A phase 2, randomized, double-blind, placebo- controlled study of chemo-immunotherapy combination using motolimod with pegylated liposomal doxorubicin in recurrent or persistent ovarian cancer: a Gynecologic Oncology Group partners study

<span class="paragraphSection"><div class="boxTitle">Background</div>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.<div class="boxTitle">Patients and methods</div>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.<div class="boxTitle">Results</div>The addition of motolimod to PLD did not significantly improve overall survival (OS; log rank one-sided <span style="font-style:italic;">P</span> = 0.923, HR = 1.22) or progression-free survival (PFS; log rank one-sided <span style="font-style:italic;">P</span> = 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 <span style="font-style:italic;">in vitro</span> 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.<div class="boxTitle">Conclusions</div>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 <span style="font-style:italic;">in vitro</span> immune responses. Collectively, these data may provide important clues for identifying patients for treatment with immunomodulatory agents in novel combinations and/or delivery approaches.<div class="boxTitle">Trial registration</div>Clinicaltrials.gov, NCT 01666444.</span>

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