Randomized controlled clinical study evaluating the efficacy and safety of intratumoral treatment of canine mast cell tumors with tigilanol tiglate (EBC‐46)

Abstract

Objective To evaluate the efficacy and safety of tigilanol tiglate (TT) for local intratumoral treatment of mast cell tumors (MCTs) in dogs. Methods A randomized controlled clinical study in 2 phases involving 123 dogs with cytologically diagnosed MCT. Phase 1 compared 81 TT‐treated dogs with 42 control dogs; phase 2 allowed TT treatment of control dogs and retreatment of dogs that failed to achieve tumor resolution after TT treatment in phase 1. Tigilanol tiglate (1 mg/mL) was injected intratumorally with dose based on tumor volume. Concomitant medications were used to minimize potential for MCT degranulation. Modified response evaluation criteria in solid tumors were used to evaluate treatment response at 28 and 84 days. Adverse events and quality of life were also assessed. Results A single TT treatment resulted in 75% complete response (CR) (95% confidence interval [CI] = 61‐86) by 28 days, with no recurrence in 93% (95% CI = 82‐97) of dogs by 84 days. Eight TT‐treated dogs that did not achieve CR in phase 1 achieved CR after retreatment, increasing the overall CR to 88% (95% CI = 77‐93). Control dogs had 5% CR (95% CI = 1‐17) at 28 days. Wound formation after tumor slough and wound size relative to tumor volume were strongly associated with efficacy. Adverse events typically were low grade, transient, and directly associated with TT's mode of action. Conclusions Tigilanol tiglate is efficacious and well tolerated, providing a new option for the local treatment of MCTs in dogs.

Use of the Intratumoural Anticancer Drug Tigilanol Tiglate in Two Horses

“…In respect to dose rate, it is interesting that despite the 30% lower tigilanol tiglate dose per unit of tumor volume, the progression and timing of critical clinical events associated with the mode of action of tigilanol tiglate in tumor destruction and subsequent wound resolution (viz. induction of the acute inflammatory response, haemorrhagic necrosis of the tumor, and tumor slough) in these equine cases was very similar to that reported previously in treatment of canine and human tumors (1,4). This is consistent with horses having a higher sensitivity to inflammatory challenges and apparently lower thresholds, compared to canines and humans, for activation of key pro-inflammatory mediators (such as IL-1β and TNF-α) that are induced by tigilanol tiglate and which are involved in early stage initiation and amplification of acute phase responses (10,11).…”

“…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.…”

“…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). At efficacious doses, these processes lead to haemorrhagic necrosis and destruction of the tumor within 7 days followed by resolution of the resulting wound (tissue defect) with good functional and cosmetic outcomes (1). Because this multifactorial mode of action relies in significant part on treatment response by "host" tissues (e.g., immune cell recruitment and effects on tumor vasculature), rather than intrinsic sensitivity of the tumor cells per se, tigilanol tiglate can be considered "tumor agnostic" and has potential for efficacy against a range of different tumor types (irrespective of cells of origin or specific cancer gene mutations) across different animal species.…”

Potent Antibacterial Prenylated Acetophenones from the Australian Endemic Plant Acronychia crassipetala

“…More recently, an epoxy-tigliane diterpene, tigilanol tiglate (formerly EBC46), from the Queensland tropical endemic species Fontainea picrosperma C. T. White, has been discovered and shown to have significant anticancer activity [ 7 ]. Tigilanol tiglate has been approved by the European Medicines Authority [ 8 ] as a novel canine therapy for mast cell tumours [ 9 ] and is currently in clinical trials to assess its potential as a human anticancer therapeutic [ 10 ].…”