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

Study Overview
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Brief Summary
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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.

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

Conditions
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Colorectal Neoplasms

Intervention / Treatment
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* Drug: Oxaliplatin intravenous
* Drug: 5 FU bolus
* Drug: Folinic acid
* Drug: Oxaliplatin intra-arteriel
* Drug: Panitumumab
* Drug: Bevacizumab
* Drug: 5 FU continuous
* Drug: Irinotecan


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Experimental arm FOLFOX with oxaliplatin intraarterial + targeted therapy to RAS status<br>Panitumumab (6 mg/kg if RAS wild) or Bevacizumab (5 mg/Kg if RAS mutated) Oxaliplatin (85 mg/m²) intraarterially Folinic Acid (400 mg/m²) intravenously 5Fu: 400 mg/m² in bolus of 10 minutes 5Fu: 2400 mg/m² intravenously over 46 hours | Drug: 5 FU bolus<br>* 5 fluorouracil : 400 mg/m² in bolus of 10 minutes (intravenous) following by 2400 mg/m² during 46 hours in intravenous<br>* Other names: 5 FU;Drug: Folinic acid<br>* 400 mg/m² in intravenous<br>* Other names: Folinic Acid IV;Drug: Oxaliplatin intra-arteriel<br>* 85 mg/m² in intra-arterial. 1 cycle each 15 days<br>* Other names: Oxaliplatin IA;Drug: Panitumumab<br>* Only for patient RAS wild: 6 mg/Kg at each cycle in intravenous<br>* Other names: Pani;Drug: Bevacizumab<br>* 5 mg/kg at each cycle in intravenous<br>* Other names: Beva;Drug: 5 FU continuous<br>* 2400 mg/m² intravenously over 46 hours<br>* Other names: 5 FU;|
| Active Comparator: Reference arm FOLFOX with oxaliplatin intravenous + targeted therapy to RAS status<br>Panitumumab (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 | Drug: Oxaliplatin intravenous<br>* 85 mg/m² in intravenous. 1 cycle each 15 days<br>* Other names: Oxaliplatin IV;Drug: 5 FU bolus<br>* 5 fluorouracil : 400 mg/m² in bolus of 10 minutes (intravenous) following by 2400 mg/m² during 46 hours in intravenous<br>* Other names: 5 FU;Drug: Folinic acid<br>* 400 mg/m² in intravenous<br>* Other names: Folinic Acid IV;Drug: Panitumumab<br>* Only for patient RAS wild: 6 mg/Kg at each cycle in intravenous<br>* Other names: Pani;Drug: Bevacizumab<br>* 5 mg/kg at each cycle in intravenous<br>* Other names: Beva;Drug: 5 FU continuous<br>* 2400 mg/m² intravenously over 46 hours<br>* Other names: 5 FU;|
| Experimental: Experimental arm mFOLFIRINOX with oxaliplatin intraarterial + Bevacizumab<br>Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intraarterially Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours | Drug: Folinic acid<br>* 400 mg/m² in intravenous<br>* Other names: Folinic Acid IV;Drug: Oxaliplatin intra-arteriel<br>* 85 mg/m² in intra-arterial. 1 cycle each 15 days<br>* Other names: Oxaliplatin IA;Drug: Bevacizumab<br>* 5 mg/kg at each cycle in intravenous<br>* Other names: Beva;Drug: 5 FU continuous<br>* 2400 mg/m² intravenously over 46 hours<br>* Other names: 5 FU;Drug: Irinotecan<br>* 150 mg/m² intravenous<br>* Other names: IRI;|
| Active Comparator: Reference arm mFOLFIRINOX with oxaliplatin intravenous + Bevacizumab<br>Bevacizumab (5 mg/Kg) Oxaliplatin (85 mg/m²) intravenously Irinotecan (150 mg/m²) intravenously Folinic Acid (400 mg/m²) intravenously 5Fu: 2400 mg/m² intravenously over 46 hours | Drug: Oxaliplatin intravenous<br>* 85 mg/m² in intravenous. 1 cycle each 15 days<br>* Other names: Oxaliplatin IV;Drug: Folinic acid<br>* 400 mg/m² in intravenous<br>* Other names: Folinic Acid IV;Drug: Bevacizumab<br>* 5 mg/kg at each cycle in intravenous<br>* Other names: Beva;Drug: 5 FU continuous<br>* 2400 mg/m² intravenously over 46 hours<br>* Other names: 5 FU;Drug: Irinotecan<br>* 150 mg/m² intravenous<br>* Other names: IRI;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| progression-free survival | comparison of radiological/clinical progression free survival | 24 months after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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colorectal, cancer, metastasis, hepatic