BACKGROUND: A phase 2, randomized, placebo-controlled trial was conducted in 
women with recurrent epithelial ovarian carcinoma to evaluate the efficacy and 
safety of motolimod-a Toll-like receptor 8 (TLR8) agonist that stimulates robust 
innate immune responses-combined with pegylated liposomal doxorubicin (PLD), a 
chemotherapeutic that induces immunogenic cell death.
PATIENTS AND METHODS: Women with ovarian, fallopian tube, or primary peritoneal 
carcinoma were randomized 1 : 1 to receive PLD in combination with blinded 
motolimod or placebo. Randomization was stratified by platinum-free interval (≤6 
versus >6-12 months) and Gynecologic Oncology Group (GOG) performance status (0 
versus 1). Treatment cycles were repeated every 28 days until disease 
progression.
RESULTS: The addition of motolimod to PLD did not significantly improve overall 
survival (OS; log rank one-sided P = 0.923, HR = 1.22) or progression-free 
survival (PFS; log rank one-sided P = 0.943, HR = 1.21). The combination was 
well tolerated, with no synergistic or unexpected serious toxicity. Most 
patients experienced adverse events of fatigue, anemia, nausea, decreased white 
blood cells, and constipation. In pre-specified subgroup analyses, 
motolimod-treated patients who experienced injection site reactions (ISR) had a 
lower risk of death compared with those who did not experience ISR. 
Additionally, pre-treatment in vitro responses of immune biomarkers to TLR8 
stimulation predicted OS outcomes in patients receiving motolimod on study. 
Immune score (tumor infiltrating lymphocytes; TIL), TLR8 single-nucleotide 
polymorphisms, mutational status in BRCA and other DNA repair genes, and 
autoantibody biomarkers did not correlate with OS or PFS.
CONCLUSIONS: The addition of motolimod to PLD did not improve clinical outcomes 
compared with placebo. However, subset analyses identified statistically 
significant differences in the OS of motolimod-treated patients on the basis of 
ISR and in vitro immune responses. Collectively, these data may provide 
important clues for identifying patients for treatment with immunomodulatory 
agents in novel combinations and/or delivery approaches.
TRIAL REGISTRATION: Clinicaltrials.gov, NCT 01666444.