Randomized, Phase III, Multicenter Trial Comparing Two Different Sequences of therapyFOLFOX-4 vs FOLFOX-4 Followed by Irinotecan/Cetuximab in Metastatic Colorectal Patients Treated With FOLFIRI /Bevacizumab as First Line Chemotherapy
Overview
- Phase
- Phase 3
- Intervention
- Irinotecan/Cetuximab
- Conditions
- Metastatic Colorectal Cancer
- Sponsor
- Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
- Enrollment
- 110
- Locations
- 32
- Primary Endpoint
- Overall Survival
- Status
- Completed
- Last Updated
- 10 years ago
Overview
Brief Summary
Primary Objectives:
Aim of this study is to compare the efficacy and safety of two different sequences of chemotherapeutic agents in order to optimize the treatment of patients with metastatic colorectal cancer progressed to a first line chemotherapy with FOLFIRI and bevacizumab. Primary endpoint will be overall survival, defined as the time elapsed from the date of randomization to the date of patient death due to any cause, or the last date the patient was known to be alive.
Secondary Objectives Progression free survival, Quality of life, Health resource utilisation and economic evaluation, Toxicity and incidence of adverse events
The study regimen includes:
Strategy A: FOLFOX-4 followed, after progression, by irinotecan/cetuximab Strategy B: irinotecan/cetuximab followed, after progression, by FOLFOX-4 Patients will be randomly assigned to one of the two treatment sequences (with 1:1 ratio) using a block design randomization procedure stratified according to center.
The patient accrual period is planned for approximately 36 months. To assess OS, all pts will be followed for up to 18 months after the last patient is randomised. The maximum estimated study duration is approximately 54 months.All statistical analyses will be based on an intention-to-treat approach. CONSORT rules will be applied to describe study flow and protocol deviations.
Detailed Description
Target population: Patients with histologically confirmed metastatic colorectal cancer progressed after a first line treatment containing FOLFIRI and BEV Inclusion criteria: * Age \>18 \< 75 years of age * Diagnosis of histologically proven adenocarcinoma of the colon or rectum, stage IV * K-ras wild-type * ECOG performance status 0-1 at study entry Endpoints: - Response Rate, Disease control rate, The duration of overall response, Overall survival, PFS, Time to treatment failure, Quality of Life, Incidence of AEs, Frequency and nature of serious adverse reactions (SADRs), Premature withdrawals Statistical methods: Assuming a randomization ratio of 1:1, 282 deaths are required in order to achieve a power of 80% of detecting a hazard ratio of 0.72 in favour of one of the two sequences, translating in an increase of median survival time from 10 to 14 months, with a type I error of 5%, two-sided, using the Mantel-Cox version of the log-rank test. With a uniform accrual period of 3 years and a follow-up of 18 months, about 350 patients will be needed to reach the target number of events. All statistical analyses will be based on an intention-to-treat approach. CONSORT rules will be applied to describe study flow and protocol deviations. All OS and PFS curves will be drawn with the Kaplan-Meier method. Results will be presented as Hazard Ratio (HRs) and their 95% Confidence Interval (CIs). On annual basis, starting from the second year, an interim analysis will be conducted. In principle, no formal stopping rule will be applied, unless otherwise suggested by the DSMC. Safety reports will be drawn on annual basis.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Age \>18 \<75 years of age
- •Diagnosis of histologically proven adenocarcinoma of the colon or rectum, stage IV
- •K-ras wild-type
- •Performance Status (ECOG-PS) 0-1 at study entry
- •Neutrophils ≥ 1.5 x 1039/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL
- •Bilirubin level either normal or \< 1.5 x upper limit of normal (ULN)
- •Asparagine aminotransferase (ASAT) and alanine aminotransferase (ALAT) ≤ 2.5 X ULN (≤ 5 x ULN if liver metastasis are present)
- •Serum creatinine \< 1.5 x ULN
- •Effective contraception for both male and female patients
- •Life expectancy of ≥ 3 months
Exclusion Criteria
- •History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications
- •Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix)
- •History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake
- •Known grade 3 or 4 allergic reaction to any of the components of the treatment
- •Known drug abuse/ alcohol abuse
Arms & Interventions
Cetuximab/Irinotecan
Cetuximab/irinotecan followed, after progression, by FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil)
Intervention: Irinotecan/Cetuximab
FOLFOX 4
FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil) followed, after progression, by irinotecan/cetuximab
Intervention: FOLFOX-4
Outcomes
Primary Outcomes
Overall Survival
Time Frame: the time from the date of randomisation to the date of death
Secondary Outcomes
- Progression free survival(the time relapsed from the date of randomization and the date of progression after third-line treatment or death)