Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia.

Abstract

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/m2/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/m2). Transient reversible methemoglobinemia was documented in 11 of 15 patients enrolled at the 75 mg/ m2 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/m2/day of 3-AP on days 2-5 given prior to cytarabine administered at a dose of 1,000 mg/m2/day over 5 consecutive days. Methemoglobinemia is a common toxicity of this combination and requires close monitoring.

• Authors: Olatoyosi M Odenike, Richard A Larson, Devika Gajria, M Eileen Dolan, Shannon M Delaney, Theodore G Karrison, Mark J Ratain, Wendy Stock
• Journal: Investigational new drugs (Invest New Drugs) Vol. 26 Issue 3 Pg. 233-9 (Jun 2008) ISSN: 0167-6997 [Print] United States
• PMID: 18217206 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Pyridines
• Thiosemicarbazones
• Cytarabine
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone

Topics

• Antineoplastic Combined Chemotherapy Protocols (administration & dosage, adverse effects, therapeutic use)
• Cytarabine (administration & dosage)
• Drug Monitoring
• Female
• Humans
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Leukemia, Myeloid, Acute (drug therapy)
• Male
• Maximum Tolerated Dose
• Methemoglobinemia (chemically induced)
• Middle Aged
• Pyridines (administration & dosage)
• Recurrence
• Thiosemicarbazones (administration & dosage)