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.
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.
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 IFNɣ (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 IFNɣ at 1549 pg/ml. Concomitant increases in IL-10 & IL-6 were observed. Plasma (median) levels TNFα 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.
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.
Clinical trial identification
NIH RAC 1407-1335
Legal entity responsible for the study
ZIOPHARM Oncology, Inc.
ZIOPHARM Oncology, Inc.
All authors have declared no conflicts of interest.