Biomarker-Guided Fluorouracil in Treating Patients With Colorectal Cancer Receiving Combination Chemotherapy

Study Overview
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Brief Summary
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RATIONALE: Drugs used in chemotherapy, such as fluorouracil, oxaliplatin, and leucovorin calcium, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug, combination chemotherapy, may kill more tumor cells. Studying samples of blood in the laboratory from patients with cancer receiving fluorouracil in combination with oxaliplatin and leucovorin calcium may help doctors learn how fluorouracil works in the body and how patients will respond to treatment. PURPOSE: This phase I trial is studying biomarker-guided fluorouracil in treating patients with colorectal cancer receiving combination chemotherapy.

Detailed Description
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OBJECTIVES: Primary To determine whether 4 courses of pharmacokinetic (PK)-guided 5-fluorouracil chemotherapy improves the ability to achieve a targeted area under the curve (20 to 25 mg*hr/L) in patients with colorectal cancer receiving mFOLFOX6 chemotherapy as compared to historical non-PK-guided therapy in patients treated with a similar FOLFOX regimen. Secondary To determine and compare the incidence of neutropenia and diarrhea in patients treated with these regimens. OUTLINE: This is a multicenter study. Standard mFOLFOX6 (course 1): Patients receive fluorouracil IV bolus over 1-5 minutes followed by fluorouracil IV continuously over 46 hours, oxaliplatin IV over 2 hours, and leucovorin calcium IV over 2 hours on day 1. Patients undergo plasma sample collection periodically during study for pharmacokinetic (PK)-guided fluorouracil dose determination for courses 2-4. PK-guided mFOLFOX6 (courses 2-4): Patients receive fluorouracil bolus, oxaliplatin, and leucovorin calcium as in course 1. Patients also receive fluorouracil* IV continuously as determined by the PK-guided analysis. NOTE: *The continuous infusion fluorouracil dose adjustment is calculated based on the results of PK plasma concentrations and the corresponding AUC from the preceding course.

Official Title
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Multicenter Study Investigating Utilization of Pharmacokinetic-Guided 5-Fluorouracil in Patients Receiving mFOLFOX6 With or Without Bevacizumab

Conditions
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Colorectal Cancer, Diarrhea, Neutropenia

Intervention / Treatment
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* Drug: fluorouracil
* Drug: leucovorin
* Drug: oxaliplatin


Participation Criteria
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Eligibility Criteria
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DISEASE CHARACTERISTICS: Histologically confirmed colorectal cancer Patients scheduled to receive mFOLFOX6 (in the adjuvant setting or for metastatic disease) as part of their chemotherapy regimen PATIENT CHARACTERISTICS: ECOG performance status 0-2 Life expectancy > 6 months ANC ≥ 1,500/mm³ Platelet count ≥ 100,000/mm³ Serum creatinine ≤ 1.5 mg/dL Total bilirubin ≤ 1.5 times upper limit of normal (ULN) AST and ALT ≤ 2.5 times ULN (≤ 5 times ULN in the presence of liver metastases) Fertile patients must use effective contraception Negative pregnancy test Not pregnant or nursing No serious concomitant systemic disorders, including active infection that, in the opinion of the investigator, would compromise the patient's safety or ability to complete the study No altered mental status precluding understanding of the informed consent process and/or completion of the necessary studies Must be able to follow protocol requirements and give informed consent PRIOR CONCURRENT THERAPY: See Disease Characteristics Concurrent bevacizumab allowed No concurrent warfarin (Coumadin®) Concurrent enoxaparin (Lovenox®) allowed No concurrent theophylline or aminophylline No chocolate beginning 12 hours before day 1 of each course and through the end of that course's fluorouracil continuous IV
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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: mFOLFOX6<br>Patients will receive cycle 1 of standard dose mFOLFOX6, with the same dose of mFOLFOX6 continued in subsequent cycles, once patient achieves the target AUC. mFOLFOX 6 is a regimen comprised of Oxaliplatin + Leucovorin +5-Fluorouracil (FU) | Drug: fluorouracil<br>* 200-400 mg/m2 intravenously, 1 -5 minutes, once every 2 weeks 2400 mg/m2 intravenously over a period of 46 hours, once every 2 weeks<br>* Other names: 5FU;Drug: leucovorin<br>* 200-400 mg/m2, intravenously over a period of 2 hours, once every 2 weeks<br>* Other names: leucovorin calcium;Drug: oxaliplatin<br>* 85 mg/m2, intravenously for 2 hours, once every 2 weeks<br>* Other names: Eloxatin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Achievement of targeted AUC using pharmacokinetic (PK)-guided 5 fluorouracil as part of mFOLFOX6 therapy |  | During first 4 cycles of drug therapy | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Toxicity differences between PK-guided therapy versus non-PK-guided therapy |  | 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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neutropenia, diarrhea, stage I colon cancer, stage II colon cancer, stage III colon cancer, stage IV colon cancer, recurrent colon cancer, stage I rectal cancer, stage II rectal cancer, stage III rectal cancer, stage IV rectal cancer, recurrent rectal cancer