VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: Preclinical and phase I data by the Gynecologic Oncology Group.

Abstract

3077 Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor micro-environment with immunotherapy is an emerging approach. VTX-2337 is a potent, small molecule agonist of TLR8 which stimulates the innate immune response, and was previously evaluated as a single agent in cancer patients. We report data combining VTX-2337 with chemotherapy in recurrent ovarian cancer. Methods: VTX-2337 was tested in an ovarian cancer mouse model with an intact human immune system. Additionally, an open-label phase I study of VTX-2337 + pegylated liposomal doxorubicin (PLD) in recurrent ovarian cancer (NCT01294293, N=13) was performed. PLD (40 mg/m2) was given on day 1 of a 28-day cycle. Three dose levels of VTX-2337 (2.5, 3.0, 3.5 mg/m2, N=13) were serially tested and given by SC injection on days 3, 10, and 17. VTX-2337 (3.0 mg/m2) was also tested with paclitaxel (80 mg/m2; N=7) given on days 1, 8, and 15 of a 28 day cycle. Responses were evaluated using RECIST1.1. PK and serum immune cytokines were measured. Patients remained on therapy until toxicity or progression. Results: In the mouse model, clinical responses to PLD were increased. Innate immunity along with CD8+ T cell responses were also induced. In humans, treatment with PLD + VTX-2337 increased various cytokines and chemokines (G-CSF, MCP-1, MIP-1β, TNF-α). The PK of PLD was not affected by VTXE2337. The combination was well tolerated with no DLTs. AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities, N=6) or VTXE2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms). There was 1 partial response (13%) and 63% had stable disease. Paclitaxel + VTX-2337 was also well tolerated. Conclusions: VTX-2337 enhances the effect of PLD in a preclinical model of ovarian cancer, and the combination is well-tolerated in patients. Clinical data and biomarkers consistent with immunostimulation, provide rationale for the on-going randomized, placebo-controlled, phase II trial comparing PLD vs PLD + VTX-2337 (GOG-3003, NCT01666444). Clinical trial information: NCT01666444.