Clinical trial NCT01442935: Chemotherapies Associated With Targeted Therapies on the Resection Rate of Hepatic Metastases
Official title: Phase II Multicentric Randomized Trial, Evaluating the Best Protocol of Chemotherapy, Associated With Targeted Therapy According to the Tumor KRAS Status, in Metastatic Colorectal Cancer (CCRM) Patients With Initially Non-resectable Hepatic Metastases
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Colorectal Cancer
Keywords: Adenocarcinoma
Non-resectable hepatic metastases
First-line treatment
Lead sponsor: UNICANCER
Sponsor class: OTHER
First posted: 2011-09-29
Enrollment: 256
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: The main objective is to compare resection rates (R0 or R1) for hepatic metastases
timeFrame: at least 4-6 weeks after the end of chemotherapy
Secondary outcomes:
measure: The objective response rate (CR and PR) after 4 cycles of treatment
timeFrame: after 8 weeks
measure: Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)
timeFrame: 6 months
measure: Specific resection rates R0/R1/R2
timeFrame: 24 weeks
measure: Complete pathological response
timeFrame: 24 weeks
measure: Toxicity of treatment
timeFrame: Every 2 weeks
measure: Post operatory complications
timeFrame: after 4 weeks
measure: Progression-free survival (PFS)
timeFrame: 8 months
measure: Overall survival (OS)
timeFrame: 14 months
Other outcomes:
Locations:
city: Montpellier
country: France
facility: Centre Val d'Aurelle
Study officials:
affiliation: Centre Val d'Aurelle
name: Marc YCHOU, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Antoine Lacassagne-NICE
name: Eric FRANCOIS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Ste Catherine-AVIGNON
name: Laurent MINEUR, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU de Reims
name: Olivier BOUCHE, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier Lyon Sud-PIERRE BENITE
name: Driffa MOUSSATA, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier Rangueil-TOULOUSE
name: Rosine GUIMBAUD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHD Vendée -LA ROCHE SUR YON
name: Roger FAROUX, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Côte de Nacre-CAEN
name: Karine BOUHIER-LEPORRIER, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHU Dijon - Hôp. Du Bocage
name: Alice GAGNAIRE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Bergonié Bordeaux
name: Yves BECOUARN, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre G. F. Leclerc-DIJON
name: François GHIRINGHELLI, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre hospitalier Purpan-TOULOUSE
name: Rosine GUIMBAUD, Pr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre Hospitalier Saint-Joseph-PARIS
name: Gaël DEPLANQUE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Hôpital Edouard Herriot-LYON
name: Julien FORESTIER, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Institut Curie Paris
name: Pascale MARIANI, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: CHR d'Orléans - La Source
name: Jean-Louis LEGOUX, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Polyclinique de Bordeaux Nord
name: Cédric LECAILLE, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Centre François Baclesse-CAEN
name: Marie-Pierre GALAIS, Dr
role: PRINCIPAL_INVESTIGATOR
affiliation: Clinique Claude Bernard, Albi
name: Philippe HOUYAU, Dr
role: PRINCIPAL_INVESTIGATOR
References:
citation: Bidard FC, Kiavue N, Ychou M, Cabel L, Stern MH, Madic J, Saliou A, Rampanou A, Decraene C, Bouche O, Rivoire M, Ghiringhelli F, Francois E, Guimbaud R, Mineur L, Khemissa-Akouz F, Mazard T, Moussata D, Proudhon C, Pierga JY, Stanbury T, Thezenas S, Mariani P. Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial. Cells. 2019 May 28;8(6):516. doi: 10.3390/cells8060516.