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

NCT ID: NCT02821559

Last Updated: 2016-07-01

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE2
• Total Enrollment: 37 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2012-07-31

Brief Summary

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.

Conditions

Metastatic Colorectal Cancer

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

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).

Group Type: EXPERIMENTAL

TOMOX

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.

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.

Group Type: EXPERIMENTAL

TOMOX

Intervention Type: DRUG

Bevacizumab

Intervention Type: DRUG

Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.

Interventions

TOMOX

Intervention Type: DRUG

Bevacizumab

Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.

Intervention Type: DRUG

Other Intervention Names

Tomudex-Oxaliplatin; Raltitrexed-Oxaliplatin

Eligibility Criteria

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

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 80 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Hospira, now a wholly owned subsidiary of Pfizer

INDUSTRY

Sponsor Role: collaborator

Centre Hospitalier Universitaire de Besancon

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Locations

CHRU de Besançon

Besançon, , France

Countries

France

Other Identifiers

2011-005811-96

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

EROS

Identifier Type: -

Identifier Source: org_study_id