(P 164) INTRATUMORAL INT230-6 (CISPLATIN, VINBLASTINE, SHAO) ALONE OR WITH IPILIMUMAB PROLONGED SURVIVAL WITH FAVORABLE SAFETY AND IMMUNE ACTIVATION IN ADULTS WITH REFRACTORY SARCOMAS (NCT 03058289)

Objective: Sarcomas are a rare and diverse group of solid tumors from mesenchymal cells; chemotherapy provides limited benefit for metastatic disease. INT230-6 is a novel formulation of cisplatin (CIS), vinblastine (VIN) and a tissue dispersion enhancer (SHAO) designed for intratumoral (IT) delivery. The drug diffuses into cancer cells, causes apoptosis and recruits dendritic and T-cells to the tumor. Adding ipilimumab (IPI) appears to improve INT230-6 responses in models. The primary objective of this study was to understand the safety of INT230-6 monotherapy or in combination with IPI. Secondary objectives were to understand efficacy disease control rate (DCR) and overall survival (OS) of the drug alone or with intravenous (IV) IPI in various highly refractory sarcoma subtypes.

Methods: IT-01 is an open-label phase1/2 study in adults with locally advanced, unresectable or metastatic solid tumors, including sarcoma. INT230-6 dose was set by tumor diameter or volume. INT230-6 was dosed IT Q2W for up to 5 doses alone or with IPI at 3mg/kg Q3 weeks for 4 doses. Maintenance INT230-6 dosing was Q9 weeks. Immunohistochemistry was conducted on biopsied tissue from pre- and post-dosed tumors2.

Results: The study enrolled 30 sarcoma patients (15 INT230-6 alone, 14 combination) with 11 subtypes (primarily leiomyosarcoma, liposarcoma, pleomorphic, chondrosarcoma and chordoma) baseline demographics in Table 2. There were no dose limiting toxicities in treating sarcoma at doses up 175 mL (87.5 mg of CIS, 17.5 mg VIN) following injection into 1 or more tumors, amounts that approach or exceed an IV dose of CIS or VIN. PK analysis shows that 95% to 99.5% of VIN remained in the tumor. Cisplatin is rapidly degraded and only platinum metal is measured. Data showed that INT230-6 induced an immune response in sarcoma subtypes as a monotherapy with increased CD4+ T-cell influx. Of 29 evaluable patients for efficacy, the DCR was 93% for monotherapy and 86% combined with IPI. RECIST measurements are confounded by IT injections due to the large volume of highly retained INT230-6 and the influx of immune infiltrates; however, 27% of sarcoma subjects receiving only local INT230-6 uninjected tumors shrink (many nontarget tumors were unreported). Analysis of median overall survival (mOS) for INT230-6 alone (n=15) was 21.3 months. It was observed empirically during the study that subjects having a cumulative dose of INT230-6 at greater than 40% drug volume to total tumor burden (TTB) had extended survival. For monotherapy subjects receiving a dose of ≥40% of TTB (n=11) the mOS had not been reached after 13.5 months of median follow-up . The mOS of the combination has also not been reached with over 12 months of median follow-up. The treatment-related adverse events (TRAEs) in evaluable monotherapy patients were mild; 13.3% grade1 and 60% grade 2. Grade 3 TRAEs occurred in 20% and 7% of patients in the monotherapy and combination arms respectively. There were no grade 4 or 5 events. The >20% Treatment Emergent Adverse Events Related to Drug Regimen in Evaluable Patients are shown in the below Table 1

Conclusion: INT230-6 use was associated with immune infiltration and a clinically relevant mOS particularly when ≥40% of the TTB was injected. Uninjected tumors shrank in a high percentage of monotherapy subjects. INT230-6 dosed IT alone or with IPI had favorable safety in diverse sarcomas. A randomized phase 3 trial protocol vs. SOC in selected sarcoma subtypes with an OS endpoint has been reviewed by the US FDA.