Chemotherapies Associated With Targeted Therapies on the Resection Rate of Hepatic Metastases

Colorectal Cancer Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01442935
• Other study ID #: PRODIGE 14 / ACCORD 21/0905
• Secondary ID: 2009-012813-22
• Status: Completed
• Phase: Phase 2
• Start date: February 2011
• Est. completion date: January 2021

Study information

• Verified date: June 2021
• Source: UNICANCER
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 256
• Est. completion date: January 2021
• Est. primary completion date: December 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Colorectal Cancer
• Colorectal Neoplasms
• Neoplasm Metastasis

Intervention

Drug:
• Oxaliplatin
85mg/m² over 120 mn every 2 weeks up to progression or toxicity
• Folinic Acid
400mg/m² over 120 mn every 2 weeks up to progression or toxicity
• 5-FU
400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity
• Irinotecan
180mg/m² over 90 mn every 2 weeks up to progression or toxicity
• Irinotecan
150mg/m² over 30-90 mn every 2 weeks up to progression or toxicity
• Bevacizumab
5mg/kg over 90 mn every 2 weeks up to progression or toxicity
• Cetuximab
500mg/m² over 90 mn every 2 weeks up to progression or toxicity

Locations

Country	Name	City	State
France	Centre Val d'Aurelle	Montpellier

Sponsors (1)

Lead Sponsor	Collaborator
UNICANCER

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The main objective is to compare resection rates (R0 or R1) for hepatic metastases	Number of patients (%) with hepatic metastases R0 or R1 resection.	at least 4-6 weeks after the end of chemotherapy
Secondary	The objective response rate (CR and PR) after 4 cycles of treatment	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	after 8 weeks
Secondary	Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)	Number of patients (%) with complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)	6 months
Secondary	Specific resection rates R0/R1/R2	Specific resection rates (%) R0/R1/R2 is the rate of patients with a R0, R1 or R2 resection.	24 weeks
Secondary	Complete pathological response	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	24 weeks
Secondary	Toxicity of treatment	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)	Every 2 weeks
Secondary	Post operatory complications	Each post operatory complications (Hemorrhage, fistula, insufficiency, heart failure,..) will be graduated using Dindo classification (2004)	after 4 weeks
Secondary	Progression-free survival (PFS)	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.	8 months
Secondary	Overall survival (OS)	Overall survival is defined as the time from randomization to death any cause or last follow-up news for patients alive (censored data).	14 months