Intratumoral (IT) INT230-6 can cause tumor necrosis in vivo: Preliminary results of a phase II randomized presurgical window-of-opportunity study in early breast cancers (the INVINCIBLE study).

605 Background: The INVINCIBLE study is a randomized, Phase 2 presurgical Window-Of-Opportunity trial for IT INT230-6 (comprising VINblastine (VIN) Cisplatin (VIN)) evaluating clinical and BioLogical Effects in patients with early-stage operable Breast Cancer. INT230-6 also contains a dispersion enhancer molecule designed to facilitate diffusion of the cytotoxic agents into cancer cells and cause tumor necrosis. We have previously demonstrated that INT230-6 halts cancer cell replication and induces apoptosis while maturing dendritic cells and recruiting 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 potential for an immune response in the tumor microenvironment and host prior to surgical resection. Methods: Up to 90 women with newly diagnosed operable early-stage intermediate or high-grade T1-T2 invasive breast cancers are randomly allocated (2:1) prior to resection to IT injections of INT230-6, no treatment or saline sham. This study has two parts. Part I (N=29) was a randomized trial comparing 1-3 doses of INT230-6 injected weekly vs no treatment prior to surgery to evaluate safety, feasibility, and optimal drug dosing. Part II is a double-blinded randomized trial of up to 60 patients where patients will receive one IT dose of INT230-6 vs saline injection (2:1). The primary endpoint is to estimate the proportion of patients who achieve a complete cell cycle arrest post-surgery compared to the diagnosis biopsy. Secondary endpoints include an evaluation of the rate of pathological complete response, the percent of residual cancer, and safety. The study will also profile changes in CD4/CD8 and the T-cell repertoire. Results: Part I demonstrated feasibility, safety and tolerability of presurgical IT injections in breast cancer patients. Twenty patients with tumors ranging from 1-4.4cm were injected with at least one dose up to 48 hours prior to surgery. No surgeries were delayed or altered and the most common (>10%) AEs were injection site pain (100%), infusion site extravasation, injection site reaction and vomiting (10% each). Preliminary data show histologic evidence of up to 95% tumor necrosis in varying biologic subtypes and an increase in intratumoral TILs in injected tumors compared to controls. Part II is ongoing. Conclusions: Preliminary evidence shows that a single dose of INT230-6 can cause intratumoral necrosis and stimulate an immune response in breast cancers prior to surgery with minimal adverse effects and good tolerability. The results of Part II of the study will further evaluate the potential cytotoxic, immunomodulatory and other biologic effects of INT230-6 and its role as a potential cancer therapy in breast cancer patients awaiting surgery. Clinical trial information: NCT04781725.