塞利尼索（一种新型核输出抑制剂）用于晚期难治性骨或软组织肉瘤患者的1B期研究。
Phase IB Study of Selinexor, a First-in-Class Inhibitor of Nuclear Export, in Patients With Advanced Refractory Bone or Soft Tissue Sarcoma.
作者信息
Gounder Mrinal M, Zer Alona, Tap William D, Salah Samer, Dickson Mark A, Gupta Abha A, Keohan Mary Louise, Loong Herbert H, D'Angelo Sandra P, Baker Stephanie, Condy Mercedes, Nyquist-Schultz Kjirsten, Tanner Lanier, Erinjeri Joseph P, Jasmine Francis H, Friedlander Sharon, Carlson Robert, Unger Thaddeus J, Saint-Martin Jean-Richard, Rashal Tami, Ellis Joel, Kauffman Michael, Shacham Sharon, Schwartz Gary K, Abdul Razak Albiruni Ryan
机构信息
Mrinal M. Gounder, William D. Tap, Mark A. Dickson, Mary Louise Keohan, Sandra P. D'Angelo, Mercedes Condy, Lanier Tanner, Joseph P. Erinjeri, and Francis H. Jasmine, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College; Gary K. Schwartz, Columbia University Medical Center, New York, NY; Alona Zer, Samer Salah, Abha A. Gupta, Herbert H. Loong, Stephanie Baker, Kjirsten Nyquist-Schultz, and Albiruni Ryan Abdul Razak, Princess Margaret Cancer Center, Toronto, Ontario, Canada; and Sharon Friedlander, Robert Carlson, Thaddeus J. Unger, Jean-Richard Saint-Martin, Tami Rashal, Joel Ellis, Michael Kauffman, and Sharon Shacham, Karyopharm Therapeutics, Newton, MA.
出版信息
J Clin Oncol. 2016 Sep 10;34(26):3166-74. doi: 10.1200/JCO.2016.67.6346. Epub 2016 Jul 25.
PURPOSE
We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease.
PATIENTS AND METHODS
Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m(2), 50 mg/m(2), or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes.
RESULTS
The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma.
CONCLUSION
Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.
目的
我们评估了核输出化合物口服选择性抑制剂塞利尼索在疾病进展的晚期软组织或骨肉瘤患者中的药代动力学（PKs）、药效学、安全性和疗效。
患者与方法
54例患者每周两次口服塞利尼索（第1天和第3天），剂量为三种剂量之一（30mg/m²、50mg/m²或固定剂量60mg），持续给药或采用3周用药、1周停药的方案。在空腹和进食状态（低脂或高脂含量）下以及使用塞利尼索的各种制剂（片剂、胶囊或混悬液）进行PK分析。治疗前和治疗期间的肿瘤活检进行药效学变化评估。
结果
最常报告的与药物相关的不良事件（1级或2级）为恶心、呕吐、厌食和疲劳，通过支持治疗可得到良好控制。常见报告的3级或4级毒性为疲劳、血小板减少、贫血、淋巴细胞减少和白细胞减少。塞利尼索以固定剂量间歇给药时耐受性明显更好。塞利尼索的PK分析显示，与食物同服时药物暴露量有临床意义不显著的增加（约15%至20%）。配对肿瘤活检的免疫组织化学分析显示，肿瘤抑制蛋白的核积累增加、细胞增殖减少、凋亡增加和基质沉积。在52例可评估反应的患者中，根据RECIST（1.1版）均未出现客观反应；然而，17例（33%）显示疾病持续稳定（≥4个月），包括15例可评估的去分化脂肪肉瘤患者中的7例（47%）。
结论
塞利尼索在60mg固定剂量、3周用药、1周停药的方案下耐受性良好。食物对PKs没有临床意义上的显著影响。已证明在肉瘤中有抗癌活性的初步证据。
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