Abstract OT1-01-05: Phase 1b/2 study of intratumoral Ad-RTS-hIL-12 + veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer
Authors: McArthur HL , Page D , Proverbs-Singh T , Solomon S , Hudis C , Norton L , Patil S , Barrett JA , Lebel F 
Published: May 2016

Abstract
Background: Immune-based strategies involving T-cell activation have recently shown significant activity in multiple tumor types. The presence of immune elements in breast cancers has prognostic and predictive impact. Thus, strategies that optimize the interplay between a breast cancer and the effected individual's immune system may be therapeutic. Interleukin-12 (IL-12), a pro-inflammatory cytokine, reverses immune escape mechanisms induced by myeloid derived suppressor and dendritic cells which, in turn, improves the function of activated CD8+ T cells and promotes tumor stroma collapse. Because tumor neoantigens may be generated in response to chemotherapy, IL12-mediated immune modulation may be optimal in patients with chemotherapy-sensitive metastatic breast cancer. 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).
Trial Design: Open-label, phase 1b/2, single-arm, single-center study of Ad+V in women with stable or responsive disease after ≥ 12-weeks of 1st or 2nd-line chemotherapy. Eligible patients will be placed on chemotherapy-holiday and enter the immunotherapy phase, consisting of a single cycle of Ad administered intratumorally (Day 1), along with V (80 mg QDx7). HER2-directed antibody therapy may be continued during the immunotherapy phase for women with HER2- disease.
Key Eligibility Criteria: Women ≥18 years with histologically-confirmed locally advanced or metastatic breast cancer of any subtype who have achieved a partial response (PR) or stable disease (SD) to 1st or 2nd-line chemotherapy are eligible. Exclusion criteria include use of immunosuppressive drugs, compromised immune function, autoimmune disorder, or brain metastases.
Specific Aims: To evaluate the safety and tolerability of Ad+V immunotherapy in eligible women. Secondary endpoints include 12 week overall response rate, 12 week disease control rate and the impact of treatment on exploratory immune biomarkers.
Statistical Methods: Safety and efficacy will be evaluated separately for HER2-/HER2+ patients. Tumor response will be evaluated by RECIST v1.1 at 6 and 12 weeks. To ensure safety, stopping rules defined by grade 3/4 adverse events and12-week progression rate were adopted.
Target Accrual: Up to 40 patients, including up to 8 patients (20%) with HER2+ disease.
Summary: Ad+V is a novel gene therapy which controls local expression of IL-12 and may induce tumor stroma collapse and stimulation of an anti-cancer T cell immune response. The ability to regulate the production of IL-12 by modulating V dosing may result in an improved therapeutic index in combination with standard of care. The data from this study will directly inform future studies.
Study Contact (Clinical Trials.gov: NCT02423902).
Citation Format: McArthur HL, Page D, Proverbs-Singh T, Solomon S, Hudis C, Norton L, Patil S, Barrett JA, Lebel F. Phase 1b/2 study of intratumoral Ad-RTS-hIL-12 + veledimex in patients with chemotherapy-responsive locally advanced or metastatic breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr OT1-01-05.