Biweekly Versus Triweekly Raltitrexed With Oxaliplatin (With or Without Bevacizumab) in First-line Metastatic Colorectal Cancer (EROS)

June 29, 2016 updated by: Centre Hospitalier Universitaire de Besancon

Raltitrexed is a potent thymidylate synthase (TS) inhibitor. Conversely to 5-fluorouracil (5FU), raltitrexed can be administered safely in patients with cardiovascular disease, as well as in patients with dihydropyrimidine dehydrogenase deficit. Since raltitrexed is administered in 15-minutes infusion, complications related to continuous infusion can be avoided, and it becomes a potential good candidate for locoregional treatments as hepatic intra-arterial or intra-peritoneal infusion. Despite these potential benefits over 5FU, clinical trials failed in their temptation to replace the 5FU in colorectal cancer patients, mainly due to raltitrexed toxicity at 3mg/m2 every 3 weeks. Oxaliplatin has demonstrated a synergic effect when combined with TS inhibitors, and its association with raltitrexed was evaluated at 130mg/m2 of oxaliplatin and 3mg/m2 of raltitrexed, every 3 weeks. Actually, one of the first-line standard regimens in metastatic colorectal cancer patients is the biweekly FOLFOX (85mg/m2 of oxaliplatin, and infusional 5FU) plus bevacizumab regimen, since a significant progression-free survival (PFS) benefit was observed over FOLFOX plus placebo. Biweekly administration of raltitrexed at 2mg/m2 demonstrated a favorable toxicity profile even in patients aged >65 years. Besides, the association of raltitrexed, oxaliplatin and bevacizumab seems safe.

Then, the investigators decided to perform a randomized pharmacokinetic comparative study between biweekly TOMOX (raltitrexed 2 mg/m2 and oxaliplatin 85mg/m2) and triweekly TOMOX (raltitrexed 3 mg/m2 and oxaliplatin 130mg/m2) regimens in metastatic colorectal cancer patients, in a "ping-pong" crossover strategy to reduce the intra-individual variability. Bevacizumab was allowed at the dose of 5mg/kg or 7.5mg/kg, in biweekly and triweekly schedules, respectively. The secondary end-points were, objective response rate evaluated by RECIST 1.1 criteria, PFS, overall survival (OS), toxicity, and the comparison of toxicity between two arms for the first 2 cycles.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Study Type

Interventional

Enrollment (Actual)

37

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • France
      • Besançon, France
        • CHRU De Besancon

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 80 years (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • performance status (ECOG-PS) of 0 or 1
  • patient with histologically proven colorectal cancer with distant metastases
  • measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1
  • life expectancy > 12 months
  • signed written informed consent

Exclusion Criteria:

  • prior chemotherapy at metastatic stage
  • presence of brain or meningeal metastases
  • other malignancies in the past 5 years with the exception of adequately treated carcinoma in situ of the cervix and squamous or basal cell carcinoma of the skin
  • preexisting peripheral neuropathy
  • known hypersensitivity to any component of the study treatment
  • any psychiatric condition compromising the understanding of information or conduct of the study
  • pregnancy, breast-feeding or absence of adequate contraception for fertile patients
  • patient under guardianship, curator or under the protection of justice

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: RANDOMIZED
  • Interventional Model: CROSSOVER
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: triweekly then biweekly
The arm A consisted of 2 cycles of triweekly TOMOX (standard dose 3mg/m2 of Raltitrexed in 15-minutes infusion, and 130mg/m2 of oxaliplatin in 2h infusion, every 3 weeks), followed by 2 cycles of biweekly TOMOX (2mg/m2 of Raltitrexed in 15-minutes infusion, and 85mg/m2 of oxaliplatin in 2h infusion, every 2 weeks).
Drug: TOMOX
Other Names:
  • Tomudex-Oxaliplatin
  • Raltitrexed-Oxaliplatin
Drug: Bevacizumab
Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.
EXPERIMENTAL: biweekly then triweekly
The arm B consisted of the reserve sequence starting with 2 cycles of biweekly TOMOX followed by 2 cycles of triweekly TOMOX regimen.
Drug: TOMOX
Other Names:
  • Tomudex-Oxaliplatin
  • Raltitrexed-Oxaliplatin
Drug: Bevacizumab
Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Evolution of Raltitrexed plasma levels
Time Frame: at 5 minutes, at 40 minutes, at 2 hours, at 7,5 hours, at 24 hours and at 14 days after each raltitrexed administration
pharmacokinetic study
at 5 minutes, at 40 minutes, at 2 hours, at 7,5 hours, at 24 hours and at 14 days after each raltitrexed administration

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
treatment-related adverse events as assessed by CTCAE v4.0
Time Frame: 3 months
comparison of number of treatment-related adverse events between two arms
3 months
objective response rate evaluated by RECIST 1.1 criteria
Time Frame: 3 months
3 months
progression-free survival (PFS)
Time Frame: through study completion, an average of 2 years
from date to randomization to date of first progression of the disease
through study completion, an average of 2 years
overall survival (OS)
Time Frame: through study completion, an average of 2 years
from date to randomization to date of death from any cause
through study completion, an average of 2 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Centre Hospitalier Universitaire de Besancon

Collaborators

Hospira, now a wholly owned subsidiary of Pfizer

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

July 1, 2012

Primary Completion (ACTUAL)

August 1, 2014

Study Registration Dates

First Submitted

March 29, 2016

First Submitted That Met QC Criteria

June 29, 2016

First Posted (ESTIMATE)

July 1, 2016

Study Record Updates

Last Update Posted (ESTIMATE)

July 1, 2016

Last Update Submitted That Met QC Criteria

June 29, 2016

Last Verified

March 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • EROS
  • 2011-005811-96 (EUDRACT_NUMBER)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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