Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma.

Abstract

9025^ Background: Interleukin-12 (IL-12) promotes anti-tumor activity through multiple mechanisms, including augmentation of adaptive and innate immune responses. Intratumoral (IT) delivery of IL-12 via electroporation (EP) avoids systemic toxicity while promoting systemic antitumor immunity. This phase 2 study explores the systemic efficacy, clinical response and safety of IT plasmid IL-12 injection (pIL-12) followed by EP in patients (pts) with advanced melanoma. Methods: This single-arm, open-label phase 2 study plans to enroll 30 pts with in-transit or M1a melanoma. One treatment cycle consists of IT pIL-12-EP on days 1, 5, 8 in up to four lesions per cycle. A maximum of four cycles at 12-week intervals are allowed. ORR was assessed by a modification of RECIST for cutaneous lesions with restaging performed every 12 weeks. The primary endpoint is best ORR within 24 weeks of first treatment. Pre- and post-treatment tumor biopsies were obtained in all patients. Ongoing analyses to assess safety and emerging efficacy data are being utilized to inform future studies. Results: 29 pts have been enrolled and have received at least one treatment cycle. The ORR is 33% (9/27), with 11% CR (3/27). Regression of non-injected lesions was seen in 62% (13/21) of pts with evaluable lesions. Transient pain (56.5%) and inflammation (17.4%) at the treatment site were the most common grade 1/2 drug-related adverse events (AEs), with no grade 3/4 drug-related AEs. Exploratory analyses indicate a doubling of intratumoral NK cells from pre-treatment through day 11 and at day 39, and increased frequency in activated circulating NK cells. Conclusions: Local treatment with pIL-12-EP is well tolerated without severe systemic side effects. Regression of treated and non-treated tumors suggests successful induction of systemic anti-tumor response. Local and systemic increases in NK cells are consistent with the expected pharmacodynamic effect of IL-12. Based on these data, an expansion protocol to evaluate increased treatment frequency is planned for melanoma patients. Clinical trial information: NCT01502293.