YY-20394, an oral phosphatidylinositol 3-kinase delta (PI3Kδ) inhibitor, was investigated in a first-in-human study of patients with relapsed or refractory B-cell malignancies. During dose escalation, 25 patients received 20–200 mg of YY-20394 daily. The primary outcome measures were tolerability and dose-limiting toxicity (DLT). The secondary outcomes were pharmacokinetic parameters, progression-free survival (PFS) and the objective response rate (ORR). Since no patients experienced DLT, the maximum tolerated dose (MTD) was not reached. The majority (≥ 5%) of drug-related adverse events were ≥ grade III, being neutropenia (44.0%), pneumonia (16.0%), hyperuricemia (12.0%), lymphocythemia (8.0%), leukopenia (8.0%) and pneumonitis (8.0%). The overall ORR was 64.0% (95% confidence interval (CI): 45.2, 82.8%) including 5 patients with complete remission (CR), 11 with partial remission (PR), 2 with stable disease (SD) and 7 with progressive disease (PD), while the disease control rate (DCR) was 72.0% (95% CI: 54.4, 89.6%). The ORR of 10 patients with follicular lymphoma was 90%. The median PFS time was 255 days. One PR patient with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who received 40 mg q.d. had a durable response of around 36 months. The median PFS time of 10 patients with follicular lymphoma was 300 days. A recommended phase 2 dose of 80 mg q.d. was established. Considering that YY-20394 was well-tolerated with promising preliminary efficacy, further development is warranted. Trial registration clinicaltrials.gov, NCT03757000, retrospectively registered, November 28, 2018, https://clinicaltrials.gov/ct2/show/NCT03757000?term=NCT03757000&draw=2&rank=1 .

中文翻译：

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PI3Kδ 抑制剂 YY-20394 在 B 细胞血液系统恶性肿瘤患者中的 1 期临床试验

YY-20394 是一种口服磷脂酰肌醇 3-激酶δ (PI3Kδ) 抑制剂，在对复发或难治性 B 细胞恶性肿瘤患者的首次人体研究中进行了研究。在剂量递增期间，25 名患者每天接受 20-200 毫克 YY-20394。主要结果指标是耐受性和剂量限制性毒性 (DLT)。次要结果是药代动力学参数、无进展生存期 (PFS) 和客观反应率 (ORR)。由于没有患者经历 DLT，因此未达到最大耐受剂量 (MTD)。大多数（≥ 5%）药物相关不良事件≥ III 级，为中性粒细胞减少症（44.0%）、肺炎（16.0%）、高尿酸血症（12.0%）、淋巴细胞增多症（8.0%）、白细胞减少症（8.0%）和肺炎(8.0%)。总体 ORR 为 64.0%（95% 置信区间 (CI)：45.2、82。8%），其中完全缓解（CR）5例，部分缓解（PR）11例，病情稳定（SD）2例，疾病进展（PD）7例，疾病控制率（DCR）为72.0%（95 % CI: 54.4, 89.6%)。10 名滤泡性淋巴瘤患者的 ORR 为 90%。中位 PFS 时间为 255 天。一名患有慢性淋巴细胞白血病/小淋巴细胞淋巴瘤 (CLL/SLL) 的 PR 患者接受 40 mg qd 的持久反应大约为 36 个月。10 名滤泡性淋巴瘤患者的中位 PFS 时间为 300 天。确定了推荐的 2 期剂量 80 mg qd。考虑到 YY-20394 具有良好的耐受性和有希望的初步疗效，有必要进一步开发。试验注册clinicaltrials.gov，NCT03757000，追溯注册，2018年11月28日，https://clinicaltrials。