Clinical trial NCT01164215: Biomarker-Guided Fluorouracil in Treating Patients With Colorectal Cancer Receiving Combination Chemotherapy
Official title: Multicenter Study Investigating Utilization of Pharmacokinetic-Guided 5-Fluorouracil in Patients Receiving mFOLFOX6 With or Without Bevacizumab
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Colorectal Cancer
Diarrhea
Neutropenia
Keywords: 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
Lead sponsor: UNC Lineberger Comprehensive Cancer Center
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2010-07-16
Enrollment: 76
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Achievement of targeted AUC using pharmacokinetic (PK)-guided 5 fluorouracil as part of mFOLFOX6 therapy
timeFrame: During first 4 cycles of drug therapy
Secondary outcomes:
measure: Toxicity differences between PK-guided therapy versus non-PK-guided therapy
timeFrame: 24 months
Other outcomes:
Locations:
city: Asheville
country: United States
facility: Cancer Care of Western North Carolina
state: North Carolina
city: Greensboro
country: United States
facility: Moses Cone Regional Cancer Center at Wesley Long Community Hospital
state: North Carolina
city: Greenville
country: United States
facility: Leo W. Jenkins Cancer Center at ECU Medical School
state: North Carolina
city: Raleigh
country: United States
facility: Rex Cancer Center at Rex Hospital
state: North Carolina
city: Washington
country: United States
facility: Marion L. Shepard Cancer Center
state: North Carolina
Study officials:
affiliation: UNC Lineberger Comprehensive Cancer Center
name: Christine M. Walko, PharmD, BCOP
role: PRINCIPAL_INVESTIGATOR
References:
citation: Williams GR, Deal AM, Shachar SS, Walko CM, Patel JN, O'Neil B, McLeod HL, Weinberg MS, Choi SK, Muss HB, Sanoff HK. The impact of skeletal muscle on the pharmacokinetics and toxicity of 5-fluorouracil in colorectal cancer. Cancer Chemother Pharmacol. 2018 Feb;81(2):413-417. doi: 10.1007/s00280-017-3487-2. Epub 2017 Nov 20.
citation: Patel JN, O'Neil BH, Deal AM, Ibrahim JG, Sherrill GB, Olajide OA, Atluri PM, Inzerillo JJ, Chay CH, McLeod HL, Walko CM. A community-based multicenter trial of pharmacokinetically guided 5-fluorouracil dosing for personalized colorectal cancer therapy. Oncologist. 2014 Sep;19(9):959-65. doi: 10.1634/theoncologist.2014-0132. Epub 2014 Aug 12.