COMETS: Trial Comparing Two Two Sequences of Therapy in Colorectal Metastatic Patients

Sponsor

Gruppo Italiano per lo studio dei Carcinomi dell'Apparato Digerente (Other)

Overall Status

Completed

CT.gov ID

NCT01030042

Collaborator

(none)

110

Enrollment

Locations

Arms

Duration (Months)

3.4

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: FOLFOX-4 Drug: Irinotecan/Cetuximab	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

110 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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 Start Date :

Sep 1, 2009

Actual Primary Completion Date :

Apr 1, 2015

Actual Study Completion Date :

Jun 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Cetuximab/Irinotecan Cetuximab/irinotecan followed, after progression, by FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil)	Drug: Irinotecan/Cetuximab CET 400 mg/m2 intravenously via infusion pump given over a 120 min time and weekly CET infusions at a maintenance dose of 250 mg/m2 given over a 60 min time. IRI 180 mg/m2 iv infusion over 30-90 min. Cycle length is 2 weeks and it is to be repeated until disease progression. Other Names: CPT11/Cetuximab
Active Comparator: FOLFOX 4 FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil) followed, after progression, by irinotecan/cetuximab	Drug: FOLFOX-4 Day 1: OXA will be administered as a 85 mg/m2 iv infusion over 2 hours; Leucovorin as a 100 mg/m2 infusion over 2 hours, 5-FU will be given as a 400 mg/m2 bolus injection, and then as a 600 mg/m2 continuous infusion over 22 hours after the first infusion Day 2: Leucovorin 100 mg/m2 (alone), followed by 5-FU 400 mg/m2 bolus injection, and 5-FU 600 mg/m2 continuous infusion after the first infusion Cycle length is 2 weeks comprising approximately 48 hours of infusion and 12 days of rest. Cycles are to be repeated every second week for a total of either 6 (12 weeks) or 12 cycles (24 weeks). Other Names: Oxaliplatin, 5FU, Leucovorin

Arm

Intervention/Treatment

Experimental: Cetuximab/Irinotecan

Cetuximab/irinotecan followed, after progression, by FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil)

Drug: Irinotecan/Cetuximab

CET 400 mg/m2 intravenously via infusion pump given over a 120 min time and weekly CET infusions at a maintenance dose of 250 mg/m2 given over a 60 min time. IRI 180 mg/m2 iv infusion over 30-90 min. Cycle length is 2 weeks and it is to be repeated until disease progression.

Other Names:

CPT11/Cetuximab

Active Comparator: FOLFOX 4

FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil) followed, after progression, by irinotecan/cetuximab

Drug: FOLFOX-4

Day 1: OXA will be administered as a 85 mg/m2 iv infusion over 2 hours; Leucovorin as a 100 mg/m2 infusion over 2 hours, 5-FU will be given as a 400 mg/m2 bolus injection, and then as a 600 mg/m2 continuous infusion over 22 hours after the first infusion Day 2: Leucovorin 100 mg/m2 (alone), followed by 5-FU 400 mg/m2 bolus injection, and 5-FU 600 mg/m2 continuous infusion after the first infusion Cycle length is 2 weeks comprising approximately 48 hours of infusion and 12 days of rest. Cycles are to be repeated every second week for a total of either 6 (12 weeks) or 12 cycles (24 weeks).

Other Names:

Oxaliplatin, 5FU, Leucovorin

Outcome Measures

Primary Outcome Measures

Overall Survival [the time from the date of randomisation to the date of death]

Secondary Outcome Measures

Progression free survival [the time relapsed from the date of randomization and the date of progression after third-line treatment or death]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 75 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Ospedale Profili	Fabriano	AN	Italy	60044
2	Usl 11 Ospedale Murri	Fermo	AP	Italy	63023
3	A.O. Treviglio-Caravaggio, P.le Ospedale n1	Treviglio	Bergamo	Italy	24047
4	Spedali Civili	Brescia	BS	Italy	25100
5	AUSL di Lanciano-Vasto	Lanciano	CH	Italy	66034
6	Istituto Oncologico del Mediterraneo	Catania	CT	Italy	95029
7	ASL 11	Empoli	FI	Italy	50010
8	Università	Firenze	FI	Italy	50139
9	Ospedale Maggiore	Lodi	LO	Italy	26900
10	Ospedale S.Vincenzo	Taormina	ME	Italy	98039
11	Ospedale Serbelloni	Gorgonzola	MI	Italy	20064
12	Istituto di Ricerca S.Raffaele	Milano	MI	Italy	20100
13	Ospedale Fatebenefratelli	Milano	MI	Italy	20100
14	A.O. S.Gerardo	Monza	MI	Italy	20052
15	Istituto Oncologico Veneto	Padova	PD	Italy	35124
16	A.O. S.Salvatore	Pesaro	PS	Italy	61100
17	Ospedale Civile	Urbino	PS	Italy	61029
18	Azienda Ospedaliera San Carlo	Potenza	PZ	Italy	85100
19	Università Policlinico Umberto I	Roma	RM	Italy	00186
20	Ospedale Sant'Andrea	Roma	RM	Italy	00189
21	AULSS 18 di Rovigo	Rovigo	RO	Italy	45100
22	Ospedale Morelli	Sondalo	SO	Italy	23100
23	Università degli Studi	Candiolo	TO	Italy	10060
24	Ospedale Mater Salutis	Legnago	VR	Italy	37045
25	A.O. Ospedale Umberto I - Università - Località Torretta	Ancona		Italy	60020
26	Ospedali Riuniti, Largo Barozzi, 1	Bergamo		Italy	24128
27	Fondazione Poliambulanza, Via Bissolati 57	Brescia		Italy	25100
28	A.O. Ospedale S.Anna	Como		Italy	22100
29	A.O. Carlo Poma - Via Albertoni, 1	Mantova		Italy	46100
30	Istituto Tumori - Fondazione Pascale	Napoli		Italy	80131
31	Università Campus Biomedico, Via Emilio Longoni, 83	Roma		Italy	00155
32	A.O. S.Giovanni Calabita Fatebenefratelli	Roma		Italy	00186