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

Metastatic Colorectal Cancer Clinical Trial

— EROS  

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02821559
• Other study ID #: EROS
• Secondary ID: 2011-005811-96
• Status: Completed
• Phase: Phase 2
• First received: March 29, 2016
• Last updated: June 29, 2016
• Start date: July 2012

Study information

• Verified date: March 2016
• Source: Centre Hospitalier Universitaire de Besancon
• Contact: n/a
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santé
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 37
• Est. primary completion date: August 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 80 Years

Eligibility

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

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacokinetics Study, Intervention Model: Crossover Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Colorectal Neoplasms
• Metastatic Colorectal Cancer

Intervention

Drug:
• TOMOX

• Bevacizumab
Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.

Locations

Country	Name	City	State
France	CHRU de Besançon	Besançon

Sponsors (2)

Lead Sponsor	Collaborator
Centre Hospitalier Universitaire de Besancon	Hospira, Inc.

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Evolution of Raltitrexed plasma levels	pharmacokinetic study	at 5 minutes, at 40 minutes, at 2 hours, at 7,5 hours, at 24 hours and at 14 days after each raltitrexed administration	No
Secondary	treatment-related adverse events as assessed by CTCAE v4.0	comparison of number of treatment-related adverse events between two arms	3 months	Yes
Secondary	objective response rate evaluated by RECIST 1.1 criteria		3 months	No
Secondary	progression-free survival (PFS)	from date to randomization to date of first progression of the disease	through study completion, an average of 2 years	No
Secondary	overall survival (OS)	from date to randomization to date of death from any cause	through study completion, an average of 2 years	No