Mechanism of Action
In non-clinical pharmacology studies, tigilanol tiglate has been shown to have three inter-related effects that are responsible for its anti-tumor effectiveness. The first effect is to cause oncolysis of tumor cells that are in direct contact with tigilanol tiglate. The oncolysis occurs within the first hours following treatment and results from the disruption of mitochondrial functioning. Secondly, at the same time, tigilanol tiglate activates a protein kinase C (PKC) signaling cascade which propagates throughout the tumor, resulting in an acute inflammatory response with swelling and erythema extending to the tumor margins and immediate surroundings. This inflammatory response is normal and necessarily contributes to the activity of tigilanol tiglate by (a) restricting blood and oxygen supply to the tumor (causing localized hypoxia) and (b) recruiting and activating innate immune cells (principally neutrophils and macrophages), which then target the tumor and release reactive oxygen species, proteases, and cytokines that function in an antimicrobial role. This acute inflammatory response generally resolves within 48 to 96 hours. The third component of the antitumor activity of tigilanol tiglate is associated with direct effects of the drug in increased permeability of the tumor vasculature (via activation of the Beta-II isoform of PKC) leading to tumor vascular destruction. The resulting outcome is tumor destruction with a deficit or wound remaining where the tumor was located. Complete healing of the resulting wound following tumor destruction by STELFONTA is typically within 6 weeks.
Pharmacokinetic properties of STELFONTA were evaluated in a pilot study monitoring systemic levels following intratumoral injection, with a dose delivered according to the size of the mast cell tumor. A dose of 0.5 mg/cm3 (0.5 mL/cm3) was used in dogs with tumor volumes ranging from 0.1 to 6.8 cm3 resulting in doses ranging from 0.002 mg/kg to 0.145 mg/kg and total doses ranging from 0.05 mg to 3.4 mg per dog. A total of 6 cutaneous and 5 subcutaneous mast cell tumors were treated in 10 dogs (one dog had two tumors treated consecutively). The following range of pharmacokinetic parameters were determined for STELFONTA in plasma: 1) elimination half-life (t½): 2.85 to 36.87 hours; 2) maximum plasma concentration (Cmax): 0.356 ng/mL to 13.8 ng/mL; and 3) area under the plasma concentration time-curve to the last quantifiable plasma concentration (AUClast): 2.25 h*ng/mL to 31.24 h*ng/mL. There was no relationship between drug exposure (Cmax and AUClast) with tumor location (cutaneous or subcutaneous) or with total dose. In an evaluation of the pharmacokinetic data from the 5 dogs with cutaneous tumors, dose levels ranged from 0.002 mg/kg to 0.145 mg/kg. The highest Cmax was 11.1 ng/mL and the highest AUClast was 31.24 h*ng/mL at a dose of 0.125 mg/kg. For the other 5 dogs with subcutaneous tumors, doses ranged from 0.049 mg/kg to 0.094 mg/kg. The highest Cmax was 13.8 ng/mL and the highest AUClast was 30.81 h*ng/mL at a dose of 0.094 mg/kg.
The effectiveness of STELFONTA was evaluated in a well-controlled, multi-center, randomized, double-masked, field study in client-owned dogs. Enrolled dogs had non-metastatic World Health Organization stages Ia (one tumor confined to the dermis, without regional lymph node involvement) and IIIa (multiple dermal tumors; large infiltrating tumors without regional lymph node involvement) mast cell tumors that were (i) cutaneous, or (ii) subcutaneous and located at or distal to the elbow or the hock). A total of 123 client-owned dogs with a mast cell tumor
measuring less than or equal to 10 cm3 were randomized to treatment with a single injection of STELFONTA (n=81) or untreated control (n=42). On the day of treatment, the average tumor volume was 1.7 cm3 (range 0.1 to 9.8 cm3).
A total of 118 dogs were included in the effectiveness analysis; 80 dogs were in the STELFONTA group and 38 dogs were in the untreated control group. Response to treatment was evaluated using the RECIST2, where complete response (CR) is resolution of the target tumor, partial response (PR) is at least a 30% decrease in the longest diameter of target tumor, stable disease (SD) is a decrease of less than 30% or increase of less than 20% of the longest diameter of the target tumor, and progressive disease (PD) is greater than a 20% increase in the longest diameter of the target tumor.
The primary effectiveness variable compared CR rates of the target tumor between groups 28 days after treatment. At 28 days after treatment, a statistically significantly greater proportion of dogs in the STELFONTA treated group (60/80; 75%) achieved CR compared to dogs in the untreated control group (2/38; 5.3%) (p<0.0001). An objective tumor response (CR + PR) was observed in 64/80 (80%) of the STELFONTA treated dogs. Of the 60 dogs in the STELFONTA group that experienced CR at Day 28, response assessment was conducted for 59 dogs at Day 42 and for 57 dogs at Day 84. At Day 42, 59/59 (100%) were disease-free at the injection site, and at Day 84, 55/57 (96%) were disease-free at the injection site.
For all dogs, corticosteroids (prednisone or prednisolone) were initiated 2 days prior to treatment at a dose of 0.5 mg/kg orally twice daily and continued for 7 days total (2 days before, on the day of treatment and 4 days after treatment), then 0.5 mg/kg once daily for an additional 3 days. An H1 receptor blocking agent (diphenhydramine [2 mg/kg orally twice daily]) and H2 receptor blocking agent (famotidine [0.5 mg/kg orally twice daily]) were initiated on the day of treatment and continued for 7 days.
Other medications prescribed based on veterinary discretion included antibiotics, analgesics, and sedatives. The majority of antibiotics were used to treat injection site infections. The majority of analgesics were used to treat tumor pain and were mainly initiated on the day of or day after treatment. Sedatives were used for treatment administration, conducting diagnostics, anxiety, and temperament issues.
Quality of Life (QoL)3 was assessed by owners throughout the study and the mean scores for the QoL assessment was similar between the STELFONTA and untreated control groups at all time points.
Eighteen of the 20 STELFONTA treated dogs without CR received a second treatment. Twenty-eight days following the second treatment, CR was observed in 8/18 (44.4%) of these dogs. Forty-two days following the second treatment, CR was observed in 7/18 (38.9%) of treated dogs.
TARGET ANIMAL SAFETY
The margin of safety and toxicity of STELFONTA was evaluated in one laboratory safety study and one laboratory cardiovascular study utilizing final market formulation, and one pilot field study that used non-commercial formulation.
In a 4-week laboratory safety study, 48 healthy Beagle dogs 6 to 8 months old were administered STELFONTA intravenously over a 15-minute infusion once a week for four weeks on Days 1, 8, 15, and 22, at doses of 0, 0.025, 0.05, or 0.075 mg/kg body weight (ranges between 0.02-0.036, 0.039-0.056, and 0.06-0.08 mg/kg, respectively due to dosing variability). Control dogs (0 mg/kg) received a vehicle control at a volume equal to the 0.075 mg/kg dose. The intravenous route was chosen for this study because subcutaneous injection was too toxic and intratumoral administration was not possible.
There were twelve dogs per group (6 male, 6 female). Four dogs/sex/group were necropsied two days following the last dose and two dogs/sex/group were necropsied following a 2-week recovery period.
All dogs survived the study, and there were no STELFONTA-related effects on body weight, body temperature, ophthalmic exam, electrocardiographic parameters, and organ weights.
The following were observed only in dogs in the groups administered STELFONTA: decreased food consumption from Days 22-29, vomiting/retching during infusion or immediately post-infusion, wound formation at the infusion site after the second or third dose, decrease in activity sporadically throughout the study, and elevations in alanine aminotransferase on Day 23. The following were observed in all groups, including vehicle control and increased in a dose dependent manner: limited use of the leg that received the infusion occurred soon after dosing, weakness after the first dose, salivation and infusion site edema and erythema increased in frequency and severity throughout the study, and tremors occurred immediately post-infusion and increased in severity with dose.
Vomiting, retching, or tremors were typically transient and resolved within 1 hour of dosing while salivation also typically resolved within 4 hours. Loose feces were observed in all groups in a non-dose dependent manner. Polydipsia occurred in the control, 0.05 and 0.075 mg/kg groups. Trending towards decreasing hematocrit (but still within reference intervals) was observed in all groups. One dog in the 0.05 mg/kg group was mildly anemic during recovery. Monocytosis and elevated fibrinogen were seen on Days 2 and 23 in a dosedependent manner.
Gross pathology findings at the infusion site included inflammation, redness, and thickening of the skin. Correlative histopathology findings of the infusion site included hemorrhage, edema, inflammation, mixed cell infiltration, fibrosis, and chronic organizing thrombosis. Only one of the recovery dogs had changes at the infusion site consisting of proliferation of the intima. One dog in the 0.075 mg/kg group had a severe wound, confirmed on histopathology as ulcerative inflammation and severe necrosis with bacteria present. Gross pathology findings also included red, mottled, firm, and enlarged lymph nodes in all dose groups, including recovery dogs, confirmed on histopathology as inflammation, lymphoid hypercellularity, hemorrhage, and sinus histiocytosis. Pituitary cysts were observed in 7 dogs in all STELFONTA treated groups. One dog each from the 0.075 mg/kg group was observed to have kidney tubular vacuolation, dilation of the ventricles of the brain, and chronic inflammation of both the left thigh skeletal muscle and left sciatic nerve.
Laboratory Cardiovascular Study
In a 12-day laboratory cardiovascular study, 4 healthy male conscious telemeterized Beagle dogs approximately 2-4 years old were administered STELFONTA as a single intravenous infusion. Treatment consisted of four groups: vehicle control and STELFONTA at doses of 0.01, 0.025 and 0.075 mg/kg body weight. All four dogs received all treatments with at least a 3-day wash-out period.
All dogs survived the study and there were no STELFONTA-related effects on body temperatures, blood pressure, or electrocardiograms. The following were observed only after administration of STELFONTA in all dose groups: salivation, vocalization, incoordination, tremors, red feces, and decreased feces output. Retching, vomiting, incoordination, and changes in activity levels (increased and decreased) occurred in the 0.075 mg/kg group only. Tachycardia was seen for the first 2.5 hours after the 0.075 mg/kg dose only. The following were observed after administration of control or STELFONTA: excessive panting, decreased appetite, and limited usage/swelling of leg or paw. All dogs lost weight during the study. Clinical signs resolved around 4 hours post dosing.
Pilot Field Study
In a 28-day unmasked field study, 10 client-owned dogs, 6-14 years old were administered tigilanol tiglate (non-commercial formulation) once as an intratumoral injection at a dose of 0.5 mg tigilanol tiglate per cubic centimeter (cm3) of tumor volume, not exceeding 0.25 mg/kg body weight (maximum dose of 5 mg). One dog was enrolled a second time to treat a second mast cell tumor after successful treatment of the first tumor. See pharmacokinetic results from this study under Clinical Pharmacology.
The most common observations after tigilanol tiglate administration were injection site reactions including necrosis, swelling (localized edema and edema extending well beyond the tumor injection site), pain, restlessness, inflammation, erythema, bleeding ulcerations, bruising/discoloration, sloughing of tissue, open wound, mild drainage, malodor, and presence of granulation tissue. Three dogs experienced dermatitis with or without skin necrosis in a region nearby but distinct from the tumor injection site. One dog experienced non-weight bearing lameness, muscle atrophy and enlarged popliteal lymph node. One dog vomited after administration. Three dogs required longer healing times beyond 28 days, with the longest requiring 5 months. Hypoalbuminemia was observed in 5 dogs with hypoproteinemia observed in 1 of these 5 dogs on Day 7 and was resolved by Day 28.
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