A Phase I And Pharmacogenetic Study Of CPT-11, Oxaliplatin, And Capecitabine In Patients With Solid Tumors
A Phase I And Pharmacogenetic Study Of CPT-11, Oxaliplatin, And Capecitabine In Patients With Solid Tumors
Drugs used in chemotherapy, such as irinotecan, oxaliplatin, and capecitabine, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one chemotherapy drug may kill more tumor cells. This phase I trial is studying the side effects and best dose of irinotecan, oxaliplatin, and capecitabine in treating patients with unresectable solid tumors.
OBJECTIVES:
I. To define the maximally tolerated dose of the combination of CPT-11 (irinotecan hydrochloride), oxaliplatin, and capecitabine in three different populations, based on UDP glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1) genotype (6/6, 6/7, and 7/7).
II. To identify any activity of this treatment combination in patients with metastatic cancer.
III. To examine the differences in the toxicity profile, especially pertaining to hematologic and gastrointestinal (GI), and the maximally tolerated dose of the combination of CPT-11, oxaliplatin and capecitabine with respect to the UGT1A1 haplotypes.
IV. Examine the effect of the UGT1A1 genotype on the pharmacokinetics of CPT-11 and its metabolites.
OUTLINE: This is a dose-escalation study. Patients are stratified according to UGT1A1 genotype (6/6 vs 6/7 [closed to accrual as of 8/24/06] vs 7/7).
Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes and oxaliplatin IV over 2 hours on day 1 and capecitabine orally (PO) twice daily (QD) on days 2-15. Courses repeat every 3 weeks in the absence of disease progression or unacceptable toxicity.
Cohorts of 3-6 patients receive escalating doses of irinotecan hydrochloride, oxaliplatin, and capecitabine until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Once the MTD is determined, an additional 6-10 patients (for a total of 12 patients) receive treatment at that dose.
After completion of study treatment, patients are followed up at 3 months.
PROJECTED ACCRUAL: A total of 54-84 patients (12-22 for stratum I, 18-28 for stratum II [closed to accrual as of 8/24/06], and 24-34 for stratum III) will be accrued for this study within approximately 4.4 years.
Inclusion Criteria:
Histologically confirmed solid tumor for which there is no known standard therapy that is potentially curative or capable of extending life expectancy
Willing to provide biologic specimens to determine UGT1A1 genotype
No CNS metastases
Performance status - ECOG 0-2
At least 12 weeks
Absolute neutrophil count at least 1,500/mm^3
Platelet count at least 100,000/mm^3
Hemoglobin at least 9.0 g/dL
Bilirubin no greater than upper limit of normal (ULN) for patients with 6/6 UGT1A1 genotype (1.5 times ULN for patients with 6/7 [closed to accrual as of 8/24/06] or 7/7 UGT1A1 genotype)
AST no greater than 3 times ULN (5 times ULN if there is liver involvement)
Creatinine no greater than 1.5 times ULN
No New York Heart Association class III or IV heart disease
Not pregnant or nursing
Negative pregnancy test
Fertile patients must use effective contraception
No prior allergy to platinum compounds, irinotecan, or to antiemetics or antidiarrheals appropriate for administration with study therapy
No uncontrolled infection
No seizure disorder
No peripheral neuropathy grade 2 or greater
More than 4 weeks since prior biologic therapy
More than 4 weeks since prior immunotherapy
No concurrent immunotherapy
No concurrent prophylactic colony-stimulating factor therapy
More than 4 weeks since prior chemotherapy (6 weeks for mitomycin or nitrosoureas) and recovered
No other concurrent chemotherapy
See Disease Characteristics
More than 4 weeks since prior radiotherapy
No prior radiotherapy to more than 25% of the bone marrow
No concurrent radiotherapy
See Disease Characteristics
No other concurrent investigational therapy
No concurrent sorivudine, brivudine, lamivudine, or stavudine
No concurrent enrollment in any other study involving a pharmacologic agent for symptom control or therapeutic intent