Clinical trial NCT02842580: De-escalation Chemotherapies Versus Escalation in Non Pre-treated Unresectable Patients With Metastatic Colorectal Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Colorectal Neoplasms
Keywords: colorectal
cancer
metastasis
Lead sponsor: Federation Francophone de Cancerologie Digestive
Sponsor class: OTHER
First posted: 2016-07-25
Enrollment: 21
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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
* 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.

Primary outcomes:
measure: The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the Randomization.
timeFrame: 16 months after randomization
Secondary outcomes:
measure: Best Response Rate (Using RECIST Version 1.1)
timeFrame: At 16 months
measure: Overall Survival (OS)
timeFrame: Up to 3 years after the treatment start
measure: Progression Free Survival (PFS)
timeFrame: up to 24 months after randomization
Other outcomes:
Locations:
city: Bourgoin-Jallieu
country: France
facility: Hopital Pierre Oudot - Service de Gastroenterologie
city: Cholet
country: France
facility: Ch de Cholet - Service Maladies de L4Appareil Digestif Du Dr Kaasis
city: La Roche-sur-Yon
country: France
facility: Chd Vendee - Service D'Hge
city: Pringy
country: France
facility: Ch Annecy Genevois - Service Hge
city: Pringy
country: France
facility: CH - Annecy Genevois
city: Reims CEDEX
country: France
facility: Chu Robert Debre - Medecine Ambulatoire-Cancerologie
city: Reims
country: France
facility: CHU Robert DEBRE
city: Rouen CEDEX 01
country: France
facility: Chu Charles Nicolle - Service D'Hge
city: Saint-Grégoire
country: France
facility: Hopital Prive Saint Gregoire - Service de Radiotherapie
city: Saint-Malo
country: France
facility: Centre Hospitalier de St Malo - Service Hepato-Gastro-Enterologie
city: Saint-Priest-en-Jarez
country: France
facility: Chu de Saint Etienne-Hopital Nord - Service Hge
Study officials:
affiliation: CHU St Etienne
name: Jean Marc PHELIP, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References: