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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 9 Issue 97 Pg. 37042-37053 (Dec 11 2018) ISSN: 1949-2553 [Electronic] United States
• PMID: 30651934 (Publication Type: Journal Article)