Como usar los Inhibidores Yrosin quinasa y la

Como usar los Inhibidores Yrosin quinasa y la

Como usar los Inhibidores 1rosin quinasa y la quimioterapia metronomica Luis Feo Bernabe ECVIM-­‐CA Resident (Internal Medicine) Ars Veterinaria Hospital Barcelona Introducción Avances importantes en el campo de la biología molecular oncológica han permi1do iden1ficar importantes anormalidades en proteínas que regulan: –  Señales de transducción –  Supervivencia celular –  Proliferación celular Introducción •  Este 1po de anormalidades en muchos casos están relacionadas con proteínas llamadas "rosin quinasas, que actúan fosforilando otras proteínas en la célula, que regulan numerosos procesos celulares. •  Estas 1rosin quinasas pueden ser expresadas en células tumorales, y también en células normales. Tirosin quinasas •  En condiciones normales (células NO tumorales): –  Factores de crecimiento (GF) específicos ac1van las 1rosin quinasas, promoviendo la división y proliferación celular. 142 Chapter 5: Growth Factors, Receptors, and Cancer
–  Sin estos GF, los receptores de 1rosin quinasa se man1enen INACTIVOS. (A)
cancer cell
normal cell
GF
or
mutations
affecting
structure
ligand
binding
plasma
membrane
tyrosine
kinase
domain
liganddependent
firing
overexpression
normal
receptor
ligand-independent
firing
Tirosin quinasas 142
Chapter 5: Growth Factors, Receptors, and Cancer
(A)
•  Tumores: normal cell
–  Algunas células tumorales GF
1enen mutaciones o sobre-­‐
ligand
expresión de receptores de binding
1rosin quinasa –  Estos receptores pueden estar tyrosine
kinase
ac1vados sin la presencia de un domain
factor de crecimiento ligand- (GF) normal
dependent
receptor
especifico firing
–  Las células pueden encontrarse en constante división y proliferación. (B)
cancer cell
(C)
or
mutations
affecting
structure
plasma
membrane
ligand-independent
firing
overexpression
normal paracrine signaling
TGF-α
n
Tyrosine kinases •  Ejemplos de receptores de 1rosin quinasa: –  Kit, Met, Axl y EGFR –  Todos ellos se encuentran desregulados algunos 1pos de tumores. •  Además de regular funciones normales en las células, algunos receptores de Tirosin quinasa son importantes promoviendo el crecimiento de vasos sanguineos tumorales (angiogenesis tumoral). –  VEGFR, PDGFR, FGFR y Tie1/2. Inhibidores de 1rosin quinasa (TKI) •  Una gran variedad de “small molecule inhibitors” que 1enen como obje1vo especifico los 1rosin quinasas (TKI) han sido aprobados recientemente para el tratamiento del cáncer en humanos, y más recientemente también para el tratamiento del cáncer en perros. ! Dog ! Protein ! Kinase ! Inhibitor
several small molecule inhibitors that have been approved by the FDA to treat human
cancers.
KEY POINTS
Table 1
Mutations identified in various tumor types
Tumor Type
Human cutaneous melanoma
Hematopoietic neoplasms, lung cancer,
colon cancer, others
Canine mast cell tumor (30% high grade)
! Recent advances in molecular biology have permitted the identi
tion of specific abnormalities regarding cell signaling and functi
! Proteins that are found to be dysregulated in cancer cells can se
Mutationstherapeutic
Identified intervention.
Point mutation
BRAFthere
(60%are
of several
human approaches to block proteins th
! Although
tumors) dysfunction, the one most commonly used involves a class of
KIT mutations
molecule inhibitors.
! Such RAS
inhibitors work by disrupting critical pathways/processes
Point mutation
disrupting their ability to grow and survive.
There are
now 2 small molecule inhibitors approved/conditionall
Internal !tandem
duplications
erinary
medicine,
toceranib
(Palladia)
and masitinib (Kinavet), an
juxtamembrane domain KIT
(exon 11)
or
will
be
approved
in
the
future.
extracellular ligand binding domain
(exon 8)
GIST (50%–80% human tumors, some dog
tumors)
Deletions juxtamembrane domain KIT
AML, acute myelogenous leukemia
Lung carcinomas
FLT-3 internal tandem duplications
INTRODUCTION
EGFR point mutations
Various carcinomas
PI3Ka With recent advances in genetics and molecular techn
Breast & ovarian carcinomas
contribute
to dysregulation of cancer cells are now being ide
HER2/neu
overexpression
Glioblastoma & squamous cell carcinoma
These proteins play essential roles in regulating cell surviva
and migration, among other processes. Although many of
abnormal in cancer cells are kinases that phosphorylate
BCR-ABL fusion protein
and are integral components of cell signaling, others are tran
TEL-PDGFRb
that block apoptosis (cell death), heat shock proteins, a
EML4-ALK
export, among others. Given their known role in driving the d
sion of tumors, substantial effort has been directed at block
Myc-Igh
proteins.
TGFb and
EGFR Monoclonal antibodies are primarily directed at c
Breast & colorectal cancer
IGF (insulinlike growth factor) and IGF1R
Melanoma & glioblastoma
VEGF and VEGFR
Canine OSA
Biosciences, The Ohio State University, 454 VMAB, 1925
MET andVeterinary
HGF
Canine hemangiosarcoma
KIT and E-mail
SCF address: [email protected]
Lung, bladder, cervical, ovarian, renal,
pancreatic
CML (90% of patients)
Leukemia
Non-small cell lung cancer
Burkitt lymphoma
Data from Refs.8,15,20–54
EGFR (up to 60 gene copies/cell)
43210, USA
Vet Clin Small Anim 44 (2014) 893–908
i n Ve t e r i n a r y O n c o l o g y
Practice
Table 2
Small molecule inhibitors currently approved by the FDA
Agent
Targets
FDA-Approved Indications
Axitinib (Inlyta)
KIT, PDGFRb, VEGFR1/2/3
Renal cell carcinoma
Bortezomib (Velcade)
Proteasome
Bosutinib (Bosulif)
ABL
CherylMultiple
A. London,
DVM, PhD
myeloma
Mantle cell lymphoma
CML (Philadelphia chromosome
positive, Ph1)
KEYWORDS
Cabozantinib (Cometriq)
FLT3, KIT, MET, RET, VEGFR2
Crizotinib (Xalkori)
ALK, MET
Dasatinib (Sprycel)
ABL
Erlotinib (Tarceva)
EGFR (HER1/ERBB1)
Everolimus (Afinitor)
mTOR
Medullary thyroid cancer
! Dog ! Protein ! Kinase ! Inhibitor
Non-small cell lung cancer (ALK
fusion)
KEY
CML (Ph1)
POINTS
Acute
lymphoblastic leukemia
(ALL, Ph1)
! Recent
advances
molecular
Non-small
cell in
lung
cancer biology have permitted the identification and character
tionPancreatic
of specificcancer
abnormalities regarding cell signaling and function in cancer cells.
Pancreatic
neuroendocrine
! Proteins
that are
found to be dysregulated in cancer cells can serve as relevant targets
tumor intervention.
therapeutic
Renal cell carcinoma
! Although
there aregiant
several
Subependymal
cell approaches to block proteins that contribute to cell
dysfunction,
the one
most commonly
used involves a class of therapeutics called sm
astrocytoma
associated
with
molecule
inhibitors.
tuberous
sclerosis
Gefitinib (Iressa)
EGFR (HER1/ERBB1)
Imatinib (Gleevec)
KIT, PDGFR, ABL
Non-small
cell
lung
! Such
inhibitors
work
bycancer
disrupting critical pathways/processes in cancer cells, ther
GIST
disrupting
their ability to grow and survive.
Dermatofibrosarcoma
! Thereprotuberans
are now 2 small molecule inhibitors approved/conditionally approved for use in
erinary
medicine,
toceranib (Palladia) and masitinib (Kinavet), and it is likely several m
Multiple
hematologic
will be
approved in including
the future.Ph1
malignancies
ALL and CML
Lapatinib (Tykerb)
HER2 (ERBB2/neu), EGFR
(HER1/ERBB1)
Breast cancer (HER21)
Nilotinib (Tasigna)
ABL
CML (Ph1)
Pazopanib (Votrient)
VEGFR, PDGFR, KIT
Renal cell carcinoma
Ponatinib (Iclusig)
ABL, FGFR1–3, FLT3, VEGFR2 INTRODUCTION
CML and AML (Ph1)
Regorafenib (Stivarga)
KIT, PDGFRb, RAF, RET,
VEGFR1/2/3
Romidepsin (Istodax)
HDAC
Ruxolitinib (Jakafi)
JAK1/2
Sorafenib (Nexavar)
VEGFR, PDGFR, KIT, RAF
Sunitinib (Sutent)
VEGFR, PDGFR, KIT, RET
Temsirolimus (Torisel)
mTOR
Vandetanib (Caprelsa)
EGFR (HER1/ERBB1), RET, VEGFR2
Vemurafenib (Zelboraf)
BRAF
Vorinostat (Zolinza)
HDAC
Colorectal cancer
With GIST
recent advances in genetics and molecular techniques, key protein
contribute
to dysregulation
of cancer cells are now being identified and characte
Cutaneous
T-cell lymphoma
TheseMyelofibrosis
proteins play essential roles in regulating cell survival, growth, different
Hepatocellular
carcinoma
and migration,
among
other processes. Although many of the proteins found
Renalincell
carcinoma
abnormal
cancer
cells are kinases that phosphorylate other proteins in th
GIST
and are
integral components of cell signaling, others are transcription factors, pr
Dermatofibrosarcoma
that block
apoptosis (cell death), heat shock proteins, and regulators of n
protuberans
Hematologic
malignancies
export,
among others.
Given their known role in driving the development and pr
including Ph1 ALL and CML
sion ofPancreatic
tumors, substantial
effort has been directed at blocking the function of
neuroendocrine
proteins.tumor
Monoclonal antibodies are primarily directed at cell surface protein
Renal cell carcinoma
Renal cell carcinoma
Medullary thyroid cancer
Veterinary
Biosciences,
Ohio State University, 454 VMAB, 1925 Coffey Road, Columbu
Melanoma
(BRAFThe
V600
43210, USA
mutation)
E-mailCutaneous
address: [email protected]
T-cell lymphoma
Vet Clin Small Anim 44 (2014) 893–908
TOPICAL REVIEW
Tyrosine Kinase Inhibitors in Veterinary Medicine
Cheryl A. London, DVM, PhD, Dipl. ACVIM (Oncology)
Volume 24, Number 3, August 2009
Volume 24, Number 3, August 2009
Substantial progress in the field of molecular biology has permitted the identification of key abnormalities in
cancer cells involving cell proteins that regulate signal transduction, cell survival, and cell proliferation. Such
abnormalities often involve a class of proteins called tyrosine kinases that act to phosphorylate other proteins
in the cell, tightly regulating a variety of cellular processes. A variety of small molecule inhibitors that target
specific tyrosine kinases (known as tyrosine kinase inhibitors [TKIs]) have now been approved for the treatment
of human cancer, and it is likely many more will become available in the near future. In some instances these
inhibitors have exhibited significant clinical efficacy, and it is likely their biologic activity will be further
enhanced as combination regimens with standard treatment modalities are explored. Although TKIs have been
used extensively in humans, their application to cancers in dogs and cats is relatively recent. The TKIs Palladia
(toceranib), Kinavet (masitinib), and Gleevec (imatinib) have been successfully used in dogs, and more recently
Gleevec in cats. This article will review the biology of tyrosine kinase dysfunction in human and animal cancers,
and the application of specific TKIs to veterinary cancer patients.
© 2009 Elsevier Inc. All rights reserved.
Table 1. Tyrosine Kinase Inhibitors in Dogs and Cats
TKI
Targets
Tumor Types
S
Palladia (Toceranib) Kit, VEGFR,
MCTs, sarcomas, carcinomas, D
PDGFR, Flt-3
melanoma, myeloma
Keywords: cancer, inhibitor, kinase, target, therapy
Kinavet (Masitinib) Kit, (PDGFR)
MCTs
D
Gleevec (Imatinib)
Kit, Abl, PDGFR MCTs, sarcomas
D
T
Abbreviations: TKI, tyrosine kinase inhibitors; VEGFR, vascular endothelial growth factor re
yrosine kinases are proteins that phosphorylate other
proteins on tyrosine residues. They are key players in
normal cell signal transduction, acting to tightly regulate cell
growth and differentiation. Tyrosine kinases bind adenosine
triphosphate (ATP) and use this to add phosphate groups to
key residues on themselves (termed “autophosphorylation”)
and on other molecules, resulting in the generation of intracellular signaling, ultimately leading to alterations in gene
transcription that impact cell proliferation and survival (reviewed in1). This process is usually initiated in response to
external signals generated from growth factors or other stimuli that begin the cascade of tyrosine phosphorylation. Protein kinases may be located at the cell surface, in the cytoplasm, or in the nucleus.
Those tyrosine kinases expressed on the cell surface often
ulating normal cell function, certain
tyrosine
kinase receptors
Figure
1. Tyrosine
kinase dysfunction in cell signaling. Rec
The growth
are important in promoting themonomers.
growth of tumor
blood factor
ves- (ligand) for these receptors wi
autophosphorylation
downstream signaling and regulate
sels, also known as tumor angiogenesis.
These include and
vascumutation,(VEGFR),
the growthplateletfactor is no longer needed for receptor a
lar endothelial growth factor receptor
resulting
in unregulated
downstream signaling, thereb
derived growth factor receptor rylated,
(PDGFR),
fibroblast
growth
factor receptor (FGFR), and Tie1/2.8-11 VEGFRs are expressed on vascular endothelium, and VEGF-VEGFR interactions are important for endothelial
migration
and
proliferThere
are now
several
well-characterized instances of tyexpressed
in
stroma
ation.8 PDGF and PDGFR arerosine
kinase dysfunctionand
in human cancers (Fig 1). Perhaps
10,11 Lastly,
pericytes, and PDGF can promote
angiogenesis.
the most
studied example
is that of the Bcr-Abl fusion protein
fibroblast growth factor is synergistic
with
VEGF to induce
found in
approximately
90% of human patients with chronic
myelogenous
(CML).
the expression of VEGF, thereby
enhancing leukemia
the process
of 15,16 The generation of the fusion
protein
occurs through
the
cytoplasmic
kinases,chromosomal translocation and
angiogenesis.10 With respect to
inducesthey
constitutive
activation of the cytoplasmic tyrosine
many are not tyrosine kinases; rather,
are serine-threokinase
Given the high
nine kinases that work similarly
but Abl.
phosphorylate
otherprevalence of this specific mutationCytoplasmic
in CML, it tyrosine
represents
proteins on serine and threonine.
ki-a unique target for therapeutic
MCT, mast cell tumor; EOD, every other day; SID, once a day.
•  Es muy posible que en un futuro muy próximo haya muchos más… cancers in dogs and cats, and 2 TKIs (Palladia, Pfizer; blood concen
treat
and Kinavet, AB Science, Short Hills, NJ, USA) have undergone registrational studies in dogs with MCTs. These studies
assessed in tu
phosphorylat
Inhibidores de 1rosin quinasa Phase I Dose-Escalating Study of SU11654, a Small Molecule
Receptor Tyrosine Kinase Inhibitor, in Dogs with
Spontaneous Malignancies ,
Cheryl A. London, Alison L. Hannah, Regina Zadovoskaya, et al.
Clin Cancer Res 2003;9:2755-2768.
•  57 perros con varios 1pos de tumores: carcinomas, sarcomas, MCTs, melanomas, ymphomas, etc. Access the lmost
recent version of
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•  La primera evaluación de TKI en veterinaria (Ensayo clinico fase 1) Cited Articles This article cites 74 articles, 21 of which you can access for free at:
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Inhibidores de 1rosin quinasa 2762 Clinical
Trial of a Kinase Inhibitor
in Dogof
Tumors
Phase
I Dose-Escalating
Study
SU11654, a Small Molecule
Receptor Tyrosine Kinase Inhibitor, in Dogs with
Spontaneous Malignancies ,
Cheryl A. London, Alison L. Hannah, Regina Zadovoskaya, et al.
3, and dose (either 2.5 o
lymph node involvement
Objective
lihood of response to th
response
SD
Access
the
most
recent
version
of
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at:
Updated Version
Number
(tumor
" 10 Biological
respectively). Interestingl
http://clincancerres.aacrjournals.org/content/9/7/2755
Tumor type
enrolled shrinkage) weeks activity
and lymph node involve
MCT
22
11
2
13 (59%)
whose disease had not yet
ITD positive
11
9
1
10 (91%)
complete or partial respo
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ITD negative
11 21 of which
2 you can1 access3for
(27%)
http://clincancerres.aacrjournals.org/content/9/7/2755.full.html#ref-list-1
wild-type Kit and lymph
Lymphoma
6
0
1
1 (17%)
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article
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Mammary carcinoma
5
2
2
5 (80%)
response
(Table 5).
http://clincancerres.aacrjournals.org/content/9/7/2755.full.html#related-urls
Soft tissue sarcoma
4
2
0
2 (50%)
The effect of Kit ITD
Bladder carcinoma
4
0
3
3 (75%)
of dogs with MCTs wa
Malignant melanoma
3
0
2
2 (67%)
3
0
0 article0or(0%)
differences in the time to
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Osteosarcoma
3
0
2
2 (67%)
dogs treated with SU1165
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Multiple myeloma
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0
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cellrequest
carcinoma
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Lung carcinoma
1
0
1
1 (100%)
versus 15.4 weeks), but th
Table 4 Response rate by tumor type
Clin Cancer Res 2003;9:2755-2768.
Inhibidores de 1rosin quinasa Phase I Dose-Escalating Study of SU11654, a Small Molecule
Receptor Tyrosine Kinase Inhibitor, in Dogs with
Spontaneous Malignancies ,
Cheryl A. London, Alison L. Hannah, Regina Zadovoskaya, et al.
Clin Cancer Res 2003;9:2755-2768.
•  La respuesta mas marcada se produjo en MCTS, 10/11 perros con Access
most recent version
this article at:
Updated
Version
mutaciones del thereceptor KIT ofmostraron respuestas completas/
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parciales. •  La media de progresión en perros con MCT que tenian ITD fue de 21 This article cites 74 articles, 21 of which you can access for free at:
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but they can occur as primary tumors in t
or spleen (1). Canine MCTs possess a wide
DOI:10.1158/1078-0432.CCR-08-1860
Inhibidores de 1rosin quinasa Cancer Therapy: Clinical
Authors' Affiliations: 1 School of Veterinary Me
California, Davis, California; 2Pfizer Animal Health,
3
Animal Clinical Investigation at Friendship Hospital
ton, District of Columbia; 4Veterinary Cancer Refer
fornia; 5 Department of Veterinary Medicine and S
Missouri, Columbia, Missouri; 6Angel Care Canc
Memphis, Tennessee; 7Southwest Veterinary Onco
8
Veterinary Specialty Center, Buffalo Grove, Illinois
ter, New York, New York; 10College of Veterinary Me
University, Columbus, Ohio; and 11School of Veterina
State University, Baton Rouge, Louisiana
Received 7/10/08; revised 12/4/08; accepted 12/16/08; publ
The costs of publication of this article were de
payment of page charges. This article must theref
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
June 1, 200
or Distant) Mast Cell Tumor Following Surgical Excision Clin Cancer Res 2009;15(11)
Downloaded from
Copyright ©
• 
Cheryl A. London,1 Phyllis B. Malpas,2 Stacey L. Wood-Follis,2 Joseph F. Boucher,2
Anthony W. Rusk,3 Mona P. Rosenberg,4 Carolyn J. Henry,5 Kathy L. Mitchener,6
Mary K. Klein,7 John G. Hintermeister,8 Philip J. Bergman,9 Guillermo C. Couto,10
2
Perros con l11
a and
mutación KIT respondieron mejor al tratamiento con Palladia Guy
N. Mauldin,
Gina M. Michels
que aquellos que no tenían la mutación. Abstract Purpose: The purpose of this study was to determine the objective response rate (ORR)
•  Los pacientes con treatment
MCT gofrado recidivaron antes que Mphosphate
CT grado II. following
canineIII mast
cell tumors (MCT)
with toceranib
(Palladia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity through
inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ. Secondary
objectives were to determine biological response rate, time to tumor progression, dura•  Este arRculo confirma que PALLADIA "ene ac"vidad biológica tion 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 placontra MCT y sugiere que la administración de Palladia cebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs received open-label Palladia.
posiblemente aumente la supervivencia 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
but they can occur as primary tumors in t
or spleen (1). Canine MCTs possess a wide
DOI:10.1158/1078-0432.CCR-08-1860
Inhibidores de 1rosin quinasa Cancer Therapy: Clinical
Authors' Affiliations: 1 School of Veterinary Me
California, Davis, California; 2Pfizer Animal Health,
3
Animal Clinical Investigation at Friendship Hospital
ton, District of Columbia; 4Veterinary Cancer Refer
fornia; 5 Department of Veterinary Medicine and S
Missouri, Columbia, Missouri; 6Angel Care Canc
Memphis, Tennessee; 7Southwest Veterinary Onco
8
Veterinary Specialty Center, Buffalo Grove, Illinois
ter, New York, New York; 10College of Veterinary Me
University, Columbus, Ohio; and 11School of Veterina
State University, Baton Rouge, Louisiana
Received 7/10/08; revised 12/4/08; accepted 12/16/08; publ
The costs of publication of this article were de
payment of page charges. This article must theref
Multi-center, Placebo-controlled, Double-blind, Randomized Study
of Oral Toceranib Phosphate (SU11654), a Receptor Tyrosine Kinase
Inhibitor, for the Treatment of Dogs withDOI:10.1158/1078-0432.CCR-08-1860
Recurrent (Either Local
June 1, 200
or Distant) Mast Cell Tumor Following Surgical Excision Clin Cancer Res 2009;15(11)
Downloaded from
Palladia
Treatm
Copyright ©
Cheryl A. London,1 Phyllis B. Malpas,2 Stacey L. Wood-Follis,2 Joseph F. Boucher,2
Anthony W. Rusk,3 Mona P. Rosenberg,4 Carolyn J. Henry,5 Kathy L. Mitchener,6
Mary K. Klein,7 John G. Hintermeister,8 Philip J. Bergman,9 Guillermo C. Couto,10 Safety. Of 87 dogs treated w
with placebo in the blinded ph
Guy N. Mauldin,11 and Gina M. Michels2
Abstract
respectively, entered the open
tion of Palladia treatment for t
one dose of Palladia in the co
Purpose: The purpose of this study was to determine the objective response rate (ORR)
phases was 68 days (mean, 14
following treatment of canine mast cell tumors (MCT) with toceranib phosphate (Pallaladia through
treatment continued in 24
dia, SU11654), a kinase inhibitor with both antitumor and antiangiogenic activity
months.
The most common (
inhibition of KIT, vascular endothelial growth factor receptor 2, and PDGFRβ.
Secondary
adverse duraevents in these 145 d
objectives were to determine biological response rate, time to tumor progression,
tion of objective response, health-related quality of life, and safety of Palladia.
Among the 21 dogs with comp
Experimental Design: Dogs were randomized to receive oral Palladia 3.25 verse
mg/kgevents
or pla-that were possibly
cebo every other day for 6 weeks in the blinded phase. Thereafter, eligible dogs reacute pancreatitis 56 days after
ceived open-label Palladia.
achieving
complete response. T
Results: The blinded phase ORR in Palladia-treated dogs (n = 86) was 37.2%
(7 comperforation 221 days after init
plete response, 25 partial response) versus 7.9% (5 partial response) in placebo-treated
achieving complete response.
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.
Thein either case.
at necropsy
ORR for all 145 dogs receiving Palladia was 42.8% (21 complete response,Concomitant
41 partial treatments and
Fig. 1. Time to tumor progression in placebo-treated and Palladia-treated
Inhibidores de 1rosin quinasa Original Article
DOI: 10.1111/j.1476-5829.2011.00275.x
Preliminary evidence for biologic activity
of toceranib phosphate (Palladia®) in solid
tumours∗
• 
C. London1 , T. Mathie1 , N. Stingle1 , C. Clifford2 , S. Haney2 , M. K. Klein3 ,
L. Beaver3 , K. Vickery3 , D. M. Vail4 , B. Hershey5 , S. Ettinger6 , A. Vaughan7 ,
F. Alvarez8 , L. Hillman9 , M. Kiselow10 , D. Thamm11 , M. L. Higginbotham12 ,
15
16
M. Gauthier13 ,(E.
Krick14 , B. Phillips
, T.eLaDue
, P. Jones17 ,tJ.umores: Bryan18 , V. Gill19 ,
Toceranib Palladia) s
e u
só n d
iferentes A. Novasad20 , L. Fulton21 , J. Carreras22 , C. McNeill23 , C. Henry24 and S. Gillings25
ü 
Apocrine gland College
anal ofsVeterinary
ac adenocarcinoma (AGASACA) Department
of Veterinary Biosciences,
Medicine, The Ohio State University,
Columbus,
OH, USA; Red Bank Veterinary Hospital, Tinton Falls, NJ, USA; Southern Arizona Veterinary Specialty and
ü  Metasta1c oUSA;
steosarcoma (OSA) Emergency
Center, Tuscon, AZ,
Department of Medical
Sciences, School of Veterinary Medicine,
University of Wisconsin, Madison, Madison, WI, USA; Integrative Veterinary Center, Phoenix, AZ, USA;
ü 
Thyroid carcinoma Animal
Specialty Center,
Yonkers, NY, USA; Las Vegas Veterinary Referral Center, Las Vegas, NV, USA;
Coral Springs Animal Hospital, Coral Springs, FL, USA; MedVet Memphis, Memphis, TN, USA;
ü 
Head and neck carcinoma of Clinical Sciences, College of
Veterinary
Medical
Specialists,
San Mateo,
CA, USA; Department
Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA;
ü 
Nasal carcinoma. Veterinary Medicine, Kansas State University, Manhattan, KS,
Department
of Clinical
Sciences, College of
1
2
3
4
5
6
7
8
10
9
11
12
USA; 13 Mississauga Oakville Veterinary Emergency Hospital, Oakville, ON, Canada; 14 Department of Clinical
Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 15 Veterinary
Specialty Hospital of San Diego, San Diego, CA, USA; 16 Southeast Veterinary Oncology, Orange Park, FL,
USA; 17 Capital Area Veterinary Specialists, Austin, TX, USA; 18 Department of Veterinary Clinical Sciences,
College of Veterinary Medicine, Washington State University, Pullman, WA, USA; 19 Katonah-Bedford
Inhibidores de 1rosin quinasa Original Article
DOI: 10.1111/j.1476-5829.2011.00275.x
Preliminary evidence for biologic activity
of toceranib phosphate (Palladia®) in solid
tumours∗
• 
C. London1 , T. Mathie1 , N. Stingle1 , C. Clifford2 , S. Haney2 , M. K. Klein3 ,
L. Beaver3 , K. Vickery3 , D. M. Vail4 , B. Hershey5 , S. Ettinger6 , A. Vaughan7 ,
F. Alvarez8 , L. Hillman9 , M. Kiselow10 , D. Thamm11 , M. L. Higginbotham12 ,
13
14
17
18 Clinical benefit (CB) as o15bserved n Jones
63/85 (74%) M. Gauthier
, E. Krick
, B.w
Phillips
, T. LaDue16 ,iP.
, J. Bryan
, V. Gill19 ,
20
21
22
23
24
25
A. Novasad
, L. Fulton
Carreras
C. McNeill
ü 
AGASACA: CB in 8,8 J.%
(8 PR a, nd 20 SD) , C. Henry and S. Gillings
1
Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus,
ü 
B in 48% Hospital,
(1 PR Tinton
and Falls,
10 SNJ,D) OH,OSAs: USA; 2 RedCBank
Veterinary
USA; 3 Southern Arizona Veterinary Specialty and
Emergency
Center,cTuscon,
AZ, USA; 4 Department
of Medical
Sciences,
School
of
Veterinary Medicine,
ü 
Thyroid arcinomas: C
B i
n 8
0% (
4 P
R a
nd 8
S
D) 5
University of Wisconsin, Madison, Madison, WI, USA; Integrative Veterinary Center, Phoenix, AZ, USA;
6
Animal
Specialty
Center,
Yonkers,
NY, USA; 7 Las Vegas
Center,
ü 
Head a
nd n
eck c
arcinomas: CB Veterinary
in 88% Referral
(1 CR, 5 PLasR Vegas,
and NV,
1 SUSA;
D) 8 Coral Springs Animal Hospital, Coral Springs, FL, USA; 9 MedVet Memphis, Memphis, TN, USA;
ü 
CR and of4 Clinical
SD). Sciences, College of
10 Nasal carcinoma: CB in 71% (1 Veterinary Medical Specialists, San Mateo, CA, USA; 11 Department
Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, USA;
12 Department of Clinical Sciences, College of Veterinary Medicine, Kansas State University, Manhattan, KS,
USA; 13 Mississauga Oakville Veterinary Emergency Hospital, Oakville, ON, Canada; 14 Department of Clinical
Studies, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 15 Veterinary
Specialty Hospital of San Diego, San Diego, CA, USA; 16 Southeast Veterinary Oncology, Orange Park, FL,
USA; 17 Capital Area Veterinary Specialists, Austin, TX, USA; 18 Department of Veterinary Clinical Sciences,
College of Veterinary Medicine, Washington State University, Pullman, WA, USA; 19 Katonah-Bedford
given to 25/32 dogs and 7 were hypercalcaemic
secondary to disease. Metastasis was present in
most dogs (n = 28) including sublumbar lymph
weeks, range 10–47 weeks). The median duration
of treatment for all 32 dogs treated with toceranib
was 25 weeks (range 0–47+ weeks).
Figure 1. Response of AGASACA to toceranib. (A) An 8-year-old MC mix breed with metastatic AGASACA to the
sublumbar lymph nodes and lungs was treated with toceranib after recurrence postsurgery, radiation therapy and
chemotherapy. Pictured above are radiographs before the start of Palladia and again at day 46 of therapy. Regression of
200 C. London et al.
Toceranib dose and regimen
Data regarding toceranib dose and regiment for all
85 dogs are summarized in Table 1. CB secondary
to toceranib therapy was noted in 63 (74%) cases
(2CR, 18 PR and 43 SD) and the median dose for all
85 dogs was 2.8 mg kg−1 (range 2.2–3.25 mg kg−1 ).
Within the 63 dogs that experienced CB, 37 (59%)
were dosed on a MWF basis, 46 (73%) received less
than 3 mg kg−1 and 47 (75%) were on therapy
for 4 months or longer. The median dose was
2.8 mg kg−1 for dogs that experienced SD and the
median dose was 2.8 mg kg−1 for dogs with PR/CR.
These data did not differ from the 20 dogs that
experienced PD: the median dose of toceranib was
2.8 mg kg−1 , 13 (59%) were dosed on a MWF basis
and 14 (64%) received less than 3 mg kg−1 .
Influence of metronomic treatments
Figure 4. Regression of oral SCC after toceranib therapy. A
Metronomic therapy is now being used in
canine cancer therapy as part of a variety of
therapeutic regimens. As previously mentioned,
this generally involves the use of an NSAID and a
chemotherapeutic given at a low dose continuously.
The chemotherapeutic agent typically used is
cyclophosphamide at 10–12 mg m−1 .2 In this
Palladia en AGASACA y TC •  En estudios previos, Toceranib tuvo unas respuestas parciales del 25% en AGASACA y carcinoma 1roideo (TC). También tuvo enfermedad estable en 50-­‐60% de los casos. •  Las causa de estas respuestas a toceranib era desconocida. •  El obje1vo de este estudio era evaluar la expresión y ac1vación de de VEGFR2, PDGFRα, PDGFRβ, KIT y RET en AGASACA y TC Palladia en AGASACA y TC •  Algunos de los “targets” de toceranib son expresados por AGASACA y TC: ü VEGFR, PDGFRα/β y RET Palladia en combinación con otros fármacos •  Este ensayo clínico es un fase I en “non MCTs”. Trataron de establecer la seguridad de administrar conjuntamente Toceranib/piroxicam a dosis estándares. •  Se observó respuesta en diferentes 1pos de tumores. •  Piroxicam EOD, alternado con toceranib (3.25 mg/kg) es generalmente seguro y no aumenta los efectos adversos con respecto a toceranib Palladia en combinación con otros fármacos •  Este estudio se realizó para evaluar si vinblas1na y toceranib podía ser combinada de manera efec1va y segura. •  La “dose-­‐ limi1ng toxicity “ para estos dos fármacos fue neutropenia. •  Se requirió una reducción de vinblas1na del 50%. •  Aunque se redujo la dosis de vinblas1na, la respuesta obje1va fue del 71%, por lo que se sugirió el posible efecto sinergico. Palladia en combinación con otros fármacos J Vet Intern Med 2012;26:135–141
Multicenter Prospective Trial of Hypofractionated Radiation
Treatment, Toceranib, and Prednisone for Measurable Canine Mast
Cell Tumors
K.S. Carlsten, C.A. London, S. Haney, R. Burnett, A.C. Avery, and D.H. Thamm
Background: Mast cell tumors (MCT) are common cutaneous tumors in dogs and when not amenable to surgical
excision can present a therapeutic challenge. New treatment protocols for unresectable MCT are needed.
Hypothesis: The combination of toceranib, prednisone, and hypofractionated radiation treatment (RT) will be well
tolerated and efficacious.
Animals: Seventeen client-owned dogs with measurable MCT amenable to RT.
Methods: Prospective clinical trial. All dogs received prednisone, omeprazole, diphenhydramine, and toceranib. Toceranib was administered for 1 week before initiating RT, consisting of 24 Gy delivered in 3 or 4 fractions.
Results: On an intent-to-treat basis, the overall response rate was 76.4%, with 58.8% of dogs achieving a complete
response and 17.6% a partial response. The median time to best response was 32 days, and the median progression-free
interval was 316 days. The overall median survival time was not reached with a median follow-up of 374 days. The most
common toxicoses were gastrointestinal and hepatic.
Conclusions and Clinical Importance: The combination of hypofractionated RT, toceranib, and prednisone was tolerated and efficacious in the majority of dogs. Response rates and durations were higher than those reported for toceranib
as a single-agent treatment for MCT. This combination is a viable treatment option for unresectable MCT.
Key words: Palladia; Palliative.
•  La radioterapia es un tratamiento adyuvante muy efec1vo en MCTs reseccionados de manera incompleta, pero no como tratamiento único en enfermedad macroscópica. •  Este estudio se realizó en mastocitomas reseccionados de manera incompleta que recibían prednisona, omeoprazol, difenhidramina y toceranib (2.75 mg/kg) lunes, miercoles y viernes, empezando 1 semana después de radioterapia. M
ast cell tumors (MCT) are the most common
cutaneous tumor in the dog, accounting for
between 16 and 21% of all cutaneous tumors.1,2
Surgery is the treatment of choice for cutaneous MCT
in areas amenable to excision, but locally recurrent,
Abbreviations:
FFPE
ITD
TKI
formalin-fixed, paraffin wax-embedded
internal tandem duplication
tyrosine kinase inhibitor
Palladia en combinación con otros fármacos J Vet Intern Med 2012;26:135–141
Multicenter Prospective Trial of Hypofractionated Radiation
Treatment, Toceranib, and Prednisone for Measurable Canine Mast
Cell Tumors
K.S. Carlsten, C.A. London, S. Haney, R. Burnett, A.C. Avery, and D.H. Thamm
Background: Mast cell tumors (MCT) are common cutaneous tumors in dogs and when not amenable to surgical
excision can present a therapeutic challenge. New treatment protocols for unresectable MCT are needed.
Hypothesis: The combination of toceranib, prednisone, and hypofractionated radiation treatment (RT) will be well
tolerated and efficacious.
Animals: Seventeen client-owned dogs with measurable MCT amenable to RT.
Methods: Prospective clinical trial. All dogs received prednisone, omeprazole, diphenhydramine, and toceranib. Toceranib was administered for 1 week before initiating RT, consisting of 24 Gy delivered in 3 or 4 fractions.
Results: On an intent-to-treat basis, the overall response rate was 76.4%, with 58.8% of dogs achieving a complete
response and 17.6% a partial response. The median time to best response was 32 days, and the median progression-free
interval was 316 days. The overall median survival time was not reached with a median follow-up of 374 days. The most
common toxicoses were gastrointestinal and hepatic.
Conclusions and Clinical Importance: The combination of hypofractionated RT, toceranib, and prednisone was tolerated and efficacious in the majority of dogs. Response rates and durations were higher than those reported for toceranib
as a single-agent treatment for MCT. This combination is a viable treatment option for unresectable MCT.
Key words: Palladia; Palliative.
•  La respuesta obje1va fue 76,4%, con 58% respuesta completa y 17% con respuesta parcial. •  Posiblemente este plan terapéu1co tuvo un beneficio clínico en MCTs no reseccionados. •  Es importante destacar que no hubo mayor toxicidad asociado a la radioterapia. M
ast cell tumors (MCT) are the most common
cutaneous tumor in the dog, accounting for
between 16 and 21% of all cutaneous tumors.1,2
Surgery is the treatment of choice for cutaneous MCT
in areas amenable to excision, but locally recurrent,
Abbreviations:
FFPE
ITD
TKI
formalin-fixed, paraffin wax-embedded
internal tandem duplication
tyrosine kinase inhibitor
Quimioterapia metronómica •  Es una aproximación a la quimioterapia diferente basado en una exposición con"nua, con una reducción o eliminación de los periodos de descanso entre dosis. •  Los mecanismos an1tumorales de la quimioterapia metronómica son: –  An1angiogenesis –  Immunomodulacion –  Actuación directa frente a las células tumorales Quimioterapia metronómica •  It is a different approach based on more con1nuous exposure 1me, with reduc1on or elimina1on of the break period between each dose. •  The an1tumor mechanism of metronomic chemotherapy are: –  An1angiogenesis –  Immunomodula1on –  Direct Cancer cell targe1ng Nature Reviews Cancer 4, 423-­‐436 (June 2004) Quimioterapia metronómica •  Las pautas de quimioterapia metronómica incluyen dosis bajas diarias de ciclofosfamida combinadas con piroxicam. •  Las celulas T reguladoras (Tregs) inhiben la respuesta inmune y por lo tanto suprimen la respuesta inmune y suprimen la respuesta frente a tumores. •  La administración de quimio metronómica modula el numero y ac"vidad de los Tregs que ayuda a general una respuesta inmune frente al tumor Quimioterapia metronómica J Vet Intern Med 2012;26:355–362
Clinical and Immunomodulatory Effects of Toceranib Combined
with Low-Dose Cyclophosphamide in Dogs with Cancer
L. Mitchell, D.H. Thamm, and B.J. Biller
Background: Tyrosine kinase inhibitors (TKIs) and metronomic dosing of cyclophosphamide (CYC) can improve
•  En este estudio, los perros con cáncer que recibieron toceranib durante tumor control by suppression of regulatory T cells (Treg) and restoration of T cell-mediated immune responses in mice
and humans. The immunomodulatory effects of the TKI toceranib, as a single agent or in combination with metronomic
2 semanas tuvieron una reducción significa1va en el numero y CYC,
have not been previously
investigated
in dogs.
Hypothesis: The primary objectives of this study were to determine the effects of toceranib and metronomic CYC treatporcentaje de Treg en la sangre periférica, con un incremento ment on lymphocyte subsets including Treg and on interferon-gamma (IFN-c) secretion in dogs with cancer. We hypothesized that toceranib would
selectively
decrease Tregenumbers
and
increase IFN-c production and that addition of CYC
concomitante e
n i
nterferon-­‐g n e
l s
uero. would further enhance these effects.
Animals: Fifteen client-owned dogs with advanced tumors were entered into a prospective clinical trial.
Methods: Dogs received toceranib at 2.75 mg/kg once every other day. After 2 weeks, oral CYC was added at 15 mg/
2
m daily. Numbers of Treg and lymphocyte subsets were measured in blood by flow cytometry during the 8-week study
period. Serum concentrations of IFN-c were measured by ELISA.
Results: Administration of toceranib significantly decreased the number and percentage of Treg in the peripheral blood
of dogs with cancer. Dogs receiving toceranib and CYC demonstrated a significant increase in serum concentrations of
IFN-c, which was inversely correlated with Treg numbers after 6 weeks of combination treatment.
Conclusions: In addition to antitumor effects, these data support further investigations into the immunomodulatory
effects of toceranib, administered alone or in combination with CYC in dogs with cancer.
Key words: Metronomic; Neoplasia; Regulatory T cell; Tyrosine kinase inhibitor.
•  Interesantemente la adición de ciclofosfamida después de 2 semanas no aumento el efecto en los Tregs. •  Por lo tanto, es posible que la administración de toceranib puede ser muy u"l en los protocolos de quimioterapia metronómica. oceranib phosphatea is a receptor tyrosine kinase
Efectos adversos •  Prác1camente TODOS los “Small molecule inhibitors” producen algún 1po de efecto adverso durante su administración. •  Para muchos de esos fármacos, fa1ga, letargia, pérdida de ape1to, y efectos GI como diarrea son comunes. •  Los efectos adversos más frecuentes en Toceranib y masi1nib están relacionados con el tracto GI (perdida de ape1to, diarrea, y ocasionalmente vómitos) Adverse effects •  Otros efectos adversos que se han observado, pero mucho menos frecuente: –  Hepatotoxicidad –  Neutropenia (rara vez relevante) –  Dolor muscular y coagulopa`as. –  PLN e hipertensión. Tratamiento de los efectos adversos •  Ulceras GI: –  Par1cularmente omeoprazol parace tener un beneficio en mi1gar el riesgo de ulceras GI. •  Perdida de ape1to: –  Bastante frecuente, y suele responder a tratamientos con: metoclopramide, ondansetron, maropitant y mirtazapina •  Diarrea: –  Metronidazol y loperamide son muy ú1les, sobre todo en diarreas intermitentes. –  En algunos casos, los perros requieren administración con1nua de metronidazol para prevenir episodios recurrentes. Reducir efectos adversos •  Palladia fue aprobado para su uso en 2009 a una dosis de 3.25 mg/kg dias alternos. •  Aunque datos prelimenares mostraron que probablemente dosis más bajas podian r e d u c i r l o s e f e c t o s a d v e r s o s p e r o manteniendo su efec1vidad biológica. Bernabe et al. BMC Veterinary Research 2013, 9:190
http://www.biomedcentral.com/1746-6148/9/190
Reducing adverse events… RESEARCH ARTICLE
Open Access
Evaluation of the adverse event profile and
pharmacodynamics of toceranib phosphate
administered to dogs with solid tumors at doses
below the maximum tolerated dose
Luis Feo Bernabe1, Roberta Portela2, Sandra Nguyen3, William C Kisseberth3, Michael Pennell4, Mark F Yancey5
and Cheryl A London1,3*
• Abstract
Las dosis de toceranib de entre 2.4-­‐2.9 mg/kg EOD mostró Background:
The receptor kinase
inhibitor toceranib
(Palladia) was approved
dogs in 2009
una inhibición adecuada de phosphate
los receptores TK yfor suse
e pin rodujo using a dose of 3.25 mg/kg administered every other day. Preliminary data suggests that lower doses of toeceranib
reducción sustancial de lwhile
os emaintaining
fectos sufficient
adversos. may una be associated
with a reduced
adverse event profile
drug exposure to provide
biologic activity. The purpose of this study was to determine the Cmax of toceranib in dogs with solid tumors
• receiving
Por 2.5-2.75
tanto, sta other
dosis debe considerarse dosis with
estándar. mg/kgeevery
day and
to document
the adverse eventsla associated
this dose rate.
Secondary objectives included determination of plasma VEGF concentrations in treated dogs and response to
therapy.
Results: Dogs with solid tumors were administered toceranib at an intended target dose ranging from
2.5-2.75 mg/kg every other day and plasma samples were obtained for analysis of toceranib and VEGF plasma
concentrations on days 0, 7, 14 and 30 of the study at 6 and 8 hours post drug administration. Additionally, plasma
samples were obtained at 0, 1, 2, 6, 8, and 12 hours from dogs on day 30 for confirmation of Cmax. Response to
Masi1nib (Kinavet®) Original Article
DOI: 10.1111/vco.12053
Masitinib mesylate for metastatic
and non-resectable canine cutaneous mast
cell tumours
O. A. Smrkovski, L. Essick, B. W. Rohrbach and A. M. Legendre
Department of Small Animal Clinical Sciences, The University of Tennessee, C247 Veterinary Teaching
Hospital, Knoxville, TN, USA
•  Inhibidor selec1vo aprobado para su uso en MCTs Abstract
Masitinib mesylate is a tyrosine kinase inhibitor approved for the treatment of gross, non-metastatic
(grado II y III), que actúa frente a receptores KIT, grade II and III canine mast cell tumours (MCTs). This study evaluated the use of masitinib as a
frontline and rescue agent for metastatic and non-metastatic canine MCTs. Identification of toxicities
PDGFR, y kinase Lyn citoplasmá1co. and prognostic factors in these dogs was of secondary interest. Twenty-six dogs were included in this
study. The overall response rate to masitinib was 50%. The median survival time for dogs that
•  Más recientemente, un estudio retrospec1vo en MCTs responded to masitinib was 630 days versus 137 days for dogs that did not respond (P = 0.0033).
Toxicity was recorded in 61.5% of treated dogs, but the majority of adverse events were mild and
mostró na respuesta en grade,
el 5stage
0% or dlocation,
e los asos. self-limiting.u
Response
to masitinib, not tumour
wasc
the
most significant
s
cell, tyrosine
ibitor
prognostic factor for survival in dogs with MCTs.
Introduction
effective local tumour control in 85 –90% of grade
ywords
nical pathology,
cology, small animal,
mour biology, tyrosine
nase
Masi1nib (Kinavet®) Original Article
DOI: 10.1111/vco.12157
Masitinib monotherapy in canine
epitheliotropic lymphoma
N. Holtermann1 , M. Kiupel2 , M. Kessler3 , E. Teske4 , D. Betz5 and J. Hirschberger1
1
Medizinische Kleintierklinik, Ludwig Maximilians University Munich, Munich, Germany
Department of Pathology and Diagnostic Investigations, College of Veterinary Medicine, Michigan State
University, Diagnostic Center for Population and Animal Health, Lansing, MI, USA
3
Tierklinik Hofheim, Im Langgewann 9, 65719 Hofheim/Taunus, Germany
4
Department of Clinical Sciences of Companion Animals, Veterinary Faculty, Utrecht University, Utrecht, The
Netherlands
5
Klinik für Kleintiere, Tierärztliche Hochschule Hannover, Hannover, Germany
2
Abstract
This study evaluated efficacy and side effects of masitinib in canine epitheliotropic lymphoma.
Complete remission occurred in 2 of 10 dogs and lasted for median 85 days. Five dogs went into
partial remission for median 60.5 days. Three pretreated dogs did not respond to therapy. Side effects
occurred in six dogs and were mostly mild to moderate. Immunohistochemistry was available for
eight dogs. KIT receptor was negative in all of them, six of eight lymphomas stained strongly positive
for stem cell factor (SCF). platelet-derived growth factor (PDGF)-AA was weakly positive in two and
negative in six. PDGF-BB was negative in four tumours, weakly positive in one and strongly positive in
three. One was strongly positive for PDGF receptor (PDGFR)-𝛽, seven were negative for that receptor.
Five showed strong expression of PDGFR-𝛼, two showed weak expression, one was negative. In
conclusion, masitinib is effective in treating canine epitheliotropic lymphoma. But its effects are most
likely not generated through the KIT receptor.
Aaron Harper and Laura Blackwood
Toceranib (Palladia®) en gatos Abstract
Objectives Toceranib phosphate is a tyrosine kinase inhibitor licensed for the treatment of non-resectable Patnaik
643124grade II/III recurrent cutaneous mast cell tumours in dogs. There is no information in cats regarding the tolerated
article2016
JFM0010.1177/1098612X16643124Journal of Feline Medicine and SurgeryHarper and Blackwood
dose, toxicity or tumour response of this drug. The aim of this study was to analyse retrospectively a cohort of cats
with advanced neoplasia treated with toceranib to identify toxicity and response.
Methods The medical records of the Small Animal Teaching Hospital were reviewed. Cats were included if they
had received
for at least 2 weeks for the treatment of histologically or cytologically confirmed neoplastic
Original toceranib
Article
disease, and had at least one set of monitoring blood tests (haematology, biochemistry) performed after baseline
Journal of Feline Medicine and Surgery
tests. Toxicity was graded according to Veterinary Comparative Oncology Group – common
terminology criteria for
1–5
The Author(s)
2016(RECIST) criteria.
adverse events and response was measured according to Response Evaluation In©Solid
Tumors
Reprints and permissions:
Results Fourteen cats met the inclusion criteria, the majority of which (13/14) had
received previous therapy
sagepub.co.uk/journalsPermissions.nav
DOI:
10.1177/1098612X16643124
(surgery, radiotherapy, chemotherapy). The most common tumour types were mast cell tumours or malignant
jfms.com
epithelial tumours. Toxicity occurred in 10/14 cats – 10 cats had mild myelosuppression or gastrointestinal effects.
This paper was handled and processed
Two cats developed severe hepatoxicity. One cat died from congestive heart failure,
although
whether
this was
by the European
Editorial
Office (ISFM)
for publication in JFMS
related to toceranib therapy is unknown. Regarding response, one cat achieved complete response; two cats
achieved partial response and five cats achieved stable disease: overall biological response rate was 57.1%. All
Harper
andeither
Laura
Blackwood
of theAaron
cats that
achieved
partial
or complete response were treated for mast cell disease. Overall median
duration of response was 90 days (range 14–570 days). None of the cats with squamous cell carcinoma achieved
a response.
Conclusions and relevance Toceranib phosphate is generally well tolerated in cats with the majority (10/14) of
Abstract
toxicity limited to mild gastrointestinal or myelosuppressive effects; however, hepatotoxicity is a concern. Response
Objectives Toceranib phosphate is a tyrosine kinase inhibitor licensed for the treatment of non-resectable Patnaik
to treatment
in this small cohort was similar to that reported in dogs.
grade II/III recurrent cutaneous mast cell tumours in dogs. There is no information in cats regarding the tolerated
Toxicity and response in cats with
neoplasia treated with toceranib
phosphate
dose, toxicity or tumour response of this drug. The aim of this study was to analyse retrospectively a cohort of cats
Accepted:
14 March
2016 treated with toceranib to identify toxicity and response.
with advanced
neoplasia
Methods The medical records of the Small Animal Teaching Hospital were reviewed. Cats were included if they
had received toceranib for at least 2 weeks for the treatment of histologically or cytologically confirmed neoplastic
disease, and had at least one set of monitoring blood tests (haematology, biochemistry) performed after baseline
tests. Toxicity was graded according to Veterinary Comparative Oncology Group – common terminology criteria for
Introduction
adverse events and response was measured according to Response Evaluation In Solid Tumors (RECIST) criteria.
4 However,
Results
Fourteen (Palladia;
cats met the
inclusion
criteria,
which (13/14)
had of
received
previous therapy
for theofprimary
treatment
renal carcinoma.
Toceranib
phosphate
Zoetis)
belongs
to the
the majority
(surgery, radiotherapy, chemotherapy). The most common tumour types were mast cell tumours or malignant
Toceranib (Palladia®) en gatos Original Article
DOI: 10.1111/vco.12211
Retrospective evaluation of toceranib
phosphate (Palladia®) toxicity in cats
C. H. Merrick1 , J. Pierro2 , S. E. Schleis3 , E. A. Sones4 , Z. M. Wright5 ,
R. C. Regan6 , C. T. Siedlecki1 and P. J. Bergman7
1
VCA Bay Area Veterinary Specialists & Emergency Hospital, San Leandro, CA, USA
Department of Small Animal Medicine & Surgery, College of Veterinary Medicine, University of Georgia,
Athens, GA, USA
3
Department of Clinical Sciences, College of Veterinary Medicine, Auburn University, Auburn, AL, USA
4
Animal Cancer Care Clinic, Ft. Lauderdale, FL, USA
5
VCA Animal Diagnostic Clinic, Dallas, TX, USA
6
Blue Pearl Georgia Veterinary Specialists, Sandy Springs, GA, USA
7
Department of VCA Clinical Studies, VCA Katonah Bedford Veterinary Center, Bedford Hills, NY, USA
2
Abstract
Keywords
cancer, feline, Palladia,
toceranib, toxicity
The purpose of this study was to describe the toxicity profile of toceranib phosphate in tumour
bearing cats. Medical records were reviewed from seven institutions. Patients with incomplete
medical records and those receiving concurrent chemotherapy or NSAIDs (non-steroidal
anti-inflammatory) were excluded. Fifty-five cats met the inclusion criteria. Carcinoma was diagnosed
in 55% of cases. Median oral toceranib dose was 2.7 mg kg−1 and was most commonly administered
on Monday, Wednesday and Friday. Thrombocytopenia (16.3%) and neutropenia (9.1%) were the
most common haematologic toxicities. Azotemia (14.5%) and alanine aminotransferase (ALT)
elevations (7.2%) were the most frequently encountered biochemical alterations. Gastrointestinal (GI)
toxicity was seen in 21.8% of cats, and was lower than previously reported in dogs. The results of this
study showed that treatment of cats with toceranib is well-tolerated and toxicity is uncommon.
Additional studies to define a more structured dosing schedule and to evaluate the efficacy of
toceranib in the treatment of feline cancers are needed.
Mastocitoma 1 semana inico de tratamiento Labrador retriever. Female. Metasta1c MCT Respuesta aToceranib Respuesta a Gleevec Respuesta a ima1nib en GIST con mutación en KIT Respuesta a Iressa (gefi1nib) en cancer de pulmon con mutación de EGFR. Respuesta a crizo"nib en cancer de pulmon EML4-­‐ALK+ Respuesta a vemurafenib en melanoma BRAF V600E THANK YOU