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

SummaryPurpose-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.

Methemoglobin Formation by Triapine, Di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), and Other Anticancer Thiosemicarbazones: Identification of Novel Thiosemicarbazones and Therapeutics That Prevent This Effect

“…Hypoxia and methemoglobinemia are major concerns for patients undergoing anticancer therapies who have compromised cardiopulmonary function (Yen et al, 2004;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010). Recent studies demonstrated that 3-AP led to metHb generation and hypoxia in patients, limiting its usefulness (Yen et al, 2004;Gojo et al, 2007;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010).…”

“…Recent studies demonstrated that 3-AP led to metHb generation and hypoxia in patients, limiting its usefulness (Yen et al, 2004;Gojo et al, 2007;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010). The mechanism responsible was not known and in consideration of the interest in the development of novel thiosemicarbazones as anticancer agents (Yu et al, 2009), it was crucial to investigate their effect on oxyHb, as this would facilitate the development of these compounds (Yu et al, 2009).…”

“…However, other studies suggest some positive results after 3-AP was coadministered with cisplatin and daily pelvic radiation in patients with locally advanced cervical and vaginal cancer (Kunos et al, 2010). The notable side effects of 3-AP include hypoxia and methemoglobinemia (Yen et al, 2004;Gojo et al, 2007;Knox et al, 2007;Odenike et al, 2008;Traynor et al, 2010), which are major concerns for patients with compromised cardiopulmonary function.…”

Development and validation of a model that predicts early death among cancer patients participating in phase I clinical trials investigating cytotoxics

“…Nevertheless, we enter to a new era of phase 1 clinical trials investigating associations of cytotoxic agents plus molecular targeted therapies. In these new studies, the cytotoxic agents drive the toxicity profile and are the key-element that determines the dose-limiting toxicity and then maximal tolerated dose [28][29][30][31][32]. Phase I trials investigating cytotoxic drugs enroll vulnerable patients not amenable to forms of treatment with established efficacy.…”

Cytotoxic activities of new iron(III) and nickel(II) chelates of some S-methyl-thiosemicarbazones on K562 and ECV304 cells

“…Research on cytotoxic properties of thiosemicarbazone-metal complexes have been centralized to platinum and palladium chelates. The object of the published papers is the ONS and NNS chelators such as benzaldehyde, 2-acetyl pyridine, phenanthrenequinone, and 2-benzoylpyridine derivatives which have no substituent on sulphur atom of thiosemicarbazone [9,10,[20][21][22][23].…”