Trial of BIBW 2992 (Afatinib) + Cetuximab in Non-Small Cell Lung Cancer
Condition: Carcinoma, Non-Small-Cell Lung
MeSH terms: Carcinoma, Non-Small-Cell Lung
Intervention: Cetuximab; Cetuximab; BIBW 2992; BIBW 2992
Intervention description: BIBW 2992 medium dose plus high dose level of cetuximab; BIBW 2992 medium dose monotherapy, upon progression, cetuximab high dose is added; BIBW 2992 medium dose plus high dose level of cetuximab; BIBW 2992 medium dose monotherapy, upon progression, cetuximab high dose is added
Intervention MeSH terms: Cetuximab; Afatinib
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 171.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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