Faculty Collaboration Database

The maximum tolerated dose and biologic effects of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) in combination with irinotecan for patients with refractory solid tumors. Cancer Chemother Pharmacol 2010 Oct;66(5):973-80

Date

02/04/2010

Pubmed ID

20127092

Pubmed Central ID

PMC2921466

DOI

10.1007/s00280-010-1250-z

Scopus ID

2-s2.0-77956225836 (requires institutional sign-in at Scopus site)   17 Citations

Abstract

PURPOSE: 3-AP is a ribonucleotide reductase inhibitor and has been postulated to act synergistically with other chemotherapeutic agents. This study was conducted to determine the toxicity and antitumor activity of 3-AP with irinotecan. Correlative studies included pharmacokinetics and the effects of ABCB1 and UGT1A1 polymorphisms.

METHODS: The treatment plan consisted of irinotecan on day 1 with 3-AP on days 1-3 of a 21-day cycle. Starting dose was irinotecan 150 mg/m(2) and 3-AP 85 mg/m(2) per day. Polymorphisms of ABCB1 were evaluated by pyrosequencing. Drug concentrations were determined by HPLC.

RESULTS: Twenty-three patients were enrolled, 10 men and 13 women. Tumor types included seven patients with pancreatic cancer, four with lung cancer, two with cholangiocarcinoma, two with mesothelioma, two with ovarian cancer, and six with other malignancies. Two patients experienced dose-limiting toxicity (DLT) at dose level 1, requiring amendment of the dose-escalation scheme. Maximal tolerated dose (MTD) was determined to be 3-AP 60 mg/m(2) per day and irinotecan 200 mg/m(2). DLTs consisted of hypoxia, leukopenia, fatigue, infection, thrombocytopenia, dehydration, and ALT elevation. One partial response in a patient with refractory non-small cell lung cancer was seen. Genotyping suggests that patients with wild-type ABCB1 have a higher rate of grade 3 or 4 toxicity than those with ABCB1 mutations.

CONCLUSIONS: The MTD for this combination was 3-AP 60 mg/m(2) per day on days 1-3 and irinotecan 200 mg/m(2) on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.

Author List

Choi BS, Alberti DB, Schelman WR, Kolesar JM, Thomas JP, Marnocha R, Eickhoff JC, Ivy SP, Wilding G, Holen KD

Author

James P. Thomas MD, PhD Professor in the Medicine department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols
Camptothecin
Chromatography, High Pressure Liquid
Dose-Response Relationship, Drug
Drug Synergism
Female
Glucuronosyltransferase
Humans
Male
Maximum Tolerated Dose
Middle Aged
Neoplasms
Polymorphism, Genetic
Pyridines
Thiosemicarbazones
Treatment Outcome