Metastatic Colorectal Cancer
Conditions
Keywords
Chemotherapy refractory, wtKRAS metastatic colorectal cancer, cross over
Brief summary
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
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.
Interventions
DRUGCetuximab + Afatinib
Afatinib taken orally, cetuximab administered intravenously
DRUGCetuximab
Cetuximab administered intravenously
Sponsors
UNICANCER
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Metastatic colorectal cancer expressing the wtKRAS status 2. No previous EGFR targeted therapy. 3. Must have failed a prior regimen containing irinotecan for metastatic disease and a prior regimen containing oxaliplatin for metastatic disease 4. Must have previously received a thymidylate synthase inhibitor (eg, fluorouracil, capecitabine, raltitrexed, or fluorouracil-uracil) at any point for treatment of colorectal cancer (CRC) 5. Life expectancy of at least 3 months. 6. Patient with ECOG ≤ 1 7. Patients aged ≥ 18. 8. 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 9. Patient able to receive adequate oral nutrition of ≥ 1500 calories per day and free of significant nausea and vomiting 10. 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) 11. Adequate contraception if applicable. 12. Ability to take oral medication in the opinion of the investigator 13. Patient able and willing to comply with study procedures as per protocol 14. 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 15. Patient affiliated to a social security regimen
Exclusion criteria
1. Previous EGFR targeted therapy. 2. Mutant KRAS status 3. Prior severe reaction to a monoclonal antibody 4. 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 5. 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%) 6. Symptomatic brain metastases requiring treatment 7. Major surgery within 28 days or minor surgery within 14 days of the start of the study treatment 8. Radiotherapy less than two weeks prior to the start of the study treatment 9. Systemic chemotherapy, hormonal therapy, immunotherapy ≤ 21 days before study treatment 10. No major comorbidity that may preclude the delivery of treatment or active infection (HIV or chronic hepatitis B or C) or uncontrolled diabetes. 11. 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. 12. Known pre-existing interstitial lung disease 13. 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 14. Pregnant woman or lactating woman. 15. Persons deprived of liberty or under guardianship. 16. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule. 17. Previous history of keratitis, ulcerative keratitis or severe dry eye.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Non progression rate at 6 months | 6 months | The progression rate is defined as percentage of patients without progression at 6 months after observation of all patients at 6 months |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall response rate (OR) | 6 months | Overall response rate is defined as percentage of subjects with a confirmed complete or partial response as per RECIST V1.1 criteria |
| Progression free survival | until progression or death, expected average approximately 4 months | It is define as the time of from randomization to date of first documented progression or any cause of death |
| Overall and specific survival | until death, on average approximately 14 months | Overall and specific survival is defined from time of randomization to the date of documented death |
| Quality of life | During treatment, on average approximately 4 months | EORTC QLQ-C30 and QLQ-CR29 are questionnaires developed to assess the quality of life of cancer patients |
| Tolerance of the treatment | until progression, expected approximately 4 months | Safety of the study treatment will be assessed on occurrence of Adverse Events (AEs) |
Countries
France
Outcome results
None listed