Abstract PD11-02: PD11-02 A Phase II Randomized Window of Opportunity Trial Evaluating Cytotoxic and Immunomodulatory effects of Intratumoral INT230-6 in Early Stage Breast Cancer: the INVINCIBLE Trial
Authors: Arnaout Angel , Robertson Susan , Keyhanian Kianoosh , Hopkins Megan , Liao Linda , Talebian Vida , Awan Arif , Bartlett John MS , Pond Gregory R. , Radvanyi Lazlo , Bender Lewis H. , Walters Ian B. , Ozuna Vanessa Lopez , Spears Melanie 
Published: March 2023

Abstract
Background: The majority of breast cancers outside of the triple negative subtype are considered immunological quiescent and are therefore minimally responsive to immunotherapies. One potential method to combat this is through local therapies that induce cell death, thereby exposing tumor antigens, providing adjuvants for anti-tumor immune priming, and potentially increasing responsiveness to immunotherapies. We have conducted a randomized, Phase 2 presurgical Window-Of-Opportunity trial for intratumoral (IT) INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer (the INVINCIBLE trial- https://clinicaltrials.gov/ct2/show/NCT04781725). INT230-6 contains a dispersion enhancer molecule (SHAO) with the cytotoxic agents and is designed to cause tumor necrosis by dispersion throughout the tumor and diffusion into cancer cells. Previous in vitro studies have demonstrated that INT230-6 halts cancer cell replication and induces cell death recruiting dendritic cells and T-cells to the tumor microenvironment. In this trial, IT injections of INT230-6 are conducted to 1) exploit the potential of regional cytotoxic chemotherapy on breast cancer in vivo and 2) assess the immune response within the tumor, microenvironment and systemically in the host blood prior to surgical resection. Methods: Women with newly diagnosed and awaiting surgery for early-stage intermediate or high-grade T1-T2 invasive breast cancers were recruited to the trial. The study has two parts. Part I was a randomized (2:1) open label trial comparing 1-3 doses of INT230-6 injected weekly versus no treatment prior to surgery to evaluate safety, feasibility, and optimal drug dosing. Part II was a double-blinded randomized (2:1) trial where patients received one IT dose of INT230-6 vs saline injection. The primary objective was to estimate the proportion of patients with tumor necrosis and complete cell cycle arrest (CCCA) at the time of surgery compared to control. In addition, we performed targeted sequencing and proteomic profiling in tumour samples from the INT230-6 clinical trial. Results: The study recruited 90 patients with age ranges of 40-77 yrs (mean = 60 yrs) with tumors ranging from 1.5-4.3 cm (mean = 2.4cm). No surgeries were delayed or altered as a result of trial participation and the most common (&gt;10%) AEs were injection site pain, injection site reaction and nausea/vomiting. Compared to the control group, up to 95% tumor necrosis was present in varying biologic subtypes and histologies, including invasive lobular carcinoma. Preliminary gene expression analysis showed significant differential gene expression between the baseline biopsy and surgical specimens. Pathway analysis identified genes associated with TCR signaling, B cells, T cells, chemokine signaling and NF-κB signaling were significantly changed in the post treatment samples. There was a relative increase in CD4 and CD8 T cells and B and NK cells within the tumor and in the tumour microenvironment. Conclusion: Preliminary evidence shows that a single dose of INT230-6 can cause substantial tumor necrosis and stimulate an immune response in breast cancers prior to surgery with minimal adverse effects and good tolerability. This window of opportunity clinical trial demonstrates that INT230-6 injection is a novel and simple method to convert traditionally immune quiescent breast cancers into immunogenic tumors. This can open the door to future potential immunotherapeutic options in early stage breast cancer.
Citation Format: Angel Arnaout, Susan Robertson, Kianoosh Keyhanian, Megan Hopkins, Linda Liao, Vida Talebian, Arif Awan, John MS Bartlett, Gregory R. Pond, Lazlo Radvanyi, Lewis H. Bender, Ian B. Walters, Vanessa Lopez Ozuna, Melanie Spears. PD11-02 A Phase II Randomized Window of Opportunity Trial Evaluating Cytotoxic and Immunomodulatory effects of Intratumoral INT230-6 in Early Stage Breast Cancer: the INVINCIBLE Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD11-02.