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A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis

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收录情况： ◇ SCIE

作者：
Liu Yaxin[1] * ; Wang Wei[2] * ; Yin Rutie[3] * ; Zhang Youzhong[4] ; Zhang Yu[5] ; Zhang Keqiang[6] ; Pan Hongming[7] ; Wang Ke[8] ; Lou Ge[9] ; Li Guiling[10] ; Zhang Ruyan[1] ; Li Kun[1] ; Rao Jing[11] ; Zhang Ben[11] ; Wang Yuting[11] ; Wang Quanren[11] ; Gao Yunong[12] ; Li Huiping[13] ;
机构： [1]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Beijing, China. [2]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gynecologic Cancer Surgery Unit, Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Beijing, China. [3]Radiation Therapy and Chemotherapy for Gynecologic Cancer, West China Second University Hospital, Sichuan University, Chengdu, China. [4]Department of Obstetrics and Gynecology, Qilu Hospital of Shangdong University, Jinan, China. [5]Medical Ethics Committee, Xiangya Hospital, Central South University, Changsha, China. [6]Gynecologic Oncology Ward V, Hunan Cancer Hospital, Changsha, China. [7]Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. [8]Department of Gynecologic Oncology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. [9]Gynecology Ward 1, Harbin Medical University Cancer Hospital, Harbin, China. [10]Department of Gynecologic Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. [11]Jiangsu Hengrui Pharmaceuticals Co., Ltd, Shanghai, China. [12]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gynecologic Cancer Surgery Unit, Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Beijing, China. [13]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Beijing, China.
出处：
DOI： 10.1186/s12916-023-03046-8

关键词： Ovarian cancer Triple-negative breast cancer PARP inhibitor Anti-angiogenic therapy gBRCA

摘要：
The effect of the combination of an anti-angiogenic agent with a poly (ADP-ribose) polymerase (PARP) inhibitor in cancer treatment is unclear. We assessed the oral combination of fuzuloparib, a PARP inhibitor, and apatinib, a VEGFR2 inhibitor for treating advanced ovarian cancer (OC) or triple-negative breast cancer (TNBC).This dose-escalation and pharmacokinetics-expansion phase 1 trial was conducted in China. We used a standard 3 + 3 dose-escalation design, with 7 dose levels tested. Patients received fuzuloparib orally twice daily, and apatinib orally once daily. The study objectives were to determine the safety profile, recommended phase 2 dose (RP2D), pharmacokinetics, preliminary efficacy, and efficacy in relation to germline BRCA mutation (gBRCAmut).Fifty-two pre-treated patients were enrolled (30 OC/22 TNBC). 5 (9.6%) patients had complete response, 14 (26.9%) had partial response, and 15 (28.8%) had stable disease. Objective response rate (ORR) and disease control rate were 36.5% (95% CI 23.6-51.0) and 65.4% (95% CI 50.9-78.0), respectively. At the highest dose level of fuzuloparib 100 mg plus apatinib 500 mg, the ORR was 50.0% (4/8; 95% CI 15.7-84.3); this dose was determined to be the RP2D. Patients with gBRCAmut had higher ORR and longer median progression-free survival (PFS) than those with gBRCAwt, both in OC (ORR, 62.5% [5/8] vs 40.9% [9/22]; PFS, 9.4 vs 6.7 months) and TNBC (ORR, 66.7% [2/3] vs 15.8% [3/19]; PFS, 5.6 vs 2.8 months). Two dose-limiting toxicities occurred: grade 4 febrile neutropenia (fuzuloparib 100 mg plus apatinib 250 mg) and thrombocytopenia (fuzuloparib 100 mg plus apatinib 375 mg). Maximum tolerated dose was not reached. The most common treatment-related grade ≥ 3 toxicities in all patients were hypertension (19.2%), anaemia (13.5%), and decreased platelet count (5.8%). Exposure of apatinib increased proportionally with increasing dose ranging from 250 to 500 mg, when combined with fuzuloparib 100 mg.Fuzuloparib plus apatinib had acceptable safety in patients with advanced OC or TNBC. Fuzuloparib 100 mg bid plus apatinib 500 mg qd was established as the RP2D. With the promising clinical activity observed, this combination is warranted to be further explored as a potential alternative to chemotherapy.ClinicalTrials.gov, NCT03075462 (Mar. 9, 2017).© 2023. BioMed Central Ltd., part of Springer Nature.

基金：
This study was funded by Jiangsu Hengrui Pharmaceuticals.
语种：
外文
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中科院(CAS)分区：
出版当年[2023]版：
大类 | 1 区 医学
小类 | 1 区 医学：内科
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 医学：内科
JCR分区：
出版当年[2023]版：
Q1 MEDICINE, GENERAL & INTERNAL
最新[2023]版：
Q1 MEDICINE, GENERAL & INTERNAL

影响因子： 最新[2023版] 最新五年平均 出版当年[2023版] 出版当年五年平均 出版前一年[2022版]

第一作者：
第一作者机构： [1]Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, No. 52 Fucheng Road, Beijing, China.
共同第一作者：
通讯作者：
推荐引用方式(GB/T 7714)：
Liu Yaxin,Wang Wei,Yin Rutie,et al.A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis[J].BMC medicine.2023,21(1):376.doi:10.1186/s12916-023-03046-8.
APA：
Liu Yaxin,Wang Wei,Yin Rutie,Zhang Youzhong,Zhang Yu...&Li Huiping.(2023).A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis.BMC medicine,21,(1)
MLA：
Liu Yaxin,et al."A phase 1 trial of fuzuloparib in combination with apatinib for advanced ovarian and triple-negative breast cancer: efficacy, safety, pharmacokinetics and germline BRCA mutation analysis".BMC medicine 21..1(2023):376

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[1]Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis. [2]Tumor angiogenesis and anti-angiogenic therapy [3]Epigenetics of Triple-negative breast cancer via natural compounds. [4]An open-label, multi-center, single-arm, phase 2 study of fluzoparib in patients with germline BRCA1/2 mutation and platinum-sensitive recurrent ovarian cancer. [5]Aurora A kinase activates YAP signaling in triple-negative breast cancer [6]Management of triple-negative breast cancer by natural compounds through different mechanistic pathways [7]Immune Profiles of Tumor Microenvironment and Clinical Prognosis among Women with Triple-Negative Breast Cancer. [8]MiR-940 Inhibited Cell Growth and Migration in Triple-Negative Breast Cancer. [9]Nuclear receptor NR4A1 is a tumor suppressor down-regulated in triple-negative breast cancer. [10]LncRNA LUCAT1 facilitates tumorigenesis and metastasis of triple-negative breast cancer through modulating miR-5702

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