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
Overview
- Phase
- Phase 2
- Intervention
- 5 FLUOROURACYL
- Conditions
- Colorectal Neoplasms
- Sponsor
- Federation Francophone de Cancerologie Digestive
- Enrollment
- 21
- Locations
- 11
- Primary Endpoint
- The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization.
- Status
- Terminated
- Last Updated
- last year
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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
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
Arms & Interventions
Standard arm (escalation strategy - arm A)
LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
Intervention: 5 FLUOROURACYL
Standard arm (escalation strategy - arm A)
LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
Intervention: acide folinique
Standard arm (escalation strategy - arm A)
LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
Intervention: irinotecan
Standard arm (escalation strategy - arm A)
LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
Intervention: Oxaliplatin
Standard arm (escalation strategy - arm A)
LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
Intervention: capécitabine
Standard arm (escalation strategy - arm A)
LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
Intervention: bevacizumab
Experimental arm (de-escalation strategy -arm B)
(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
Intervention: 5 FLUOROURACYL
Experimental arm (de-escalation strategy -arm B)
(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
Intervention: acide folinique
Experimental arm (de-escalation strategy -arm B)
(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
Intervention: irinotecan
Experimental arm (de-escalation strategy -arm B)
(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
Intervention: Oxaliplatin
Experimental arm (de-escalation strategy -arm B)
(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
Intervention: capécitabine
Experimental arm (de-escalation strategy -arm B)
(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine
Intervention: bevacizumab
Outcomes
Primary Outcomes
The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization.
Time Frame: 16 months after randomization
The failure of the strategy is defined by the following events: * Progression (under certain condition) using RECIST version 1.1 and defined as a 20% increase in the sum of the longest diameter of target lesions compared the little sum of diameters observed durin the study (NADIR), or a measurable increase in a nontarget lesion, or the appearance of new lesions * Death (all causes) * Toxicity leading to definitive stop of chemotherapy (oxaliplatine and/or irinotecan).
Secondary Outcomes
- Best Response Rate (Using RECIST Version 1.1)(At 16 months)
- Overall Survival (OS)(Up to 3 years after the treatment start)
- Progression Free Survival (PFS)(up to 24 months after randomization)