Pharmacodynamic, safety, and efficacy results of a phase I/II trial of intratumoral INT230-6 alone (IT-01) or in combination with pembrolizumab (PEM) (Keynote A10) in patients with advanced solid tumors.

Abstract

3016 Background: INT230-6 is comprised of cisplatin (CIS), vinblastine (VIN) and an amphiphilic penetration enhancer which facilitates dispersion throughout tumors and diffusion into cancer cells when given IT. Preclinical experiments show strong synergy with a PD1 antibody. Methods: Solid tumors pts that progressed on standard treatment were enrolled. INT230-6 dose was set by tumor volume, injected Q2weeks x 5. Escalation occurred by increasing number of tumors injected, loading per tumor, and total dose. In another arm, PEM (200mg IV Q3weeks) was combined with INT230-6. Patients were monitored for safety weekly while on INT230-6. Blood and tumors were assessed for PK and PD. Results: 46 pts (17 unique cancer types) were enrolled in the monotherapy arm and 4 pts in the PEM combo arm with a median of 3 prior treatments. Doses from 0.3 ml up to-160 ml of INT230-6 (80 mg CIS and 16mg of VIN) were injected. PK results indicate 95% of the drugs are retained in the tumor when compared to historical IV dosing. No dose limiting toxicity was reported. Two pts experienced drug-related SAE’s of tumor pain. The most frequent treatment-related AEs were: pain at injected site (48%), fatigue (40%) and nausea (33%). Most AE’s were grade 1 and 2, 17% were grade 3, and none ≥ grade 4. Several injected and non-injected tumors had > 30% decreases in diameter. Assessments revealed substantial reductions in tumor volume ( > 50%). Stable pts had a median increase of 50% in circulating CD4 and CD8 T-cells, while PD subjects showed decreases in circulating T-cells (p < 0.05). Dose-response suggests that monotherapy subjects receiving > 50% of tumors injected at dose/tumor volume ratio of > 1:4 (target dosing), predicts for prolonged SD with 88%(7/8) having SD ≥ 4mo, correlating with reduced tumor viability on IHC, and increase in tumor-infiltrating lymphocytes (TIL’s). Conclusions: Proof of concept was demonstrated that INT230-6 delivers high drug doses into the tumor without systemic exposure and typical cytotoxic AEs. Systemic and local immune activation was observed. INT230-6 was safe and well tolerated in > 175 deep tumor injections with tumor burden reduction in injected and non-injected tumors (an abscopal effect). Patients who received target dosing often had prolonged disease control post treatment. Updated safety, response and biomarker data from the monotherapy and PEM combo arm will be presented. Clinical trial information: 03058289 .