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

Centre Hospitalier Universitaire de Besancon

Status and phase: Completed; Phase 2

Conditions: Metastatic Colorectal Cancer

Treatments: Drug: TOMOX; Drug: Bevacizumab

Study type: Interventional

Funder types: Other; Industry

Identifiers

NCT02821559

EROS

2011-005811-96 (EudraCT Number)

Details and patient eligibility

About

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.

Enrollment: 37 patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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37 participants in 2 patient groups

triweekly then biweekly

Experimental group

Description:

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).

Treatment:

Drug: Bevacizumab

Drug: TOMOX

biweekly then triweekly

Experimental group

Description:

The arm B consisted of the reserve sequence starting with 2 cycles of biweekly TOMOX followed by 2 cycles of triweekly TOMOX regimen.

Treatment:

Drug: Bevacizumab

Drug: TOMOX