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

Study Overview
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Brief Summary
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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
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Metastatic Colorectal Cancer

Intervention / Treatment
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* Drug: TOMOX
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: triweekly then biweekly<br>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<br> <br> * Other names: Raltitrexed-Oxaliplatin;Drug: Bevacizumab<br>* Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.<br>|
| Experimental: biweekly then triweekly<br>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<br> <br> * Other names: Raltitrexed-Oxaliplatin;Drug: Bevacizumab<br>* Bevacizumab was allowed and used at 7,5 mg/kg or 5 mg/kg every 2 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| treatment-related adverse events as assessed by CTCAE v4.0 | comparison of number of treatment-related adverse events between two arms | 3 months | 
| objective response rate evaluated by RECIST 1.1 criteria |  | 3 months | 
| progression-free survival (PFS) | from date to randomization to date of first progression of the disease | through study completion, an average of 2 years | 
| overall survival (OS) | from date to randomization to date of death from any cause | through study completion, an average of 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal cancer, raltitrexed, oxaliplatin, bevacizumab, biweekly, triweekly