Phase Ib/II open-label study of Ad-RTS-hIL-12 + veledimex gene therapy in chemotherapy-responsive locally advanced or metastatic breast cancer patients

Abstract

Background: Ad‐RTS‐hIL‐12 (Ad) is a novel gene therapy candidate expressing IL‐12 under the control of an orally administered activator ligand, veledimex (V), through the proprietary RheoSwitch Therapeutic System (RTS) gene switch. Ad + V controls local IL‐12 expression and stimulates anti‐cancer T cell immune response. Methods: Patients with stable or responsive disease to 1st or 2nd line chemotherapy were injected intratumorally with Ad 1 x1012 vp and received up to 7 daily V doses. The primary endpoint is safety and tolerability. Secondary endpoints including 12 week (wk) progression rate and comparison of responses by Immune‐Related Response Criteria (irRC) vs. RECIST. Results: As of April 28, 2016, 8 subjects (7 HER2‐, 1 HER2+) have been treated (33‐63 yo): 6 have completed 6wk and 3 have completed 12 wk imaging. At 12wks, 1 achieved a partial response that was durable until wk 18, 1 maintained stable disease until wk 35, and 1 had progression per irRC. Tumor levels showed increased and persisting elevation of IFNgamma (51 @ baseline vs. 183 pg/g @ 6 wks), demonstrating sustained activation of immune system in the tumor microenvironment. Plasma cytokines were assessed at baseline, day (D) 1, D3, D8, Wk 6 and 12. IL‐12 plasma level increased peaking at D3 with a median value of 5 pg/ml and downstream IFNgamma at 1549 pg/ml. Concomitant increases in IL‐10 & IL‐6 were observed. Plasma (median) levels TNFalpha significantly increased from 1 pg/ml (baseline) to 5 pg/ml at D3‐8. Plasma cytokines returned to baseline after discontinuation of V. Immunohistochemistry (IHC) and flow cytometry correlates are underway. Expected treatment‐related AEs (TRAE) were reported in all subjects. There were related grade 3 events in 3 subjects, including 2 AST/ALT increased (1 SAE), 1 fatigue (SAE) and 1 leukopenia. All related SAEs and grade 3 AEs resolved with discontinuance of V. Conclusions: Intratumoral regulated IL‐12 expression using AD + V in locally advanced or metastatic breast cancer patients was associated with expected toxicities that resolved with discontinuance of V. Clinical and biologic activity have been observed, warranting continued investigation.