Clinical trial NCT02821559: Biweekly Versus Triweekly Raltitrexed With Oxaliplatin (With or Without Bevacizumab) in First-line Metastatic Colorectal Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Metastatic Colorectal Cancer
Keywords: Colorectal cancer
raltitrexed
oxaliplatin
bevacizumab
biweekly
triweekly
Lead sponsor: Centre Hospitalier Universitaire de Besancon
Sponsor class: OTHER
Collaborators: name: Hospira, now a wholly owned subsidiary of Pfizer
First posted: 2016-07-01
Enrollment: 37
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.


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

Primary outcomes:
measure: Evolution of Raltitrexed plasma levels
timeFrame: 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:
measure: treatment-related adverse events as assessed by CTCAE v4.0
timeFrame: 3 months
measure: objective response rate evaluated by RECIST 1.1 criteria
timeFrame: 3 months
measure: progression-free survival (PFS)
timeFrame: through study completion, an average of 2 years
measure: overall survival (OS)
timeFrame: through study completion, an average of 2 years
Other outcomes:
Locations:
city: Besançon
country: France
facility: CHRU de Besançon
Study officials:
References: