First-in-human phase I/II study of EN002-gel, a first-in-class drip inhibitor, in non-melanoma skin cancer and actinic keratosis.

e21567 Background: The high global incidence of skin cancer severely impairs patients' quality of life and even poses a life-threatening risk. Traditional therapies carry severe local adverse reactions, long treatment courses and high recurrence rates. EN002 is a novel anticancer compound we developed based on the novel anticancer targets, DNA Replication-Initiation Proteins (DRIPs) that we have established. It selectively induces apoptosis of cancer cells but not normal cells and can eradicate tumors in mouse xenograft models. Phase II clinical study of EN002 gel for non-melanoma skin cancer (NMSC) and precancerous lesions in China and Australia is near completion, with an emphasis on actinic keratosis (AK) which is a common precancerous skin lesion with a risk of developing into skin cancer. Methods: This is a multicenter, multiple-arm, partially randomized, open-label, Phase I/II clinical study to evaluate the safety, tolerability and efficacy of EN002-gel in the treatment of adult patients with AK or NMSC including basal cell carcinoma (BCC), Bowen's disease (BD), and low-risk squamous cell carcinoma (SCC). In Phase I, dose escalation was performed using the BOIN design, encompassing six dose levels from 0.008 to 0.12 mg/cm², and 0.06 mg/cm² was confirmed as the recommended Phase II dose (RP2D). Two dosing frequencies at the RP2D are under investigation in Phase II: each dosing cycle consists of either 11 once-every-other-day doses or 14 once-daily doses, both with a 5-day drug-free period preceding the next cycle. Treatment duration was up to three cycles for patients with AK, and six cycles for patients with NMSC. Patients underwent 28-day and 56-day follow-up periods after the last dose for Phase I and Phase II, respectively. Results: Drug-related adverse events were predominantly Grade 1 or 2 local cutaneous reactions at the application sites, with no drug-related serious adverse events reported. In Phase I, lesions exhibited varying degrees of clearance with no disease progression observed. In the ongoing Phase II study, among the first 20 evaluable AK patients (Olson grades 1-3; 1-7 lesions on the face and/or limbs per patient) who completed the study, 90% (18/20) achieved complete lesion clearance either at the end of treatment or during the follow-up period. Among six evaluable patients with one or more BD lesions who completed the study, 66.7% (4/6) attained complete clinical clearance. Significant tumor shrinkage was also observed in patients with BCC and SCC, although complete clearance has not been achieved to date. Conclusions: The Phase I/II studies provided clinical evidence of a favorable benefit-risk profile of a novel topical therapy for patients with BD, BCC, SCC or AK, who represent unmet medical needs. Phase II drug treatment for AK is expected to be completed in May 2026 and new results will be presented at this meeting. Clinical trial information: China-CTR20221021; also Australian-ACTRN12623001219673.