| Reference | 1. Vet Comp Oncol. 2012 Sep;10(3):174-83. doi: 10.1111/j.1476-5829.2011.00261.x.
Epub 2011 Jan 31.
<br>
Safety evaluation of combination vinblastine and toceranib phosphate (Palladia®)
in dogs: a phase I dose-finding study.
<br>
Robat C(1), London C, Bunting L, McCartan L, Stingle N, Selting K, Kurzman I,
Vail DM.
<br>
Author information: <br>
(1)School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI,
USA.
<br>
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.
<br><br>
2. Vet Radiol Ultrasound. 2012 May-Jun;53(3):348-57. doi:
10.1111/j.1740-8261.2012.01925.x. Epub 2012 Feb 24.
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Preliminary evaluation of serial (18) FDG-PET/CT to assess response to toceranib
phosphate therapy in canine cancer.
<br>
Leblanc AK(1), Miller AN, Galyon GD, Moyers TD, Long MJ, Stuckey AC, Wall JS,
Morandi F.
<br>
Author information: <br>
(1)Department of Small Animal Clinical Sciences, University of Tennessee College
of Veterinary Medicine, Knoxville, TN 37996, USA. [email protected]
<br>
Palladia(TM) (toceranib phosphate-Pfizer Animal Health) is a novel orally
administered receptor tyrosine kinase inhibitor (TKI) approved for treatment of
canine mast cell tumors. Receptor tyrosine kinase dysregulation leads to tumor
growth, progression, and metastasis. Toceranib’s targets include vascular
endothelial growth factor receptor (VEGFR-2/Flk-1/KDR), platelet-derived growth
factor receptor, and kit. Positron Emission Tomography/Computed Tomography
(PET/CT) is used commonly to diagnose, prognosticate, and monitor response to
antineoplastic therapy in human patients. In this study, serial PET/CT imaging
with (18) F-fluorodeoxyglucose ((18) FDG) was used to assess response to
toceranib therapy in dogs with measurable solid malignancies. Six tumor-bearing
dogs underwent tumor assessment using both standard RECIST criteria and PET/CT
prior to and at a median of 5 weeks postinitiation of toceranib treatment.
Toceranib was prescribed initially at a target dose 3.25 mg/kg PO q48 h, with
subsequent modifications based on observed toxicity. Treatment was continued in
patients achieving stable disease with acceptable drug tolerance. One dog was
maintained on drug despite dose modification due to toxicity; measurable clinical
and image-based responses were seen after 10 weeks of therapy. All others had
stable or progressive disease based on clinical restaging and PET/CT at first
recheck. . Due to discordance with anatomic and metabolic imaging, further
studies are needed to investigate the role of molecular imaging in assessment of
drug response and identify other potential molecular targets of toceranib.
<br><br>
3. J Vet Pharmacol Ther. 2010 Apr;33(2):154-61. doi:
10.1111/j.1365-2885.2009.01120.x.
<br>
Distribution, metabolism, and excretion of toceranib phosphate (Palladia,
SU11654), a novel tyrosine kinase inhibitor, in dogs.
<br>
Yancey MF(1), Merritt DA, White JA, Marsh SA, Locuson CW.
<br>
Author information: <br>
(1)Pfizer Animal Health, Kalamazoo, MI 49001, USA. [email protected]
<br>
Toceranib phosphate (Palladia, SU11654), a multireceptor tyrosine kinase
inhibitor with anti-tumor and anti-angiogenic activity, has been developed for
the treatment of mast cell tumors in dogs. An overview of the distribution,
metabolism, and excretion of toceranib phosphate in dogs is presented. When
[(14)C]-toceranib was orally administered to dogs, the majority of the
radioactivity (92%) was excreted in feces and only a small portion (7%) was
excreted in urine. Seven days after a single 3.25 mg/kg oral dose, radioactivity
was the highest in bile and liver, with measurable concentrations in lymph nodes,
colon, adrenals, bone marrow, kidneys, lungs, spleen, pancreas, and skin. Plasma
protein binding of toceranib in fresh plasma ranged from 90.8% to 92.8% at
concentrations between 20 ng/mL and 500 ng/mL and was independent of
concentration. Microsomal and hepatocyte incubations resulted in the formation of
a single metabolite. Spectrometric analysis of the metabolite was consistent with
the formation of an alicyclic N-oxide of toceranib. The combination of the high
rate of fecal excretion and the long elimination half-life of toceranib indicate
enterohepatic recirculation of the parent compound and/or the N-oxide metabolite.
<br><br>
4. Clin Cancer Res. 2009 Jun 1;15(11):3856-65. doi: 10.1158/1078-0432.CCR-08-1860.
Epub 2009 May 26.
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Multi-center, placebo-controlled, double-blind, randomized study of oral
toceranib phosphate (SU11654), a receptor tyrosine kinase inhibitor, for the
treatment of dogs with recurrent (either local or distant) mast cell tumor
following surgical excision.
<br>
London CA(1), Malpas PB, Wood-Follis SL, Boucher JF, Rusk AW, Rosenberg MP, Henry
CJ, Mitchener KL, Klein MK, Hintermeister JG, Bergman PJ, Couto GC, Mauldin GN,
Michels GM.
<br>
Author information: <br>
(1)School of Veterinary Medicine, University of California, Davis, California,
USA.
<br>
Comment in<br>
Clin Cancer Res. 2009 Jun 1;15(11):3645-7.
<br>
PURPOSE: The purpose of this study was to determine the objective response rate
(ORR) following treatment of canine mast cell tumors (MCT) with toceranib
phosphate (Palladia, SU11654), a kinase inhibitor with both antitumor and
antiangiogenic activity through inhibition of KIT, vascular endothelial growth
factor receptor 2, and PDGFRbeta. Secondary objectives were to determine
biological response rate, time to tumor progression, duration of objective
response, health-related quality of life, and safety of Palladia.
EXPERIMENTAL DESIGN: Dogs were randomized to receive oral Palladia 3.25 mg/kg or
placebo every other day for 6 weeks in the blinded phase. Thereafter, eligible
dogs received open-label Palladia.<br>
RESULTS: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2% (7
complete response, 25 partial response) versus 7.9% (5 partial response) in
placebo-treated dogs (n = 63; P = 0.0004). Of 58 dogs that received Palladia
following placebo-escape, 41.4% (8 complete response, 16 partial response)
experienced objective response. The ORR for all 145 dogs receiving Palladia was
42.8% (21 complete response, 41 partial response); among the 62 responders, the
median duration of objective response and time to tumor progression was 12.0
weeks and 18.1 weeks, respectively. Palladia-treated responders scored higher on
health-related quality of life versus Palladia-treated nonresponders (P = 0.030).
There was no significant difference in the number of dogs with grade 3/4 (of 4)
adverse events; adverse events were generally manageable with dose modification
and/or supportive care.<br>
CONCLUSIONS: Palladia has biological activity against canine MCTs and can be
administered on a continuous schedule without need for routine planned treatment
breaks. This clinical trial further shows that spontaneous tumors in dogs are
good models to evaluate therapeutic index of targeted therapeutics in a clinical
setting.
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