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.
Similar content being viewed by others
References
Estey E, Plunkett W, Dixon D, Keating M, McCredie K, Freireich EJ (1987) Variables predicting response to high dose cytosine arabinoside therapy in patients with refractory acute leukemia. Leukemia 1:580–583
Plunkett W, Liliemark JO, Adams TM, Nowak B, Estey E, Kantarjian H, Keating MJ (1987) Saturation of 1-beta-d-arabinofuranosylcytosine 5′-triphosphate accumulation in leukemia cells during high-dose 1-beta-d-arabinofuranosylcytosine therapy. Cancer Res 47:3005–3011
Cory JG, Cory AH, Rappa G, Lorico A, Liu MC, Lin TS, Sartorelli AC (1994) Inhibitors of ribonucleotide reductase. Comparative effects of amino- and hydroxy-substituted pyridine-2-carboxaldehyde thiosemicarbazones. Biochem Pharmacol 48:335–344
Heinemann V, Xu YZ, Chubb S, Sen A, Hertel LW, Grindey GB, Plunkett W (1990) Inhibition of ribonucleotide reduction in CCRF-CEM cells by 2′,2′-difluorodeoxycytidine. Mol Pharmacol 38:567–572
Wright JA, Chan AK, Choy BK, Hurta RA, McClarty GA, Tagger AY (1990) Regulation and drug resistance mechanisms of mammalian ribonucleotide reductase, and the significance to DNA synthesis. Biochem Cell Biol 68:1364–1371
Finch RA, Liu M, Grill SP, Rose WC, Loomis R, Vasquez KM, Cheng Y, Sartorelli AC (2000) Triapine (3-aminopyridine-2-carboxaldehyde-thiosemicarbazone): a potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem Pharmacol 59:983–991
Giles FJ, Fracasso PM, Kantarjian HM, Cortes JE, Brown RA, Verstovsek S, Alvarado Y, Thomas DA, Faderl S, Garcia-Manero G, Wright LP, Samson T, Cahill A, Lambert P, Plunkett W, Sznol M, DiPersio JF, Gandhi V (2003) Phase I and pharmacodynamic study of Triapine, a novel ribonucleotide reductase inhibitor, in patients with advanced leukemia. Leuk Res 27:1077–1083
Gojo I, Tidwell ML, Greer J, Takebe N, Seiter K, Pochron MF, Johnson B, Sznol M, Karp JE (2007) Phase I and pharmacokinetic study of Triapine, a potent ribonucleotide reductase inhibitor, in adults with advanced hematologic malignancies. Leuk Res 31:1165–1173
Sigmond J, Kamphuis JA, Laan AC, Hoebe EK, Bergman AM, Peters GJ (2007) The synergistic interaction of gemcitabine and cytosine arabinoside with the ribonucleotide reductase inhibitor triapine is schedule dependent. Biochem Pharmacol 73:1548–1557
Feun L, Modiano M, Lee K, Mao J, Marini A, Savaraj N, Plezia P, Almassian B, Colacino E, Fischer J, MacDonald S (2002) Phase I and pharmacokinetic study of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) using a single intravenous dose schedule. Cancer Chemother Pharmacol 50:223–229
Murren J, Modiano M, Clairmont C, Lambert P, Savaraj N, Doyle T, Sznol M (2003) Phase I and pharmacokinetic study of triapine, a potent ribonucleotide reductase inhibitor, administered daily for five days in patients with advanced solid tumors. Clin Cancer Res 9:4092–4100
Wadler S, Makower D, Clairmont C, Lambert P, Fehn K, Sznol M (2004) Phase I and pharmacokinetic study of the ribonucleotide reductase inhibitor, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone, administered by 96-hour intravenous continuous infusion. J Clin Oncol 22:1553–1563
Dalal BI, Kollmannsberger C (2005) Drug-induced haemolysis and methaemoglobinaemia in glucose 6-phosphate dehydrogenase deficiency. Br J Haematol 129:291
Cheson BD, Cassileth PA, Head DR, Schiffer CA, Bennett JM, Bloomfield CD, Brunning R, Gale RP, Grever MR, Keating MJ et al (1990) Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. J Clin Oncol 8:813–819
Bolwell BJ, Cassileth PA, Gale RP (1988) High dose cytarabine: a review. Leukemia 2:253–260
Kalinowski DS, Richardson DR (2007) Future of toxicology—iron chelators and differing modes of action and toxicity: the changing face of iron chelation therapy. Chem Res Toxicol 20:715–720
Shao J, Zhou B, Di Bilio AJ, Zhu L, Wang T, Qi C, Shih J, Yen Y (2006) A ferrous-triapine complex mediates formation of reactive oxygen species that inactivate human ribonucleotide reductase. Mol Cancer Ther 5:586–592
Yen Y, Margolin K, Doroshow J, Fishman M, Johnson B, Clairmont C, Sullivan D, Sznol M (2004) A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother Pharmacol 54:331–342
Knoxx JJ, Hotte SJ, Kollmannsberger C, Winquist E, Fisher B, Eisenhauer E (2007) Phase II study of Triapine(R) in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). Invest New Drugs 25:471–477
Yee KW, Cortes J, Ferrajoli A, Garcia-Manero G, Verstovsek S, Wierda W, Thomas D, Faderl S, King I, O, ’Brien SM, Jeha S, Andreeff M, Cahill A, Sznol M, Giles FJ (2006) Triapine and cytarabine is an active combination in patients with acute leukemia or myelodysplastic syndrome. Leuk Res 30:813–822
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10637-008-9115-6