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.

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.

• Authors: 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
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 69 Issue 3 Pg. 835-43 (Mar 2012) ISSN: 1432-0843 [Electronic] Germany
• PMID: 22105720 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Pyridines
• Thiosemicarbazones
• 3-aminopyridine-2-carboxaldehyde thiosemicarbazone

Topics

• Administration, Oral
• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Biological Availability
• California
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Injections, Intravenous
• Male
• Maximum Tolerated Dose
• Middle Aged
• Neoplasm Staging
• Neoplasms (drug therapy, pathology)
• Pyridines (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Thiosemicarbazones (administration & dosage, adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome