Phase I dose-escalation study to determine the safety, tolerability, preliminary efficacy and pharmacokinetics of an intratumoral injection of tigilanol tiglate (EBC-46)

Abstract

Background: Tigilanol tiglate, a short-chain diterpene ester, is being developed as intratumoral treatment of a broad range of cancers. We conducted the first-inhuman study of intratumoral tigilanol tiglate in patients with solid tumors. Methods: Tigilanol tiglate was administered in a multicentre, non randomized, single-arm study, with escalating doses beginning with 0¢06 mg/m 2 in tumors estimated to be at least twice the volume of injection (dose-escalation cohorts). Patients with smaller tumors were assigned to the local effects cohort and received the appropriate dose for tumor size. Findings: Twenty-two patients were enrolled. The maximum dose was 3¢6 mg/m 2 and the maximum tolerated dose was not reached. There was one report of dose-limiting toxicity (upper airway obstruction), two serious adverse events (upper airway obstruction and septicemia), 160 treatment-emergent adverse events, and no deaths. Injection site reactions in all tumors and tumor types occurred even at the lowest dose. Six of the 22 patients experienced a treatment response, with four of the six patients achieving complete response. Interpretation: Intratumoral tigilanol tiglate was generally well tolerated, the maximum tolerated dose was not reached, and clinical activity was observed in 9 tumor types including complete response in four patients. These results support the continued development of tigilanol tiglate for intratumoral administration. Funding: QBiotics Group Limited Brisbane, Queensland, Australia was the sponsor of the study.

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 ).…”

“…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 – 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 ).…”

Antitumor Effects of Curcumin and Glycyrrhetinic Acid‐Modified Curcumin‐Loaded Cationic Liposome by Intratumoral Administration

“…A great deal of studies show that intratumoral injection of drugs has been proven to have a positive effect after many years of clinical research, can provide high drug concentrations at the tumor site with minimal exposure of nontarget tissues, and can prolong patient survival and improve quality of life [24][25][26]. Since Sugiura [27] first reported that Evidence-Based Complementary and Alternative Medicine PEI (percutaneous alcohol injection therapy) was adopted to treat liver cancer in 1983, the related research and clinical applications in the field have attracted wide attention.…”

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 ].…”