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Background <p>Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have been approved for the treatment of hormone receptor-positive (HR<sup>+</sup>) and human epidermal growth factor receptor-2 negative (HER2<sup>−</sup>) 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.</p> Methods <p>A multicenter, open-label, phase 1 trial which consisted of two parts. Part 1 evaluated bireociclib monotherapy at doses ranging from 20&#xa0;mg once-daily (QD) to 480&#xa0;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.</p> Results <p>Thirty-five patients were included in the part 1 MTD analysis and no DLTs occurred. Bireociclib 480&#xa0;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&#xa0;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.</p> Conclusions <p>Bireociclib demonstrated favorable efficacy and an acceptable safety profile both as monotherapy (RP2D-S of 480&#xa0;mg BID) and in combination therapy (RP2D-C of 360&#xa0;mg BID) for treating HR<sup>+</sup>/HER2<sup>−</sup> ABC patients.</p> Trial registration <p> Registered with ClinicalTrials.gov, identification ID: NCT04539496, registration date: 03/09/2020 (retrospectively registered).</p>

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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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月8日

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  • Jiayu Wang,
  • Tao Sun,
  • Zhongsheng Tong,
  • Xichun Hu,
  • Wei Li,
  • Min Yan,
  • Yunjiang Liu,
  • Quchang Ouyang,
  • Xiaoqing Liu,
  • Jian Fang,
  • Huiping Li,
  • Hui Li,
  • Wenyan Chen,
  • Chang Gong,
  • Yuee Teng,
  • Lingmei Xu,
  • Xianghui Duan,
  • Mingming Liu,
  • Yaping Meng,
  • Fei Liu,
  • Li Wang,
  • Binghe Xu

摘要

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.

Methods

A 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.

Results

Thirty-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).