Metastatic Colorectal Cancer
Conditions
Keywords
Colorectal cancer, raltitrexed, oxaliplatin, bevacizumab, biweekly, triweekly
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.
Interventions
DRUGTOMOX
DRUGBevacizumab
Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.
Sponsors
Centre Hospitalier Universitaire de Besancon
Hospira, now a wholly owned subsidiary of Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
France
Outcome results
None listed