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

• Type of Material: Article
• Authors: Joseph Chao, City of Hope Medical Center; Timothy W. Synold, City of Hope Medical Center; Robert J. Morgan Jr., City of Hope Medical Center; Charles Kunos, Case Western Reserve University; Jeff Longmate, City of Hope Medical Center; Heinz-Josef Lenz, University of Southern California; Dean Lim, City of Hope Medical Center; Stephen Shibata, City of Hope Medical Center; Vincent Chung, City of Hope Medical Center; Ronald G. Stoller, University of Pittsburgh; Chandra P. Belani, Penn State Hershey Cancer Institute; David R. Gandara, University of California Davis; Mark McNamara, University of Southern California; Barbara J. Gitlitz, University of Southern California; Derick H. Lau, University of California Davis; Suresh S Ramalingam, Emory University; Angela Davies, OSI Pharmaceuticals; Igor Espinoza-Delgado, National Cancer Institute; Edward M. Newman, City of Hope Medical Center; Yun Yen, City of Hope Medical Center
• Language: English
• Date: 2012-03-01
• Publisher: Springer (part of Springer Nature): Springer Open Choice Hybrid Journals
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2011 Springer-Verlag.
• Final Published Version (URL): http://dx.doi.org/10.1007/s00280-011-1779-5
• Title of Journal or Parent Work: Cancer Chemotherapy and Pharmacology
• ISSN: 0344-5704
• Volume: 69
• Issue: 3
• Start Page: 835
• End Page: 843
• Grant/Funding Information: This study was supported by the National Institutes of Health, National Cancer Institute under Cooperative Agreements with the Cancer Therapy Evaluation Program (U01 CA62505, City of Hope Medical Center and U01 CA099168, University of Pittsburgh Cancer Institute); and a Cancer Center Support Grant (P30 CA033572, City of Hope Medical Center).
• Keywords: GYNECOLOGIC-ONCOLOGY-GROUP; PROTEIN; HYDROXYUREA; Oncology; RESTING CELLS; Life Sciences & Biomedicine; Ribonucleotide reductase; Pharmacology & Pharmacy; ADVANCED CERVICAL-CANCER; 3-AP; Phase I trial; Oral triapine; DNA-DAMAGE; TRIAL; RADIATION; CISPLATIN; Science & Technology; RIBONUCLEOTIDE REDUCTASE
• Research Categories: Health Sciences, Oncology; Health Sciences, Pharmacology

Abstract

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.