Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study.
Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi-arm phase Ib study.
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DOI：
10.1007/s10637-021-01119-0
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发表时间：
2021-10
影响因子：
3.4
通讯作者：
Naing A
中科院分区：
文献类型：
--
作者：
Thein KZ;Piha-Paul SA;Tsimberidou A;Karp DD;Janku F;Zarifa A;Shah J;Milton DR;Bean S;McQuinn L;Gong J;Colen R;Carter BW;Subbiah V;Ogbonna DC;Pant S;Meric-Bernstam F;Naing A
Selinexor是一种口服选择性核输出抑制剂（SINE），可抑制Exportin-1（XPO 1），与多种化疗药物具有协同作用，对血液系统肿瘤和实体瘤具有体内抗肿瘤作用。在13个平行组中的一个中给予赛林克斯与静脉内拓扑替康。既往接受过全身治疗的晚期或转移性复发/难治性实体瘤患者，或在标准化疗基础上适当添加赛林克斯的患者，均符合入选条件。年龄22- 68岁，以妇科肿瘤最多见;卵巢癌（n = 5）、子宫内膜癌（n = 2），输卵管癌和阴道癌各1例。在接受治疗的14例患者中，12例（86%）至少发生1起治疗相关不良事件（TRAE）。最常见的TRAE为贫血（71%）、血小板减少症（57%）、低钠血症（57%）、呕吐（57%）、疲乏（50%）、恶心（50%）和中性粒细胞减少症（36%）。2例患者出现剂量限制性毒性。1例接受赛灵克斯80 mg给药的患者发生3级恶心和呕吐，1例接受赛灵克斯60 mg给药的患者发生4级中性粒细胞减少和血小板减少。在13例疗效可评价的患者中，1例（8%）子宫内膜癌患者达到了未经证实的部分缓解（uPR），至治疗失败时间（TTF）为48周，而13例患者中有6例（46%）患者病情稳定（SD），临床获益率为46%。所有患者的中位TTF为9周（范围，2- 48周）。结论每周一次的赛林克斯联合拓扑替康是可行的，并显示出一定的初步肿瘤疗效。赛林克斯的推荐II期剂量为60 mg每周一次，联合IV托泊替康。试验注册：NCT 02419495。2015年4月14日注册，https://clinicaltrials.gov/ct2/show/NCT02419495
Background Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a “basket type” expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22–68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2–48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan. Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495
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影响因子：
28.5
作者：
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通讯作者：
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