Clinical trial NCT01030042: Trial Comparing Two Two Sequences of Therapy in Colorectal Metastatic Patients
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Metastatic Colorectal Cancer
Keywords: metastatic
colorectal cancer
two sequences therapy
Lead sponsor: Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente
Sponsor class: OTHER
First posted: 2009-12-10
Enrollment: 110
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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
* Signed written informed consent

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

Primary outcomes:
measure: Overall Survival
timeFrame: the time from the date of randomisation to the date of death
Secondary outcomes:
measure: Progression free survival
timeFrame: the time relapsed from the date of randomization and the date of progression after third-line treatment or death
Other outcomes:
Locations:
city: Fabriano
country: Italy
facility: Ospedale Profili
state: AN
city: Fermo
country: Italy
facility: Usl 11 Ospedale Murri
state: AP
city: Treviglio
country: Italy
facility: A.O. Treviglio-Caravaggio, P.le Ospedale n1
state: Bergamo
city: Brescia
country: Italy
facility: Spedali Civili
state: BS
city: Lanciano
country: Italy
facility: AUSL di Lanciano-Vasto
state: CH
city: Catania
country: Italy
facility: Istituto Oncologico del Mediterraneo
state: CT
city: Empoli
country: Italy
facility: ASL 11
state: FI
city: Firenze
country: Italy
facility: Università
state: FI
city: Lodi
country: Italy
facility: Ospedale Maggiore
state: LO
city: Taormina
country: Italy
facility: Ospedale S.Vincenzo
state: ME
city: Gorgonzola
country: Italy
facility: Ospedale Serbelloni
state: MI
city: Milano
country: Italy
facility: Istituto di Ricerca S.Raffaele
state: MI
city: Milano
country: Italy
facility: Ospedale Fatebenefratelli
state: MI
city: Monza
country: Italy
facility: A.O. S.Gerardo
state: MI
city: Padova
country: Italy
facility: Istituto Oncologico Veneto
state: PD
city: Pesaro
country: Italy
facility: A.O. S.Salvatore
state: PS
city: Urbino
country: Italy
facility: Ospedale Civile
state: PS
city: Potenza
country: Italy
facility: Azienda Ospedaliera San Carlo
state: PZ
city: Roma
country: Italy
facility: Università Policlinico Umberto I
state: RM
city: Roma
country: Italy
facility: Ospedale Sant'Andrea
state: RM
city: Rovigo
country: Italy
facility: AULSS 18 di Rovigo
state: RO
city: Sondalo
country: Italy
facility: Ospedale Morelli
state: SO
city: Candiolo
country: Italy
facility: Università degli Studi
state: TO
city: Legnago
country: Italy
facility: Ospedale Mater Salutis
state: VR
city: Ancona
country: Italy
facility: A.O. Ospedale Umberto I - Università - Località Torretta
city: Bergamo
country: Italy
facility: Ospedali Riuniti, Largo Barozzi, 1
city: Brescia
country: Italy
facility: Fondazione Poliambulanza, Via Bissolati 57
city: Como
country: Italy
facility: A.O. Ospedale S.Anna
city: Mantova
country: Italy
facility: A.O. Carlo Poma - Via Albertoni, 1
city: Napoli
country: Italy
facility: Istituto Tumori - Fondazione Pascale
city: Roma
country: Italy
facility: Università Campus Biomedico, Via Emilio Longoni, 83
city: Roma
country: Italy
facility: A.O. S.Giovanni Calabita Fatebenefratelli
Study officials:
References: