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

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

doi:10.18632/oncotarget.26455

Nicholas M Szigetvari, Lindsey M Fourez + Show 13 more

Open Access

https://doi.org/10.18632/oncotarget.26455

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Abstract

PurposeThe 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 DesignA 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.ResultsThe 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.ConclusionEC0531 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.

Highlights

Targeted chemotherapy allows the selective delivery of a cytotoxic payload to tumor cells while limiting the exposure and toxicity to normal tissues
The maximum tolerated dose (MTD) of EC0531 was 0.26 mg/kg every two weeks, with grade 3-4 neutropenia and gastrointestinal toxicity observed at higher doses
Canine neutrophils were found to express folate receptor (FR), which contributes to the neutropenia at higher doses of EC0531 in dogs

Summary

Introduction

Targeted chemotherapy allows the selective delivery of a cytotoxic payload to tumor cells while limiting the exposure and toxicity to normal tissues. The resulting preferential accumulation of drug in the tumor can increase drug activity with lower systemic exposure, i.e. increasing the therapeutic index. In this way, targeted www.oncotarget.com delivery of cytotoxic drugs allows reconsideration of compounds previously deemed clinically irrelevant due to very low therapeutic index. Non-reduced folate is utilized by tumor cells, and typically transported via high-affinity folate receptors (FRs), mainly FRα in solid tumors [4]. Folate-targeted drugs are expected to largely spare normal tissues by preferentially binding to tumor cells of select cancer types

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