Efficacy of Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab

Study Overview
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Brief Summary
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The main objective is to evaluate progression-free survival (PFS) at 4 months. The secondary objectives are to evaluate the objective response rate (OR) (= complete responses (CR) and partial responses (PR)) according to the RECIST v1.1 criteria, the progression-free survival (PFS), the overall survival (OS), the overall survival from the date of the first-line chemotherapy used on the metastatic disease, the treatment tolerance (NCI CTC AE V4 criteria, except for peripheral neurological toxicity (Lévi Scale)), the quality of life according to the EORTC QLQ-C30 criteria. The objectives of the biological study are to evaluate potentially predictive anti-EGFR and anti-VEGF response factors and CEC rates as predictive biomarkers for the efficacy of bevacizumab associated with chemotherapy in mCRC treatment.

Official Title
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Phase II, Multicentric Randomized Trial, Evaluating the Efficacy of Fluoropyrimidine-based Standard Chemotherapy, Associated to Either Cetuximab or Bevacizumab, in KRAS Wild-type Metastatic Colorectal Cancer Patients With Progressive Disease After Receiving First-line Treatment With Bevacizumab

Conditions
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Colorectal Cancer

Intervention / Treatment
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* Drug: Oxaliplatin
* Drug: Folinic Acid
* Drug: 5-fluoro-uracil
* Drug: Irinotecan
* Drug: Bevacizumab
* Drug: Cetuximab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically proven adenocarcinoma of the colon expressing non-mutated (wild-type) KRAS. Progressive metastatic disease after first-line treatment with chemotherapy alone: based on 5-FU (iv or per os) with irinotecan or oxaliplatin associated to bevacizumab. Prior adjuvant chemotherapy (of the primary tumor) with fluoropyrimidine and oxaliplatin is allowed if the time interval between the end of this chemotherapy and the beginning of the first-line metastatic treatment is ≥ 6 months. Measurable disease (at least one measurable metastatic lesion) according to the RECIST V1.1 criteria (the lesion should not be located in a previous field of radiation). Previous radiotherapy is authorized if discontinued ≥ 15 days prior to randomization and if the measurable metastatic lesions are outside the radiation area. Sites of disease evaluated within 28 days prior to randomization with thoracic-abdominal-pelvic CT scan (or abdominal-pelvic MRI plus Chest Xray) Age ≥18 years Patient with ECOG 0 or 1 Life Expectancy ≥ 3 months Hematologic function (polynuclear neutrophiles ≥ 1.5.109/L ; platelets ≥ 100.109/L ; hemoglobin ≥ 9 g/dL Hepatic transaminases ≤ 2.5 times upper limit of normal (ULN) (≤ 5 ULN in case of hepatic metastases), alkaline phosphatases ≤ 2.5 ULN (≤ 5 ULN in case of hepatic metastases), total bilirubinemia ≤ 1.5 ULN Renal function (creatinemia ≤1.5 ULN; creatine clearance ≥ 50 mL/mn (Cockcroft and Gault) ; urine test strip < 2+. If proteinuria is ≥ +2 at inclusion, the serum urea test must be redone and show proteinuria ≤ 1 g/L within 24 h) Completion of the EORTC QLQ-C30 quality of life form Negative pregnancy test for women of child-bearing age Information given to the patient and signed informed consent Public Health insurance coverage Exclusion Criteria: Known meningeal or brain metastases Pre-treatment with anti-EGFR Specific contraindication or known hypersensitivity to one treatment product Patient with known allergy or hypersensitivity to monoclonal antibodies (bevacizumab, cetuximab Clinically significant affection of the coronaries or myocardial infarction within 6 months prior to inclusion. Peripheral neuropathy of grade > 1 (CTCAE scale version 4.0). Known depletion of the dihydropyrimidine dehydrogenase (DPD). Acute intestinal obstruction or sub-obstruction, history of inflammatory intestinal disease or extended resection of the small intestine. Presence of a colic prosthesis. Uncontrolled Arterial hypertension (systolic pressure > 150 mmHg and/or diastolic pressure > 100 mmHg with and without antihypertensive medication. Patients with high hypertension are eligible if antihypertensive medication lowers their arterial pressure to the level of acceptability specified by the inclusion criteria. History of hypertensive crisis or hypertensive encephalopathy Other concomitant malignancy or history cancer (except carcinoma in situ of the cervix, or non melanoma skin cancer, with curative intent treatment, when considered in complete remission for at least 5 years before randomization. Any treatment including an experimental drug, or participation in another clinical trial within 28 days preceding inclusion. Persons deprived of liberty or under guardianship. Psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A : bevacizumab + fluoropyrimidine-based chemotherapy<br>Every 2 weeks : - mFOLFOX6 : Oxaliplatin 85 mg/m2 over 120 mn IV on D1, Folinic Acide 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h. OR - FOLFIRI : Irinotecan 180 mg/m2 en 90 mn IV on day D1, Folinic acid 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h. AND Bevacizumab 5 mg/kg IV every 2 weeks. | Drug: Oxaliplatin<br>* 85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity<br>Drug: Folinic Acid<br>* 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1 (in the same time that oxaliplatin or irinotecan) every 2 weeks up to progression or toxicity<br>Drug: 5-fluoro-uracil<br>* 400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity<br>Drug: Irinotecan<br>* 180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity<br>Drug: Bevacizumab<br>* 5 mg/kg IV over 90 mn on D1 every 2 weeks up to progression or toxicity<br>|
| Experimental: Arm B : cetuximab + fluoropyrimidine-based chemotherapy<br>Every 2 weeks : - mFOLFOX6 : Oxaliplatin 85 mg/m2 over 120 mn IV on D1, Folinic Acide 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h. OR - FOLFIRI : Irinotecan 180 mg/m2 en 90 mn IV on day D1, Folinic acid 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1, 5-fluoro-uracil 400 mg/m² in bolus IV on D1 and 5-fluoro-uracil 2400 mg/m² in infusion IV over 46 h. AND Cetuximab : 500 mg/m² IV every 2 weeks | Drug: Oxaliplatin<br>* 85mg/m² over 120 mn on D1 every 2 weeks up to progression or toxicity<br>Drug: Folinic Acid<br>* 400 mg/m² (racemic) (or 200 mg/m² if L-folinic acid) over 2 h IV on D1 (in the same time that oxaliplatin or irinotecan) every 2 weeks up to progression or toxicity<br>Drug: 5-fluoro-uracil<br>* 400mg/m² in bolus on D1, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity<br>Drug: Irinotecan<br>* 180 mg/m2 over 90 mn IV on D1 every 2 weeks up to progression or toxicity<br>Drug: Cetuximab<br>* 500mg/m² on D1 every 2 weeks up to progression or toxicity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) at 4 months | Progression-free survival is defined as the time from randomization to progression (RECIST v1.1 criteria) or death. Patients alive without progression will be censored at the last follow-up. | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Objective response rate (OR) | The objective response rate is defined as the occurence of a complete response [CR] or a partial responses [PR] according to RECIST V1.1 between date of randomization and date of end of treatment. It will be evaluated by the investigator with RECIST v1.1 criteria every 6 weeks up to disease progression. | 12 months | 
| Progression-free survival (PFS) | Progression-free survival is defined as the time from randomization to progression (RECIST v1.1 criteria) or death. Patients alive without progression will be censored at the last follow-up. | 4 months | 
| Overall survival (OS) | Overall survival is defined as the time from randomization to death any cause or last follow-up (censored data). | until death or progression (24 months) | 
| Overall survival from the date of the first-line chemotherapy used on the metastatic disease | Overall survival from the date of the first-line chemotherapy used on the metastatic disease is defined as the time from the first day of the first-line chemotherapy used on the metastatic disease to death any cause or last follow-up news (censored data). | until death or progression (24 months) | 
| Treatment tolerance | Tolerance of the treatment will be based on toxicities of evaluated products by clinical and biological measurements (NCIC/CTC (CTCAE V4) criteria, except for peripheral neuropathy toxicity (Lévi scale)). | Every 2 weeks, during the treatment. | 
| Quality of life | Quality of life will be evaluated with the EORTC QLQ - C30. | every 6 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Adenocarcinoma, Metastatic, Second-line treatment, Progressive disease after first-line treatment with bevacizumab, Non-mutated (wild-type) KRAS.