A Phase I Study of Triapine® in Combination With Doxorubicin in Refractory Tumors
I. To find the maximal tolerated dose for the combination of doxorubicin 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®/doxorubicin on the ribonucleotide reductase tyrosyl
radical in vivo by EPR spectroscopy 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®/doxorubicin on cell cycle in vivo by measuring
S-phase arrest in buccal mucosal cells.
III. To evaluate the effect of Triapine®/doxorubicin on MDR gene expression and
polymorphisms in blood.
IV. To evaluate the effect of Triapine®/doxorubicin on ribonucleotide reductase R2 mRNA and
V. To evaluate the pharmacokinetic profile of the combination. VI. To measure the
formulation of circulating isoprostanes as an indicator of oxidative stress with this
OUTLINE: This is a dose-escalation study of 3-AP (Triapine^®).
Patients receive doxorubicin IV over 15 minutes on day 1 and 3-AP (Triapine®) IV over 2
hours on days 1-4. Courses repeat every 21 days in the absence of disease progression or
Cohorts of 3-6 patients receive escalating doses of 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, an
additional 6 patients are treated at that dose level.
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 Common Toxicity Criteria (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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