Background <p>This phase I trial aimed to assess the pharmacokinetics (PK), safety, and preliminary efficacy of a single dose of HR20013 (mixed formulation of fosrolapitant and palonosetron) plus dexamethasone in patients with malignant solid tumors.</p> Methods <p>Solid tumor patients who were naive to cisplatin-based chemotherapy and scheduled to receive the single-day cisplatin-based chemotherapy were enrolled. Patients would receive a single intravenous infusion of HR20013 (Day 1) before cisplatin-based chemotherapy, alongside oral dexamethasone (Day 1, 12&#xa0;mg, once a day; Day 2–4, 3.75&#xa0;mg, twice a day). Primary endpoints were PK parameters of fosrolapitant, rolapitant, M19 (a major active metabolite of rolapitant), palonosetron, and dexamethasone.</p> Results <p>Twenty-four patients were enrolled, and 22 received study treatment. Fosrolapitant reached maximum plasma concentration (C_max) immediately at the end of the infusion of HR20013 (1&#xa0;h), followed by a short terminal phase, and it was completely hydrolyzed into rolapitant. Mean elimination half-lives of rolapitant and palonosetron were 188.2 and 51.5&#xa0;h, respectively. M19 reached C_max at approximately 166.2&#xa0;h. After a single oral administration of dexamethasone at 12&#xa0;mg, when combined with HR20013, dexamethasone reached C_max at approximately 1.5&#xa0;h, with a mean C_max of 106.0&#xa0;ng/mL. Treatment-related adverse events occurred in 54.5% of patients, with constipation (22.7%), increased blood pressure (18.2%), abdominal distension (13.6%), injection site reaction (9.1%), and increased neutrophil count (9.1%) being most common. Complete response rates (no emesis/rescue therapy) were 90.9% at the overall phase (0–120&#xa0;h) and 86.4% at the beyond delayed phase (120–168&#xa0;h).</p> Conclusions <p>HR20013 plus dexamethasone had a favorable PK profile, manageable safety, and durable antiemetic efficacy.</p> Trial registration <p>ClinicalTrials.gov, NCT05465681.</p>