Safety and tolerability of bireociclib for the treatment of advanced solid tumors as monotherapy and in combination with endocrine therapy: a multicenter, open-label, phase 1 clinical trial
机构：[1]Department of Medical Oncology and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.[2]Department of Breast Medicine, Institute of Oncology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital, Shenyang 110042, China.[3]Department of Breast Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, China.[4]Fudan University Shanghai Cancer Center, Shanghai 200032, China.[5]Cancer Center, The First Bethune Hospital of Jilin University, Changchun 130061, China.[6]The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou 450008, China.河南省肿瘤医院[7]The Fourth Hospital of Hebei Medical University, Hebei Tumor Hospital, Shijiazhuang 050011, China.河北医科大学第四医院[8]The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha 410013, China.[9]The 307, Hospital, Chinese People’s Liberation Army, Beijing 100000, China.[10]Department of Thoracic Oncology II, Peking University Cancer Hospital and Institute, Beijing 100142, China.[11]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing 100142, China.[12]Sichuan Cancer Hospital, Chengdu 610041, China.四川省肿瘤医院[13]The Third Hospital of Nangchang, Nanchang 330009, China.[14]Sun Yat‑Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.中山大学附属第二医院[15]Department of Breast Internal Medicine, The First Hospital of China Medical University, Shenyang 110001, China.[16]Clinical Science Department, Xuanzhu Biopharmaceutical Co., Ltd., Beijing 100020, China.
Background Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been approved for the treatment of hormone receptor-positive (HR+) and human epidermal growth factor receptor-2 negative (HER2-) breast cancers. The study aims were to evaluate the safety, tolerability, and antitumor activity of the novel selective small molecule CDK4/6 inhibitor bireociclib in advanced solid/breast cancer (ABC) patients. MethodsA multicenter, open-label, phase 1 trial which consisted of two parts. Part 1 evaluated bireociclib monotherapy at doses ranging from 20 mg once-daily (QD) to 480 mg twice-daily (BID), and part 2 evaluated bireociclib at the recommended dosage in combination with endocrine therapy for ABC patients, including bireociclib plus non-steroidal aromatase inhibitor (cohort A), bireociclib plus fulvestrant as first-line (cohort B), or second-line therapy (cohort C). The endpoints included observing dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD), as well as determining recommended phase 2 dosage for a single regimen (RP2D-S) and recommended phase 2 dosage for combination therapy (RP2D-C) and assessment of the general safety and efficacy of therapy. ResultsThirty-five patients were included in the part 1 MTD analysis and no DLTs occurred. Bireociclib 480 mg BID had more stable blood concentration fluctuations as well as a superior tumor response rate (objective response rate [ORR], 17.5%), which was identified as RP2D-S. In part 2, 6 patients each were enrolled in the combination study to assess MTD. One DLT occurred (a grade 3 hepatic enzyme increase), so RP2D-C was determined to be 360 mg BID. The highest incidence of any grade and grade 3 or 4 treatment-emergent adverse events in both part 1 and part 2 were diarrhea, neutropenia, and leukopenia. During the dose expansion phase in part 2, the ORR reached 57.1%, 57.1%, and 46.3% in cohorts A, B, and C, respectively. Conclusions Bireociclib demonstrated favorable efficacy and an acceptable safety profile both as monotherapy (RP2D-S of 480 mg BID) and in combination therapy (RP2D-C of 360 mg BID) for treating HR+/HER2- ABC patients. Trial registration Registered with ClinicalTrials.gov, identification ID: NCT04539496, registration date: 03/09/2020 (retrospectively registered).
基金：
the National Major Scientific and Technological Special Project for “Significant New Drugs Development” (No.
2018ZX09711002-011–027) and CAMS Innovation Fund for Medical Sciences (CIFMS, 2021-I2M-1–014 and 2023-12 M-2–004).
第一作者机构：[1]Department of Medical Oncology and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.[2]Department of Breast Medicine, Institute of Oncology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital, Shenyang 110042, China.
共同第一作者：
通讯作者：
通讯机构：[1]Department of Medical Oncology and State Key Laboratory of Molecular Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China.[2]Department of Breast Medicine, Institute of Oncology, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital, Shenyang 110042, China.
推荐引用方式(GB/T 7714)：
Wang Jiayu,Sun Tao,Tong Zhongsheng,et al.Safety and tolerability of bireociclib for the treatment of advanced solid tumors as monotherapy and in combination with endocrine therapy: a multicenter, open-label, phase 1 clinical trial[J].BMC MEDICINE.2025,23(1):doi:10.1186/s12916-025-04364-9.
APA：
Wang, Jiayu,Sun, Tao,Tong, Zhongsheng,Hu, Xichun,Li, Wei...&Xu, Binghe.(2025).Safety and tolerability of bireociclib for the treatment of advanced solid tumors as monotherapy and in combination with endocrine therapy: a multicenter, open-label, phase 1 clinical trial.BMC MEDICINE,23,(1)
MLA：
Wang, Jiayu,et al."Safety and tolerability of bireociclib for the treatment of advanced solid tumors as monotherapy and in combination with endocrine therapy: a multicenter, open-label, phase 1 clinical trial".BMC MEDICINE 23..1(2025)
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