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

Brian S. Choi, Dona B. Alberti, William R. Schelman, Jill M. Kolesar, James P. Thomas, Rebecca Marnocha, Jens C. Eickhoff, S. Percy Ivy, George Wilding, Kyle D. Holen

Research output: Contribution to journalArticlepeer-review

16 Scopus 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/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.

Original languageEnglish
Pages (from-to)973-980
Number of pages8
JournalCancer Chemotherapy and Pharmacology
Volume66
Issue number5
DOIs
StatePublished - Oct 2010

Bibliographical note

Funding Information:
Acknowledgments This study was supported by the following grants: U01CA062491 “Early Clinical Trials of Anti-Cancer Agents with Phase I Emphasis”, NCI; 1ULRR025011 “Clinical and Translational Science Award of the National Center for Research Resources”, NIH; CTEP Translational Research Initiative Funding 24XS090. The authors would like to thank Marcy Pomplun and Zhisheng Jiang of the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center (UWCCC) Analytical Instrumentation Laboratory for Pharmacokinetics, Pharmacodynamics & Pharmacogenetics (3P Lab) for support in the acquisition of 3-AP pharmacokinetics for this research. The authors would also like to thank the nurses and research specialists of the UWCCC Phase I Program for their eVorts in conducting and managing this trial.

Keywords

  • 3-AP
  • ABCB1
  • Irinotecan
  • Triapine®
  • UGT1A1

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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