- 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]).
- 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.
- 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
- 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
- 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
- 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)
Last updated: 08/02/2011
NCT ID: NCT00654160