A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells.
BACKGROUND
We tested the hypothesis that 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) may enhance response to re-treatment with gemcitabine by enhancing intracellular uptake of gemcitabine in a phase II study.


METHODS
Patients who had prior exposure to gemcitabine as a first-line treatment of advanced non-small-cell lung cancer (NSCLC) were given weekly infusions of 3-AP and gemcitabine for 3 weeks followed by 1 week of rest, repeated every 28 days. Plasma and peripheral blood mononuclear cells (PBMCs) were collected to evaluate the effect of 3-AP on pharmacokinetics and intracellular uptake of gemcitabine.


RESULTS
Twelve patients were treated with a median of two treatment cycles without objective response, hence the study was terminated at interim analysis. Four patients had stable disease and the median time to progression was 3 months (95% confidence interval, CI: 1.7 to 9.1 months). Grade 3 toxicities included neutropenia (two patients), hypoxia (three patients) and dyspnea (one patient). Four patients developed reversible symptomatic methemoglobinemia during 3-AP infusion, with mild to moderately elevated methemoglobin levels that ranged from 7.8 to 17.6% of the total hemoglobin concentration. Limited pharmacokinetic data did not suggest any clinically relevant pharmacological influence of 3-AP on gemcitabine.


CONCLUSIONS
3-AP did not enhance clinical response to gemcitabine in this cohort of patients with prior exposure to gemcitabine for advanced NSCLC. Further development of 3-AP in lung cancer is challenged by its potential of causing methemoglobinemia and hypoxia, which could be problematic in patients with compromised pulmonary reserves.
Ma
Brigette
B
Department of Clinical Oncology, Sir Y.K. Pao Center for Cancer, Hong Kong Cancer Institute, State Key Laboratory in Oncology in South China, Chinese University of Hong Kong, Ngan Shing Street, Shatin, New Territories, Hong Kong. brigette@clo.cuhk.edu.hk
Goh
Boon Cher
BC
Tan
Eng Huat
EH
Lam
Kwok Chi
KC
Soo
Ross
R
Leong
Swan Swan
SS
Wang
Ling Zhi
LZ
Mo
Frankie
F
Chan
Anthony T C
AT
Zee
Benny
B
Mok
Tony
T
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D018450:Disease Progression; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000139:chemically induced; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008708:Methemoglobinemia / Q000139:chemically induced; D008875:Middle Aged; D011725:Pyridines / Q000008:administration & dosage; D013882:Thiosemicarbazones / Q000008:administration & dosage; D016896:Treatment Outcome; D000093542:Gemcitabine
D011725:Pyridines; D013882:Thiosemicarbazones; D003841:Deoxycytidine; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D000093542:Gemcitabine