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

Primary Purpose

Colorectal Cancer

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Oxaliplatin

Folinic Acid

5-FU

Irinotecan

Bevacizumab

Cetuximab

About this trial

This is an interventional treatment trial for Colorectal Cancer focused on measuring Adenocarcinoma, Non-resectable hepatic metastases, First-line treatment

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

Centre Val d'Aurelle

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Experimental

Arm Label

Arm A1 : Folfiri + targeted therapy

Arm A2 : Folfox 4 + targeted therapy

Arm B : Folfirinox + targeted therapy

Arm Description

Every 2 weeks : irinotecan 180 mg/m² D1 Folinic acid 400 mg/m² D1 5FU 400 mg/m² bolus 5FU 2400 mg/m² infusion over 46 h, D1 And targeted therapy in function of Kras: For mutated Kras = bevacizumab: 5 mg/kg IV on D1 of each cycle of chemotherapy, every 14 days For non-mutated Kras = cetuximab : 500 mg/m² IV, on D1 of each cycle of chemotherapy, every 14 days.

Every 2 weeks : oxaliplatin 85 mg/m² D1 Folinic acid 400 mg/m² D1 5FU 400 mg/m² bolus 5FU 2400 mg/m² infusion over 46 h, D1 And targeted therapy in function of Kras: For mutated Kras = bevacizumab: 5 mg/kg IV on D1 of each cycle of chemotherapy, every 14 days For non-mutated Kras = cetuximab : 500 mg/m² IV, on D1 of each cycle of chemotherapy, every 14 days.

Every 2 weeks : oxaliplatin 85 mg/m² D1 irinotecan 150 mg/m² D1 Folinic acid 400 mg/m² D1 5FU 400 mg/m² bolus 5FU 2400 mg/m² infusion over 46 h, D1. From D7 to D12, prophylactic G-CSF such as Granocyte® will be administered. And targeted therapy in function of Kras: For mutated Kras = bevacizumab: 5 mg/kg IV on D1 of each cycle of chemotherapy, every 14 days For non-mutated Kras = cetuximab : 500 mg/m² IV, on D1 of each cycle of chemotherapy, every 14 days.

Outcomes

Primary Outcome Measures

The main objective is to compare resection rates (R0 or R1) for hepatic metastases

Number of patients (%) with hepatic metastases R0 or R1 resection.

Secondary Outcome Measures

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

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)

Specific resection rates R0/R1/R2

Specific resection rates (%) R0/R1/R2 is the rate of patients with a R0, R1 or R2 resection.

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

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)

Post operatory complications

Each post operatory complications (Hemorrhage, fistula, insufficiency, heart failure,..) will be graduated using Dindo classification (2004)

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.

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).

Full Information

NCT ID

NCT01442935

First Posted

August 10, 2011

Last Updated

June 14, 2021

Sponsor

UNICANCER

1. Study Identification

Unique Protocol Identification Number

NCT01442935

Brief Title

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

2. Study Status

Record Verification Date

June 2021

Overall Recruitment Status

Completed

Study Start Date

February 2011 (Actual)

Primary Completion Date

December 2015 (Actual)

Study Completion Date

January 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

UNICANCER

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Colorectal Cancer

Keywords

Adenocarcinoma, Non-resectable hepatic metastases, First-line treatment

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

256 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A1 : Folfiri + targeted therapy

Arm Type

Active Comparator

Arm Description

Arm Title

Arm A2 : Folfox 4 + targeted therapy

Arm Type

Active Comparator

Arm Description

Arm Title

Arm B : Folfirinox + targeted therapy

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

Oxaliplatin

Intervention Description

85mg/m² over 120 mn every 2 weeks up to progression or toxicity

Intervention Type

Drug

Intervention Name(s)

Folinic Acid

Intervention Description

400mg/m² over 120 mn every 2 weeks up to progression or toxicity

Intervention Type

Drug

Intervention Name(s)

5-FU

Other Intervention Name(s)

5-Fluoro uracil

Intervention Description

400mg/m² in bolus, then 2400mg/m² over 46 h every 2 weeks up to progression or toxicity

Intervention Type

Drug

Intervention Name(s)

Irinotecan

Intervention Description

180mg/m² over 90 mn every 2 weeks up to progression or toxicity

Intervention Type

Drug

Intervention Name(s)

Irinotecan

Intervention Description

150mg/m² over 30-90 mn every 2 weeks up to progression or toxicity

Intervention Type

Drug

Intervention Name(s)

Bevacizumab

Intervention Description

5mg/kg over 90 mn every 2 weeks up to progression or toxicity

Intervention Type

Drug

Intervention Name(s)

Cetuximab

Intervention Description

500mg/m² over 90 mn every 2 weeks up to progression or toxicity

Primary Outcome Measure Information:

Title

The main objective is to compare resection rates (R0 or R1) for hepatic metastases

Description

Number of patients (%) with hepatic metastases R0 or R1 resection.

Time Frame

at least 4-6 weeks after the end of chemotherapy

Secondary Outcome Measure Information:

Title

The objective response rate (CR and PR) after 4 cycles of treatment

Description

Time Frame

after 8 weeks

Title

Complete remission rate (CR) 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)

Description

Number of patients (%) with complete remission (CR) at 6 months after the last study treatment (hepatic surgery or last chemotherapy cycle)

Time Frame

6 months

Title

Specific resection rates R0/R1/R2

Description

Specific resection rates (%) R0/R1/R2 is the rate of patients with a R0, R1 or R2 resection.

Time Frame

24 weeks

Title

Complete pathological response

Description

Time Frame

24 weeks

Title

Toxicity of treatment

Description

Time Frame

Every 2 weeks

Title

Post operatory complications

Description

Each post operatory complications (Hemorrhage, fistula, insufficiency, heart failure,..) will be graduated using Dindo classification (2004)

Time Frame

after 4 weeks

Title

Progression-free survival (PFS)

Description

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.

Time Frame

8 months

Title

Overall survival (OS)

Description

Overall survival is defined as the time from randomization to death any cause or last follow-up news for patients alive (censored data).

Time Frame

14 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

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.

Overall Study Officials: