Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Department of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan.
Cancer Med. 2021 Feb;10(3):843-856. doi: 10.1002/cam4.3658. Epub 2021 Jan 20.
Olaratumab is a monoclonal antibody that specifically binds to platelet-derived growth factor receptor alpha (PDGFRα) and blocks receptor activation. We conducted a phase 1 trial to evaluate the safety of olaratumab and determine a recommended dose in combination with three different chemotherapy regimens in children. Patients <18 years with relapsed/refractory solid or central nervous system tumors were enrolled to two dose levels of olaratumab. Patients received olaratumab monotherapy at 15 mg/kg (Part A) or 20 mg/kg (Part B) on Days 1 and 8 of the first 21-day cycle, followed by olaratumab combined with standard fixed doses of chemotherapy with doxorubicin, vincristine/irinotecan, or high-dose ifosfamide by investigator choice for subsequent 21-day cycles. In Part C, patients received olaratumab 20 mg/kg plus assigned chemotherapy for all cycles. Parts A-C enrolled 68 patients across three chemotherapy treatment arms; olaratumab in combination with doxorubicin (N = 16), vincristine/irinotecan (N = 26), or ifosfamide (N = 26). Three dose-limiting toxicities (DLTs) occurred during olaratumab monotherapy (at 15 mg/kg, grade [G] 4 alanine aminotransferase [ALT]; at 20 mg/kg, G3 lung infection and G3 gamma-glutamyl transferase). One DLT occurred during vincristine/irinotecan with olaratumab 20 mg/kg therapy (G3 ALT). Treatment-emergent adverse events ≥G3 in >25% of patients included neutropenia, anemia, leukopenia, lymphopenia, and thrombocytopenia. Pharmacokinetic profiles of olaratumab with chemotherapy were within the projected range based on adult data. There was one complete response (rhabdomyosarcoma [Part B vincristine/irinotecan arm]) and three partial responses (two rhabdomyosarcoma [Part A doxorubicin arm and Part C doxorubicin arm]; one pineoblastoma [Part B vincristine/irinotecan arm]). Olaratumab was tolerable and safely administered in combination with chemotherapy regimens commonly used in children and adolescents.
奥拉单抗是一种单克隆抗体，可特异性结合血小板衍生生长因子受体α（PDGFRα）并阻断受体激活。我们进行了一项 1 期临床试验，以评估奥拉单抗的安全性，并确定其与三种不同化疗方案联合应用在儿童中的推荐剂量。入组的患者为年龄<18 岁的复发性/难治性实体瘤或中枢神经系统肿瘤患者，接受两个剂量水平的奥拉单抗治疗。患者在第 1 个 21 天周期的第 1 天和第 8 天接受 15mg/kg（A 部分）或 20mg/kg（B 部分）的奥拉单抗单药治疗，随后根据研究者选择，奥拉单抗与阿霉素、长春新碱/伊立替康或高剂量异环磷酰胺联合固定剂量化疗用于后续的 21 天周期。在 C 部分，患者接受 20mg/kg 的奥拉单抗联合指定化疗方案用于所有周期。A、B 和 C 部分在三个化疗治疗臂中招募了 68 名患者；奥拉单抗联合阿霉素（N=16）、长春新碱/伊立替康（N=26）或异环磷酰胺（N=26）。奥拉单抗单药治疗时出现 3 例剂量限制性毒性（DLT）（15mg/kg 时，G4 丙氨酸氨基转移酶[ALT]；20mg/kg 时，G3 肺部感染和 G3 谷氨酰转肽酶）。奥拉单抗联合 20mg/kg 长春新碱/伊立替康治疗时出现 1 例 DLT（G3 ALT）。≥G3 级的治疗出现的不良事件在>25%的患者中发生，包括中性粒细胞减少、贫血、白细胞减少、淋巴细胞减少和血小板减少。基于成人数据，奥拉单抗联合化疗的药代动力学特征在预期范围内。有 1 例完全缓解（横纹肌肉瘤[B 部分长春新碱/伊立替康组]）和 3 例部分缓解（2 例横纹肌肉瘤[A 部分阿霉素组和 C 部分阿霉素组]；1 例松果体细胞瘤[B 部分长春新碱/伊立替康组]）。奥拉单抗与儿科和青少年常用的化疗方案联合应用是耐受良好且安全的。
