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

被引：41

作者：

Chao, Joseph ^{[1
]}

Synold, Timothy W. ^{[1
]}

Morgan, Robert J., Jr. ^{[1
]}

Kunos, Charles ^{[2
]}

Longmate, Jeff ^{[1
]}

Lenz, Heinz-Josef ^{[3
]}

Lim, Dean ^{[1
]}

Shibata, Stephen ^{[1
]}

Chung, Vincent ^{[1
]}

Stoller, Ronald G. ^{[4
]}

Belani, Chandra P. ^{[5
]}

Gandara, David R. ^{[6
]}

McNamara, Mark ^{[3
]}

Gitlitz, Barbara J. ^{[3
]}

Lau, Derick H. ^{[6
]}

Ramalingam, Suresh S. ^{[7
]}

Davies, Angela ^{[8
]}

Espinoza-Delgado, Igor ^{[9
]}

Newman, Edward M. ^{[1
]}

Yen, Yun ^{[1
]}

机构：

[1] City Hope Natl Med Ctr, Duarte, CA 91010 USA

[2] Case Western Reserve Univ, Cleveland, OH 44106 USA

[3] Univ So Calif, Norris Canc Ctr, Los Angeles, CA USA

[4] Univ Pittsburgh, Inst Canc, Pittsburgh, PA USA

[5] Penn State Hershey Canc Inst, Hershey, PA USA

[6] Univ Calif Davis, Ctr Canc, Sacramento, CA 95817 USA

[7] Emory Univ, Winship Canc Inst, Atlanta, GA 30322 USA

[8] OSI Pharmaceut, Ardsley, NY USA

[9] NCI, Canc Therapy Evaluat Program, Bethesda, MD 20892 USA

来源：

CANCER CHEMOTHERAPY AND PHARMACOLOGY | 2012年 / 69卷 / 03期

基金：

美国国家卫生研究院;

关键词：

3-AP; Phase I trial; Oral triapine; Ribonucleotide reductase; GYNECOLOGIC-ONCOLOGY-GROUP; ADVANCED CERVICAL-CANCER; RIBONUCLEOTIDE REDUCTASE; DNA-DAMAGE; RESTING CELLS; TRIAL; HYDROXYUREA; CISPLATIN; RADIATION; PROTEIN;

D O I：

10.1007/s00280-011-1779-5

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

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.

引用

页码：835 / 843

页数：9

共 23 条

[1]

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas [J].