Dose Characterization of the Investigational Anticancer Drug Tigilanol Tiglate (EBC-46) in the Local Treatment of Canine Mast Cell Tumors

Abstract

Mast cell tumor (MCT) is the most common cutaneous neoplasm in dogs and wide surgical resection is the current first-line treatment. However, recurrence is common and often requires more specialist and expensive therapies. Tigilanol tiglate is a novel small molecule drug delivered by intratumoral injection that is currently under development to provide a new option for treating MCT. The aim of this study was to characterize a safe and effective dose of tigilanol tiglate for canine MCT and to gather preliminary data on the drug's pharmacokinetics. A multicenter, open-label, uncontrolled, non-randomized, dose de-escalation design was used. Eligibility was MCT stage I/IIa and a tumor size of 0.1–6.0 cm 3 . Dosing was based on tumor size (50% v/v tumor) and 3 drug concentrations (1.0, 0.5, 0.2 mg/mL) were evaluated. Twenty-seven dogs were treated in 3 dose de-escalation cohorts (10, 10, and 7 dogs, respectively). Efficacy at 21 days was defined using international accepted solid tumor response criteria (RECIST). Greatest efficacy (90% complete response) was observed at the highest drug concentration (1.0 mg/mL) and adverse events were generally low grade, mild and transient, and directly associated with the mode of action of the drug. Hematological and serum biochemistry were generally unremarkable with plasma concentration curves typical of a non-intravenous parenteral medication. Intratumoral treatment of MCT with tigilanol tiglate at a concentration of 1.0 mg/mL was highly efficacious and well-tolerated. These results support the drug's further development for the treatment of MCT and other solid tumors.

Use of the Intratumoural Anticancer Drug Tigilanol Tiglate in Two Horses

“…Following treatment with tigilanol tiglate, the tumors in both equine patients followed a pattern of clinical response consistent with that seen and reported with the drug in other species and tumor types including canine mast cell tumors ( 1 , 3 ), a variety of human neoplasias ( 4 ), and murine tumors ( 2 , 5 ). This clinical response is directly related to the mode of action of tigilanol tiglate in tumor destruction and involves localized bruising and inflammation/oedema developing at the treatment site within the first 24 h, followed by haemorrhagic necrosis of the tumor mass and finally slough of the necrotic tumor leaving a treatment site wound which usually heals uneventfully via secondary intention without the need for bandaging or other interventions ( 1 ).…”

“…The results reported here show that our equine-specific protocol has been effective in these two initial cases in managing the drug-induced inflammatory response at the treatment site, and resulting wound size, through a combination of: i. A 30% lower intratumoural dose rate (0.35 mg drug/cm 3 tumor volume) compared to that required for efficacious treatment of canine mast cell tumors (1,3) and of a range of neoplasia in humans (4); and, ii. A regime of concomitant non-steroidal anti-inflammatory medications (NSAIDs) administered at, and in the days following, treatment.…”

“…A 30% lower intratumoural dose rate (0.35 mg drug/cm 3 tumor volume) compared to that required for efficacious treatment of canine mast cell tumors ( 1 , 3 ) and of a range of neoplasia in humans ( 4 ); and,…”

“…Tigilanol tiglate (also known as EBC-46) is a novel small molecule approved in the European Union and United Kingdom as an intratumourally-administered, veterinary pharmaceutical for treatment of non-metastatic, non-resectable canine mast cell tumors (1). It is also under clinical evaluation as an intratumoural treatment for a range of other cutaneous and subcutaneous cancers in humans and companion animals (2)(3)(4). Tigilanol tiglate is a potent cellular signaling molecule with a multifactorial mode of action that induces (a) a rapid, acute and highly localized inflammatory response in and immediately surrounding the tumor mass, (b) recruitment of immune cells, (c) loss of tumor vasculature integrity and (d) induction of tumor cell death by oncosis (5).…”

Macrocyclic Diterpenoids from Euphorbiaceae as A Source of Potent and Selective Inhibitors of Chikungunya Virus Replication

“…Others are currently in preclinical or clinical studies. Tigilanol tiglate (EBC-46 ® ) has completed safety and efficacy studies for the treatment of solid tumors in dogs [64] and is currently in clinical study for the treatment of head and neck tumors in human adults [65].…”