Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1M59 Bunting Blaustein Cancer Research Building, 1650 Orleans Street, Baltimore, MD, 21287, USA.
University of Arizona Cancer Center, Tucson, AZ, USA.
Invest New Drugs. 2018 Dec;36(6):1060-1071. doi: 10.1007/s10637-018-0625-6. Epub 2018 Jul 7.
Background Aurora kinase overexpression or amplifications are associated with high proliferation, poor prognosis, and therapeutic resistance in human tumors. AMG 900 is an investigational, oral, selective pan-Aurora kinase inhibitor. Methods This first-in-human trial included dose-escalation and dose-expansion phases ( ClinicalTrials.gov : NCT00858377). Dose escalation evaluated the safety, tolerability, and pharmacokinetics of AMG 900 in advanced solid tumors and determined the maximum tolerated dose (MTD) with/without granulocyte colony-stimulating factor (G-CSF) prophylaxis. Dose expansion evaluated clinical activity in three tumor types: taxane- and platinum-resistant ovarian cancer, taxane-resistant triple-negative breast cancer (TNBC), and castration-resistant and taxane- or cisplatin/etoposide-resistant prostate cancer (CRPC). AMG 900 was administered 4 days on/10 days off at 1-50 mg/day during escalation and at the MTD with G-CSF during expansion. Results AMG 900 showed rapid absorption with fast clearance, supporting once-daily dosing. The MTD was 25 mg/day, increasing to 40 mg/day with G-CSF. Grade ≥ 3 treatment-related adverse events included neutropenia (37%), anemia (23%), leukopenia (14%), and thrombocytopenia (12%). During dose expansion, 3/29 (10.3%, 95% CI: 2.0%-28.0%) evaluable patients with ovarian cancer experienced partial response by central imaging per RECIST 1.1; median duration of response was 24.1 weeks (95% CI: 16.1-34.1). Seven patients (24.1%, 95% CI: 10.3%-43.5%) experienced partial response per Gynecologic Cancer InterGroup criteria; 5/9 patients positive for p53 expression responded to treatment. No objective responses were observed in patients with TNBC or CRPC per RECIST 1.1. Conclusions AMG 900 40 mg/day with G-CSF had manageable toxicity and demonstrated single-agent activity in patients with heavily pretreated, chemotherapy-resistant ovarian cancer.
极光激酶的过度表达或扩增与人类肿瘤的高增殖、预后不良和治疗耐药有关。AMG 900 是一种研究性的、口服的、选择性的泛极光激酶抑制剂。
这项首次人体试验包括剂量递增和剂量扩展阶段（ClinicalTrials.gov：NCT00858377）。剂量递增评估了 AMG 900 在晚期实体肿瘤中的安全性、耐受性和药代动力学，并确定了最大耐受剂量（MTD），有/无粒细胞集落刺激因子（G-CSF）预防。剂量扩展评估了三种肿瘤类型的临床活性：紫杉烷和铂类耐药性卵巢癌、紫杉烷耐药性三阴性乳腺癌（TNBC）以及去势抵抗性和紫杉烷或顺铂/依托泊苷耐药性前列腺癌（CRPC）。在递增期，AMG 900 每 4 天给药 1 次/10 天停药，剂量为 1-50mg/天，在扩展期，AMG 900 在 MTD 时与 G-CSF 联合给药。
AMG 900 显示出快速吸收和快速清除，支持每日一次给药。MTD 为 25mg/天，G-CSF 增加至 40mg/天。3/29（10.3%，95%CI：2.0%-28.0%）名可评估的卵巢癌患者发生了 3 级及以上与治疗相关的不良事件，包括中性粒细胞减少症（37%）、贫血（23%）、白细胞减少症（14%）和血小板减少症（12%）。在剂量扩展期，根据 RECIST 1.1 标准，中心影像学评估的 29 名（10.3%，95%CI：2.0%-28.0%）可评估的卵巢癌患者中有 3 名（10.3%，95%CI：2.0%-28.0%）出现部分缓解；中位缓解持续时间为 24.1 周（95%CI：16.1-34.1）。根据妇科肿瘤学研究组标准，7 名（24.1%，95%CI：10.3%-43.5%）患者出现部分缓解；5 名 p53 表达阳性患者对治疗有反应。根据 RECIST 1.1 标准，在 TNBC 或 CRPC 患者中未观察到客观缓解。
AMG 900 联合 G-CSF 每日 40mg 剂量具有可管理的毒性，在化疗耐药的、预处理广泛的卵巢癌患者中显示出单药活性。
