Liu Dan, Gong Jifang, Zhang Jian, Shu Yongqian, Wu Hao, Liu Tianshu, Xu Yanhua, Zhang Lijia, Li Min, Hu Xichun, Shen Lin
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Early Drug Development Center, Peking University Cancer Hospital and Institute, Hai-Dian District, Beijing, 100142, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
Invest New Drugs. 2025 Apr;43(2):250-261. doi: 10.1007/s10637-025-01512-z. Epub 2025 Feb 20.
RMX1002 (grapiprant) is a selective E-type prostanoid receptor 4 (EP4) antagonist and a promising candidate for cancer therapy, potentially enhancing anti-tumor immune responses. This study aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and efficacy of RMX1002 as monotherapy and in combination with anti-PD-1 antibody toripalimab for advanced solid tumors. This multicenter, phase I trial enrolled patients with histologically or cytologically confirmed advanced solid tumors. This study included three phases: Ia (dose-escalation of RMX1002 monotherapy from 200 to 650 mg BID), Ib (dose-escalation from 500 to 650 mg BID in combination with toripalimab), and Ic (dose-expansion of 500 mg BID with toripalimab). Safety, pharmacokinetics, pharmacodynamics, and efficacy were assessed. A total of 45 patients were enrolled (17 in phase Ia, 12 in phase Ib, and 16 in phase Ic). No dose-limiting toxicity was reported, and the MTD was not reached. Overall, 21 patients experienced RMX1002-related adverse events with CTCAE grade ≥ 3. Pharmacokinetics revealed rapid absorption of RMX1002 with the maximum concentration (C) reached within 2 to 5 h, and dose-dependent increases in C and area under the concentration-time curve. The increase in urinary metabolite of PGE2 suggested the inhibition of EP4 signaling pathway. The best response was stable disease, reported in 64.7%, 28.6%, and 18.8% of patients in phase Ia, Ib, and Ic, respectively. RMX1002 was well tolerated and showed a best response of stable disease. RMX1002 500 mg BID with toripalimab 240 mg every 3 weeks is the recommended dose for future trials.
RMX1002（格拉普兰特）是一种选择性E型前列腺素受体4（EP4）拮抗剂，是癌症治疗的一个有前景的候选药物，可能增强抗肿瘤免疫反应。本研究旨在评估RMX1002作为单药疗法以及与抗PD-1抗体托瑞帕利单抗联合用于晚期实体瘤的安全性、药代动力学、药效学和疗效。这项多中心I期试验纳入了经组织学或细胞学确诊的晚期实体瘤患者。本研究包括三个阶段：Ia期（RMX1002单药疗法剂量从200毫克每日两次递增至650毫克）、Ib期（与托瑞帕利单抗联合剂量从500毫克每日两次递增至650毫克）和Ic期（与托瑞帕利单抗联合500毫克每日两次的剂量扩展）。评估了安全性、药代动力学、药效学和疗效。总共招募了45名患者（Ia期17名、Ib期12名和Ic期16名）。未报告剂量限制性毒性，未达到最大耐受剂量（MTD）。总体而言，21名患者发生了CTCAE分级≥3级的与RMX1002相关的不良事件。药代动力学显示RMX1002吸收迅速，在2至5小时内达到最大浓度（C），且C和浓度-时间曲线下面积呈剂量依赖性增加。PGE2尿代谢物的增加提示EP4信号通路受到抑制。最佳反应为病情稳定，分别在Ia期、Ib期和Ic期的患者中占64.7%、28.6%和18.8%。RMX1002耐受性良好，最佳反应为病情稳定。RMX1002 500毫克每日两次与托瑞帕利单抗每3周240毫克是未来试验的推荐剂量。
