Phase I clinical trial evaluating calcium electroporation for management of cutaneous tumors in dogs
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Traditionally, cutaneous tumors in dogs are managed with surgery, and adjuvant radiation therapy is considered in cases where complete resection is not achieved. Electrochemotherapy (ECT), with both cisplatin and bleomycin, has shown promise as an alternative treatment in both the macroscopic and microscopic disease settings for many different types of cutaneous tumors in dogs. Although ECT is typically a well-tolerated therapeutic option, potential complications include personnel exposure to chemotherapy and chemotherapy side effects. Previous studies in human ((Falk et al., 2018); Plaschke et al. (2019)) and equine medicine (Galant et al. (2019); Frandsen, Gehl, et al. (2020)) have substituted calcium for chemotherapy in electroporation protocols for cutaneous tumors as calcium plays an active role in many aspects of physiologic cellular function, including cellular proliferation and cell death (Patergnani et al. (2020)). Calcium electroporation involves combining calcium injected intratumorally with electroporation. Pulsed, high-voltage charges are then applied to the tumor to alter the cell membrane via transient electroporation which allows calcium to enter the cell and ultimately lead to cell death. In this phase I clinical trial, we aimed to determine the maximum tolerated dose (MTD) of intralesional calcium and establish a safety profile for this treatment. We hypothesized that injecting calcium intratumorally based on tumor volume would be safe and only lead to transient hypercalcemia. As a secondary aim, we documented treatment responses as an early indicator of efficacy. We hypothesize that calcium electroporation, using a 9 mg/mL concentration of calcium chloride (CaCl), could serve as a reasonable alternative to cytotoxic ECT. Ten client owned dogs with different cutaneous lesions (5 soft tissue sarcomas (STS), 3 mast cell tumors (MCT), 1 eccrine gland adenocarcinoma, 1 epithelial hyperplasia) were prospectively enrolled and treated with two sessions of calcium electroporation fourteen days apart. During the first calcium electroporation treatment, ionized calcium measurements were evaluated at baseline, 30 minutes post CaCl injection, and 2 hours post CaCl injection. Total calcium volume to inject intratumorally was determined by individual tumor size and the cohort of each dog. At day 14 and day 28, tumor response was evaluated, and all adverse events (AE(s)) experienced throughout the trial were compiled for each dog. Results revealed that AEs included pruritus, ulceration, erythema, and swelling of the treated site. One dog did experience grade I vomiting (Leblanc et al. (2021)) one day following the second calcium electroporation treatment that resolved without any medical intervention. No dog experienced clinical hypercalcemia. Early response rates included 80 percent (8/10) stable disease, 10 percent (1/10) partial response, and 10 percent (1/10) progressive disease. The MTD was not identified during this clinical trial. Overall, calcium electroporation was well-tolerated. Improved clinical outcomes in dogs with cutaneous tumors may be possible with use of higher calcium concentration.
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M.S.