Early results of intratumoral INT230-6 alone or in combination with ipilimumab in subjects with advanced sarcomas.
Authors: Ingham Matthew , Hu James S. , Whalen Giles Francis , Thomas Jacob Stephen , El-Khoueiry Anthony B. , Hanna Diana L. , Olszanski Anthony J. , Meyer Christian Frederick , Azad Nilofer Saba , Mahmood Syed , Bender Lewis H. , Walters Ian B. , Abdul Razak Albiruni Ryan , Siu Lillian L. 
Published: June 2021

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Background: Patients have limited treatment options following initial chemotherapy failure. INT230-6, a novel formulation of cisplatin (CIS) and vinblastine (VIN) with an amphiphilic cell penetration enhancer, is designed for intratumoral (IT) administration. Study IT-01 (BMS # CA184-592, NCT 03058289) evaluates INT230-6 alone or in combination with ipilimumab (IPI), an antibody to CTLA-4. INT230-6 dosing is set by a % of the volume of the tumor to be injected. The product has been shown to disperse throughout an injected tumor and diffuse into cancer cells. Cell death leads to recruitment of dendritic and T cells, the effect of which may be augmented by CTLA-4 inhibition as evidenced by increased efficacy of the combination in preclinical models. Historically, checkpoint inhibitors have limited activity in sarcoma. Considering the large volume of drug injected and retained in the tumor, coupled with immune infiltration on biopsies, RECIST response methodology may not capture the benefits of INT230-6 treatment. Methods: IT-01 is an open-label phase 1/2 study that is enrolling adult subjects with locally advanced, unresectable or metastatic sarcoma. INT230-6 was administered IT Q2W for 5 doses alone or with IPI 3mg/kg IV Q3W for 4 doses. The study objectives are to assess the safety and efficacy of IT INT230-6 alone and in combination with IPI. Results: 16 heterogenous sarcoma subjects (13 monotherapy, 3 IPI combination) having a median of 3 prior therapies (0, 8) were enrolled to date. The INT230-6 dose was up to 145 mL (72.5 mg of CIS, 14.5 mg VIN) in a single session (an amount of each agent in excess of standard IV doses). The most common ( > 20%) related TEAEs in sarcoma subjects (n = 16) were localized pain (63%), fatigue (38%), decreased appetite (31%), nausea (31%), and vomiting (25%) most of which were low grade; with only grade 3 TEAE above 5% being anemia (13%). There were no related grade 4 or 5 TEAEs. In 11 evaluable monotherapy subjects, the disease control rate (DCR = CR+PD+SD) was 82%. Basket studies of sarcomas, including chordoma, with Royal Marsden Hospital index (RMHI) scores of 2 or higher report median overall survival (mOS) of 4 months. In this study 75% of monotherapy subjects had a RMHI score of 2 and preliminary estimates of mOS was 21.3 (4.67, NA) months. Pilot immunohistochemistry analysis of 5 paired (pre- and 28 days post-dose) biopsy samples showed substantial tumor necrosis, reduction of viable cancer, a decreased cancer proliferation as measured by Ki67, and increased TILs. Conclusions: Preliminary data shows that INT230-6 administered intratumorally alone or in combination with ipilimumab is well-tolerated in this small, heterogenous sarcoma population. The preclinical cancer cell death and immune infiltration mechanism of action appears to translate to sarcoma subjects. There are early signs of efficacy, DCR and potentially OS, that need to be confirmed in randomized studies. Clinical trial information: 03058289.