Irinotecan, Fluorouracil, and Leucovorin in Treating Patients With Advanced Gastrointestinal Cancer

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by:
Mayo Clinic
ClinicalTrials.gov Identifier:
NCT00654160
First received: April 4, 2008
Last updated: March 24, 2014
Last verified: March 2014

April 4, 2008
March 24, 2014
June 2008
June 2015   (final data collection date for primary outcome measure)
Maximum tolerated dose of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy [ Designated as safety issue: Yes ]
Maximum tolerated dose (MTD) of genotype-based dosing of FOLFIRI with or without monoclonal antibody therapy [ Designated as safety issue: Yes ]
Complete list of historical versions of study NCT00654160 on ClinicalTrials.gov Archive Site
Response rate of genotype-based dosing in the subset of patients that has colorectal cancer [ Designated as safety issue: No ]
Same as current
Not Provided
Not Provided
 
Irinotecan, Fluorouracil, and Leucovorin in Treating Patients With Advanced Gastrointestinal Cancer
A Pharmacogenetic-Based Phase I Trial of Irinotecan, 5-Fluorouracil, and Leucovorin (FOLFIRI) in Patients With Advanced Gastrointestinal Cancer

RATIONALE: Drugs used in chemotherapy, such as irinotecan, fluorouracil, and leucovorin, 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.

PURPOSE: This phase I trial is studying the side effects and best dose of irinotecan when given together with fluorouracil and leucovorin in treating patients with advanced gastrointestinal cancer.

OBJECTIVES:

Primary

  • To determine the maximum tolerated dose of irinotecan hydrochloride in FOLFIRI for each respective UGT1A1 TA indel genotype grouping (group 1 [7/7, 7/8, 8/8], group 2 [6/7, 5/7, 5/8 ,6/8], and group 3 [6/6, 5/6, 5/5]).

Secondary

  • Determine the molecular basis of toxicity, other than UGT1A1 variants, in FOLFIRI-treated cancer patients.
  • Determine the pharmacodynamic molecular profiles of cell signaling pathways associated with the development and severity of early and late specific toxicities in cancer patients treated with FOLFIRI.

OUTLINE: This is a dose-escalation study of irinotecan hydrochloride. Patients are stratified according to genotype of UGT1A1 TA indel.

  • Group 1 ( TA genotype 7/7, 7/8, 8/8): Patients receive irinotecan hydrochloride IV over 90 minutes and leucovorin calcium IV over 2 hours on day 1 and fluorouracil IV bolus over 5 minutes followed by IV continuously over 46 hours on days 1-3.
  • Group 2 (TA genotype 6/7, 6/7, 5/8, 6/8): Patients receive treatment as in group 1 with a higher initial dose of irinotecan hydrochloride.
  • Group 3 (TA genotype 5/5, 5/6, 6/6): Patients receive treatment as in group 2. In all groups, treatment repeats every 14 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood collection at baseline and periodically during study for pharmacokinetics, dihydropyridine deaminase enzyme assay, and pathway expression analysis.

After completion of study treatment, patients are followed every 6 weeks for up to 2 years.

Interventional
Phase 1
Primary Purpose: Treatment
  • Anal Cancer
  • Carcinoma of the Appendix
  • Colorectal Cancer
  • Esophageal Cancer
  • Extrahepatic Bile Duct Cancer
  • Gallbladder Cancer
  • Gastric Cancer
  • Gastrointestinal Carcinoid Tumor
  • Gastrointestinal Stromal Tumor
  • Liver Cancer
  • Pancreatic Cancer
  • Small Intestine Cancer
  • Drug: fluorouracil
  • Drug: irinotecan hydrochloride
  • Drug: leucovorin calcium
  • Other: pharmacogenomic studies
  • Other: pharmacological study
Not Provided
Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Active, not recruiting
70
Not Provided
June 2015   (final data collection date for primary outcome measure)

DISEASE CHARACTERISTICS:

  • Biopsy confirmed diagnosis of gastrointestinal cancer

    • Advanced, unresectable disease
  • Confirmation of UGT1A1 TA indel genotype
  • Measurable or evaluable (non-measurable) disease

    • Measurable disease is defined as ≥ 1 lesion that can be accurately measured (longest diameter to be recorded) as ≥ 2.0 cm with conventional techniques or as ≥ 1.0 cm with spiral CT scan

      • Clinical lesions will only be considered measurable when they are superficial (e.g., skin nodules, palpable lymph nodes)
      • Lesions on chest x-ray are acceptable as measurable lesions when they are clearly defined and surrounded by aerated lung
    • The following are considered non-measurable disease:

      • Bone lesions
      • Leptomeningeal disease
      • Ascites
      • Pleural/pericardial effusions
      • Lymphangitis cutis/ pulmonis
      • Inflammatory breast disease
      • Abdominal masses (not followed by CR scan or MRI)
      • Cystic lesions
      • All other lesions (or sites of disease), including small lesions (longest diameter < 2.0 cm with conventional techniques or as < 1.0 cm with spiral CT)
  • No known central nervous system metastases or carcinomatous meningitis

PATIENT CHARACTERISTICS:

Inclusion criteria

  • Life expectancy ≥ 12 weeks.
  • ECOG performance status 0-2
  • ANC ≥ 1,500/mm³
  • Platelet count ≥ 100,000/mm³
  • SGOT ≤ 2.5 times upper limit of normal (ULN) (≤ 5 times ULN if liver metastases)
  • Total Bilirubin ≤ ULN for patients in group 3 and ≤ 2.0 times ULN for patients in groups 1 and 2
  • Hemoglobin ≥ 9.0 g/dL
  • Creatinine ≤ 1.5 times ULN or creatinine clearance ≥ 60 mL/min
  • Not pregnant or nursing
  • Negative pregnancy test
  • Fertile patients must use effective contraception for the duration of study treatment
  • Willing to provide blood samples for mandatory translational studies

Exclusion criteria

  • Known allergy to irinotecan hydrochloride-related agents (e.g., topotecan), 5-fluorouracil, and/or leucovorin calcium
  • Active or uncontrolled infection
  • Evidence of serious intercurrent illness (e.g., unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia)

PRIOR CONCURRENT THERAPY:

  • Recovered from all toxicities
  • More than 4 weeks since prior major surgery
  • More than 2 weeks since completion of prior radiotherapy

    • No prior radiotherapy to > 25% of bone marrow
  • More than 2 week since prior cytotoxic chemotherapy, biologic therapy, or immunotherapy
  • No concurrent sargramostim (GM-CSF)
Both
18 Years and older
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00654160
CDR0000592931, P30CA015083, MC064G, NCI-2009-01216
Yes
Robert R. McWilliams, M.D., Mayo Clinic Cancer Center
Mayo Clinic
National Cancer Institute (NCI)
Principal Investigator: Robert McWilliams, MD Mayo Clinic
Mayo Clinic
March 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP