Phase I/II clinical trial of the targeted chemotherapeutic drug, folate-tubulysin, in dogs with naturally-occurring invasive urothelial carcinoma
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Nicholas M. Szigetvari1, Deepika Dhawan1, José A. Ramos-Vara2, Christopher P. Leamon3, Patrick J. Klein3, A. Audrey Ruple2, Hock Gan Heng1, Michael R. Pugh3, Satish Rao3, Iontcho R. Vlahov3, Pierre L. Deshuillers2, Philip S. Low4,5, Lindsey M. Fourez1, Ashleigh M. Cournoyer1 and Deborah W. Knapp1,5
1Department of Veterinary Clinical Sciences, Purdue University, West Lafayette, IN, USA
2Department of Comparative Pathobiology, Purdue University, West Lafayette, IN, USA
3Endocyte Inc., West Lafayette, IN, USA
4Department of Chemistry, Purdue University, West Lafayette, IN, USA
5Purdue University Center for Cancer Research, West Lafayette, IN, USA
Deborah W. Knapp, email: [email protected]
Keywords: animal model; bladder cancer; canine, clinical trial; targeted chemotherapy
Received: August 02, 2018 Accepted: November 26, 2018 Published: December 11, 2018
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.
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