Aims: Trebananib, a peptide-Fc fusion protein, inhibits angiogenesis by inhibiting binding of angiopoietin-1/2 to the receptor tyrosine kinase Tie2. This randomized, double-blind, placebocontrolled phase 3 study evaluated whether trebananib plus pegylated liposomal doxorubicin (PLD) improved progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer. Methods:Women with recurrent ovarian cancer (platinum-free interval ≤12 months) were randomized to intravenous PLD 50 mg/m 2 once every 4 weeks plus weekly intravenous trebananib 15 mg/kg or placebo. PFS was the primary endpoint; key secondary endpoints were objective response rate (ORR) and duration of response (DOR). Owing to PLD shortages, enrollment was paused for 13 months; the study was subsequently truncated.Results: Two hundred twenty-three patients were enrolled. Median PFS was 7.6 months (95%CI, 7.2─9.0) in the trebananib arm and 7.2 months (95%CI, 4.8─8.2) in the placebo arm, with a hazard ratio of 0.92 (95%CI, 0.68─1.24). However, because the proportional hazards assumption was not fulfilled, the standard Cox model did not provide a reliable estimate of the hazard ratio. ORR in the trebananib arm was 46% versus 21% in the placebo arm (odds ratio, 3.43; 95%CI, 1.78-6.64). Median DOR was improved (trebananib, 7.4 [95%CI,.6] months; placebo, 3.9 [95%CI, 2.3-6.5] months). Adverse events with a greater incidence in the trebananib arm included localized edema (61% versus 32%), ascites (29% versus 9%), and vomiting (45% versus 33%). Conclusions

• Trebananib did not improve overall survival in the intent-to-treat population.• Trebananib improved overall survival in patients with baseline ascites.• Trebananib prolonged time to second disease progression. Purpose. Trebananib, a peptibody that blocks binding of angiopoietin-1 and -2 to Tie2, significantly prolonged progression-free survival (PFS) in patients with recurrent epithelial ovarian cancer in the phase 3 TRINOVA-1 study. We report overall survival (OS) in the intent-to-treat population and clinically relevant subgroups and time to second disease progression (PFS-2). Patients and methods. Women with recurrent disease (platinum-free interval b 12 months) were randomized to receive intravenous paclitaxel 80 mg/m 2 (3 weeks on/1 week off) plus intravenous trebananib 15 mg/kg or placebo, weekly. OS in the intent-to-treat population was a key secondary endpoint. Exploratory analysis of PFS-2 was conducted according to guidance by the European Medicines Agency. Results. Median OS was not significantly improved with trebananib compared with placebo (19.3 versus 18.3 months; HR, 0.95; 95% CI, 0.81-1.11; P = 0.52) in the intent-to-treat population (n = 919). In subgroup analysis, trebananib improved median OS compared with placebo (14.5 versus 12.3 months; HR, 0.72; 95% CI, 0.55-0.93; P = 0.011) in patients with ascites at baseline (n = 295). In the intent-to-treat population, trebananib significantly improved median PFS-2 compared with placebo (12.5 versus 10.9 months; HR, 0.85; 95% CI, 0.74-0.98; P = 0.024). The incidence and type of adverse events in this updated analysis was consistent with that described in the primary analysis; no new safety signals were detected. a b s t r a c t a r t i c l e i n f oConclusions. OS was not significantly longer in the intent-to-treat population, although there was an improvement in OS in patients with ascites receiving trebananib. PFS-2 confirmed that the PFS benefit associated with trebananib was maintained through the second disease progression independent of the choice of subsequent therapy.

Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group.

In this meta-analysis of 14 eligible RCTs, we found that in patients with LPR, PPI therapy could improve reflux symptoms significantly compared with placebo.