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

NCT02821559 | Completed Phase 2

• 2 other identifiers: EROS2011-005811-96
• Study Type: interventional
• Target: 37
• Locations: 1 country
• Sites: 1

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.

Conditions

Metastatic Colorectal Cancer

Keywords

Colorectal cancer; raltitrexed; oxaliplatin; bevacizumab; biweekly; triweekly

Outcome Measures

Primary Outcomes (1)

• 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

Secondary Outcomes (4)

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

  3 months

• objective response rate evaluated by RECIST 1.1 criteria

  3 months

• progression-free survival (PFS)

  through study completion, an average of 2 years

• overall survival (OS)

  through study completion, an average of 2 years

Study Arms (2)

triweekly then biweekly

EXPERIMENTAL

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).

Drug: TOMOX; Drug: Bevacizumab

biweekly then triweekly

EXPERIMENTAL

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

Drug: TOMOX; Drug: Bevacizumab

Interventions

TOMOX DRUG

Also known as: Tomudex-Oxaliplatin, Raltitrexed-Oxaliplatin

biweekly then triweekly; triweekly then biweekly

Bevacizumab DRUG

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

biweekly then triweekly; triweekly then biweekly

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Centre Hospitalier Universitaire de Besancon: lead
• Hospira, now a wholly owned subsidiary of Pfizer: collaborator

Study Sites (1)

CHRU de Besançon

Besançon, France

Location

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Bevacizumab

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 29, 2016
• First Posted: July 1, 2016
• Study Start: July 1, 2012
• Primary Completion: August 1, 2014
• Last Updated: July 1, 2016

Record last verified: 2016-03

Locations

FR (1)