Abstract AS27: VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: preclinical and phase 1 data by the gynecologic oncology group
Authors: Monk Bradley J. , Brady William E. , Lankes Heather A. , Facciabene Andrea , Manjarrez Kristi L. , Hershberg Robert M. , Fracasso Paula M. , Bell-McGuinn Katherine M. , Walker Joan L. , McCourt Carolyn K. , Aghajanian Carol , Coukos George 
Published: August 2015

Abstract
Background: Given the absence of clear molecular drivers in high-grade serous ovarian cancer, targeting the tumor microenvironment with immunotherapy is an emerging approach. Stimulation of the innate immune system via Toll-like receptors (TLRs) may augment the antitumor activity of cytotoxic chemotherapies, including anthracyclines. VTX-2337 is a potent, small molecule agonist of TLR8 which was previously evaluated as a single agent in patients with advanced cancer. We report both pre-clinical and clinical data combining VTX-2337 with pegylated liposomal doxorubicin (PLD; Doxil®) chemotherapy in recurrent ovarian cancer.
Methods: VTX-2337 was tested in an ovarian tumor model in immunocompromised mice reconstituted with a human immune system. Additionally, an open-label Phase 1 study of VTX-2337 + PLD in recurrent platinum-resistant ovarian cancer (NCT0129493, n=13) was performed. (The clinical study also evaluated the combination of VTX 2337 + weekly paclitaxel [n=7]; data is not reported herein.) 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) were sequentially tested and given by SC injection on days 3, 10, and 17 of each treatment cycle. Responses were evaluated using RECIST 1.1. The pharmacokinetics (PK) of VTX-2337 and PLD, and plasma levels of mediators induced by TLR8 activation were assessed. Patients remained on study treatment until disease progression or unacceptable toxicity.
Results: In the murine tumor model, the efficacy of the combination of VTX-2337 + PLD was increased compared to that of either agent alone. The development of an adaptive CD8+ T cell response to tumor cells was also enhanced. In humans, treatment with VTX-2337 + PLD increased levels of multiple cytokines and chemokines (G-CSF, MCP-1, MIP-1β, TNFα) consistent with TLR8 stimulation and innate immune activation. The PK of PLD was not affected by VTX-2337. The combination was well tolerated with no dose limiting toxicities and no serious, unexpected treatment-related adverse events (AEs). AEs consisted of those seen with single-agent PLD (Gr 3/4 toxicities; n=6) or VTX-2337 (Gr 1/2 injection site reaction, transient fever, flu-like symptoms; n=13). One subject with non-measurable disease achieved a complete response, 1 subject enrolled based on biochemical evidence of recurrent disease achieved a complete biochemical response, 7 subjects had stable disease, and 3 subjects had progressive disease. One subject discontinued treatment prematurely and did not undergo tumor response assessment. Overall, subjects treated with the combination of VTX 2337 + PLD experienced a response rate of 15.4% (n=2) and a disease control rate of nearly 70% (n=9; 69.2%).
Conclusions: VTX-2337 enhances the therapeutic effects 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 2 trial comparing PLD vs PLD + VTX-2337 (GOG-3003; NCT01666444). This trial is fully enrolled.
Citation Format: Bradley J. Monk, William E. Brady, Heather A. Lankes, Andrea Facciabene, Kristi L. Manjarrez, Robert M. Hershberg, Paula M. Fracasso, Katherine M. Bell-McGuinn, Joan L. Walker, Carolyn K. McCourt, Carol Aghajanian, George Coukos. VTX-2337, a TLR8 agonist, plus chemotherapy in recurrent ovarian cancer: preclinical and phase 1 data by the gynecologic oncology group [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS27.