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首页> 外文期刊>Molecular cancer therapeutics >A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma
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A Phase I Study of the SMAC-Mimetic Birinapant in Adults with Refractory Solid Tumors or Lymphoma

机译：我在难治性实体肿瘤或淋巴瘤中研究了成人中的SMAC模拟桦木的阶段

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The inhibitor of apoptosis (IAP) family of antiapoptotic proteins has been identified as a target for small molecule inhibitors in cancer. Second mitochondrial-derived activator of caspases (SMAC) efficiently and naturally antagonizes IAPs, and preclinical studies have determined that SMAC mimetics have potent anticancer properties. Here, we report a first-in-human trial designed to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics/pharmacodynamics (PK/PD) of birinapant, a novel SMAC mimetic. Patients with advanced solid tumors or lymphoma were enrolled in a 3+3 dose escalation design with birinapant administered intravenously from 0.18 to 63 mg/m(2) once weekly every 3 of 4 weeks. Fifty patients were enrolled to 12 dose cohorts. Birinapant 47 mg/m(2) was determined to be the MTD. At 63 mg/m(2), dose-limiting toxicities included headache, nausea, and vomiting. Two cases of Bell's palsy (grade 2) also occurred at 63 mg/m(2). Birinapant had a plasma half-life of 30 to 35 hours and accumulated in tumor tissue. Birinapant suppressed cIAP1 and increased apoptosis in peripheral blood mononuclear cells and tumor tissue. Prolonged stable disease was observed in 3 patients: non-small cell lung cancer (5 months), colorectal cancer (5 months), and liposarcoma (9 months). Two patients with colorectal cancer had radiographic evidence of tumor shrinkage. In conclusion, birinapant was well tolerated with an MTD of 47 mg/m(2) and exhibited favorable PK and PD properties. Several patients demonstrated stable disease and evidence of antitumor activity. These results support the ongoing clinical trials of birinapant in patients with cancer. (C) 2015 AACR.
机译：已经将凋亡蛋白抑制剂（IAP）抑制剂（IAP）含有癌细胞中的小分子抑制剂的靶标。半胱天冬酶（SMAC）的第二个线粒体衍生的激活剂有效，天然拮抗IAP和临床前研究已经确定SMAC模拟物具有有效的抗癌性能。在这里，我们报告了一项旨在确定疏水剂的最大耐受剂量（MTD），安全性和药代动力学/药物动力学（PK / PD）的一种新型试验，这是一种新的SMAC模拟物。晚期固体肿瘤或淋巴瘤的患者纳入3 + 3剂量升级设计，每周3个周每3个每周一次静脉注射3 + 3剂升级设计，静脉注射一次静脉注射0.18至63mg / m（2）。五十名患者注册到12剂队列。将Birinapant 47mg / m（2）确定为MTD。在63mg / m（2）中，剂量限制毒性包括头痛，恶心和呕吐。两种贝尔麻痹（2级）也发生在63毫克/平方米（2）。桦皂肽的血浆半衰期为30至35小时，积聚在肿瘤组织中。桦树包抑制CIAP1和外周血单核细胞和肿瘤组织的细胞凋亡增加。 3例患者观察到延长稳定的疾病：非小细胞肺癌（5个月），结直肠癌（5个月）和脂肪瘤（9个月）。两名结肠直肠癌患者具有肿瘤收缩的放射线射读证据。总之，硼皂苷耐受47mg / m（2）的MTD耐受，并且表现出有利的PK和PD性能。几名患者表现出稳定的疾病和抗肿瘤活性的证据。这些结果支持癌症患者的Birinapant正在进行的临床试验。 （c）2015年AACR。

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