Journal article
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 chemotherapy and pharmacology, Vol.66(5), pp.973-980
10/01/2010
DOI: 10.1007/s00280-010-1250-z
PMCID: PMC2921466
PMID: 20127092
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/m2 and 3-AP 85 mg/m2 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/m2 per day and irinotecan 200 mg/m2. 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/m2 per day on days 1-3 and irinotecan 200 mg/m2 on day 1 every 21 days. Antitumor activity in a patient with refractory non-small cell lung cancer was noted at level 1.
Details
- Title: Subtitle
- 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
- Creators
- Brian S. Choi - University of Wisconsin Carbone Cancer CenterDona B. Alberti - University of Wisconsin Carbone Cancer CenterWilliam R. Schelman - University of Wisconsin Carbone Cancer CenterJill M. Kolesar - University of Wisconsin Carbone Cancer CenterJames P. Thomas - The Ohio State UniversityRebecca Marnocha - University of Wisconsin Carbone Cancer CenterJens C. Eickhoff - University of Wisconsin Carbone Cancer CenterS. Percy Ivy - National Cancer InstituteGeorge Wilding - University of Wisconsin Carbone Cancer CenterKyle D. Holen - University of Wisconsin Carbone Cancer Center
- Resource Type
- Journal article
- Publication Details
- Cancer chemotherapy and pharmacology, Vol.66(5), pp.973-980
- DOI
- 10.1007/s00280-010-1250-z
- PMID
- 20127092
- PMCID
- PMC2921466
- NLM abbreviation
- Cancer Chemother Pharmacol
- ISSN
- 0344-5704
- eISSN
- 1432-0843
- Publisher
- Springer Nature
- Number of pages
- 8
- Grant note
- 24XS090 / CTEP Translational Research Initiative UL1RR025011 / NATIONAL CENTER FOR RESEARCH RESOURCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Center for Research Resources (NCRR) U01CA062491 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) U01CA062491 / NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) 1ULRR025011 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 10/01/2010
- Academic Unit
- Pharmacy; Pharmaceutical Sciences and Experimental Therapeutics
- Record Identifier
- 9984696553002771
Metrics
5 Record Views