磷丙泊酚和帕洛诺司琼混合制剂（HR20013）联合地塞米松用于计划接受高致吐性顺铂化疗的实体瘤患者的药代动力学、安全性及疗效：一项I期试验
Pharmacokinetics, safety, and efficacy of mixed formulation of fosrolapitant and palonosetron (HR20013) in combination with dexamethasone in patients with solid tumors scheduled for highly emetogenic cisplatin-based chemotherapy: a phase I trial.
作者信息
Zhao Yuanyuan, Ma Yuxiang, Yin Tengrui, Qin Zhiquan, Liu Linlin, Kong Guoqiang, Zhang Ranran, Huang Yuanyuan, Zhang Li, Zhao Hongyun
机构信息
Department of Medical oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Department of Clinical Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, 510060, China.
出版信息
BMC Med. 2025 Aug 27;23(1):501. doi: 10.1186/s12916-025-04314-5.
BACKGROUND
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.
METHODS
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 mg, once a day; Day 2-4, 3.75 mg, twice a day). Primary endpoints were PK parameters of fosrolapitant, rolapitant, M19 (a major active metabolite of rolapitant), palonosetron, and dexamethasone.
RESULTS
Twenty-four patients were enrolled, and 22 received study treatment. Fosrolapitant reached maximum plasma concentration (C) immediately at the end of the infusion of HR20013 (1 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 h, respectively. M19 reached C at approximately 166.2 h. After a single oral administration of dexamethasone at 12 mg, when combined with HR20013, dexamethasone reached C at approximately 1.5 h, with a mean C of 106.0 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 h) and 86.4% at the beyond delayed phase (120-168 h).
CONCLUSIONS
HR20013 plus dexamethasone had a favorable PK profile, manageable safety, and durable antiemetic efficacy.
TRIAL REGISTRATION
ClinicalTrials.gov, NCT05465681.
背景
本I期试验旨在评估单剂量HR20013（福沙吡坦和帕洛诺司琼的混合制剂）联合地塞米松在恶性实体瘤患者中的药代动力学（PK）、安全性和初步疗效。
方法
纳入对基于顺铂的化疗初治且计划接受单日基于顺铂化疗方案的实体瘤患者。患者在基于顺铂的化疗前接受单次静脉输注HR20013（第1天），同时口服地塞米松（第1天，12毫克，每日一次；第2 - 4天，3.75毫克，每日两次）。主要终点为福沙吡坦、罗拉吡坦、M19（罗拉吡坦的主要活性代谢物）、帕洛诺司琼和地塞米松的PK参数。
结果
共纳入24例患者，22例接受了研究治疗。福沙吡坦在输注HR20013结束时（1小时）立即达到最大血浆浓度（Cmax），随后是短暂的终末相，并完全水解为罗拉吡坦。罗拉吡坦和帕洛诺司琼的平均消除半衰期分别为188.2小时和51.5小时。M19在约166.2小时达到Cmax。单次口服12毫克地塞米松并与HR20013联合使用时，地塞米松在约1.5小时达到Cmax，平均Cmax为106.0纳克/毫升。54.5%的患者发生了与治疗相关的不良事件，最常见的是便秘（22.7%）、血压升高（18.2%）、腹胀（13.6%）、注射部位反应（9.1%）和中性粒细胞计数增加（9.1%）。总体阶段（0 - 120小时）的完全缓解率（无呕吐/抢救治疗）为90.9%，延迟期后阶段（120 - 168小时）为86.4%。
结论
HR20013联合地塞米松具有良好的药代动力学特征、可控的安全性和持久的止吐疗效。
试验注册
ClinicalTrials.gov，NCT05465681。
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