Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, first-in-human phase 1 study.
Conteltinib (CT-707) in patients with advanced ALK-positive non-small cell lung cancer: a multicenter, open-label, first-in-human phase 1 study.
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康替尼（CT-707）治疗晚期ALK阳性非小细胞肺癌患者：一项多中心、开放标签、首次人体I期研究
DOI：
10.1186/s12916-022-02646-0
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发表时间：
2022-11-23
期刊：
影响因子：
9.3
通讯作者：
Shi, Yuankai
中科院分区：
文献类型：
--
作者：
Xing, Puyuan;Zhao, Qian;Zhang, Li;Wang, Hanping;Huang, Dingzhi;Hu, Pei;Sun, Yinghui;Shi, Yuankai
关键词：
康泰替尼（CT-707）是一种有效的第二代间变性淋巴瘤激酶（ALK）酪氨酸激酶抑制剂（TKI），在临床前研究中显示出良好的抗肿瘤活性。本研究旨在评估康替尼在ALK阳性非小细胞肺癌（NSCLC）患者中的安全性、药代动力学（PK）和疗效。在这项多中心、单组、开放标签、首次人体I期研究中，在剂量递增阶段口服50 - 800 mg quaque die（QD）剂量的康泰替尼。如果在剂量递增阶段的剂量队列中观察到缓解，则开始剂量扩展。主要终点是最大耐受剂量（MTD）、剂量限制性毒性（DLT）和研究者评估的不良事件。2016年4月13日至2020年2月8日期间，入组了64例ALK阳性NSCLC患者，包括41例（64.1%）ALK TKI初治患者和23例（35.9%）既往接受过克唑替尼治疗的患者。在剂量递增阶段，26例患者接受康替尼治疗，剂量为50 mg、100 mg、200 mg、300 mg、450 mg、600 mg和800 mg QD。在600 mg剂量下报告了1起DLT事件。未达到MTD。总体而言，58例（90.6%）患者发生治疗相关不良事件（TRAE），9例（14.1%）患者发生≥ 3级TRAE。最常见的TRAE为腹泻（46例[71.9%]）、血清肌酐升高（29例[45.3%]）、天冬氨酸转氨酶升高（25例[39.1%]）和恶心（24例[37.5%]）。在39例ALK TKI初治患者中，总缓解率（ORR）为64.1%（25/39; 95%置信区间[CI]，47.2-78.8），中位无进展生存期（PFS）为15.9个月（95% CI，9.26-23.3），中位缓解持续时间（DoR）为15.0个月（95% CI，9.06-25.8）。在21例既往接受过克唑替尼治疗的患者中，ORR为33.3%（7/21; 95% CI，14.6-57.0），中位PFS为6.73个月（95% CI，4.73-8.54），中位DoR为6.60个月（95% CI，3.77-13.3）。在这项研究中，康替尼在晚期ALK阳性NSCLC患者中显示出可管理的安全性特征、有利的PK特性和抗肿瘤活性。ALK TKI初治患者的推荐II期剂量确定为600 mg QD，既往接受过克唑替尼治疗的患者的推荐II期剂量确定为300 mg BID。ClinicalTrials.gov，NCT02695550。在线版本包含补充材料，可通过10.1186/s12916-022-02646-0获得。
Conteltinib (CT-707) is a potent second-generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor (TKI) showing promising anti-tumor activities in preclinical studies. This study aimed to assess the safety, pharmacokinetic (PK), and efficacy of conteltinib in patients with ALK-positive non-small cell lung cancer (NSCLC). In this multicenter, single-arm, open-label, first-in-human phase 1 study, conteltinib was taken orally at doses of 50 to 800 mg quaque die (QD) in a dose-escalation phase. If the response was observed in a dose cohort of the dose-escalation phase, dose expansion was started. The primary endpoints were maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and adverse events assessed by investigators. Between April 13, 2016, and February 8, 2020, 64 ALK-positive NSCLC patients were enrolled, including 41 (64.1%) patients with ALK TKI-naïve and 23 (35.9%) patients who received crizotinib previously. In the dose-escalation phase, 26 patients were treated with conteltinib at doses of 50 mg, 100 mg, 200 mg, 300 mg, 450 mg, 600 mg, and 800 mg QD. One DLT event was reported at the dose of 600 mg. MTD was not reached. Overall, 58 (90.6%) patients experienced treatment-related adverse events (TRAEs) and 9 (14.1%) patients had grade ≥ 3 TRAEs. The most common TRAEs were diarrhea (46 [71.9%]), serum creatinine elevated (29 [45.3%]), aspartate aminotransferase elevated (25 [39.1%]), and nausea (24 [37.5%]). Among 39 ALK TKI-naïve patients, the overall response rate (ORR) was 64.1% (25 of 39; 95% confidence interval [CI], 47.2–78.8), median progression-free survival (PFS) was 15.9 months (95% CI, 9.26–23.3), and median duration of response (DoR) was 15.0 months (95% CI, 9.06–25.8). Among 21 patients who received crizotinib previously, the ORR was 33.3% (7 of 21; 95% CI, 14.6–57.0), median PFS was 6.73 months (95% CI, 4.73–8.54), and median DoR was 6.60 months (95% CI, 3.77–13.3). In this study, conteltinib showed manageable safety profile, favorable PK properties, and anti-tumor activity in advanced ALK-positive NSCLC patients. The recommended phase 2 dose was determined to be 600 mg QD for ALK TKI-naïve patients and 300 mg bis in die (BID) for patients who received crizotinib previously. ClinicalTrials.gov, NCT02695550. The online version contains supplementary material available at 10.1186/s12916-022-02646-0.
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DOI：
10.1093/annonc/mdy121
发表时间：
2018-06-01
期刊：
Annals of oncology : official journal of the European Society for Medical Oncology
影响因子：
--
作者：
Novello S;Mazières J;Oh IJ;de Castro J;Migliorino MR;Helland Å;Dziadziuszko R;Griesinger F;Kotb A;Zeaiter A;Cardona A;Balas B;Johannsdottir HK;Das-Gupta A;Wolf J
通讯作者：
Wolf J
影响因子：
45.3
作者：
Kim, Dong-Wan;Tiseo, Marcello;Camidge, D. Ross
通讯作者：
Camidge, D. Ross
影响因子：
51.1
作者：
Gadgeel, Shirish M.;Gandhi, Leena;Ou, Sai-Hong Ignatius
通讯作者：
Ou, Sai-Hong Ignatius
CT-707通过靶向FAK激活PDPK1-AKT1通路克服克唑替尼耐药
影响因子：
3
作者：
Liang, Caixia;Zhang, Ningning;Han, Xiaohong
通讯作者：
Han, Xiaohong
影响因子：
8.4
作者：
Lin, Yen-Ting;Chiang, Chi-Lu;Shih, Jin-Yuan
通讯作者：
Shih, Jin-Yuan