Journal
INVESTIGATIONAL NEW DRUGS
Volume 26, Issue 3, Pages 233-239Publisher
SPRINGER
DOI: 10.1007/s10637-008-9115-6
Keywords
3-aminopyridine-2-carboxaldehyde-thiosemicarbazone; 3-AP; myeloid leukemia; triapine; cytarabine; methemoglobinemia
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Funding
- NCI NIH HHS [P30 CA014599, U01 CA69852-09, P30 CA14599-32, U01 CA069852] Funding Source: Medline
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Purpose: This Phase I dose escalation study was based on the hypothesis that the addition of 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) to cytarabine would enhance cytarabine cytotoxicity. The primary objective of the study was to establish the maximum tolerated dose of 3-AP when given in combination with a fixed dose of cytarabine. Experimental design: Twenty-five patients with relapsed or refractory myeloid leukemia were enrolled to three dose levels of 3-AP. Cytarabine was administered as a 2 h infusion at a fixed dose of 1,000 mg/m(2)/day for 5 consecutive days. Escalating doses of 3-AP as a 2 h infusion were administered on days 2 through 5. The 3-AP infusion preceded the start of the cytarabine infusion by 4 h. Results: In general, the toxicities observed with the combination were similar to the expected toxicity profile for cytarabine when utilized as a single agent at this dose and schedule. However, two of three patients developed dose-limiting methemoglobinemia at the highest 3-AP dose studied (100 mg/m(2)). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/m(2) dose level. Objective evidence of clinical activity was observed in four patients. Conclusions: The combination of 3-AP and cytarabine given on this schedule is feasible in advanced myeloid leukemia. The recommended Phase II dose is 75 mg/m(2)/day of 3-AP on days 2-5 given prior to cytarabine administered at a dose of 1,000 mg/m(2)/day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.
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