Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma.
Phase II study of the oral selective inhibitor of nuclear export (SINE) KPT-335 (verdinexor) in dogs with lymphoma.
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DOI：
10.1186/s12917-018-1587-9
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发表时间：
2018-08-24
影响因子：
2.6
通讯作者：
London CA
中科院分区：
文献类型：
--
作者：
Sadowski AR;Gardner HL;Borgatti A;Wilson H;Vail DM;Lachowicz J;Manley C;Turner A;Klein MK;Waite A;Sahora A;London CA
几十年来，治疗犬淋巴瘤的化疗选择没有改变，因此需要寻找新的治疗方法来改善患者的预后。KPT-335（verdinexor）是一种新型口服生物可利用的选择性核输出抑制剂（SINE），在先前的I期研究中显示出对非霍奇金淋巴瘤的抗肿瘤活性。本II期研究的目的是扩展初步结果，并在更大的淋巴瘤犬群体中评估活性和安全性。本临床试验入组了58只患有初治或进行性B细胞和T细胞淋巴瘤的犬。基于先前确定的生物活性剂量1.5 mg/kg，每周三次，在三个给药组之一中经口给予KPT-335。单药口服KPT-335治疗的客观缓解率（ORR）为37%，其中T细胞淋巴瘤犬的ORR为71%。KPT-335在所有剂量组中耐受性良好，1-2级厌食症是最常见的不良事件。厌食症对对症和支持性药物（包括泼尼松）有反应。这些数据表明，KPT-335在犬淋巴瘤中具有生物活性，并支持继续评价SINE化合物如KPT-335与标准化疗药物联合治疗犬淋巴瘤。本文的在线版本（10.1186/s12917-018-1587-9）包含补充材料，可供授权用户使用。
Chemotherapeutic options for the treatment of canine lymphoma have not changed in several decades necessitating the identification of new therapeutics to improve patient outcome. KPT-335 (verdinexor) is a novel orally bioavailable selective inhibitor of nuclear export (SINE) that exhibited anti-tumor activity against non-Hodgkin lymphoma in a prior phase I study. The objective of this phase II study was to expand upon the initial findings and assess the activity and safety in a larger population of dogs with lymphoma. Fifty-eight dogs with naïve or progressive B-cell and T-cell lymphoma were enrolled in this clinical trial. KPT-335 was administered orally in one of three dosing groups, based on the previously established biologically active dose of 1.5 mg/kg three times weekly. Treatment with single-agent, orally administered KPT-335 resulted in an objective response rate (ORR) of 37%, of which dogs with T-cell lymphoma had an ORR of 71%. KPT-335 was well tolerated in all dose groups with grade 1–2 anorexia being the most common adverse event. Anorexia was responsive to symptomatic and supportive medications, including prednisone. These data demonstrate that KPT-335 has biologic activity in canine lymphoma, and support continued evaluation of SINE compounds such as KPT-335 in combination with standard chemotherapeutics in canine lymphoma. The online version of this article (10.1186/s12917-018-1587-9) contains supplementary material, which is available to authorized users.
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