Department of Thoracic Oncology, National Kyushu Cancer Center, Fukuoka, Japan.
Cancer Chemother Pharmacol. 2013 Sep;72(3):619-27. doi: 10.1007/s00280-013-2234-6. Epub 2013 Jul 28.
AZD7762, a potent Chk1/Chk2 inhibitor, has shown chemosensitizing activity with gemcitabine in xenograft models.
This open-label, Phase I, dose-escalation study evaluated the safety, pharmacokinetics (PK) and preliminary efficacy (RECIST) of AZD7762 alone and in combination with gemcitabine in Japanese patients with advanced solid tumours (NCT00937664). Patients received intravenous AZD7762 alone on days 1 and 8 of a 14-day cycle (cycle 0), followed by AZD7762 plus gemcitabine 1,000 mg/m(2) on days 1 and 8 of 22-day cycles, in ascending AZD7762 dose cohorts.
Twenty patients received AZD7762 at doses of 6 mg (n = 3), 9 mg (n = 3), 21 mg (n = 6) and 30 mg (n = 8). Dose-limiting toxicities occurred in 2/6 evaluable patients in the 30-mg cohort: one, CTCAE grade 3 elevated troponin T (cycle 0: AZD7762 monotherapy); one, neutropenia, thrombocytopenia, and elevated aspartate aminotransferase and alanine aminotransferase (cycle 1: combination therapy). The 30 mg dose was therefore regarded as non-tolerable. The most common adverse events (AEs) in cycle 0 (AZD7762 monotherapy) were bradycardia (50 %), hypertension (25 %) and fatigue (15 %). Overall, the most common AEs were bradycardia (55 %), neutropenia (45 %) and hypertension, fatigue and rash (30 % each). Grade ≥3 AEs were reported in 11 patients, the most common being neutropenia (45 %) and leukopenia (25 %). AZD7762 exposure increased approximately linearly. Gemcitabine did not appear to affect AZD7762 PK. There were no objective responses; five patients (all lung cancer) had stable disease.
The maximum tolerated dose of AZD7762 in combination with gemcitabine, 1,000 mg/m(2) was determined as 21 mg in Japanese patients.
AZD7762 是一种强效的 Chk1/Chk2 抑制剂，在异种移植模型中与吉西他滨联合显示出化学增敏活性。
这是一项开放标签、I 期、剂量递增研究，评估了 AZD7762 单药及与吉西他滨联合用于日本晚期实体瘤患者的安全性、药代动力学（PK）和初步疗效（RECIST）（NCT00937664）。患者在 14 天周期的第 1 和第 8 天接受静脉注射 AZD7762 单药（周期 0），随后在 22 天周期的第 1 和第 8 天接受 AZD7762 加吉西他滨 1000mg/m²，递增 AZD7762 剂量组。
20 名患者接受了 6mg（n=3）、9mg（n=3）、21mg（n=6）和 30mg（n=8）剂量的 AZD7762。30mg 剂量组的 2 名可评估患者出现剂量限制毒性：1 例为 CTCAE 3 级肌钙蛋白 T升高（周期 0：AZD7762 单药治疗）；1 例为中性粒细胞减少症、血小板减少症以及天冬氨酸转氨酶和丙氨酸转氨酶升高（周期 1：联合治疗）。因此，30mg 剂量被认为不可耐受。周期 0（AZD7762 单药治疗）中最常见的不良事件（AE）为心动过缓（50%）、高血压（25%）和疲劳（15%）。总体而言，最常见的 AE 为心动过缓（55%）、中性粒细胞减少症（45%）以及高血压、疲劳和皮疹（各 30%）。11 名患者报告了≥3 级 AE，最常见的是中性粒细胞减少症（45%）和白细胞减少症（25%）。AZD7762 暴露量呈近似线性增加。吉西他滨似乎不会影响 AZD7762 的 PK。无客观缓解，5 名患者（均为肺癌）疾病稳定。
在日本患者中，AZD7762 联合吉西他滨的最大耐受剂量确定为 1000mg/m²时的 21mg。
