Clinical Trials /

Systemic Oxaliplatin or Intra-arterial Chemotherapy Combined With LV5FU2 and an Target Therapy in First Line Treatment of Metastatic Colorectal Cancer Restricted to the Liver

NCT02885753

Description:

Colorectal cancer is the 3rd most common cancer in France and the 2nd cause of death from cancer. Between 30 to 60% of patients develop limited or predominant liver metastases. Surgical resection of these metastases, only curative treatment is not immediately possible in 10-15% of cases. In unresectable patients, current palliative treatments are based on systemic chemotherapy associated or not with the targeted therapies (anti-EGFR (panitumumab), anti-VEGF (bevacizumab)). In this patient population, special attention was paid to intensified treatment regimens in order to improve their efficiency and improving the tumoral response rate, the intensity of the response and its earliness correlate with improved overall and progression-free survival. The intra-arterial use of oxaliplatin coupled with IV chemotherapy has yielded OR levels of 64% in patients having survived one or more lines of chemotherapy IV and 62% in patients who have progressed on oxaliplatin IV. In addition, the HIA administration of oxaliplatin limits systemic and especially neurological toxicities, thanks to a greater hepatic clearance. In conclusion, the combination of systemic chemotherapy, targeted therapy and HIAC with oxaliplatin has showed promising efficacy results associated with good tolerance from the first line onwards. Indeed, we can expect from the Phase II recent data, a control rate close to 100%, with high response rates associated with early maturity and depth responses as well as prolonged survival. However, to date, in the absence of randomized trial testing this combination, this strategy does not have sufficient evidence to be integrated in our routine practices, and HIAC remains limited to a few expert centers in treatment catch-up.

Related Conditions:
  • Colorectal Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Systemic Oxaliplatin or Intra-arterial Chemotherapy Combined With LV5FU2 and an Target Therapy in First Line Treatment of Metastatic Colorectal Cancer Restricted to the Liver
  • Official Title: Systemic Oxaliplatin or Intra-arterial Chemotherapy Combined With LV5FU2 and an Target Therapy in First Line Treatment of Metastatic Colorectal Cancer Restricted to the Liver

Clinical Trial IDs

  • ORG STUDY ID: PRODIGE 49
  • NCT ID: NCT02885753

Conditions

  • Colorectal Neoplasms

Interventions

DrugSynonymsArms
Oxaliplatin intravenousReference arm with oxaliplatin intravenous
5 FuExperimental arm with oxaliplatin intra-arterial
Folinic AcidExperimental arm with oxaliplatin intra-arterial
Oxaliplatin intra-arterielExperimental arm with oxaliplatin intra-arterial
PanitumumabExperimental arm with oxaliplatin intra-arterial
BevacizumabExperimental arm with oxaliplatin intra-arterial

Purpose

Colorectal cancer is the 3rd most common cancer in France and the 2nd cause of death from cancer. Between 30 to 60% of patients develop limited or predominant liver metastases. Surgical resection of these metastases, only curative treatment is not immediately possible in 10-15% of cases. In unresectable patients, current palliative treatments are based on systemic chemotherapy associated or not with the targeted therapies (anti-EGFR (panitumumab), anti-VEGF (bevacizumab)). In this patient population, special attention was paid to intensified treatment regimens in order to improve their efficiency and improving the tumoral response rate, the intensity of the response and its earliness correlate with improved overall and progression-free survival. The intra-arterial use of oxaliplatin coupled with IV chemotherapy has yielded OR levels of 64% in patients having survived one or more lines of chemotherapy IV and 62% in patients who have progressed on oxaliplatin IV. In addition, the HIA administration of oxaliplatin limits systemic and especially neurological toxicities, thanks to a greater hepatic clearance. In conclusion, the combination of systemic chemotherapy, targeted therapy and HIAC with oxaliplatin has showed promising efficacy results associated with good tolerance from the first line onwards. Indeed, we can expect from the Phase II recent data, a control rate close to 100%, with high response rates associated with early maturity and depth responses as well as prolonged survival. However, to date, in the absence of randomized trial testing this combination, this strategy does not have sufficient evidence to be integrated in our routine practices, and HIAC remains limited to a few expert centers in treatment catch-up.

Trial Arms

NameTypeDescriptionInterventions
Experimental arm with oxaliplatin intra-arterialExperimentalPanitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intra-arterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours
  • 5 Fu
  • Folinic Acid
  • Oxaliplatin intra-arteriel
  • Panitumumab
  • Bevacizumab
Reference arm with oxaliplatin intravenousActive ComparatorPanitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours
  • Oxaliplatin intravenous
  • 5 Fu
  • Folinic Acid
  • Panitumumab
  • Bevacizumab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically proven colorectal adenocarcinoma with hepatic metastasis(es)

          -  At least one measurable hepatic metastasis according to the criteria RECIST v1.1

          -  No other metastatic sites except lung nodules if number ≤ 3 and < 10 mm

          -  RAS mutation status known (determination of KRAS mutation (exons 2,3 and 4) and
             determination of the NRAS mutation (exons 2,3 and 4))

          -  Age ≥ 18

          -  WHO ≤ 2 (Appendix 4)

          -  No prior treatment by chemotherapy except perioperative or adjuvant chemotherapy
             discontinued for more than 12 months

          -  Life expectancy > 3 months

          -  PNN > 1500/mm3, platelets > 100 000/mm3, Hb > 9 g/dLq

          -  Bilirubin < 25 mmol/L, AST < 5x ULN, ALT < 5 x ULN, ALP < 5 x ULN, TP > 60%,
             proteinuria from 24H < 1 g

          -  Creatinine clearance > 50 mL/min according to MDRD formula (Appendix 4)

          -  Patient affiliated to a social security scheme

          -  Patient information and signature of the informed consent

        Exclusion Criteria:

          -  Contraindications specific to the installation of a KTHIA: thrombosis of the hepatic
             artery, arterial vascular anatomy may compromise a secondary hepatic resection.

          -  Patient immediately eligible for a curative therapy (surgical and/or percutaneous)
             after discussion in CPR

          -  Following alterations in the 6 months prior to inclusion: myocardial infarction,
             angina, severe/unstable angina, coronary artery bypass surgery, congestive heart
             failure NYHA class II, III or IV, stroke or transient ischemic attack

          -  Hypertension not controlled by medical treatment (SBP > 140 mmHg and/or DBP> 90 mmHg
             with blood pressure taken according to the diagram of the HAS)

          -  A history of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess
             or active gastrointestinal bleeding in the 6 months preceding the start of treatment

          -  Progressive gastroduodenal ulcer, wound or fractured bone

          -  Abdominal or major extra-abdominal surgery (except diagnostic biopsy) or irradiation
             in the 4 weeks before starting the treatment

          -  Transplant patients, HIV positive or other immune deficiency syndromes

          -  Any progressive pathology not balanced over the past 6 months: hepatic failure, renal
             failure, respiratory failure

          -  Peripheral neuropathy > 1

          -  Patient with interstitial pneumonitis or pulmonary fibrosis

          -  History of chronic diarrhea or inflammatory disease of the colon or rectum, or
             unresolved occlusion or sub-occlusion in symptomatic treatment

          -  History of malignant pathologies during the past 5 years except basocellular skin
             carcinoma considered in complete remission or in situ cervical carcinoma, properly
             treated

          -  Patient already included in another clinical trial with an experimental molecule

          -  Any known specific contraindication or allergy or hypersensitivity to the drugs used
             in the study (cf RCP Appendix 7)

          -  Known deficit in DPD

          -  QT/QTc range > 450 msec for men and > 470 msec for women

          -  K+ < LNL, Mg2+ < LNL, Ca2+ < LNL

          -  Lack of effective contraception in patients (men and/or women) of childbearing age,
             pregnant or breastfeeding women, women of childbearing age not having had a pregnancy
             test

          -  Persons deprived of liberty or under supervision

          -  Impossibility of undergoing medical monitoring during the trial for geographic, social
             or psychological reasons
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:hepatic progression-free survival
Time Frame:24 months after randomization
Safety Issue:
Description:

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Federation Francophone de Cancerologie Digestive

Trial Keywords

  • colorectal
  • cancer
  • metastasis
  • hepatic

Last Updated

March 27, 2020