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

• ClinicalTrials.gov Identifier: NCT02842580
• Recruitment Status: Terminated
• First Posted: July 25, 2016
• Last Update Posted: November 6, 2020
• Sponsor: Federation Francophone de Cancerologie Digestive
• Information provided by (Responsible Party): Federation Francophone de Cancerologie Digestive

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Colorectal Neoplasms	Drug: 5 FLUOROURACYL; Drug: acide folinique; Drug: irinotecan; Drug: Oxaliplatin; Drug: capécitabine; Drug: bevacizumab	Phase 2

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: September 2016
• Actual Primary Completion Date: October 2020
• Actual Study Completion Date: October 2020

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Standard arm (escalation strategy - arm A); LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.	Drug: 5 FLUOROURACYL; 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.; Other Name: FLUOROURACILE EBEWE; Drug: acide folinique; 200 mg/m² if Elvorine; Other Name: ELVORINE; Drug: irinotecan; 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.; Other Name: CAMPTO; Drug: Oxaliplatin; 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.; Other Name: ELOXATINE 5 mg/ml; Drug: capécitabine; For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.; Other Name: XELODA; Drug: bevacizumab; 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; Other Name: AVASTIN
Experimental: 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	Drug: 5 FLUOROURACYL; 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.; Other Name: FLUOROURACILE EBEWE; Drug: acide folinique; 200 mg/m² if Elvorine; Other Name: ELVORINE; Drug: irinotecan; 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.; Other Name: CAMPTO; Drug: Oxaliplatin; 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.; Other Name: ELOXATINE 5 mg/ml; Drug: capécitabine; For this 1st line chemotherapy, the investigator has the choice of using capecitabine instead of LV5FU2; in this case the cycle lasts 21 days.; Other Name: XELODA; Drug: bevacizumab; 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; Other Name: AVASTIN

Outcome Measures

Primary Outcome Measures :

1. The primary objective is 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:

   • Progression (under certain condition) using RECIST version 1.1
   • Death (all causes)
   • Toxicity leading to definitive stop of chemotherapy (oxaliplatine and/or irinotecan).

Secondary Outcome Measures :

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

France

Hopital Pierre Oudot - Service de Gastroenterologie

Bourgoin-Jallieu, France, 38300

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

Cholet, France, 49325

Chd Vendee - Service D'Hge

La Roche-sur-Yon, France, 85925

Ch Annecy Genevois - Service Hge

Pringy, France, 74374

CH - Annecy Genevois

Pringy, France

Chu Robert Debre - Medecine Ambulatoire-Cancerologie

Reims CEDEX, France, 51092

CHU Robert DEBRE

Reims, France

Chu Charles Nicolle - Service D'Hge

Rouen CEDEX 01, France, 76031

Hopital Prive Saint Gregoire - Service de Radiotherapie

Saint-Grégoire, France, 35768

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

Saint-Malo, France, 35403

Chu de Saint Etienne-Hopital Nord - Service Hge

Saint-Priest-en-Jarez, France, 42270

Sponsors and Collaborators

Federation Francophone de Cancerologie Digestive

Investigators

• Principal Investigator: Jean Marc PHELIP, MD-PhD; CHU St Etienne

More Information

• Responsible Party: Federation Francophone de Cancerologie Digestive
• ClinicalTrials.gov Identifier: NCT02842580
• Other Study ID Numbers: PRODIGE 45
• First Posted: July 25, 2016
• Last Update Posted: November 6, 2020
• Last Verified: November 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Keywords provided by Federation Francophone de Cancerologie Digestive:

colorectal; cancer; metastasis

Additional relevant MeSH terms:

Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Leucovorin; Bevacizumab; Capecitabine; Oxaliplatin; Irinotecan; Levoleucovorin; Antineoplastic Agents, Immunological; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Physiological Effects of Drugs; Growth Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Topoisomerase I Inhibitors; Topoisomerase Inhibitors; Enzyme Inhibitors