Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®) in dogs: a phase I dose‐finding study

Abstract

Combining drugs with known single-agent activity that lack overlapping dose-limiting toxicities and exert antitumor activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed on the combination in dogs with mast cell tumors. The dose-limiting toxicity for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg/m2 every other week) concurrent with toceranib (3.25 mg/kg PO, every other day). This represents greater than a 50% reduction in dose-intensity for vinblastine (compared to single-agent use) and as such does not support this combination based on current drug combination paradigms. While a strict adherence to dose paradigms speaks against the combination, evidence of significant activity (71% objective response) and enhanced myelosuppression suggest additive or synergistic activity. A prospective randomized evaluation comparing this combination with standard single-agent treatments would seem prudent to interrogate this potential.

A pilot study of toceranib/vinblastine therapy for canine transitional cell carcinoma

“…Dogs were administered vinblastine every 2 weeks and toceranib on a Monday/Wednesday/Friday basis. The dose for vinblastine was 1.6 mg/m 2 given IV every 2 weeks based on a previously published study combining toceranib with vinblastine [37]. The starting dose for toceranib was 2.75 mg/kg with dose de-escalation down to 2.25 mg/kg permitted in the face of adverse events.…”

Pulse‐Administered Toceranib Phosphate Plus Lomustine for Treatment of Unresectable Mast Cell Tumors in Dogs

“…In addition, several studies have identified potentiation of the efficacy of paclitaxel, doxorubicin, and vincristine by the TKI imatinib in human preclinical models of KIT‐positive melanoma and Ewing's sarcoma, presumably owing to down‐regulation of important antiapoptotic pathways. A recent phase I study evaluating the safety of the combination vinblastine and TOC in dogs reported the necessity for substantial dose reductions of vinblastine in this combination therapy to prevent frequent and severe neutropenia . Together, these data suggest that combination therapies with TKIs may improve efficacy over single‐agent treatments alone.…”

The radiosensitizing effect of the aurora kinase inhibitors, ENMD‐2076, on canine mast cell tumours in vitro

“…Clinically, it might be a challenge to find the optimum dose of small molecule drugs because patients exhibit a variation of tumour sensitivity to the drug relative to normal tissues. Toceranib phosphate (Palladia, SU11654) has been approved for the treatment of canine mast cell tumours, and it is beginning to be widely used to treat a variety of tumours in dogs . The current recommended dose of toceranib phosphate is 3.25 mg kg −1 , every other day (three times/week), and with this dosage, optimum plasma concentrations of 40 ng mL −1 were attained .…”

“…The most commonly used chemotherapy drugs for mast cell tumours are CCNU and vinblastine . Targeted therapy also has been attempted for canine mast cell tumours because this tumour expresses c‐kit and contains a mutated constitutively activated form . The c‐kit receptor is a one of a family of tyrosine kinase receptors that regulate cell signal transduction, cell survival, cell proliferation, and differentiation .…”