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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

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Summary

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.

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Acknowledgement

Supported in part by U01 CA69852-09 NIH/NCI, P30 CA14599-32-NIH/NCI: University of Chicago Cancer Center Support Grant and NCI Translational Research funds.

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Authors and Affiliations

  1. Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637-1470, USA

    Olatoyosi M. Odenike, Richard A. Larson, M. Eileen Dolan, Shannon M. Delaney, Mark J. Ratain & Wendy Stock

  2. Cancer Research Center, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637-1470, USA

    Olatoyosi M. Odenike, Richard A. Larson, M. Eileen Dolan, Mark J. Ratain & Wendy Stock

  3. Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Avenue, MC 7082, Chicago, IL, 60637-1470, USA

    Devika Gajria

  4. Department of Health Studies, University of Chicago, 5841 S. Maryland Avenue, MC 2007, Chicago, IL, 60637-1470, USA

    Theodore G. Karrison

  5. Committee on Clinical Pharmacology and Pharmacogenomics, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL, 60637-1470, USA

    Mark J. Ratain

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  1. Olatoyosi M. Odenike
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  2. Richard A. Larson
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  3. Devika Gajria
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  4. M. Eileen Dolan
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  5. Shannon M. Delaney
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  6. Theodore G. Karrison
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  7. Mark J. Ratain
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  8. Wendy Stock
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Correspondence to Olatoyosi M. Odenike.

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Odenike, O.M., Larson, R.A., Gajria, D. et al. 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. Invest New Drugs 26, 233–239 (2008). https://doi.org/10.1007/s10637-008-9115-6

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  • DOI: https://doi.org/10.1007/s10637-008-9115-6

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