Toceranib phosphate

Toceranib is an inhibitor which blocks various tyrosine kinases expressed on the cell surface. Receptor tyrosine kinases (RTKs) are excellent candidates for molecular targeted therapy, because they play key roles in controlling cell proliferation and survival and are frequently dysregulated in a variety of malignancies. It is marketed as Palladia as its phosphate salt, toceranib phosphate (INN) by Pfizer. 

In vitro: Toceranib inhibited KIT phosphorylation and cell proliferation in a dose-dependent manner in the treatment-naïve, parental C2 line (IC50 < 10 nM). In addition, chronic TOC exposure resulted in c-kit mRNA and KIT protein overexpression in the TOC-resistant sublines [1].

In vivo: Fourteen dogs with advanced mast cell tumors (MCTs) were enrolled in a prevoius study, among which 11 dogs were evaluable for KIT target modulation. Of these, eight MCTs showed reduced levels of phosphorylated KIT relative to total KIT after treatment with Toceranib, compared with pretreatment biopsies. All four evaluable MCTs expressing ITD mutant c-kit showed modulation of KIT phosphorylation, as did four of seven tumors expressing non-ITD c-kit. [2].

Clinical trials: Currenlty no clinical data are available.

References:[1] Halsey CH, Gustafson DL, Rose BJ, Wolf-Ringwall A, Burnett RC, Duval DL, Avery AC, Thamm DH.  Development of an in vitro model of acquired resistance to toceranib phosphate (Palladia®) in canine mast cell tumor. BMC Vet Res. 2014;10:105. doi: 10.1186/1746-6148-10-105.[2] Pryer NK, Lee LB, Zadovaskaya R, Yu X, Sukbuntherng J, Cherrington JM, London CA.   Proof of target for SU11654: inhibition of KIT phosphorylation in canine mast cell tumors. Clin Cancer Res. 2003;9(15):5729-34.

Safety evaluation of combination doxorubicin and toceranib phosphate (Palladia(R)) in tumour bearing dogs: a phase I dose-finding study.[Pubmed:27146577]

Vet Comp Oncol. 2017 Sep;15(3):919-931.

Combination chemotherapy holds promise for improving outcomes in malignancy when compared with single-agent approaches. Care must be taken to avoid overlapping toxicity and to utilize agents with differing mechanisms of action. A phase I dose-finding trial was performed to determine the maximally tolerated dose (MTD) of a concurrent toceranib and doxorubicin (DOX) combination protocol where toceranib dose was maintained at or near 2.75 mg kg(-1) by mouth every other day (PO EOD) while escalating DOX dosage. The dose-limiting toxicity was found to be neutropenia and the MTD of the combination was determined to be 25 mg m(-2) of DOX q 21 days given concurrently with toceranib 2.75 mg kg(-1) PO EOD. This combination was well tolerated with no excessive gastrointestinal toxicity nor novel adverse events (AEs) noted. Anti-tumour activity was observed in the majority of cases. This combination warrants further investigation in the context of phase II/III clinical trials to characterize efficacy and long-term AE profiles.

Effects of Toceranib Phosphate on Systolic Blood Pressure and Proteinuria in Dogs.[Pubmed:27149912]

J Vet Intern Med. 2016 Jul;30(4):951-7.

BACKGROUND: Systemic hypertension and proteinuria are established adverse effects of tyrosine kinase inhibitor treatment in people. OBJECTIVE: The objective of this study was to investigate changes in systolic blood pressure and the incidence of proteinuria secondary to treatment with Toceranib phosphate in dogs with cancer. ANIMALS: Twenty-six control dogs and 30 dogs with cancer were evaluated for the first part of the study (baseline characteristics). For the second part (effect of Toceranib phosphate treatment), 48 client-owned dogs were evaluated, including 20 control dogs and 28 dogs with various types of neoplasia. METHODS: Prospective cohort study. Client-owned healthy control dogs and dogs with cancer were enrolled. Blood pressure and urine protein:creatinine ratios were measured before treatment and 2 weeks after initiation of Toceranib phosphate treatment. RESULTS: Systolic blood pressure was significantly (P = 0.0013) higher in previously normotensive treatment dogs after initiation of treatment with Toceranib phosphate (152 mmHg +/- 19) compared to baseline (136 mmHg +/- 14). 37% of treated dogs developed SBP >/= 160 mmHg. The prevalence of systemic hypertension (37%) and proteinuria (21%) at baseline in treatment dogs did not differ from that of age-matched healthy controls (15% [P = 0.13] and 0% [P = 0.069], respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Toceranib phosphate treatment might result in increased systolic blood pressures in dogs. Systemic hypertension should be considered a potential adverse effect of this drug in dogs. Systemic hypertension and proteinuria were detected at clinically relevant frequencies in the dogs with cancer before antineoplastic therapies suggesting that monitoring of these variables might be warranted in this population.

Skin depigmentation associated with toceranib phosphate in a dog.[Pubmed:28164401]

Vet Dermatol. 2017 Aug;28(4):400-e95.

BACKGROUND: Drug-induced depigmentation is frequently observed in humans undergoing tyrosine kinase inhibitor therapy, whereas it is not reported in dogs. The skin depigmentation can occur after the first week of treatment and it is reversible within a few weeks after drug discontinuation. OBJECTIVES: To report the clinical and histopathological features of an episode of cutaneous adverse drug reaction associated with short term administration of Toceranib phosphate. CASE REPORT: An 11-year-old intact male Bernese mountain dog was presented for investigation of a subcutaneous mast cell tumour (MCT) including treatment options. The major abnormality on physical examination was a 7.5 x 10 cm subcutaneous mass located cranial to the left shoulder joint consistent with a MCT. Toceranib phosphate therapy was initiated. Fourteen days after initiating treatment, the dog presented with skin erosions near the lateral canthus of the left eye. Three weeks later there were multiple skin lesions characterized by alopecia and depigmentation involving left and right eyelids; leukotrichia of the periorbital areas and depigmentation of the nasal planum and all paw pads. Histopathological findings were nonspecific; they were supportive of vitiligo. Resolution of skin lesions was observed after stopping the Toceranib phosphate therapy. CONCLUSION AND CLINICAL IMPORTANCE: Based on the gross lesions, histopathological features before and after tyrosine kinase inhibitor therapy, and Naranjo score, this case was considered to be consistent with cutaneous adverse drug effects. To the best of the authors' knowledge, this is the first report describing the clinical and histopathological features of presumed drug-induced skin depigmentation in a dog receiving Toceranib phosphate.

Successful treatment of a metastatic, gastrointestinal stromal tumour in a dog with toceranib phosphate (Palladia).[Pubmed:28199021]

J Small Anim Pract. 2017 Jul;58(7):416-418.

A ten-year-old, female-entire English springer spaniel presented with a large intra-abdominal mass but no other clinical signs. Gastrointestinal stromal tumour of the caecum with widespread abdominal metastasis was confirmed. Treatment with Toceranib phosphate resulted in complete response, despite the absence of exon-8 or exon-11 c-kit mutation. There was no clinical evidence of tumour recurrence nine months after diagnosis.

Toceranib phosphate (SU11654 phosphate) is an orally active receptor tyrosine kinase (RTK) inhibitor, and it potently inhibits PDGFR, VEGFR, and Kit with Kis of 5 and 6 nM for PDGFRβ and Flk-1/KDR, respectively. Toceranib phosphate (SU11654 phosphate) has antitumor and antiangiogenic activity, and used in the treatment of canine mast cell tumors .

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