一项评估新型 Wee1 抑制剂adavosertib（AZD1775）单药治疗晚期实体瘤患者的安全性、耐受性和疗效的 Ib 期研究。
A Phase Ib Study Assessing the Safety, Tolerability, and Efficacy of the First-in-Class Wee1 Inhibitor Adavosertib (AZD1775) as Monotherapy in Patients with Advanced Solid Tumors.
机构信息
Sarah Cannon Research Institute, Nashville, TN, USA.
Tennessee Oncology, PLLC, Nashville, TN, USA.
出版信息
Target Oncol. 2023 Jul;18(4):517-530. doi: 10.1007/s11523-023-00965-7. Epub 2023 Jun 6.
BACKGROUND
Adavosertib (AZD1775) is a first-in-class, selective, small-molecule inhibitor of Wee1.
OBJECTIVE
The safety, tolerability, pharmacokinetics, and efficacy of adavosertib monotherapy were evaluated in patients with various solid-tumor types and molecular profiles.
PATIENTS AND METHODS
Eligible patients had the following: confirmed diagnosis of ovarian cancer (OC), triple-negative breast cancer (TNBC), or small-cell lung cancer (SCLC); previous treatment for metastatic/recurrent disease; and measurable disease. Patients were grouped into six matched cohorts based on tumor type and presence/absence of biomarkers and received oral adavosertib 175 mg twice a day on days 1-3 and 8-10 of a 21-day treatment cycle.
RESULTS
Eighty patients received treatment in the expansion phase; median total treatment duration was 2.4 months. The most common treatment-related adverse events (AEs) were diarrhea (56.3%), nausea (42.5%), fatigue (36.3%), vomiting (18.8%), and decreased appetite (12.5%). Treatment-related grade ≥ 3 AEs and serious AEs were reported in 32.5% and 10.0% of patients, respectively. AEs led to dose interruptions in 22.5%, reductions in 11.3%, and discontinuations in 16.3% of patients. One patient died following serious AEs of deep vein thrombosis (treatment related) and respiratory failure (not treatment related). Objective response rate, disease control rate, and progression-free survival were as follows: 6.3%, 68.8%, 4.5 months (OC BRCA wild type); 3.3%, 76.7%, 3.9 months (OC BRCA mutation); 0%, 69.2%, 3.1 months (TNBC biomarker [CCNE1/MYC/MYCL1/MYCN] non-amplified [NA]); 0%, 50%, 2 months (TNBC biomarker amplified); 8.3%, 33.3%, 1.3 months (SCLC biomarker NA); and 0%, 33.3%, 1.2 months (SCLC biomarker amplified).
CONCLUSION
Adavosertib monotherapy was tolerated and demonstrated some antitumor activity in patients with advanced solid tumors.
TRIAL REGISTRATION
ClinicalTrials.gov identifier NCT02482311; registered June 2015.
背景
Adavosertib（AZD1775）是一种首创的、选择性的、小分子 Wee1 抑制剂。
目的
评估 adavosertib 单药治疗各种实体肿瘤类型和分子特征患者的安全性、耐受性、药代动力学和疗效。
患者和方法
符合条件的患者有以下特征：经确认诊断为卵巢癌（OC）、三阴性乳腺癌（TNBC）或小细胞肺癌（SCLC）；先前接受转移性/复发性疾病的治疗；以及可测量的疾病。患者根据肿瘤类型和生物标志物的存在/缺失分为六个匹配队列，并接受口服 adavosertib 175mg，每日两次，在 21 天治疗周期的第 1-3 天和第 8-10 天给药。
结果
80 名患者在扩展阶段接受了治疗；中位总治疗持续时间为 2.4 个月。最常见的治疗相关不良事件（AE）是腹泻（56.3%）、恶心（42.5%）、疲劳（36.3%）、呕吐（18.8%）和食欲下降（12.5%）。32.5%的患者发生治疗相关≥3 级 AE，10.0%的患者发生严重 AE。AE 导致 22.5%的患者中断剂量，11.3%的患者减少剂量，16.3%的患者停止治疗。1 名患者因深静脉血栓形成（治疗相关）和呼吸衰竭（与治疗无关）的严重 AE 而死亡。客观缓解率、疾病控制率和无进展生存期如下：6.3%，68.8%，4.5 个月（OC BRCA 野生型）；3.3%，76.7%，3.9 个月（OC BRCA 突变型）；0%，69.2%，3.1 个月（TNBC 生物标志物[CCNE1/MYC/MYCL1/MYCN]非扩增[NA]）；0%，50%，2 个月（TNBC 生物标志物扩增）；8.3%，33.3%，1.3 个月（SCLC 生物标志物 NA）；0%，33.3%，1.2 个月（SCLC 生物标志物扩增）。
结论
adavosertib 单药治疗在晚期实体瘤患者中耐受良好，并显示出一定的抗肿瘤活性。
试验注册
ClinicalTrials.gov 标识符 NCT02482311；2015 年 6 月注册。
Zotero 插件