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.
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.
Odenike
Olatoyosi M
OM
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
Larson
Richard A
RA
Gajria
Devika
D
Dolan
M Eileen
ME
Delaney
Shannon M
SM
Karrison
Theodore G
TG
Ratain
Mark J
MJ
Stock
Wendy
W
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
D011725:Pyridines; D013882:Thiosemicarbazones; D003561:Cytarabine; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone