Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma

Patrick Grierson, Andrea Teague, Rama Suresh, Kian Huat Lim, Manik Amin, Katrina Pedersen, Benjamin Tan, Jesse Huffman, Nick Boice, Lingling Du, Jingxia Liu, A. Craig Lockhart, Andrea Wang-Gillam

Research output: Contribution to journalArticle

Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options. We evaluated the safety and efficacy of the aminopeptidase inhibitor tosedostat with capecitabine in advanced PDAC. Methods: We conducted a phase Ib/II trial of tosedostat with capecitabine as second-line therapy for advanced PDAC. Planned enrollment was 36 patients. Eligible patients were treated with capecitabine 1,000 mg/m2 oral twice-daily days 1–14 and oral tosedostat in a dose de-escalation design on days 1–21 of each 21-day cycle. Primary endpoints were the recommended phase 2 dose (RP2D) and progression-free survival (PFS). Results: Sixteen patients were enrolled. Tosedostat 120 mg oral twice daily with capecitabine 1,000 mg/m2 oral twice daily was the RP2D. There was one dose-limiting toxicity (DLT) (grade 3 acute coronary syndrome) during phase Ib. The most common treatment-related adverse events were gastrointestinal (nausea, diarrhea), cardiac [QTc prolongation, decreased ejection fraction (EF)], and fatigue. The median PFS was 7.1 months, and the median treatment failure free survival was 3 months. Eight patients experienced stable disease for greater than 3 months. The study was closed early due to lack of drug availability. Conclusions: Tosedostat with capecitabine displayed tolerable toxicity, and prolonged disease control in a subset of patients. These data encourage further exploration of aminopeptidase inhibitors in pancreatic cancer.

Original languageEnglish (US)
Pages (from-to)61-67
Number of pages7
JournalJournal of Gastrointestinal Oncology
Volume11
Issue number1
DOIs
StatePublished - Feb 1 2020

Keywords

  • Aminopeptidase inhibitor
  • Pancreatic cancer
  • Tosedostat

ASJC Scopus subject areas

  • Oncology
  • Gastroenterology

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    Grierson, P., Teague, A., Suresh, R., Lim, K. H., Amin, M., Pedersen, K., Tan, B., Huffman, J., Boice, N., Du, L., Liu, J., Lockhart, A. C., & Wang-Gillam, A. (2020). Phase Ib/II study combining tosedostat with capecitabine in patients with advanced pancreatic adenocarcinoma. Journal of Gastrointestinal Oncology, 11(1), 61-67. https://doi.org/10.21037/jgo.2019.11.06