A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.
A phase I study of MK-5108, an oral aurora a kinase inhibitor, administered both as monotherapy and in combination with docetaxel, in patients with advanced or refractory solid tumors.
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在患有晚期或难治性实体瘤的患者中，MK-5108的I阶段研究是一种口服Aurora A激酶抑制剂，既作为单一疗法和与多西他赛的结合进行给药。
DOI：
10.1007/s10637-015-0306-7
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发表时间：
2016-02
影响因子：
3.4
通讯作者：
Lockhart AC
中科院分区：
文献类型：
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作者：
Amin M;Minton SE;LoRusso PM;Krishnamurthi SS;Pickett CA;Lunceford J;Hille D;Mauro D;Stein MN;Wang-Gillam A;Trull L;Lockhart AC
MK-5108是一种强效/高选择性的Aurora a激酶抑制剂。一项随机I期研究MK-5108，在14-21天的周期中，1-2天p.o. BID Q12h单独（MT; Panel1/n=18； 200至1800 mg）或联合（CT; Panel2/n=17； 100至225 mg）与静脉多西他赛60 mg/m2，测定了晚期实体瘤患者的最大耐受剂量（MTD）、药代动力学（PK）、药效学（Panel1，仅限）和肿瘤反应。由于MK-5108剂量低于预期的PK暴露目标时，Panel2中的毒性，该研究提前终止。35例患者入组（33例可评估肿瘤反应）。Panel1未观察到剂量限制性毒性（dlt）；3例Panel2患者有3个dlt （G3和G4发热性中性粒细胞减少，分别为200和450 mg/天；G3感染，450 mg/天）。在Panel1中，第一次MT给药后，AUC0-12hr和Cmax的增加低于剂量比例，但在第4次MT给药后，在200至3600 mg/天期间，AUC0-12hr和Cmax的增加大致呈剂量比例。两组的t1/2小时在6.6-13.5小时之间。对免疫组织化学标志物无明显影响；然而，治疗前后基因表达明显增加。最佳反应是9/17稳定疾病（SD） （Panel1）以及1/16 PR和7/16 SD (Panel2) （450 mg/天）。MK-5108 MT在高达3600毫克/天的剂量下耐受性良好，血浆水平超过最低日暴露目标（83 μM*hr）。MK-5108 +多西他赛（CT）的MTD设定为300 mg/天，低于暴露目标。使用药效学基因表达测定来确定靶标接合是有效的。
MK-5108 is a potent/highly selective Aurora A kinase inhibitor. A randomized Phase I study of MK-5108, administered p.o. BID Q12h on days 1–2 in 14–21 day cycles either alone (MT; Panel1/n=18; 200 to 1800 mg) or in combination (CT; Panel2/n=17; 100 to 225 mg) with IV docetaxel 60 mg/m2, determined the maximum tolerated dose (MTD), pharmacokinetics (PK), pharmacodynamics (Panel1, only) and tumor response in patients with advanced solid tumors. This study was terminated early due to toxicities in Panel2 at MK-5108 doses below the anticipated PK exposure target. 35 patients enrolled (33 evaluable for tumor response). No dose-limiting toxicities (DLTs) were observed in Panel1; 3 patients had 3 DLTs in Panel2 (G3 and G4 febrile neutropenia at 200 and 450 mg/day, respectively; G3 infection at 450 mg/day). In Panel1, AUC0-12hr and Cmax increased less than dose proportionally following the first MT dose but increased roughly dose proportionally across 200 to 3600 mg/day after 4th dose. The t1/2 ranged from 6.6–13.5 hours across both panels. No clear effects on immunohistochemistry markers were observed; however, significant dose-related increases in gene expression were seen pre-/post-treatment. Best responses were 9/17 stable disease (SD) (Panel1) as well as 1/16 PR and 7/16 SD (Panel2) (450 mg/day). MK-5108 MT was well tolerated at doses up to 3600 mg/day with plasma levels exceeding the minimum daily exposure target (83 μM*hr). The MTD for MK-5108 + docetaxel (CT) was established at 300 mg/day, below the exposure target. Use of pharmacodynamic gene expression assays to determine target engagement was validated.