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卡博替尼治疗1型神经纤维瘤相关丛状神经纤维瘤的2期临床试验结束
作者:小柯机器人 发布时间:2021/1/17 16:09:24

美国印第安纳大学D. Wade Clapp、约翰霍普金斯大学Jaishri O. Blakeley等研究人员合作完成卡博替尼治疗1型神经纤维瘤相关丛状神经纤维瘤的2期临床试验。2021年1月13日,国际知名学术期刊《自然—医学》发表了这一成果。

研究人员表示,1型神经纤维瘤病(NF1)丛状神经纤维瘤(PN)是进行性多细胞肿瘤,可引起发病并可能转变为肉瘤。用多种酪氨酸激酶抑制剂卡博替尼治疗Nf1fl/fl; Postn-Cre小鼠,可导致PN大小和数量减少以及细胞谱系中促PN激酶的差异调节。

根据这些发现,神经纤维瘤病临床试验联盟进行了II期、开放标签、非随机化的Simon两阶段研究,以评估卡博替尼在≥1岁、患有NF1且进行性或有症状的、不可手术的PN患者中的安全性、疗效和生物学活性(NCT02101736)。该试验达到了其主要结果,定义为经过12个疗程的患者达到部分缓解的≥25%(PR,通过磁共振成像(MRI)评估的目标病变体积减少≥20%)。

次要结果包括不良事件(AE),评估疼痛和生活质量(QOL)的患者报告结果(PRO)、药代动力学(PK)以及循环内皮细胞和细胞因子的水平。19位可评估的参与者中有8位(42%)达到了PR。肿瘤体积的中位变化为15.2%(范围为+2.2%至-36.9%),并且没有患者在治疗期间出现疾病进展。9名患者因AE而需要减少剂量或中止治疗;常见的不良事件包括胃肠道毒性、甲状腺功能减退、疲劳和Palmar-Plantar Erythrodysesthesia综合症。8例患者共发生11例3级不良事件。PR患者的肿瘤疼痛强度和日常生活中的疼痛干扰显著降低,但总体QOL得分无变化。这些数据表明卡博替尼在与NF1相关的PN中具有活性,并导致肿瘤体积减少和疼痛改善。

附:英文原文

Title: Cabozantinib for neurofibromatosis type 1–related plexiform neurofibromas: a phase 2 trial

Author: Michael J. Fisher, Chie-Schin Shih, Steven D. Rhodes, Amy E. Armstrong, Pamela L. Wolters, Eva Dombi, Chi Zhang, Steven P. Angus, Gary L. Johnson, Roger J. Packer, Jeffrey C. Allen, Nicole J. Ullrich, Stewart Goldman, David H. Gutmann, Scott R. Plotkin, Tena Rosser, Kent A. Robertson, Brigitte C. Widemann, Abbi E. Smith, Waylan K. Bessler, Yongzheng He, Su-Jung Park, Julie A. Mund, Li Jiang, Khadijeh Bijangi-Vishehsaraei, Coretta Thomas Robinson, Gary R. Cutter, Bruce R. Korf, Jaishri O. Blakeley, D. Wade Clapp

Issue&Volume: 2021-01-13

Abstract: Neurofibromatosis type 1 (NF1) plexiform neurofibromas (PNs) are progressive, multicellular neoplasms that cause morbidity and may transform to sarcoma. Treatment of Nf1fl/fl;Postn-Cre mice with cabozantinib, an inhibitor of multiple tyrosine kinases, caused a reduction in PN size and number and differential modulation of kinases in cell lineages that drive PN growth. Based on these findings, the Neurofibromatosis Clinical Trials Consortium conducted a phase II, open-label, nonrandomized Simon two-stage study to assess the safety, efficacy and biologic activity of cabozantinib in patients ≥16 years of age with NF1 and progressive or symptomatic, inoperable PN (NCT02101736). The trial met its primary outcome, defined as ≥25% of patients achieving a partial response (PR, defined as ≥20% reduction in target lesion volume as assessed by magnetic resonance imaging (MRI)) after 12 cycles of therapy. Secondary outcomes included adverse events (AEs), patient-reported outcomes (PROs) assessing pain and quality of life (QOL), pharmacokinetics (PK) and the levels of circulating endothelial cells and cytokines. Eight of 19 evaluable (42%) trial participants achieved a PR. The median change in tumor volume was 15.2% (range, +2.2% to 36.9%), and no patients had disease progression while on treatment. Nine patients required dose reduction or discontinuation of therapy due to AEs; common AEs included gastrointestinal toxicity, hypothyroidism, fatigue and palmar plantar erythrodysesthesia. A total of 11 grade 3 AEs occurred in eight patients. Patients with PR had a significant reduction in tumor pain intensity and pain interference in daily life but no change in global QOL scores. These data indicate that cabozantinib is active in NF1-associated PN, resulting in tumor volume reduction and pain improvement.

DOI: 10.1038/s41591-020-01193-6

Source: https://www.nature.com/articles/s41591-020-01193-6

期刊信息

Nature Medicine:《自然—医学》,创刊于1995年。隶属于施普林格·自然出版集团,最新IF:30.641
官方网址:https://www.nature.com/nm/
投稿链接:https://mts-nmed.nature.com/cgi-bin/main.plex