A Phase I Open-Label Study Of Ad-Rts-Hil-12, An Adenoviral Vector Engineered To Express Hil-12 Under The Control Of An Oral Activator Ligand, In Subjects With Unresectable Stage Iii/Iv Melanoma

3022 Background: IL-12 is a pleiotropic cytokine with known antitumor activity; however, clinical use was limited by toxicity when delivered systemically. Ad-RTS-hIL-12 is an adenoviral vector engineered for controlled expression of IL-12 with the RheoSwitch Therapeutic System (RTS) and an oral activator, INXN-1001. Methods: In a phase I, 3+3 dose escalation study, subjects with unresectable stage III/IV melanoma were administered 1e12 viral particles (Ad-RTS-hIL-12) intratumorally on the first day of up to six 21-day cycles, and INXN-1001 (5, 20, 100, and 160 mg) orally on days 1-7 of each cycle. Results: Dose escalation is complete with 14 subjects treated. Median prior therapeutic agents was 3 (range 1-4). Common related adverse events included chills (11, 78.6%), pyrexia (11, 78.6%), fatigue (10, 71.4%), and nausea (10, 71.4%). With a biologically effective dose of 160 mg, MTD for INXN-1001 was not reached. One death unrelated to study drug was secondary to septicemia. Clinical activity was observed in 5 of 7 subjects treated at doses of INXN-1001 ≥100 mg, but not at <100 mg, and included prominent inflammatory responses in injected and non-injected lesions, decreases in size of injected and non-injected lesions, and reduction in tumor-associated pain. One subject at the 160-mg dose had stable disease for 20 weeks. Clinical activity in dose cohorts ≥100 mg coincided with a 4-fold median increase from baseline in peak serum levels of IL-12 and IFN-γ compared with lower dose cohorts. Flow cytometric analyses of PBMCs revealed 7-fold (≥100 mg dose cohorts) median increases from baseline in peak levels of absolute numbers of CD3+ and CD8+ T cells. ELISPOT and T-cell proliferation assays for antigen-specific responses are ongoing. Conclusions: Intratumoral delivery of IL-12 via an adenoviral vector with RheoSwitch enabled finely-controlled expression of IL-12 levels by an oral ligand. Ad-RTS-hIL-12 plus INXN-1001 (160 mg) was well tolerated and induced biological and clinical activity in subjects with advanced melanoma. Phase II studies are ongoing at the biologically effective dose. Clinical trial information: NCT01397708.