Chapter 79

Drug Update


Toceranib phosphate (Palladia) is an orally bioavailable small-molecule inhibitor that blocks a variety of receptor tyrosine kinases (RTKs) expressed on the cell surface by acting as a reversible competitive inhibitor of adenosine triphosphate binding; it thereby prevents receptor phosphorylation and subsequent downstream signaling. The published inhibitory profile of toceranib includes the RTKs, vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor β (PDGFRβ), and stem cell factor receptor (KIT) (London et al, 2003); however, it is very closely related to another TKI called sunitinib (Sutent) that blocks the activity of several members of the split RTK family, including VEGFR2, VEGFR3, PDGFRα/β, KIT, colony-stimulating factor receptor (CSF1R), FMS-like tyrosine kinase-3 (FLT3), and “rearranged during transfection” RTK (RET) (Papaetis and Syrigos, 2009). A recent kinome analysis (London et al, n.d.) supports the broad activity of toceranib against the split kinase RTKs, RET, and possibly Janus kinase (JAK) family members. Toceranib initially was developed as an antiangiogenic agent because inhibition of VEGFR and PDGFR family members blocks angiogenesis in several mouse tumor models; however, its broad target profile including KIT, FLT3, and RET results in direct antitumor activity in some cancer types as well. The combination of antiangiogenic and antitumor activity likely provides more extensive clinical activity than that observed with narrowly targeted TKIs.

Work with Toceranib before Food and Drug Administration Approval

The first evaluation of toceranib in dogs was a phase I clinical trial in 57 dogs with a variety of cancers (London et al, 2003). In this study, objective responses were observed in 16 dogs (objective response rate [ORR], 28%) consisting of 6 complete responses (CRs) and 10 partial responses (PRs), with stable disease (SD) achieved in an additional 15 dogs for an overall clinical benefit rate of 54%. Responding tumors included sarcomas, carcinomas, melanomas, myeloma, and mast cell tumors (MCTs). The highest ORR was in dogs with MCT, with 10 of 11 dogs with activating mutations in the c-kit gene exhibiting responses (n = 9) or SD (n = 1). This study also established the maximum tolerated dose (MTD) of toceranib as 3.25 mg/kg q48h PO. Adverse events were primarily gastrointestinal (GI), including loss of appetite, diarrhea, and less commonly vomiting, although these toxicities were relatively well controlled with the addition of appropriate concomitant medications.

Based on the phase I trial results, a placebo-controlled randomized registration study of toceranib was performed subsequently in dogs with nonresectable grade II and III MCTs (London et al, 2009). During the blinded phase, the ORR in toceranib-treated dogs (n = 86) was 37.2% (7 CRs, 25 PRs) compared with 7.9% (5 PRs) in placebo-treated dogs (n = 63). Of 58 dogs that received toceranib following placebo failure, 41.4% (8 CRs, 16 PRs) experienced an objective response. The ORR for all 145 dogs was 42.8% (21 CRs, 41 PRs) with an additional 16 dogs experiencing SD for an overall clinical benefit rate of 60%. Dogs with MCTs harboring activating mutations in c-kit were roughly twice as likely to respond to toceranib than those with wild-type c-kit (69% versus 37%), and dogs without lymph node metastasis had a higher ORR than those with lymph node involvement (67% versus 46%). As expected, GI toxicity was the most common adverse effect and was generally manageable with symptomatic therapy, drug holidays, and dosage reductions.

Work with Toceranib after Food and Drug Administration Approval

Following its approval in 2009, toceranib was used off label to treat a variety of canine cancers, typically in the setting of failed primary or standard-of-care treatments. A retrospective analysis of the use of toceranib in this setting was reported recently, and biologic activity was observed in several solid tumors, including anal gland anal sac adenocarcinoma (AGASACA), metastatic osteosarcoma, thyroid carcinoma, head and neck carcinoma, and nasal carcinoma (London et al, 2012). Clinical benefit (CR, PR, plus SD of clinically relevant duration) was observed in 63 of 85 dogs (74%), including 28 of 32 dogs with AGASACA (8 PRs, 20 SD), 11 of 23 dogs with osteosarcoma (1 PRs, 10 SD), 12 of 15 dogs with thyroid carcinoma (4 PRs, 8 SD), 7 of 8 dogs with head and neck carcinomas (1 CR, 5 PRs, 1 SD), and 5 of 7 dogs with nasal carcinomas (1 CR, 4 SD). In dogs experiencing clinical benefit, the median dose of toceranib was 2.8 mg/kg; 36 of 63 (58.7%) dogs were dosed on Monday, Wednesday, and Friday, and 47 of 63 (74.6%) were treated for 4 months or longer. These data provide preliminary evidence that toceranib exhibits clinical benefit in dogs with certain solid tumors, although future prospective studies are necessary to define its true activity.

There is significant interest in the use of nonsteroidal antiinflammatory medications (NSAIDs) for the treatment of cancer in dogs and cats, not only for the management of cancer-related pain, but as part of multiagent protocols. Piroxicam, a mixed cyclooxygenase-1/cyclooxygenase-2 inhibitor, has demonstrated single-agent activity in some canine cancers, particularly carcinomas. Given that both toceranib and piroxicam exhibit dose-limiting GI toxicity, it was predicted that combining these drugs would result in a more unfavorable adverse effect profile that would preclude their concurrent use. Therefore a phase I trial was performed in dogs with tumors (non-MCT) to establish the safety of toceranib/piroxicam coadministration (Chon et al, 2012). Five escalating dosages, up to and including the approved label dosage for toceranib and the standard dosage for piroxicam, were tested and no increase was noted in the frequency of dose-limiting adverse effects necessitating drug discontinuation. Additionally, several antitumor responses were observed. Although the combination of standard dosages of both drugs (toceranib 3.25 mg/kg q48h PO and piroxicam 0.3 mg/kg q24h PO) was found to be generally safe, the dogs were not monitored long term to assess whether GI adverse effects occurred after long-term drug administration. Therefore it is generally recommended that the piroxicam be given q48h alternating with the toceranib to avoid potential GI issues.

Because the ability to combine toceranib with chemotherapy agents would be desirable, particularly in the setting of MCT, a phase I clinical trial was performed to identify an appropriate dosing regimen combining toceranib with vinblastine in canine MCT (Robat et al, 2012). These two drugs were chosen because both exhibit single-agent activity in MCT, and they have nonoverlapping primary toxicities. The dose-limiting toxicity for the toceranib/vinblastine combination was found to be neutropenia, and the MTD was vinblastine at 1.6 mg/m2 every other week with toceranib 3.25 mg/kg q48h. The 50% reduction in dose intensity for vinblastine was required because of the enhanced myelosuppression when it was combined with toceranib. Despite the reduction in vinblastine dose intensity, the ORR was 71% for the drug combination. The enhanced myelosuppression and significant biologic activity suggests the possibility of additive or synergistic activity, although a prospective randomized evaluation of this drug combination will be necessary to confirm this.

In addition to combining toceranib with chemotherapeutic drugs, there is interest in combining it with radiation therapy (RT) for the treatment of MCT and other canine cancers (Carlsten et al, 2012). Dogs with nonresectable MCTs received prednisone, omeprazole, diphenhydramine, and toceranib at 2.75 mg/kg on a Monday-Wednesday-Friday schedule for 1 week before starting coarsely fractionated RT (24 Gy delivered in three or four treatments over 21 days). The ORR was 76.4%, with 58.8% of dogs achieving CR and 17.6% experiencing PR. The overall median survival time was not reached with a median follow-up of 374 days. Importantly, there was no evidence of enhanced radiation-induced toxicities in this clinical trial. Future clinical trials are necessary to determine the long-term activity of combined RT and toceranib treatment in dogs with cancer.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Toceranib

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