De-escalation Chemotherapies Versus Escalation in Non Pre-treated Unresectable Patients With Metastatic Colorectal Cancer

Study Overview
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Brief Summary
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The intensity of tumour response appears to be correlated with the feasibility and the duration of a therapeutic pause or of a reduced maintenance therapy maintained until progression in patients initially controlled by so-called induction chemotherapy. Bevacizumab combined with cytotoxic chemotherapy (5-FU, irinotecan and/or oxaliplatin) has shown that it is possible to improve the tumour response rate and patient prognosis in 1st and 2nd lines. With a very favourable safety profile , it is an excellent candidate as induction treatment and also as maintenance treatment. Prospective data from recent trials have actually demonstrated improvement in PFS and/or overall survival with bevacizumab maintenance alone or in combination with 5FU (or capecitabine) after induction chemotherapy (FOLFIRI or FOLFOX + bevacizumab). At the same time, the maintenance of anti-angiogenic pressure after progression in 1st line metastatic has demonstrated its benefit in terms of PFS and overall survival. Bevacizumab maintenance in 2nd line metastatic, despite progression, thus appears to be a valid strategy.

Detailed Description
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Thus, the objective of this work is to combine continuous blocking of angiogenesis by bevacizumab given on the first 3 metastatic lines in a randomised phase II trial evaluating a descending strategy of immediate optimisation by 4 cycles of FOLFOXIRI-bevacizumab and 4 cycles of FOLFIRI-bevacizumab, followed by maintenance treatment with 5FU-bevacizumab until progression (re-introduction of induction in case of progression) and evaluate an ascending strategy with 5FU-bevacizumab immediately followed, at progression, by the introduction of irinotecan, then oxaliplatin, with maintenance of blocking of angiogenesis by bevacizumab.

Official Title
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Randomized Phase II Study Assessing the Efficacy and Safety of 2 Therapeutic Strategies Combining Bevacizumab With Chemotherapy: De-escalation Versus Escalation in Patients With Non-pretreated Unresectable Metastatic Colorectal Cancer

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: 5 FLUOROURACYL
* Drug: acide folinique
* Drug: irinotecan
* Drug: Oxaliplatin
* Drug: capécitabine
* Drug: bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Metastatic colorectal cancer, histologically proven (on primary tumour and/or metastases) Unresectable and non-pretreated metastases BRAF wild-type Patient considered able to receive 3 lines of chemotherapy At least one measurable target lesion > 1 cm according to RECIST 1.1 (Appendix 4) Tumour assessment according to RECIST, performed 4 weeks or less prior to randomization Age ≥ 18 years WHO performance status ≤ 2 (Appendix 5) No major surgery within 4 weeks prior to randomisation. Wound healing must be complete Life expectancy greater than 3 months Laboratory tests: Neutrophils ≥ 1500/mm3, platelets ≥ 100,000/mm3, haemoglobin > 9 g/dL Creatinine clearance > 30 mL /min (capecitabine dose modification if the creatinine clearance < 30-50 mL/min), serum creatinine < 1.25 x ULN Liver function tests: bilirubin < 1.25 x ULN, AST/ALT < 5 x ULN Women of childbearing age and men (who have sexual relations with women of childbearing age) must agree to use effective contraception without interruption throughout the duration of treatment and for 6 months after the last administration Signed informed consent Exclusion Criteria: Patient with a potentially resectable colorectal cancer; i.e. for whom the goal of chemotherapy would be to make all metastases resectable Patients with symptomatic metastases Patient with aggressive disease and a large tumour volume Active gastroduodenal ulcer, wound or bone fracture At least one of the following laboratory values: Neutrophils <1500/mm3, platelets < 100,000/mm3, haemoglobin < 9 g/dL, total bilirubin > 1.5 N, alkaline phosphatase > 2.5 N (or > 5 N in case of hepatic involvement), serum creatinine > 1.5 N, 24 hr proteinuria > 1 g Chronic inflammatory bowel disease, extensive resection of the small bowel Clinically significant coronary artery disease or a history of myocardial infraction within the last 6 months. Uncontrolled hypertension while receiving chronic medication Abdominal or major extra-abdominal surgical procedure (except diagnostic biopsy) or radiation within 4 weeks before starting treatment Previous treatment with an anti-angiogenic or irinotecan Known or suspected central nervous system metastasis CNS metastases, or suspected CNS metastases Other previous malignancies within 5 years, except for basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix - Peritoneal macro-nodular carcinomatosis History of haemoptysis ≥ grade 2 (defined as ≥ 2.5 mL of bright red blood per episode) in the month prior to inclusion Known hypersensitivity to any component of bevacizumab or to one of the study treatments Active infection requiring intravenous antibiotics at start of treatment History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or active gastrointestinal bleeding within 6 months prior to treatment start Pregnant or breastfeeding women Concomitant participation in another clinical study involving a drug during the treatment phase and 30 days before starting the study treatment Patient unable to undergo medical treatment for geographical, social, psychological or legal reasons.

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 |
| --- | --- |
| Active Comparator: Standard arm (escalation strategy - arm A)<br>LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin. | Drug: 5 FLUOROURACYL<br>* Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days. For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.<br>* Other names: FLUOROURACILE EBEWE;Drug: acide folinique<br>* 200 mg/m² if Elvorine<br>* Other names: ELVORINE;Drug: irinotecan<br>* Irinotecan is administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days.<br>* Other names: CAMPTO;Drug: Oxaliplatin<br>* Oxaliplatin is administered IV at a dose of 85 mg/m² over 120 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with oxaliplatin. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days.<br>* Other names: ELOXATINE 5 mg/ml;Drug: capécitabine<br>* For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.<br>* Other names: XELODA;Drug: bevacizumab<br>* Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy<br>* Other names: AVASTIN;|
| Experimental: Experimental arm (de-escalation strategy -arm B)<br>(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine | Drug: 5 FLUOROURACYL<br>* Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as a 2 hr infusion. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days. For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.<br>* Other names: FLUOROURACILE EBEWE;Drug: acide folinique<br>* 200 mg/m² if Elvorine<br>* Other names: ELVORINE;Drug: irinotecan<br>* Irinotecan is administered IV at a dose of 180 mg/m² over 90 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with irinotecan. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days.<br>* Other names: CAMPTO;Drug: Oxaliplatin<br>* Oxaliplatin is administered IV at a dose of 85 mg/m² over 120 minutes. Folinic acid is administered IV at a dose of 400 mg/m² (or 200 mg/m² if Elvorine) as an infusion over 2 hours, to be given in Y along with oxaliplatin. The 5FU bolus is administered in less than 10 minutes at 400 mg/m² (on D1). The continuous 5FU is administered IV at a dose of 2400 mg/m² over 46 hr (D1 and D2). The cycles will last 14 days.<br>* Other names: ELOXATINE 5 mg/ml;Drug: capécitabine<br>* For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.<br>* Other names: XELODA;Drug: bevacizumab<br>* Bevacizumab is administered IV at a dose of 5 mg/kg over 90 min at cycle 1, then 60 min at cycle 2 and 30 min in subsequent cycles. Bevacizumab is administered every 2 weeks before the start of chemotherapy<br>* Other names: AVASTIN;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The primary objective is the percentage of patients without failure of the strategy 16 months after the randomization. | The failure of the strategy is defined by: Progression (under certain condition) using RECIST version 1.1 Death (all causes) Toxicity leading to definitive stop of chemotherapy (oxaliplatine and/or irinotecan). | 16 months after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Best response rate (using RECIST version 1.1) at 16 months | Assessed on the CT scans performed during treatment | 16 months after randomization | 
| Overall survival (OS) at 2 years and at 3 years |  | 2 years and 3 years | 
| Progression free survival (PFS) at 2 years and at 3 years | Time between the date of randomization and the date of the first radiologic progression or death (all causes) | 2 years and 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal, cancer, metastasis