Byrd John C, Smith Stephen, Wagner-Johnston Nina, Sharman Jeff, Chen Andy I, Advani Ranjana, Augustson Bradley, Marlton Paula, Renee Commerford S, Okrah Kwame, Liu Lichuan, Murray Elaine, Penuel Elicia, Ward Ashley F, Flinn Ian W
Division of Hematology, Ohio State University Wexner Medical Center, Columbus, OH, USA.
Division of Medical Oncology, University of Washington, Seattle, WA, USA.
Oncotarget. 2018 Jan 22;9(16):13023-13035. doi: 10.18632/oncotarget.24310. eCollection 2018 Feb 27.
GDC-0853 is a selective, reversible, and non-covalent inhibitor of Bruton's tyrosine kinase (BTK) that does not require interaction with the Cys481 residue for activity. In this first-in-human phase 1 study we evaluated safety, tolerability, pharmacokinetics, and activity of GDC-0853 in patients with relapsed or refractory non-Hodgkin lymphoma (NHL) or chronic lymphocytic leukemia (CLL). Twenty-four patients, enrolled into 3 cohorts, including 6 patients who were positive for the C481S mutation, received GDC-0853 at 100, 200, or 400 mg once daily, orally. There were no dose limiting toxicities. GDC-0853 was well tolerated and the maximum tolerated dose (MTD) was not reached due to premature study closure. Common adverse events (AEs) in ≥ 15% of patients regardless of causality included fatigue (37%), nausea (33%), diarrhea (29%), thrombocytopenia (25%), headache (20%), and abdominal pain, cough, and dizziness (16%, each). Nine serious AEs were reported in 5 patients of whom 2 had fatal outcomes (confirmed H1N1 influenza and influenza pneumonia). A third death was due to progressive disease. Eight of 24 patients responded to GDC-0853: 1 complete response, 4 partial responses, and 3 partial responses with lymphocytosis, including 1 patient with the C481S mutation. Two additional C481S mutation patients had a decrease in size of target tumors (-23% and -44%). These data demonstrate GDC-0853 was generally well-tolerated with antitumor activity.
GDC-0853是一种选择性、可逆且非共价的布鲁顿酪氨酸激酶（BTK）抑制剂，其活性不需要与Cys481残基相互作用。在这项首次人体1期研究中，我们评估了GDC-0853在复发或难治性非霍奇金淋巴瘤（NHL）或慢性淋巴细胞白血病（CLL）患者中的安全性、耐受性、药代动力学和活性。24名患者入组3个队列，其中包括6名C481S突变阳性的患者，口服GDC-0853，剂量为每日1次，100、200或400mg。未出现剂量限制性毒性。GDC-0853耐受性良好，由于研究过早结束，未达到最大耐受剂量（MTD）。无论因果关系如何，≥15%患者出现的常见不良事件（AE）包括疲劳（37%）、恶心（33%）、腹泻（29%）、血小板减少（25%）、头痛（20%）以及腹痛、咳嗽和头晕（各16%）。5名患者报告了9起严重AE，其中2例导致死亡（确诊为H1N1流感和流感肺炎）。第三例死亡归因于疾病进展。24名患者中有8名对GDC-0853有反应：1例完全缓解，4例部分缓解，3例部分缓解伴淋巴细胞增多，其中包括1例C481S突变患者。另外2例C481S突变患者的靶肿瘤大小减小（分别为-23%和-44%）。这些数据表明GDC-0853总体耐受性良好且具有抗肿瘤活性。
