Dual Targeting of EGFR With Cetuximab and Afatinib to Treat Refractory wtKRAS Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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This is a multicentric, phase II and open label study.75 patients are expected to be randomized in 35 centers. The main objective is to assess the efficacy and safety of Afatinib -cetuximab combo versus cetuximab alone in treatment of patients with refractory wtKRAS metastatic colorectal cancer.

Detailed Description
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Patients who will sign the inform consent will be enrolled into one of two groups. Group A will receive Afatinib ( 40mg per day) and Cetuximab (500mg/m2)every two weeks until progression. Group B will receive Cetuximab (500mg/m2) alone every two weeks until progression and after progression,patients from group B will receive afatinib (group A treatment) until progression. The criteria for evaluation will be tumor response and progression documented by CT scan and according to RECIST criteria version 1.1. Patient will also sign a inform consent before participating in biological study. The aim of this translational study is to collect tumor and blood sample in order to determine, the biological factors which are predictive of the response to treatment.

Official Title
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A Multicentric Randomized Phase II Trial Evaluating Dual Targeting of EGFR Using the Combination of Cetuximab and Afatinib Versus Cetuximab Alone in Patients With Chemotherapy Refractory wtKRAS Metastatic Colorectal Cancer

Conditions
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: Cetuximab + Afatinib
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic colorectal cancer expressing the wtKRAS status No previous EGFR targeted therapy. Must have failed a prior regimen containing irinotecan for metastatic disease and a prior regimen containing oxaliplatin for metastatic disease Must have previously received a thymidylate synthase inhibitor (eg, fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of colorectal cancer (CRC) Life expectancy of at least 3 months. Patient with ECOG ≤ 1 Patients aged ≥ 18. Patient with measurable lesions according to RECIST criteria (version 1.1) with spiral CT scan and defined as ≥ 10 mm in longest diameter and 2X the slice thickness for extra nodal lesions and/or > 15 mm in short axis diameter for nodal lesions Patient able to receive adequate oral nutrition of ≥ 1500 calories per day and free of significant nausea and vomiting Patient with adequate organ function: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Haemoglobin ≥ 9 g/dL Platelets (PTL) ≥ 100 x 109/L AST/ALT ≤ 3 x ULN (≤ 5 x ULN in case of liver metastases) GammaGT < 3 x ULN (< 5 x ULN in case of liver involvement) Bilirubin ≤ 1.5 x ULN Creatinine clearance ≥ 50 mL/min (Cockcroft and Gault formula) Adequate contraception if applicable. Ability to take oral medication in the opinion of the investigator Patient able and willing to comply with study procedures as per protocol Patient able to understand and willing to sign and date the written voluntary informed consent form at screening visit prior to any protocol-specific procedures Patient affiliated to a social security regimen Exclusion Criteria: Previous EGFR targeted therapy. Mutant KRAS status Prior severe reaction to a monoclonal antibody No heart failure or coronary heart disease symptoms Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, but not limited to, uncontrolled hypertension, congestive heart failure NYHA classification > III, unstable angina, myocardial infarction within six months prior to randomisation, or poorly controlled arrhythmia Cardiac left ventricular dysfunction with resting ejection fraction of less than institutional lower limit of normal (if no lower limit of normal is defined in the institution, the lower limit is 50%) Symptomatic brain metastases requiring treatment Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment Radiotherapy less than two weeks prior to the start of the study treatment Systemic chemotherapy, hormonal therapy, immunotherapy ≤ 21 days before study treatment No major comorbidity that may preclude the delivery of treatment or active infection (HIV or chronic hepatitis B or C) or uncontrolled diabetes. Concomitant occurrence of another cancer, or history of cancer within the past five years except in situ carcinoma of the cervix treated or basal cell carcinoma or squamous cell carcinoma. Known pre-existing interstitial lung disease Significant or recent acute gastrointestinal disorders with diarrhea as a major symptom e.g., Crohn's disease, malabsorption, or CTCAE grade >2 diarrhea of any etiology Pregnant woman or lactating woman. Persons deprived of liberty or under guardianship. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. Previous history of keratitis, ulcerative keratitis or severe dry eye.

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: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: Cetuximab + Afatinib<br>Afatinib 40 mg daily Cetuximab 500 mg/m2 every 2 weeks until progression | Drug: Cetuximab + Afatinib<br>* Afatinib taken orally, cetuximab administered intravenously<br>* Other names: Erbitux;|
| Active Comparator: Arm B : Cetuximab alone<br>Cetuximab 500mg/m2 every 2 weeks until progression After progression: Cetuximab 500mg/m2 + Afatinib 40 mg per day until progression | Drug: Cetuximab + Afatinib<br>* Afatinib taken orally, cetuximab administered intravenously<br>* Other names: Erbitux;Drug: Cetuximab<br>* Cetuximab administered intravenously<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Non progression rate at 6 months | The progression rate is defined as percentage of patients without progression at 6 months after observation of all patients at 6 months | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (OR) | Overall response rate is defined as percentage of subjects with a confirmed complete or partial response as per RECIST V1.1 criteria | 6 months | 
| Progression free survival | It is define as the time of from randomization to date of first documented progression or any cause of death | until progression or death, expected average approximately 4 months | 
| Overall and specific survival | Overall and specific survival is defined from time of randomization to the date of documented death | until death, on average approximately 14 months | 
| Quality of life | EORTC QLQ-C30 and QLQ-CR29 are questionnaires developed to assess the quality of life of cancer patients | During treatment, on average approximately 4 months | 
| Tolerance of the treatment | Safety of the study treatment will be assessed on occurrence of Adverse Events (AEs) | until progression, expected approximately 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Chemotherapy refractory, wtKRAS metastatic colorectal cancer, cross over