574 Preliminary results from an escalating dose cohort study of VT30, a topically formulated phosphatidylinositol 3-kinase inhibitor (PI3K), intended as a treatment for cutaneous vascular malformations associated with underlying PIK3CA or TEK mutations

Abstract

Purpose: This report gives findings from an (ongoing) Phase 1b, escalating dose, clinical trial, assessing the safety and tolerability of VT30 Topical Gel as a treatment for venous, lymphatic and mixed venolymphatic lesions of the skin (VM, LM and VLM, respectively), driven by inappropriate activation of intracellular PI3K. Methods: After giving informed consent and completing screening evaluations that included a confirmation of underlying genotype (PIK3CA or TEK mutation), adult subjects with cutaneous VM, LM or VLM lesions were allocated to receive 4 weeks (wks) of Topical VT30 Gel, applied once daily to a 140 cm2 target treatment area, with lesion involvement. Four sequential, open-label escalating dose cohorts of 3 subjects each (12 total) were designed for sequential completion as follows: Cohort 1, 2 wks of 0.12% (concentration strength) gel, followed by the final 2 wks at 0.6%; Cohort 2, 2 wks of 0.6% gel, followed by the final 2 wks at 1.2%; Cohort 3, 2 wks of 1.2 % gel, followed by the final 2 wks at 2.3%; and Cohort 4, a full 4 wks at the maximum tolerated or maximum feasible dose (MTD or MFD, respectively) concentration. Results: 23 potential subjects were screened to allocate a total of 12 - 7 were positive for a PIK3CA mutation, and 5 had an underlying TEK mutation. Over 12 subjects treated in Cohorts 1 – 4, VT30 topical gel has been generally safe and tolerated. To date, patient assessments have reflected a phenotypically heterogeneous group. Investigators have reported changes consistent with an improvement in underlying vascular lesions. Adequate tissue-drug levels have been documented in association with a pharmacodynamic readout suggesting local PI3K inhibition. No circulating drug has been detected in plasma. Conclusions: VT30 Topical Gel’s emerging profile is consistent with a potential treatment for patients with vascular malformations of the skin, driven by inappropriate PI3K activation.