Clinical Trials /

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

NCT02842580

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: PRODIGE 45
  • NCT ID: NCT02842580

Conditions

  • Colorectal Neoplasms

Interventions

DrugSynonymsArms
5 FLUOROURACYLFLUOROURACILE EBEWEStandard arm (escalation strategy - arm A)
acide foliniqueELVORINEStandard arm (escalation strategy - arm A)
irinotecanCAMPTOStandard arm (escalation strategy - arm A)
OxaliplatinELOXATINE 5 mg/mlStandard arm (escalation strategy - arm A)
capécitabineXELODAStandard arm (escalation strategy - arm A)
bevacizumabAVASTINStandard arm (escalation strategy - arm A)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Standard arm (escalation strategy - arm A)Active ComparatorLV5FU2 (5 FLUOROURACYL)+avastin. After progression: FOLFIRI + avastin. after the 2nd progression:FOLFOX4 (eloxatine)+ avastin.
  • 5 FLUOROURACYL
  • acide folinique
  • irinotecan
  • Oxaliplatin
  • capécitabine
  • 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
  • 5 FLUOROURACYL
  • acide folinique
  • irinotecan
  • Oxaliplatin
  • capécitabine
  • 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:The primary objective is the percentage of patients without failure of the strategy 16 months after the randomization.
Time Frame:16 months after randomization
Safety Issue:
Description: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

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

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Federation Francophone de Cancerologie Digestive

Trial Keywords

  • colorectal
  • cancer
  • metastasis

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