Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.
Cabozantinib for neurofibromatosis type 1-related plexiform neurofibromas: a phase 2 trial.
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DOI：
10.1038/s41591-020-01193-6
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发表时间：
2021-01
期刊：
影响因子：
82.9
通讯作者：
Clapp DW
中科院分区：
文献类型：
--
作者：
Fisher MJ;Shih CS;Rhodes SD;Armstrong AE;Wolters PL;Dombi E;Zhang C;Angus SP;Johnson GL;Packer RJ;Allen JC;Ullrich NJ;Goldman S;Gutmann DH;Plotkin SR;Rosser T;Robertson KA;Widemann BC;Smith AE;Bessler WK;He Y;Park SJ;Mund JA;Jiang L;Bijangi-Vishehsaraei K;Robinson CT;Cutter GR;Korf BR;Neurofibromatosis Clinical Trials Consortium;Blakeley JO;Clapp DW
1型神经纤维瘤病（NF1）丛状神经纤维瘤（PN）是一种进行性多细胞肿瘤，可引起发病并易发生肉瘤。Nf1flox/flox处理；服用cabozantinib（一种多种酪氨酸激酶抑制剂）的PostnCre小鼠，导致PN大小和数量的减少，以及细胞系中驱动PN生长的激酶的差异调节。基于这些发现，神经纤维瘤病临床试验联盟开展了一项II期、开放标签、非随机的Simon两期研究，以评估cabozantinib在≥16岁伴有NF1和进行性或症状性不能手术的PN （NCT02101736）患者中的安全性、有效性和生物活性。该试验达到了其主要结局，定义为≥25%的患者在12个疗程的治疗后达到部分缓解（PR，定义为通过MRI评估靶病变体积减少≥20%）。次要结局包括不良事件（AE）、评估疼痛和生活质量（QOL）的患者报告结局（PRO）、药代动力学、循环内皮细胞和细胞因子水平。19名可评估的试验参与者中有8名（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%），在治疗期间没有患者出现疾病进展。9例患者因不良事件需要减少剂量或停止治疗；常见的不良反应包括胃肠道毒性、甲状腺功能减退、疲劳和掌跖红肿。8例患者共发生11例3级ae。PR患者的肿瘤疼痛强度和日常生活疼痛干扰显著降低，但总体生活质量评分无变化。这些数据表明，卡博赞替尼在nf1相关的PN中有活性，导致肿瘤体积缩小和疼痛改善。
Neurofibromatosis Type 1 (NF1) plexiform neurofibromas (PN) are progressive, multicellular neoplasms that cause morbidity and predispose to sarcoma. Treatment of Nf1flox/flox;PostnCre 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, non-randomized 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 MRI) after 12 cycles of therapy. Secondary outcomes included adverse events (AE), patient-reported outcomes (PRO) assessing pain and quality of life (QOL), pharmacokinetics, 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 patient 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 8 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.
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影响因子：
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作者：
Estes, Myka L;Mund, Julie A;Case, Jamie
通讯作者：
Case, Jamie
DOI：
10.1056/nejmoa1605943
发表时间：
2016-12-29
期刊：
The New England journal of medicine
影响因子：
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作者：
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影响因子：
9.9
作者：
Dombi, E.;Solomon, J.;Widemann, B. C.
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Widemann, B. C.
影响因子：
9.9
作者：
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通讯作者：
Widemann, Brigitte C.
DOI：
10.1200/jco.2016.70.7398
发表时间：
2017-02-20
期刊：
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
影响因子：
--
作者：
Choueiri TK;Halabi S;Sanford BL;Hahn O;Michaelson MD;Walsh MK;Feldman DR;Olencki T;Picus J;Small EJ;Dakhil S;George DJ;Morris MJ
通讯作者：
Morris MJ