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Cancer Chemother Pharmacol (2012) 69:835843
DOI 10.1007/s00280-011-1779-5
CLINICAL TRIAL REPORT
A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249)in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study
Joseph Chao Timothy W. Synold Robert J. Morgan Jr. Charles Kunos Jeff Longmate
Heinz-Josef Lenz Dean Lim Stephen Shibata Vincent Chung Ronald G. Stoller Chandra P. Belani
David R. Gandara Mark McNamara Barbara J. Gitlitz Derick H. Lau Suresh S. Ramalingam
Angela Davies Igor Espinoza-Delgado Edward M. Newman Yun Yen
Received: 11 April 2011 / Accepted: 7 November 2011 / Published online: 22 November 2011 Springer-Verlag 2011
AbstractBackground 3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) is a novel small-molecule ribonucleotide reductase inhibitor. This study was designed to estimate the maximum tolerated dose (MTD) and oral bioavail-ability of 3-AP in patients with advanced-stage solid tumors.
Methods Twenty patients received one dose of intravenous and subsequent cycles of oral 3-AP following a 3 ? 3 patient dose escalation. Intravenous 3-AP was administered to every patient at a xed dose of 100 mg over a 2-h infusion 1 week prior to the rst oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 13, days 810, and days 1517 of every 28-day cycle. 3-AP was started at 50 mg with a planned dose escalation to 100, 150, and 200 mg. Dose-limiting toxicities (DLT) and bioavailability were evaluated.
Results Twenty patients were enrolled. For dose level 1 (50 mg), the second of three treated patients had a DLT of grade 3 hypertension. In the dose level 1 expansion cohort, three patients had no DLTs. No further DLTs were encountered during escalation until the 200-mg dose was reached. At the 200 mg 3-AP dose level, two treated patients had DLTs of grade 3 hypoxia. One additional DLT of grade 4 febrile neutropenia was subsequently observed at the de-escalated 150 mg dose. One DLT in 6 evaluable patients established the MTD as 150 mg per dose on this dosing schedule. Responses in the form of stable disease occurred in 5 (25%) of 20 patients. The oral bioavailability of 3-AP was 67 29% and was consistent with the nding that the MTD by the oral route was 33% higher than by the intravenous route.
Conclusions Oral 3-AP...