A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies
A phase 1b study of the Akt-inhibitor MK-2206 in combination with weekly paclitaxel and trastuzumab in patients with advanced HER2-amplified solid tumor malignancies
复制标题
DOI：
10.1007/s10549-016-3701-7
复制
发表时间：
2016-02-01
影响因子：
3.8
通讯作者：
Munster, Pamela N.
中科院分区：
文献类型：
--
作者：
Chien, Amy Jo;Cockerill, Alyson;Munster, Pamela N.
目的Akt在HER 2+恶性肿瘤的侵袭性发病机制中起关键作用，提示Akt抑制剂可能对HER 2+肿瘤的治疗有价值。临床前研究证明MK-2206（一种选择性变构Akt抑制剂）与紫杉醇和曲妥珠单抗之间存在协同作用。方法我们进行了一项1b期临床研究，每周一次MK-2206联合每周一次紫杉醇80 mg/m2和曲妥珠单抗2 mg/kg治疗HER 2+恶性肿瘤患者。使用改良的毒性概率区间法进行剂量递增。存档的组织样本的分子分析和有限的PK analyses.Results 16例HER 2+肿瘤患者入组（12乳腺癌，3胃，1食管）。分别有81%和75%的患者既往接受过曲妥珠单抗和紫杉烷类化疗。MK-2206 135 mg/周被确定为可耐受。观察到三种剂量限制性毒性，包括两种3级皮疹和1种3级中性粒细胞减少症，导致治疗延迟> 7天。3/4级不良事件包括中性粒细胞减少症（44%）、皮疹（13%）、周围神经病变（6%）和抑郁症（6%）。10例患者（63%）显示肿瘤缓解（3例完全缓解，7例部分缓解）。中位缓解持续时间为6个月。探索性分析确定STARD 3，TM 7SF 2和G3 BP 1作为潜在的生物标志物的respons.Conclusions MK-2206在135 mg/周的剂量与每周紫杉醇和曲妥珠单抗的组合是安全的，耐受性良好，是推荐的2期剂量为这种组合。初步数据表明，尽管既往接受过HER 2靶向治疗，但在HER 2+肿瘤患者中具有显著的临床活性。
Purpose Akt plays a key role in the aggressive pathogenesis of HER2+ malignancies, suggesting that Akt-inhibitors may be of therapeutic value in the treatment of HER2+ tumors. Preclinical studies demonstrate synergy between MK-2206, a selective allosteric Akt-inhibitor, with paclitaxel and trastuzumab. We aimed to evaluate the safety of this combination in patients with HER2+ malignancies.Methods We conducted a phase 1b study of weekly MK-2206 in combination with weekly paclitaxel 80 mg/m(2) and trastuzumab 2 mg/kg in patients with HER2+ malignancies. Dose escalation was performed using a modified toxicity probability interval method. Molecular profiling of archived tissue samples and limited PK analyses were performed.Results 16 patients with HER2+ tumors were enrolled (12 breast, 3 gastric, 1 esophageal). 81 and 75 % had received prior trastuzumab and taxane chemotherapy, respectively. MK-2206 135 mg/week was determined to be tolerable. Three dose-limiting toxicities were observed including two grade 3 rashes and 1 grade 3 neutropenia resulting in a > 7 day delay in treatment. Grade 3/4 adverse events include neutropenia (44 %), rash (13 %), peripheral neuropathy (6 %), and depression (6 %). 10 patients (63 %) demonstrated tumor response (3 complete, 7 partial). Median duration of response was 6 months. Exploratory analyses identified STARD3, TM7SF2, and G3BP1 as potential biomarkers of response.Conclusions MK-2206 at a dose of 135 mg/week in combination with weekly paclitaxel and trastuzumab is safe and well tolerated, and is the recommended phase 2 dose for this combination. Preliminary data indicate significant clinical activity in patients with HER2+ tumors despite prior HER2-directed therapy.