title: 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: OBJECTIVE
  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.
  
  
  METHODS
  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.affiliation: Section of Hematology/Oncology, Department of Medicine, University of Chicago Medical Center, 5841 S. Maryland Avenue, MC 2115, Chicago, IL 60637-1470, USA. todenike@medicine.bsd.uchicago.edu
authors.forename: Olatoyosi M
authors.initials: OM
authors.lastname: Odenike
authors.forename: Richard A
authors.initials: RA
authors.lastname: Larson
authors.forename: Devika
authors.initials: D
authors.lastname: Gajria
authors.forename: M Eileen
authors.initials: ME
authors.lastname: Dolan
authors.forename: Shannon M
authors.initials: SM
authors.lastname: Delaney
authors.forename: Theodore G
authors.initials: TG
authors.lastname: Karrison
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Ratain
authors.forename: Wendy
authors.initials: W
authors.lastname: Stock
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D003561:Cytarabine / Q000008:administration & dosage; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008708:Methemoglobinemia / Q000139:chemically induced; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage; D012008:Recurrence; D013882:Thiosemicarbazones / Q000008:administration & dosage
chemical_list: D011725:Pyridines; D013882:Thiosemicarbazones; D003561:Cytarabine; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone