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

Phase 2

Completed

• Conditions: Metastatic Colorectal Cancer
• Interventions: Drug: TOMOX; Drug: Bevacizumab

• Registration Number: NCT02821559
• Lead Sponsor: Centre Hospitalier Universitaire de Besancon

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.

Detailed Description

Not available

Study Timeline

• Study Start: 2012-07
• Primary Completion: 2014-08
• Status Verified: 2016-03
• Study First Submitted: 2016-03-29
• Study First Submitted QC: 2016-06-29
• Last Update Submitted: 2016-06-29
• Study First Posted: 2016-07-01
• Last Update Posted: 2016-07-01

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 37

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: CROSSOVER

Arm && Interventions

Group	Intervention	Description
biweekly then triweekly	TOMOX	The arm B consisted of the reserve sequence starting with 2 cycles of biweekly TOMOX followed by 2 cycles of triweekly TOMOX regimen.
triweekly then biweekly	TOMOX	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).
triweekly then biweekly	Bevacizumab	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).
biweekly then triweekly	Bevacizumab	The arm B consisted of the reserve sequence starting with 2 cycles of biweekly TOMOX followed by 2 cycles of triweekly TOMOX regimen.

Primary Outcome Measures

Name	Time	Method
Evolution of Raltitrexed plasma levels	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

Secondary Outcome Measures

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

Trial Locations

Locations (1)

CHRU de Besançon; 🇫🇷 Besançon, France