Colorectal Cancer
Conditions
Keywords
Adenocarcinoma, Non-resectable hepatic metastases, First-line treatment
Brief summary
The main objective is to compare resection rates (R0 or R1) for hepatic metastases in the experimental arm (tri chemotherapy plus targeted therapy) versus the control arm (bi chemotherapy plus targeted therapy); in both arms the targeted therapy is selected according to K-Ras status of the patient's tumor. The secondary objectives are to evaluate the objective response rate (CR and PR) after 4 cycles of treatment, according the RECIST V1.1 evaluation scale. * the rate of complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle). * the specific rates of resection R0, R1, R2. * the complete pathological response Rate, * the relapse-free survival rate in (R0 or R1) resected patients, * the response duration in non-resected patients, * the toxicity according to CTC AE V4 scale except for the neurotoxicity that will be evaluated with the Levi scale, * the post operative complications using the DINDO classification, * the progression-free survival (PFS) and overall survival (OS). The objectives of the biological study are: * to evaluate tumor-related predictive factors such as somatic mutations (KRAS, BRAF, TP53) and genetic amplification related factors (EGFR), * to evaluate patient-related predictive factors in connection with genetic polymorphisms (Fc gamma and VEGF receptors), * to evaluate ADCC activity via immunohistochemistry in order to analyze the lympho free and progression-free survival, * to study circulating of tumor cells as prognostic factor for metastatic colorectal cancer, non- resectable at presentation.
Interventions
DRUGOxaliplatin
85mg/m² over 120 mn every 2 weeks up to progression or toxicity
DRUGFolinic Acid
400mg/m² over 120 mn every 2 weeks up to progression or toxicity
DRUG5-FU
400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
DRUGIrinotecan
180mg/m² over 90 mn every 2 weeks up to progression or toxicity
DRUGBevacizumab
5mg/kg over 90 mn every 2 weeks up to progression or toxicity
DRUGCetuximab
500mg/m² over 90 mn every 2 weeks up to progression or toxicity
Sponsors
UNICANCER
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically proven colorectal adenocarcinoma, * Primary tumor of the colon or rectum, resectable or resected at least 3 weeks before randomization or 4 weeks before the beginning of the study treatment, * Metastatic disease with synchronous or metachronous (\> 3 months after diagnosis of the primary tumor) hepatic metastasis, * Non-resectable (with respect to curative intent) hepatic metastasis at presentation. This criterion must be validated by both a surgeon and a radiologist during the RCP (Multidisciplinary cancer case presentation committee) patient's evaluation meeting (either technically non-resectable metastases (absolute contraindication): i.e. impossibility to resect all metastases in a single operation while preserving at least 30% of healthy liver tissues and/or impossibility to preserve the portal vein and hepatic artery homolateral to the liver or a portal pedicle, or due to oncological non-resectability (relative contraindication): presence of \> 5 nodules and bilateral invasion), * Hepatic metastases, without spread to other sites except in case of ≤ 3 resectable pulmonary metastases of diameter \< 2 cm, detected by thoracic scanner, * K-Ras status determined before randomization, * Measurable disease according to the RECIST V1.1 criteria, * No prior treatment of the hepatic metastases, * Previous 5FU +/- oxaliplatin-based adjuvant chemotherapy administered after colorectal tumor resection is authorized if complete more than 1 year before, * Age ≥ 18 & ≤ 75 years * Performance status : ECOG 0 or 1, * Life expectancy ≥ 3 months, * Hemoglobin ≥ 9 g/dl, * Polynuclear neutrophiles ≥ 1500/mm3, * Platelets ≥ 100 000 mm3, * Creatinemia ≤ 135 µmol/l (1,35 mg/dl) * Total bilirubin ≤ 1.25 times the Upper Limit of Normal (ULN). * Hepatic enzymes ASAT and ALAT \< 5 x ULN, * Negative pregnancy test for women of child-bearing age, * Information given to the patient and signed informed consent, * Public Health insurance coverage.
Exclusion criteria
* Non metastatic and/or non measurable disease according to the RECIST v1.1 criteria. * Non-resectable primary tumor (e.g.: T4 tumors) or incomplete resection R2. * History of intestinal inflammatory disease. * Specific contraindication to any of the study treatments. * Patient who have previously received anti-EGFr (e.g., cetuximab) or anti-VEGF monoclonal antibody treatment (e.g., bevacizumab) or treatment with irinotecan. * History of cancer considered as not cured. * Stroke/CVA or pulmonary embolism within 6 months before inclusion. * Significant concomitant disease such as: coagulopathy, respiratory or cardiac congestive insufficiency, non-medically controlled/unstable angina pectoris, myocardial infarction within 6 months prior to study entry, arterial hypertension and uncontrolled arrhythmia, severe infections. * Clinical neuropathy, grade ≥1. * Patient already included in another therapeutic trial using an experimental molecule. * Pregnant women or women who might become pregnant during the study or lactating women. * Men or women who can procreate and who do not abide with the use of a contraceptive means. * Persons kept in detention or incapable of giving consent * Patient unwilling or unable to comply with the medical follow-up required by the trial because of geographic social or psychological reasons.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The main objective is to compare resection rates (R0 or R1) for hepatic metastases | at least 4-6 weeks after the end of chemotherapy | Number of patients (%) with hepatic metastases R0 or R1 resection. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle) | 6 months | Number of patients (%) with complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle) |
| Specific resection rates R0/R1/R2 | 24 weeks | Specific resection rates (%) R0/R1/R2 is the rate of patients with a R0, R1 or R2 resection. |
| Complete pathological response | 24 weeks | Number of patients with Complete pathological response, defined as the absence of tumoral residues after the last chemotherapy cycle. It will be evaluated on liver resection piece, based on total or complete tumor necrosis in all tumor nodules |
| The objective response rate (CR and PR) after 4 cycles of treatment | after 8 weeks | The objective response rate (CR and PR) will be evaluated by the investigator with RECIST v1.1 criteria after 4 cycles. Patients with symptoms suggestive of disease progression will have a tumoral evaluation when symptoms will occur |
| Post operatory complications | after 4 weeks | Each post operatory complications (Hemorrhage, fistula, insufficiency, heart failure,..) will be graduated using Dindo classification (2004) |
| Progression-free survival (PFS) | 8 months | Progression-free survival is defined as the time from randomization to progression (RECIST v1.1 criteria) or death. Patients alive without progression will be censored at the last follow-up. |
| Overall survival (OS) | 14 months | Overall survival is defined as the time from randomization to death any cause or last follow-up news for patients alive (censored data). |
| Toxicity of treatment | Every 2 weeks | Tolerance of the treatment will be based on toxicities of evaluated products by clinical and biological measurements (NCIC/CTC (CTCAE V4) criteria, except for peripheral neuropathy toxicity (Lévi scale) |
Countries
France
Outcome results
None listed