Olanzapine-based, dexamethasone-free antiemetic prophylaxis for highly emetogenic chemotherapy in children and adolescents: A multicenter phase III non-inferiority trial (CIVIC-POD).

Abstract

304 Background: Guidelines recommend dexamethasone combined with a 5-HT3 receptor antagonist and a neurokinin-1 antagonist for the prevention of chemotherapy-induced nausea and vomiting (CINV) in children and adolescents receiving highly emetogenic chemotherapy (HEC); however, dexamethasone is associated with clinically significant toxicity. The effectiveness of olanzapine as a dexamethasone-sparing option in pediatric CINV prophylaxis remains unclear. Methods: CIVIC-POD (Chemotherapy Induced Vomiting in Children-Prophylaxis Omitting Dexamethasone) is an investigator-initiated, multicenter, open-label, phase III randomized non-inferiority trial (INPHOG-SUPP-22-03) that enrolled patients aged 4–18 years receiving HEC. Participants were randomized 1:1 for one cycle to dexamethasone, palonosetron, and fosaprepitant (DEX) or olanzapine, palonosetron, and fosaprepitant (OLANZ). The primary endpoint was complete response (CR) to vomiting (no vomiting or rescue antiemetics) during the overall phase (0–120 h). A non-inferiority margin of −15% was prespecified. With an assumed CR of 70%, 310 patients provided 80% power at a one-sided α of 0.025. Absolute differences were analyzed using the Miettinen–Nurminen method; non-inferiority required the lower bound of the 95% CI to exceed −15%. Results: Between December 2022 and January 2026, 310 patients were randomized (DEX, n=156; OLANZ, n=154); 299 were included in the per-protocol analysis (DEX, n=151; OLANZ, n=148). Median age was 13 years, and 56.8% received multi-day HEC. CR to vomiting during the overall period occurred in 56.9% of the DEX arm and 63.5% of the OLANZ arm (absolute difference 6.6%; 95% CI −4.5% to 17.7%), meeting non-inferiority criteria. Results were consistent in the intention-to-treat population. For secondary endpoints, CR to nausea during the overall period was similar between DEX and OLANZ (54.3% vs 53.4%). CR to vomiting during the acute period (0-24 h) was 64.2% vs 68.9%, and during the delayed period (24-120 h) was 78.8% vs 79.1%, in the DEX and OLANZ arms, respectively. CR to nausea during the acute period was 59.6% vs 59.5%, and during the delayed period was 69.5% vs 68.9%, respectively. Grade ≥2 toxicities were uncommon and similar. Somnolence was more frequent with OLANZ (52.0% vs 25.8%), with all events ≤ grade 2. Conclusions: Olanzapine-based, dexamethasone-free prophylaxis provided non-inferior vomiting control with similar nausea outcomes and acceptable toxicity, offering an evidence-based alternative to steroid-containing regimens in pediatric HEC. Clinical trial information: CTRI/2022/08/045009 .