The Experts below are selected from a list of 189 Experts worldwide ranked by ideXlab platform
Cheryl A London - One of the best experts on this subject based on the ideXlab platform.
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c kit mutation and localization status as response predictors in mast cell tumors in dogs treated with prednisone and Toceranib or vinblastine
Journal of Veterinary Internal Medicine, 2018Co-Authors: Kristen M Weishaar, Cheryl A London, Craig A Clifford, David M Vail, E J Ehrhart, Anne C Avery, J B Charles, Robyn Elmslie, Jens C Eickhoff, Douglas H ThammAbstract:BACKGROUND KIT inhibitors, such as Toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL or TOC is superior for treating MCT without c-kit mutations. HYPOTHESIS/OBJECTIVES To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c-kit mutated MCT would have a better response to TOC than VBL. ANIMALS Eighty-eight client-owned dogs with macroscopic MCT. METHODS Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m2 weekly × 4 then EOW) by KIT localization and c-kit mutation status using an adaptive randomization scheme. RESULTS Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c-kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 [0.62-3.92]; P = 0.28). Median progression-free survival (PFS) for dogs receiving VBL was 78 days (7-1,521) and for TOC 95.5 (14-990); hazard ratio (HR) = 1.34 [0.72-2.50]; P = 0.36. Median overall survival (OS) was 241.5 days (10-1,521) for the VBL group and 159 (20-990) for the TOC group; HR = 0.80 ([0.45-1.41]; P = 0.44). CONCLUSIONS AND CLINICAL IMPORTANCE Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c-kit mutations was not different between treatment groups in this population of dogs, c-kit mutation status did not predict treatment response.
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USAadenocarcinoma and thyroid carcinoma
2016Co-Authors: Bridget K Urie, Duncan S. Russell, William C Kisseberth, Cheryl A LondonAbstract:Madison, NJ, USA) is an oral oxindole multi-targeted re-ceptor tyrosine kinase (RTK) inhibitor (TKI) that blocks the activity of VEGFR2, PDGFRα,/β, FMS-like tyrosine kinase 3 (FLT-3), stem cell factor receptor (KIT), and colony stimulating factor receptor (CSFR1) [1]. It was approved for the treatment of canine mast cell tu-mors (MCTs) based on a single agent response rate of approximately 43 % in dogs with recurrent or non-resectable grade 2 or 3 MCTs [2]. Toceranib also ex-hibited activity against multiple tumor types in the original phase 1 study, suggesting that the action of Toceranib against receptors other than KIT may play a role in the responses observed in solid tumors [3]. In support of this, Toceranib’s kinome mirrors that of sunitinib (SutentW
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impact of Toceranib piroxicam cyclophosphamide maintenance therapy on outcome of dogs with appendicular osteosarcoma following amputation and carboplatin chemotherapy a multi institutional study
PLOS ONE, 2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:Background We hypothesized that the addition of Toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy. Methods and Findings This was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without Toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 Toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 Toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 Toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine Toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More Toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and Toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and Toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving Toceranib. Conclusions The addition of Toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA.
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Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study
2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:BackgroundWe hypothesized that the addition of Toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy.Methods and FindingsThis was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without Toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 Toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 Toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 Toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine Toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More Toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and Toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and Toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving Toceranib.ConclusionsThe addition of Toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA.
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Overall Survival.
2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:Kaplain-Meier overall survival (OS) curves comparing Toceranib-treated dogs with control dogs. Hash marks denote censored observations; n = 63 Toceranib-treated dogs; n = 63 control dogs (p = 0.08).
Duncan S. Russell - One of the best experts on this subject based on the ideXlab platform.
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USAadenocarcinoma and thyroid carcinoma
2016Co-Authors: Bridget K Urie, Duncan S. Russell, William C Kisseberth, Cheryl A LondonAbstract:Madison, NJ, USA) is an oral oxindole multi-targeted re-ceptor tyrosine kinase (RTK) inhibitor (TKI) that blocks the activity of VEGFR2, PDGFRα,/β, FMS-like tyrosine kinase 3 (FLT-3), stem cell factor receptor (KIT), and colony stimulating factor receptor (CSFR1) [1]. It was approved for the treatment of canine mast cell tu-mors (MCTs) based on a single agent response rate of approximately 43 % in dogs with recurrent or non-resectable grade 2 or 3 MCTs [2]. Toceranib also ex-hibited activity against multiple tumor types in the original phase 1 study, suggesting that the action of Toceranib against receptors other than KIT may play a role in the responses observed in solid tumors [3]. In support of this, Toceranib’s kinome mirrors that of sunitinib (SutentW
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Evaluation of expression and function of vascular endothelial growth factor receptor 2, platelet derived growth factor receptors-alpha and -beta, KIT, and RET in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma
BMC Veterinary Research, 2012Co-Authors: Bridget K Urie, Duncan S. Russell, William C Kisseberth, Cheryl A LondonAbstract:Background Toceranib phosphate (Palladia) has a reported objective response rate of 25% in both canine apocrine gland anal sac adenocarcinoma (AGASACA) and thyroid carcinoma (TC), with stable disease occurring in an additional 50-60% of dogs. The basis for the observed responses to Toceranib is not known. The purpose of this study was to evaluate AGASACA and TC samples for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, KIT and RET to assess whether dysregulation of these receptor tyrosine kinases (RTKs) may contribute to the biologic activity of Toceranib. Results mRNA for VEGFR2, PDGFRα/β, KIT and RET was detected in all AGASACA samples. mRNA for VEGFR2, PDGFRα/β, and KIT was detected in all TC samples, while mRNA for RET was amplified in 10/15 samples. No phosphorylation of VEGFR2, PDGFRα/β, or KIT was observed on the arrays. However, phosphorylation of RET was detected in 54% of the primary AGASACA and 20% of TC. VEGFR2 was expressed in 19/24 primary and 6/10 metastatic AGASACA and 6/15 TC samples. KIT was present in 8/24 primary and 3/10 metastatic AGASACA and 9/15 TC samples. PDGFRα expression was noted in all tumor samples. In contrast PDGFRβ expression was found in only a few tumor samples but was evident in the stroma of all tumor specimens. Conclusions Known targets of Toceranib are expressed in both AGASAC and TC. Given the observed expression of VEGFR and PDGFRα/β and phosphorylation of RET, these RTKs merit investigation as to their roles in the biology of AGSACA and TC and their contribution to Toceranib’s activity.
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evaluation of expression and function of vascular endothelial growth factor receptor 2 platelet derived growth factor receptors alpha and beta kit and ret in canine apocrine gland anal sac adenocarcinoma and thyroid carcinoma
BMC Veterinary Research, 2012Co-Authors: Bridget K Urie, Duncan S. Russell, William C Kisseberth, Cheryl A LondonAbstract:Background Toceranib phosphate (Palladia) has a reported objective response rate of 25% in both canine apocrine gland anal sac adenocarcinoma (AGASACA) and thyroid carcinoma (TC), with stable disease occurring in an additional 50-60% of dogs. The basis for the observed responses to Toceranib is not known. The purpose of this study was to evaluate AGASACA and TC samples for the expression and activation of VEGFR2, PDGFRα, PDGFRβ, KIT and RET to assess whether dysregulation of these receptor tyrosine kinases (RTKs) may contribute to the biologic activity of Toceranib.
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calcitriol 1 25 dihydroxycholecalciferol enhances mast cell tumour chemotherapy and receptor tyrosine kinase inhibitor activity in vitro and has single agent activity against spontaneously occurring canine mast cell tumours
Veterinary and Comparative Oncology, 2010Co-Authors: E K Malone, Duncan S. Russell, Kenneth M. Rassnick, David Ruslander, Candace S. Johnson, Joseph J. Wakshlag, Ramsey Alsarraf, Donald L TrumpAbstract:: Calcitriol potentiates the effect of multiple chemotherapy agents in a variety of tumour models. In this study, we examine whether calcitriol increases chemotherapy or tyrosine kinase inhibitor in vitro cytotoxicity in canine mastocytoma C2 cells. We also evaluate the in vivo effect of DN101, a highly concentrated oral formulation of calcitriol designed specifically for cancer therapy, as a single-agent therapy in dogs with mast cell tumours (MCTs). Calcitriol exhibits synergistic, antiproliferative activity when used in combination with CCNU, vinblastine, imatinib or Toceranib in vitro. The concentrations required for 50% growth inhibition were generally two- to six-fold lower when the drugs were used in combination than when used individually. High-dose oral calcitriol induced remission in 4 of 10 dogs (one complete remission, three partial remissions), although the majority experienced toxicity, necessitating discontinuation of the trial. Further evaluation of calcitriol in combination therapy for dogs with MCTs is warranted.
Amy K. Leblanc - One of the best experts on this subject based on the ideXlab platform.
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Expression of PDGFR-β and Kit in canine anal sac apocrine gland adenocarcinoma using tissue immunohistochemistry
Veterinary and comparative oncology, 2011Co-Authors: R. J. Brown, Shelley J. Newman, D. C. Durtschi, Amy K. LeblancAbstract:Canine anal sac apocrine gland adenocarcinoma (ASAGAC) is an uncommon but highly invasive and metastatic malignancy. Toceranib phosphate (Palladia) is a receptor tyrosine kinase (RTK) inhibitor that targets several members of the split kinase RTK family. These membrane receptors are important for cell cycling, apoptosis and angiogenesis, all of which can contribute to carcinogenesis. The objective of this study was to evaluate archived, paraffin-embedded canine ASAGAC and normal canine anal sacs for immunohistochemical detection of Kit and platelet-derived growth factor receptor beta (PDGFR-β). Two of 77 neoplasms (2.6%) expressed Kit. Fifteen of the neoplasms (19.5%) were positive for PDGFR-β expression. None of the normal canine anal sac epithelium expressed Kit or PDGFR-β. Because of these results, further investigation should be considered to determine the role of RTKs in the clinical course and treatment of canine ASAGAC.
David M Vail - One of the best experts on this subject based on the ideXlab platform.
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c kit mutation and localization status as response predictors in mast cell tumors in dogs treated with prednisone and Toceranib or vinblastine
Journal of Veterinary Internal Medicine, 2018Co-Authors: Kristen M Weishaar, Cheryl A London, Craig A Clifford, David M Vail, E J Ehrhart, Anne C Avery, J B Charles, Robyn Elmslie, Jens C Eickhoff, Douglas H ThammAbstract:BACKGROUND KIT inhibitors, such as Toceranib (TOC), and vinblastine (VBL) have not been prospectively compared in the treatment of macroscopic mast cell tumors (MCTs). Also, it is unknown whether VBL or TOC is superior for treating MCT without c-kit mutations. HYPOTHESIS/OBJECTIVES To determine the value of KIT genotyping and localization in treatment decisions for dogs with macroscopic MCT. We hypothesized that c-kit mutated MCT would have a better response to TOC than VBL. ANIMALS Eighty-eight client-owned dogs with macroscopic MCT. METHODS Prospective, randomized trial. Dogs were randomized to TOC (2.75 mg/kg EOD) or VBL (2.5 mg/m2 weekly × 4 then EOW) by KIT localization and c-kit mutation status using an adaptive randomization scheme. RESULTS Sixty dogs were allocated to TOC and 28 to VBL. Of the dogs receiving TOC, 20% had c-kit mutations, compared to 30% receiving VBL (P = 0.74). Overall response rates were 46% (TOC) and 30% (VBL) (odds ratio = 1.56 [0.62-3.92]; P = 0.28). Median progression-free survival (PFS) for dogs receiving VBL was 78 days (7-1,521) and for TOC 95.5 (14-990); hazard ratio (HR) = 1.34 [0.72-2.50]; P = 0.36. Median overall survival (OS) was 241.5 days (10-1,521) for the VBL group and 159 (20-990) for the TOC group; HR = 0.80 ([0.45-1.41]; P = 0.44). CONCLUSIONS AND CLINICAL IMPORTANCE Neither PFS nor OS was significantly different between treatment groups. As the proportion of dogs with c-kit mutations was not different between treatment groups in this population of dogs, c-kit mutation status did not predict treatment response.
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impact of Toceranib piroxicam cyclophosphamide maintenance therapy on outcome of dogs with appendicular osteosarcoma following amputation and carboplatin chemotherapy a multi institutional study
PLOS ONE, 2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:Background We hypothesized that the addition of Toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy. Methods and Findings This was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without Toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 Toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 Toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 Toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine Toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More Toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and Toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and Toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving Toceranib. Conclusions The addition of Toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA.
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Impact of Toceranib/Piroxicam/Cyclophosphamide Maintenance Therapy on Outcome of Dogs with Appendicular Osteosarcoma following Amputation and Carboplatin Chemotherapy: A Multi-Institutional Study
2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:BackgroundWe hypothesized that the addition of Toceranib to metronomic cyclophosphamide/piroxicam therapy would significantly improve disease-free interval (DFI) and overall survival (OS) in dogs with appendicular osteosarcoma (OSA) following amputation and carboplatin chemotherapy.Methods and FindingsThis was a randomized, prospective clinical trial in which dogs with OSA free of gross metastatic disease (n = 126) received carboplatin chemotherapy (4 doses) following amputation. On study entry, dogs were randomized to receive piroxicam/cyclophosphamide with or without Toceranib (n = 63 each) after completing chemotherapy. Patient demographics were not significantly different between both groups. During or immediately following carboplatin chemotherapy, 32 dogs (n = 13 Toceranib; n = 19 control) developed metastatic disease, and 13 dogs left the study due to other medical conditions or owner preference. Following carboplatin chemotherapy, 81 dogs (n = 46 Toceranib; n = 35 control) received the metronomic treatment; 35 dogs (n = 20 Toceranib; n = 15 control) developed metastatic disease during the maintenance therapy, and 26 dogs left the study due to other medical conditions or owner preference. Nine Toceranib-treated and 11 control dogs completed the study without evidence of metastatic disease 1-year following amputation. Toceranib-treated dogs experienced more episodes of diarrhea, neutropenia and weight loss than control dogs, although these toxicities were low-grade and typically resolved with supportive care. More Toceranib-treated dogs (n = 8) were removed from the study for therapy-associated adverse events compared to control dogs (n = 1). The median DFI for control and Toceranib treated dogs was 215 and 233 days, respectively (p = 0.274); the median OS for control and Toceranib treated dogs was 242 and 318 days, respectively (p = 0.08). The one year survival rate for control dogs was 35% compared to 38% for dogs receiving Toceranib.ConclusionsThe addition of Toceranib to metronomic piroxicam/cyclophosphamide therapy following amputation and carboplatin chemotherapy did not improve median DFI, OS or the 1-year survival rate in dogs with OSA.
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Overall Survival.
2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:Kaplain-Meier overall survival (OS) curves comparing Toceranib-treated dogs with control dogs. Hash marks denote censored observations; n = 63 Toceranib-treated dogs; n = 63 control dogs (p = 0.08).
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Disease Free Interval.
2015Co-Authors: Cheryl A London, Roberta Portela, Michael L Pennell, Heather L Gardner, Tamra Mathie, Nicole Stingle, Craig A Clifford, Mona P Rosenberg, David M Vail, Laurel E WilliamsAbstract:Kaplan-Meier disease-free interval (DFI) curves comparing dogs treated with Toceranib to control dogs. Hash marks denote censored observations; n = 63 Toceranib-treated dogs; n = 63 control dogs. (A) Intent-to-treat analysis (p = 0.274). (B) Adherence analysis (p = 0.3).
Xuan Pan - One of the best experts on this subject based on the ideXlab platform.
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Evaluation of Toceranib for treatment of apocrine gland anal sac adenocarcinoma in dogs
Journal of veterinary internal medicine, 2020Co-Authors: Caitlin M. Heaton, Arthur Francisco Araujo Fernandes, Paulo C. Jark, Xuan PanAbstract:Background There is no widely accepted standard medical treatment for apocrine gland anal sac adenocarcinoma (AGASACA) in dogs. Targeted agents such as Toceranib may be effective in treatment of AGASACA, but the number of clinical reports investigating its efficacy is limited. Hypothesis/aim To evaluate the efficacy of Toceranib treatment of AGASACA in dogs, and to assess prognostic factors in the study population. Our hypothesis was that Toceranib would provide a clinical benefit in the treatment of dogs with AGASACA. Animals Thirty-six client-owned dogs with either a cytologic or histologic diagnosis of AGASACA that were treated with Toceranib alone or in combination with surgery, nonconcurrent chemotherapy or both. Methods Retrospective study. Result The median progression-free survival (PFS) and overall survival time (OST) for the study population was 313 days and 827 days, respectively. A clinical benefit from Toceranib treatment was observed in 69% of dogs, with 20.7% of dogs experiencing partial response and 48.3% of dogs experiencing stable disease. Dogs that responded to Toceranib treatment had significantly prolonged PFS and OST. Hypercalcemia was a negative prognostic factor for clinical outcomes. Conclusions Toceranib is effective in the treatment of AGASACA in dogs. Prospective, controlled clinical trials are needed to determine the efficacy of Toceranib in comparison to other treatment protocols for dogs with AGASACA.