A Phase I Clinical Trial to Investigate the Correlation Between UGT1A1 Genotype and Irinotecan (CPT-11) Pharmacokinetics and Toxicity in Cancer Patients
I. Classify patients with solid tumors or lymphoma according to UGT1A1 promoter (TATA box)
and coding region (Gly71Arg) mutation, and CYP3A4 promoter (G to A) polymorphisms.
II. Identify UGT1A1 enzyme glucuronidator and irinotecan oxidizer phenotypes in these
patients and determine the correlation between the two metabolic reactions in vivo.
III. Determine the relationship between UGT1A1 genotype (promoter and/or coding region
mutation) and CYP3A4 promoter genotype vs gastrointestinal or bone marrow toxicity, and
pharmacokinetics of irinotecan in these patients.
IV. Determine the pharmacokinetics of irinotecan in these patients.
OUTLINE: Patients are genotyped for UGT1A1 enzyme and classified as "Gilbert's" (7/7),
"heterozygotes" (6/7), and "homozygotes for allele 6" (6/6). The DNA is analyzed for the
UGT1A1 coding region mutation (Gly71Arg) and CYP3A4 promoter polymorphism. Patients are also
examined for glucuronidator ratio of SN-38, the active metabolite of irinotecan, and
classified as "low/slow" (very low or zero SN-38G/SN-38 ratio), "intermediate" (less than
50% normal ratio), or "normal".
Patients receive irinotecan IV over 90 minutes once every 3 weeks. Treatment continues for
at least 2 courses in the absence of disease progression or unacceptable toxicity.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Grade 3-4 diarrhea
A Cochran-Armitage test for trend will be used to determine whether there is a linear trend in the proportion of patients within each genotype experiencing grade 3-4 diarrhea. Similarly, trend analysis will be performed to determine if there is a linear trend in the proportion of patients within each phenotype experiencing grade 3-4 myelosuppression. Genotype (3 ordered levels) will be modeled as a function of metabolic ratios and biliary index to determine whether these are independent.
Up to 4 years
University of Chicago Comprehensive Cancer Center
United States: Food and Drug Administration
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