Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma

Nicholas M. Szigetvari, Deepika Dhawan, José A. Ramos-Vara, Christopher P. Leamon, Patrick J. Klein, A. Audrey Ruple, Hock Gan Heng, Michael R. Pugh, Satish Rao, Iontcho R. Vlahov, Pierre L. Deshuillers, Philip S. Low, Lindsey M. Fourez, Ashleigh M. Cournoyer, Deborah W. Knapp

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Purpose: The purpose was to determine the safety and antitumor activity of a folate-tubulysin conjugate (EC0531) in a relevant preclinical animal model, dogs with naturally-occurring invasive urothelial carcinoma (iUC). Canine iUC is an aggressive cancer with high folate receptor (FR) expression similar to that in certain forms of human cancer. Experimental Design: A 3+3 dose escalation study of EC0531 (starting dose 0.2 mg/kg given intravenously at two-week intervals) was performed in dogs with iUC expressing high levels of FRs (>50% positive tumor cells). Pharmacokinetic (PK) analysis was performed, and the maximum tolerated dose (MTD) was determined. The dose cohort at the MTD was expanded to determine antitumor activity. Results: The MTD of EC0531 was 0.26 mg/kg every two weeks, with grade 3-4 neutropenia and gastrointestinal toxicity observed at higher doses. Treatment at the MTD was well tolerated. Clinical benefit was found in 20 of 28 dogs (71%), including three dogs with partial remission and 17 dogs with stable disease. Plasma EC0531 concentrations in the dogs far exceeded those required to inhibit proliferation of FR-expressing cell in vitro. Unlike human neutrophils, canine neutrophils were found to express FRs, which contributes to the neutropenia at higher doses of EC0531 in dogs. Conclusion: EC0531 was well tolerated and had good antitumor activity in dogs with iUC. It is likely that humans will tolerate higher, potentially more effective doses of folate-tubulysin without myelotoxicity because of the absence of FRs on human neutrophils. The results clearly justify the evaluation of folate-tubulysin in human clinical trials.

Original languageEnglish (US)
Pages (from-to)37042-37053
Number of pages12
JournalOncotarget
Volume9
Issue number97
DOIs
StatePublished - Dec 1 2018

Keywords

  • Animal model
  • Bladder cancer
  • Canine
  • Clinical trial
  • Targeted chemotherapy

ASJC Scopus subject areas

  • Oncology

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