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

NCT02842580 | Terminated Phase 2 Results DMC

• 1 other identifier: PRODIGE 45
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 11

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.

Conditions

Colorectal Neoplasms

Keywords

colorectal; cancer; metastasis

Outcome Measures

Primary Outcomes (1)

• The Primary Objective Was the Percentage of Patients Without Failure of the Strategy 16 Months After the 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).

  16 months after randomization

Secondary Outcomes (3)

• 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

Study Arms (2)

Standard arm (escalation strategy - arm A)

ACTIVE COMPARATOR

LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.

Drug: 5 FLUOROURACYL; Drug: acide folinique; Drug: irinotecan; Drug: Oxaliplatin; Drug: capécitabine; Drug: bevacizumab

Experimental arm (de-escalation strategy -arm B)

EXPERIMENTAL

(4 cycles of FOLFOXIRI (campto) + avastin and 4 cycles of FOLFIRI + avastin) is followed by maintenance with capecitabine

Drug: 5 FLUOROURACYL; Drug: acide folinique; Drug: irinotecan; Drug: Oxaliplatin; Drug: capécitabine; Drug: bevacizumab

Interventions

5 FLUOROURACYL DRUG

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.

Also known as: FLUOROURACILE EBEWE

Experimental arm (de-escalation strategy -arm B); Standard arm (escalation strategy - arm A)

acide folinique DRUG

200 mg/m² if Elvorine

Also known as: ELVORINE

Experimental arm (de-escalation strategy -arm B); Standard arm (escalation strategy - arm A)

irinotecan DRUG

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.

Also known as: CAMPTO

Experimental arm (de-escalation strategy -arm B); Standard arm (escalation strategy - arm A)

Oxaliplatin DRUG

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.

Also known as: ELOXATINE 5 mg/ml

Experimental arm (de-escalation strategy -arm B); Standard arm (escalation strategy - arm A)

capécitabine DRUG

For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.

Also known as: XELODA

Experimental arm (de-escalation strategy -arm B); Standard arm (escalation strategy - arm A)

bevacizumab DRUG

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

Also known as: AVASTIN

Experimental arm (de-escalation strategy -arm B); Standard arm (escalation strategy - arm A)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Federation Francophone de Cancerologie Digestive: lead

Study Sites (11)

Hopital Pierre Oudot - Service de Gastroenterologie

Bourgoin, 38300, France

Location

Ch de Cholet - Service Maladies de L4Appareil Digestif Du Dr Kaasis

Cholet, 49325, France

Location

Chd Vendee - Service D'Hge

La Roche-sur-Yon, 85925, France

Location

Ch Annecy Genevois - Service Hge

Pringy, 74374, France

Location

CH - Annecy Genevois

Pringy, France

Location

Chu Robert Debre - Medecine Ambulatoire-Cancerologie

Reims, 51092, France

Location

CHU Robert DEBRE

Reims, France

Location

Chu Charles Nicolle - Service D'Hge

Rouen, 76031, France

Location

Hopital Prive Saint Gregoire - Service de Radiotherapie

Saint-Grégoire, 35768, France

Location

Chu de Saint Etienne-Hopital Nord - Service Hge

Saint-Priest-en-Jarez, 42270, France

Location

Centre Hospitalier de St Malo - Service Hepato-Gastro-Enterologie

St-Malo, 35403, France

Location

MeSH Terms

Conditions

Colorectal Neoplasms; Neoplasms; Neoplasm Metastasis

Interventions

Leucovorin; Irinotecan; Oxaliplatin; Capecitabine; Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Coenzymes; Enzymes and Coenzymes; Camptothecin; Alkaloids; Coordination Complexes; Organic Chemicals; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Fluorouracil; Uracil; Pyrimidinones; Deoxyribonucleosides; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Karine Le Malicot
• Organization: Fédération Francophone de Cancérologie Digestive

karine.le-malicot@u-bourgogne.fr

+33 3 80 39 34 79

Study Officials

• Jean Marc PHELIP, MD-PhD

  CHU St Etienne

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 13, 2016
• First Posted: July 25, 2016
• Study Start: September 1, 2016
• Primary Completion: October 1, 2020
• Study Completion: October 1, 2020
• Last Updated: July 10, 2024
• Results First Posted: July 10, 2024

Record last verified: 2024-07

Locations

FR (11)