title: 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 (DLT) and exert antitumour activity through different mechanisms could improve clinical outcome. As toceranib and vinblastine meet these requisites, a phase I trial was performed in combination in dogs with mast cell tumours. The DLT for the simultaneous combination was neutropenia and the maximally tolerated dose was vinblastine (1.6 mg m(-2)  every other week) concurrent with toceranib (3.25 mg kg(-1)  PO, every other day). This represents greater than a 50% reduction in dose intensity for vinblastine (compared with single-agent use) and as such does not support this combination based on current drug combination paradigms. Although 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.
authors.affiliation: School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI, USA.
authors.forename: C
authors.initials: C
authors.lastname: Robat
authors.forename: C
authors.initials: C
authors.lastname: London
authors.forename: L
authors.initials: L
authors.lastname: Bunting
authors.forename: L
authors.initials: L
authors.lastname: McCartan
authors.forename: N
authors.initials: N
authors.lastname: Stingle
authors.forename: K
authors.initials: K
authors.lastname: Selting
authors.forename: I
authors.initials: I
authors.lastname: Kurzman
authors.forename: D M
authors.initials: DM
authors.lastname: Vail
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D004283:Dog Diseases / Q000188:drug therapy*; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D007211:Indoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D008415:Mastocytosis / Q000188:drug therapy / Q000662:veterinary*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000662:veterinary*; D014747:Vinblastine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D007211:Indoles; D011758:Pyrroles; C464577:toceranib phosphate; D014747:Vinblastine; D011505:Protein-Tyrosine Kinases