Safety evaluation of combination carboplatin and toceranib phosphate (Palladia) in tumour‐bearing dogs: A phase I dose finding study

Abstract

Combining conventional cytotoxic maximum tolerated dose (MTD) chemotherapy with low-dose metronomic and/or anti-angiogenic agents is a exciting area of oncologic research. The objective of this study was to establish the MTD, safety and adverse event (AE) profile of 1 such drug combination. This prospective phase I dose-finding clinical trial assumed an open-label 3 + 3 cohort design. Client-owned dogs with 1 or more cytologically and/or histologically confirmed and macroscopically measurable, naive or recurrent, malignant tumours, were enrolled. No preference for tumour histology, grade or stage was expressed. Toceranib was administered at a dose of 2.75 mg kg by mouth (PO) every other day (EOD), and carboplatin administered intravenously (IV) every 21 days at a starting dose of 200 mg m . A total of 25% dose escalation was proposed for carboplatin, to a maximum of 300 mg m . AEs were graded according to the Veterinary Cooperative Oncology Group's common terminology criteria for AEs (VCOG-CTCAE). Grade 3 haematologic or gastrointestinal AEs were nominated dose-limiting. Response to therapy was evaluated according to the VCOG's revised RECIST criteria. Eleven dogs were enrolled. Tumour histologies included sinonasal carcinoma, osteosarcoma, thyroid carcinoma, melanoma and apocrine gland anal sac adenocarcinoma. MTDs of carboplatin and toceranib were identified as 200 mg m IV every 21 days and approximately 2.75 mg kg PO EOD, respectively. The dose-limiting toxicity was neutropenia. Two dogs experienced a partial response, and 6 maintained stable disease. Combination carboplatin and toceranib chemotherapy was well-tolerated. Clinical benefit was observed in most cases. This protocol warrants further investigation in phase II/III trials.

In vitro and in vivo effects of toceranib phosphate on canine osteosarcoma cell lines and xenograft orthotopic models

“…Today, clear indications for using TOC in canine OS treatment are not available, and recent clinical trials did not support the use of TOC as a single agent or in combination with other commonly used therapies . In conclusion, our results demonstrate that TOC is able to mildly inhibit cell growth in vitro, while its effect is more relevant in xenograft models.…”

“…However, there is increasing evidence that other solid tumours, such as anal sac, head‐neck and thyroid carcinomas, and OSA can be successfully treated with TOC . Clinical trials performed on canine OSA patients showed controversial results when using Palladia as a single agent in canine metastatic OSA or in combination with other drugs, suggesting that more data are needed to clarify its benefit . Xenograft mouse models represent important tools for investigating the in vivo response to cancer therapeutic interventions.…”

Tumour angiogenesis, anti‐angiogenic therapy and chemotherapeutic resistance

“…Toceranib and masitinib have been approved for veterinary use in dogs, particularly for mast cell tumours . However, a range of anti‐angiogenic drugs, either alone or in combination, has been used to treat a wide variety of canine and feline neoplasms, including osteosarcomas, melanomas, fibrosarcomas, histiocytic sarcomas, haemangiosarcomas, lymphomas and prostatic, thyroid, nasal, gastric, mammary, pulmonary, biliary, salivary, anal sac and urinary bladder carcinomas …”

“…In the majority of these veterinary studies, tocerinab was used, sometimes alone [29][30][31][32][33][34][35][36][37] or, more commonly, in combination with other drugs such as cyclophosphamide (belonging to the nitrogen mustard group of alkylating agents), 38,39 vinblastine (an antimitotic alkaloid), 40,41 carboplatin (a platinum-containing complex), 42,43 lomustine (1-(2-chloroethyl)-3-cyclohexyl-1-nitrosurea (or CCNU), which belongs to the nitrosurea group of alkylating agents), [44][45][46] doxorubicin (an anthracycline antibiotic) [47][48][49] and piroxicam (a nonsteroidal anti-inflammatory drug (NSAID) with cyclooxygenase (COX)-2 inhibiting properties). 38,[50][51][52] Masitinib has also been evaluated in dogs.…”

Concurrent 5‐fluorouracil and carboplatin for the treatment of canine carcinomas

“…While combination schemes are inherently important in the treatment of other canine neoplasms, especially lymphoma, little information exists for carcinomas. A recent prospective trial utilizing carboplatin in combination with toceranib showed a clinical benefit in some dogs with carcinomas (thyroid and anal sac carcinoma), with myelosuppression being the dose limiting toxicity . Despite the frequent use of 5‐FU and platinum combinations in human carcinomas, these agents used together have not been previously reported in veterinary oncology.…”