Clinical trial NCT01090011: Trial of BIBW 2992 (Afatinib) + Cetuximab in Non-Small Cell Lung Cancer
Official title: 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®)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Carcinoma, Non-Small-Cell Lung
Lead sponsor: Boehringer Ingelheim
Sponsor class: INDUSTRY
First posted: 2010-03-19
Enrollment: 171
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion criteria:

1. Pathologically or cytologically confirmed Stage IIIB/IV non-small cell lung cancer or recurrent disease following locoregional treatment
2. 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

1. Documented partial or complete response (Response Evaluation Criteria in Solid Tumors, RECIST), or
2. 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:

1. Prior treatment with EGFR targeting antibodies; prior severe infusion reaction to a monoclonal antibody
2. 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.
3. Radiotherapy less than two weeks prior to the start of the study treatment
4. Systemic chemotherapy, hormonal therapy, immunotherapy, or experimental or approved proteins/antibodies (except erlotinib/gefitinib/BIBW 2992) \<=30 days before study treatment
5. 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
6. 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.
7. Other malignancies diagnosed within the past five (5) years (other than non melanomatous skin cancer, ductal carcinoma in situ and in situ cervical cancer)
8. Known pre-existing interstitial lung disease
9. 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
10. 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

Primary outcomes:
measure: The Primary Endpoint is the Occurrence of Dose Limiting Toxicity (DLT).
timeFrame: from day 1 treatment until progression or undue toxicity, up to 28 days
Secondary outcomes:
measure: Highest CTCAE Grade
timeFrame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
measure: Frequency of Patients [N(%)] With Possible Clinically Significant Abnormalities for Selected Laboratory Parameters
timeFrame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
measure: Frequency (%) of Patients With Adverse Events Leading to Dose Reduction
timeFrame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
measure: Frequency (%) of Patients With Adverse Events Leading to Treatment Discontinuation
timeFrame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
measure: Frequency (%) of Patients With Adverse Events Leading to Death
timeFrame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
measure: Frequency (%) of Patients With Related Serious Adverse Events
timeFrame: From first drug administration to 28 days after discontinuation of drug intake up to 915 days
measure: Area Under the Concentration-time Curve (AUC) on Day 15 of Plasma Afatinib for the Combination Arm
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: Concentration of Afatinib in Plasma for the Combination Arm
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: Peak-trough Fluctuation (PTF)
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: t1/2,ss
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: MRTpo,ss
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: CL/F,ss,15
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: Vz/F,ss
timeFrame: Course 1, Visit 3 and 4, Day 15 and 16, Hours: -0:05,0,1,2,3,4,5,6,8, and 23:55
measure: Predose Plasma Concentrations of Afatinib for the Combination Arm
timeFrame: Up to 57 days
measure: Disease Control (CR, PR and Stable Disease (SD) Determined by RECIST v1.1)
timeFrame: up to 116 weeks
measure: Objective Tumor Response (Complete Response [CR] and Partial Response [PR]) Determined by RECIST v1.1)
timeFrame: up to 116 weeks
measure: Duration of Objective Response (According to RECIST v1.1)
timeFrame: up to 116 weeks
measure: Duration of Disease Control (According to RECIST v1.1)
timeFrame: up to 116 weeks
measure: Progression-Free Survival (PFS) Time
timeFrame: up to 116 weeks
Other outcomes:
Locations:
city: Aurora
country: United States
facility: 1200.71.1004 Boehringer Ingelheim Investigational Site
state: Colorado
city: New Haven
country: United States
facility: 1200.71.1003 Boehringer Ingelheim Investigational Site
state: Connecticut
city: New York
country: United States
facility: 1200.71.1001 Boehringer Ingelheim Investigational Site
state: New York
city: Nashville
country: United States
facility: 1200.71.1002 Boehringer Ingelheim Investigational Site
state: Tennessee
city: Amsterdam
country: Netherlands
facility: 1200.71.2002 Boehringer Ingelheim Investigational Site
city: Groningen
country: Netherlands
facility: 1200.71.2001 Boehringer Ingelheim Investigational Site
Study officials:
affiliation: Boehringer Ingelheim
name: Boehringer Ingelheim
role: STUDY_CHAIR
References:
citation: Horn L, Gettinger S, Camidge DR, Smit EF, Janjigian YY, Miller VA, Pao W, Freiwald M, Fan J, Wang B, Chand VK, Groen HJM. Continued use of afatinib with the addition of cetuximab after progression on afatinib in patients with EGFR mutation-positive non-small-cell lung cancer and acquired resistance to gefitinib or erlotinib. Lung Cancer. 2017 Nov;113:51-58. doi: 10.1016/j.lungcan.2017.08.014. Epub 2017 Aug 31.
citation: Janjigian YY, Smit EF, Groen HJ, Horn L, Gettinger S, Camidge DR, Riely GJ, Wang B, Fu Y, Chand VK, Miller VA, Pao W. Dual inhibition of EGFR with afatinib and cetuximab in kinase inhibitor-resistant EGFR-mutant lung cancer with and without T790M mutations. Cancer Discov. 2014 Sep;4(9):1036-45. doi: 10.1158/2159-8290.CD-14-0326. Epub 2014 Jul 29.