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首页> 外文期刊>Cancer Management and Research >First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy
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First-In-Human Phase I Study Of A Dual mTOR Kinase And DNA-PK Inhibitor (CC-115) In Advanced Malignancy

机译：第一阶段I研究高级恶性肿瘤的双mTOR激酶和DNA-PK抑制剂（CC-115）研究

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Purpose: This first-in-human Phase I study investigated the safety, pharmacokinetics (PK), pharmacodynamic profile, and preliminary efficacy of CC-115, a dual inhibitor of mammalian target of rapamycin (mTOR) kinase and DNA-dependent protein kinase. Patients and Methods: Patients with advanced solid or hematologic malignancies were enrolled in dose-finding and cohort expansion phases. In dose-finding, once-daily or twice-daily (BID) ascending oral doses of CC-115 (range: 0.5–40 mg/day) in 28-day continuous cycles identified the maximum-tolerated dose for cohort expansion in 5 specified tumor types. Twelve additional patients with mixed solid tumors participated in a bioavailability substudy. Results: Forty-four patients were enrolled in the dose-finding cohort. Dose-limiting toxicity included thrombocytopenia, stomatitis, hyperglycemia, asthenia/fatigue, and increased transaminases. CC-115 10 mg BID was selected for cohort expansion (n=74) in which fatigue, nausea, and decreased appetite were the most frequent toxicities. Dose-proportional PK was found. CC-115 distributed to glioblastoma tissue (mean tumor/plasma concentration ratio: 0.713). Total exposure of CC-115 was similar under fasting and fed conditions. A patient with endometrial carcinoma remained in complete remission 4 years. Partial response (PR; n=2) and stable disease (SD; n=4) were reported in the bioavailability substudy; SD was reached in 53%, 22%, 21%, and 64% of patients with head and neck squamous cell carcinoma, Ewing sarcoma, glioblastoma multiforme, and castration-resistant prostate cancer, respectively. Chronic lymphocytic leukemia/small lymphocytic lymphoma showed 38% PR and 25% SD. Conclusion: CC-115 was well-tolerated, with toxicities consistent with mTOR inhibitors. Together with biomarker inhibition and preliminary efficacy, oral CC-115 10 mg BID is a promising novel anticancer treatment. Clinical trial registration: NCT01353625.
机译：目的：这种第一期Ⅰ阶段研究了CC-115的安全性，药代动力学（PK），药效学平均分布和初步疗效，雷帕霉素（MTOR）激酶和DNA依赖性蛋白激酶的双重抑制剂。患者和方法：高级固体或血液学恶性肿瘤的患者注册了剂量查找和队列扩张阶段。在剂量发现中，在28天连续循环中每日或两次（范围：0.5-40mg /天）的每日或两次（出价：0.5-40mg /天）鉴定了5个规定的队列群体的最大耐受剂量肿瘤类型。 12例额外的混合实体瘤患者参与生物利用度落物。结果：44名患者注册了剂量调查队列。剂量限制毒性包括血小板减少症，口腔炎，高血糖，哮喘/疲劳和增加的转氨酶。选择CC-115 10mg BID用于队列膨胀（n = 74），其中疲劳，恶心和食欲下降是最常见的毒性。发现剂量比例PK。 CC-115分布到胶质母细胞瘤组织（平均肿瘤/血浆浓度比：0.713）。 CC-115的总暴露在禁食和喂养条件下类似。子宫内膜癌的患者保持完全缓解> 4年。在生物利用度落物中报道了部分反应（Pr; n = 2）和稳定的疾病（SD; n = 4）; SD分别达到53％，22％，21％和64％的头部和颈鳞状细胞癌，EWINGSARCOMA，胶质母细胞瘤多形态和抗阉割前列腺癌患者。慢性淋巴细胞白血病/小淋巴细胞淋巴瘤显示38％PR和25％SD。结论：CC-115耐受良好，毒性与MTOR抑制剂一致。与生物标志物抑制和初步疗效一起，口服CC-115 10 Mg竞标是一个有前途的新型抗癌治疗。临床试验注册：NCT01353625。

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