men who are able to father a child, unwilling to use a medically acceptable method of contraception during the trial; pregnancy or breast-feeding

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: combination arm<br>patients to receive medium BIBW 2992 once daily plus biweekly cetuximab infusion at low, median and high dose level | Drug: Cetuximab<br>* BIBW 2992 medium dose plus high dose level of cetuximab<br>Drug: BIBW 2992<br>* BIBW 2992 medium dose plus high dose level of cetuximab<br>|
| Experimental: sequential arm<br>patients to receive BIBW 2992 once daily, upon progression add biweekly cetuximab | Drug: Cetuximab<br>* BIBW 2992 medium dose monotherapy, upon progression, cetuximab high dose is added<br>Drug: BIBW 2992<br>* BIBW 2992 medium dose monotherapy, upon progression, cetuximab high dose is added<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT). | 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. | from day 1 treatment until progression or undue toxicity, up to 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Highest CTCAE Grade | 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 | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | 
| 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 | 
| 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 Adverse Events Leading to Treatment Discontinuation | 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 Death |  | From first drug administration to 28 days after discontinuation of drug intake up to 915 days | 
| Frequency (%) of Patients With Related Serious Adverse Events | Frequency (%) of patients with drug-related serious adverse events | 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 | 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 | Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55 | 
| Concentration of Afatinib in Plasma for the Combination Arm | 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). | 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) | 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. | 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 | Terminal half-life of Afatinib in plasma at steady state (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 | 
| MRTpo,ss | mean residence time of Afatinib in the body at steady state after oral administration (MRTpo,ss) for 15 days | 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 | Apparent clearance of afatinib in plasma at steady state after extravascular multiple dose administration (CL/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 | 
| Vz/F,ss | Apparent volume of distribution during the terminal phase λz at steady state following extravascular administration (Vz/F,ss) for 15 days | 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 | 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. | Up to 57 days | 
| Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1) | 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. | up to 116 weeks | 
| Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1) | 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. | up to 116 weeks | 
| Duration of Objective Response (According to RECIST v1.1) | 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). | up to 116 weeks | 
| Duration of Disease Control (According to RECIST v1.1) | 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. | up to 116 weeks | 
| Progression-Free Survival (PFS) Time | 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. | up to 116 weeks |