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.
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
Interventions
| Drug | Synonyms | Arms |
|---|
| Oxaliplatin intravenous | | Reference arm with oxaliplatin intravenous |
| 5 Fu | | Experimental arm with oxaliplatin intra-arterial |
| Folinic Acid | | Experimental arm with oxaliplatin intra-arterial |
| Oxaliplatin intra-arteriel | | Experimental arm with oxaliplatin intra-arterial |
| Panitumumab | | Experimental arm with oxaliplatin intra-arterial |
| Bevacizumab | | Experimental 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
| Name | Type | Description | Interventions |
|---|
| Experimental arm with oxaliplatin intra-arterial | Experimental | Panitumumab (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 intravenous | Active Comparator | 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 | - 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 30, 2020
