A Phase I Study of Triapine® in Combination With Doxorubicin in Refractory Tumors

PRIMARY OBJECTIVES: I. To find the maximal tolerated dose for the combination of doxorubicin and Triapine® in patients with refractory solid tumors. SECONDARY OBJECTIVES: I. To find the severity and frequency of toxicity associated with this combination and to observe for and record any antitumor activity. TERTIARY OBJECTIVES: 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 immunohistochemistry. 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 combination. 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 unacceptable toxicity. 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.