A Phase I Study of Triapine® in Combination With Irinotecan in Refractory Tumors
I. To find the maximal tolerated dose for the combination of irinotecan and Triapine® in
patients with refractory solid tumors.
I. To find the severity and frequency of toxicity associated with this combination and to
observe for and record any antitumor activity.
I. To evaluate the effect of Triapine®/irinotecan on the ribonucleotide reductase tyrosyl
radical in vivo by Electron Paramagnetic Spectroscopy (EPR) in buccal mucosal cells,
peripheral blood lymphocytes and in tumor biopsies. Formation of low molecular weight
iron-Triapine® chelates will also be assessed by EPR.
II. To evaluate the effect of Triapine® /irinotecan on cell cycle in vivo by measuring
S-phase arrest in buccal mucosal cells.
III. To evaluate the effect of Triapine® /irinotecan on MDR gene expression and
polymorphisms in blood.
IV. To evaluate the effect of Triapine® /irinotecan on ribonucleotide reductase R2 mRNA and
V. To evaluate the pharmacokinetic profile of the combination.
OUTLINE: This is a dose-escalation study.
Patients receive irinotecan IV over 1 hour on day 1 and 3-AP (Triapine®) IV over 2 hours on
days 1-3. Courses repeat every 21 days in the absence of disease progression or unacceptable
Cohorts of 3-6 patients receive escalating doses of irinotecan and 3-AP (Triapine®) 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, 6 additional patients are treated at that dose.
Patients are followed until disease progression.
Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
Number and severity of toxicity incidents categorized via CTC standard toxicity grading
Hematologic toxicity measures of thrombocytopenia, neutropenia and leukopenia will be assessed using the continuous variables as the outcome measures (primarily nadir and percent change from baseline values). Nonhematologic toxicities such as diarrhea and stomatitis will be evaluated via the ordinal CTC standard toxicity grading only. Frequency distributions and other descriptive measures will form the basis of the analysis of these variables.
Up to 4 years
University of Wisconsin Hospital and Clinics
United States: Food and Drug Administration
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