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, 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

研究成果: 雜誌貢獻文章同行評審

24 引文 斯高帕斯(Scopus)

摘要

Background: 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 bioavailability 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 fixed dose of 100 mg over a 2-h infusion 1 week prior to the first oral cycle. Oral 3-AP was administered every 12 h for 5 consecutive doses on days 1-3, days 8-10, and days 15-17 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 finding that the MTD by the oral route was 33% higher than by the intravenous route. Conclusions: Oral 3-AP is well tolerated and has an MTD similar to its intravenous form after accounting for the oral bioavailability. Oral 3-AP is associated with a modest clinical benefit rate of 25% in our treated patient population with advanced solid tumors.

原文英語
頁(從 - 到)835-843
頁數9
期刊Cancer Chemotherapy and Pharmacology
69
發行號3
DOIs
出版狀態已發佈 - 三月 1 2012
對外發佈Yes

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

指紋 深入研究「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」主題。共同形成了獨特的指紋。

引用此