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

Centre Hospitalier Universitaire de Besancon37 enrolled

Overview

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 Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Eligibility

Sex: ALLMin age: 18 YearsMax age: 80 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Evolution of Raltitrexed plasma levels

pharmacokinetic study

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

Secondary Outcomes

treatment-related adverse events as assessed by CTCAE v4.0

comparison of number of treatment-related adverse events between two arms

Time frame: 3 months

objective response rate evaluated by RECIST 1.1 criteria

Time frame: 3 months

progression-free survival (PFS)

from date to randomization to date of first progression of the disease

Time frame: through study completion, an average of 2 years

overall survival (OS)

from date to randomization to date of death from any cause