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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02842580
Recruitment Status : Terminated (Inclusion rythm too slow.)
First Posted : July 25, 2016
Last Update Posted : November 6, 2020
Sponsor:
Information provided by (Responsible Party):
Federation Francophone de Cancerologie Digestive

Tracking Information
First Submitted Date  ICMJE July 13, 2016
First Posted Date  ICMJE July 25, 2016
Last Update Posted Date November 6, 2020
Actual Study Start Date  ICMJE September 2016
Actual Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
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).
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: August 10, 2016)
  • 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
  • Overall survival (OS) at 2 years and at 3 years [ Time Frame: 2 years and 3 years ]
  • 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)
Original Secondary Outcome Measures  ICMJE
 (submitted: July 20, 2016)
  • 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
  • Overall survival (OS) at 2 years and at 36 months [ Time Frame: 2 years and 3 years after the last randomized patient ]
  • Progression free survival (PFS) at 2 years and at 36 months [ Time Frame: 2 years and 3 years after the last randomized patient ]
    Time between the date of randomization and the date of the first radiologic progression or death (all causes)
  • Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: Trough study completion, an average of 3 years ]
  • Dose intensity [ Time Frame: Through study completion, an average of 3 years ]
  • Treatment duration: Time from the date of the first cycle of treatment to the Day 1 of the last cycle [ Time Frame: Through study completion, an average of 3 years ]
    The treatment duration will be calculated as the time from the date of the first cycle of treatment to the Day 1 of the last cycle (+ 14 days if the patient is receiving 5FU IV or + 21 days if the patient is receiving capecitabine).
  • Time to deterioration of quality of Life (EORTC QLQ-C30) [ Time Frame: Trough study completion, an average of 3 years ]
    Time to deterioration is defined as the time between date of randomization and date of first deteroriation of more than 5 points of global health score compare to inclusion score (without any subsequent improvement).
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE De-escalation Chemotherapies Versus Escalation in Non Pre-treated Unresectable Patients With Metastatic Colorectal Cancer
Official Title  ICMJE 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
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.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Colorectal Neoplasms
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Active Comparator: Standard arm (escalation strategy - arm A)
    LV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
    Interventions:
    • Drug: 5 FLUOROURACYL
    • Drug: acide folinique
    • Drug: irinotecan
    • Drug: Oxaliplatin
    • Drug: capécitabine
    • Drug: bevacizumab
  • 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
    Interventions:
    • Drug: 5 FLUOROURACYL
    • Drug: acide folinique
    • Drug: irinotecan
    • Drug: Oxaliplatin
    • Drug: capécitabine
    • Drug: bevacizumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: February 13, 2019)
20
Original Estimated Enrollment  ICMJE
 (submitted: July 20, 2016)
168
Actual Study Completion Date  ICMJE October 2020
Actual Primary Completion Date October 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02842580
Other Study ID Numbers  ICMJE PRODIGE 45
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: Undecided
Current Responsible Party Federation Francophone de Cancerologie Digestive
Original Responsible Party Same as current
Current Study Sponsor  ICMJE Federation Francophone de Cancerologie Digestive
Original Study Sponsor  ICMJE Same as current
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jean Marc PHELIP, MD-PhD CHU St Etienne
PRS Account Federation Francophone de Cancerologie Digestive
Verification Date November 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP