Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors

被引:0
作者
Song, Yuqin [1 ]
Cao, Junning [2 ]
Zhang, Qingyuan [3 ]
Li, Caixia [4 ]
Qiu, Lugui [5 ]
Qi, Junyuan [5 ]
Zhang, Huilai [6 ]
Li, Wenyu [7 ]
Liu, Lihong [8 ]
Jing, Hongmei [9 ]
Zhou, Keshu [10 ]
Zhang, Weijing [11 ]
Zhang, Liling [12 ]
Li, Daqi [13 ]
Zou, Liqun [14 ]
Yang, Haiyan [15 ]
Qian, Wenbin [16 ]
Zhou, Hui [17 ]
Hu, Jianda [18 ]
Yin, Hongyan [19 ]
Fu, Sisi [19 ]
Fan, Songhua [19 ]
Xu, Qian [19 ]
Wang, Jian [19 ]
Jia, Xiaoyun [19 ]
Dai, Guangxiu [19 ]
Su, Weiguo [19 ]
Zhu, Jun [1 ]
机构
[1] Peking Univ Canc Hosp & Inst, Beijing, Peoples R China
[2] Fudan Univ, Shanghai Canc Ctr, Shanghai, Peoples R China
[3] Harbin Med Univ, Affiliated Tumor Hosp, Harbin, Peoples R China
[4] Soochow Univ, Affiliated Hosp 1, Suzhou, Peoples R China
[5] Chinese Acad Med Sci, Inst Hematol Blood & Dis Hosp, Tianjin, Peoples R China
[6] Tianjin Med Univ, Canc Inst & Hosp, Tianjin, Peoples R China
[7] Guangdong Prov Peoples Hosp, Guangzhou, Peoples R China
[8] Hebei Med Univ, Hosp 4, Shijiazhuang, Peoples R China
[9] Peking Univ Third Hosp, Beijing, Peoples R China
[10] Henan Canc Hosp, Zhengzhou, Peoples R China
[11] Capital Med Univ, Beijing Shijitan Hosp, Beijing, Peoples R China
[12] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Wuhan, Peoples R China
[13] Shandong First Med Univ, Jinan Cent Hosp, Jinan, Peoples R China
[14] Sichuan Univ, West China Hosp, Chengdu, Peoples R China
[15] Zhejiang Canc Hosp, Hangzhou, Peoples R China
[16] Zhejiang Univ, Sch Med, Affiliated Hosp 1, Hangzhou, Peoples R China
[17] Hunan Canc Hosp, Changsha, Peoples R China
[18] Fujian Med Univ, Union Hosp, Fuzhou, Peoples R China
[19] HUTCHMED Ltd, Shanghai, Peoples R China
关键词
CHRONIC LYMPHOCYTIC-LEUKEMIA; TYROSINE KINASE INHIBITOR; LYMPHOMA; FOSTAMATINIB; DISCOVERY; MIGRATION; EFFICACY; GS-9973; TARGET; TRIAL;
D O I
暂无
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (<= 65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenstr & ouml;m macroglobulinemia, 0%). The most common (>= 10% patients) grade >= 3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.
引用
收藏
页码:2165 / 2176
页数:12
相关论文
共 35 条
[1]   An open-label phase 2 trial of entospletinib in indolent non-Hodgkin lymphoma and mantle cell lymphoma [J].
Andorsky, David J. ;
Kolibaba, Kathryn S. ;
Assouline, Sarit ;
Forero-Torres, Andres ;
Jones, Vicky ;
Klein, Leonard M. ;
Patel-Donnelly, Dipti ;
Smith, Mitchell ;
Ye, Wei ;
Shi, Wen ;
Yasenchak, Christopher A. ;
Sharman, Jeff P. .
BRITISH JOURNAL OF HAEMATOLOGY, 2019, 184 (02) :215-222
[2]  
[Anonymous], 2015, Blood
[3]  
[Anonymous], Cancer fact sheets
[4]   Entospletinib monotherapy in patients with relapsed or refractory chronic lymphocytic leukemia previously treated with B-cell receptor inhibitors: results of a phase 2 study [J].
Awan, Farrukh T. ;
Thirman, Michael J. ;
Patel-Donnelly, Dipti ;
Assouline, Sarit ;
Rao, Arati, V ;
Ye, Wei ;
Hill, Brian ;
Sharman, Jeff P. .
LEUKEMIA & LYMPHOMA, 2019, 60 (08) :1972-1977
[5]   An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma [J].
Burke, John M. ;
Shustov, Andrei ;
Essell, James ;
Patel-Donnelly, Dipti ;
Yang, Jay ;
Chen, Robert ;
Ye, Wei ;
Shi, Wen ;
Assouline, Sarit ;
Sharman, Jeff .
CLINICAL LYMPHOMA MYELOMA & LEUKEMIA, 2018, 18 (08) :E327-E331
[6]   Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials [J].
Bussel, James ;
Arnold, Donald M. ;
Grossbard, Elliot ;
Mayer, Jiri ;
Trelinski, Jacek ;
Homenda, Wojciech ;
Hellmann, Andrzej ;
Windyga, Jerzy ;
Sivcheva, Liliya ;
Khalafallah, Alhossain A. ;
Zaja, Francesco ;
Cooper, Nichola ;
Markovtsov, Vadim ;
Zayed, Hany ;
Duliege, Anne-Marie .
AMERICAN JOURNAL OF HEMATOLOGY, 2018, 93 (07) :921-930
[7]   Long-term fostamatinib treatment of adults with immune thrombocytopenia during the phase 3 clinical trial program [J].
Bussel, James B. ;
Arnold, Donald M. ;
Boxer, Michael A. ;
Cooper, Nichola ;
Mayer, Jiri ;
Zayed, Hany ;
Tong, Sandra ;
Duliege, Anne-Marie .
AMERICAN JOURNAL OF HEMATOLOGY, 2019, 94 (05) :546-553
[8]   Preclinical Pharmacology Characterization of Sovleplenib (HMPL-523), an Orally Available Syk Inhibitor [J].
Cai, Yu ;
He, Jianlin ;
Wu, Zhipeng ;
He, Weigang ;
Dai, Xiaoming ;
Xu, Yan ;
Cheng, Min ;
Yang, Na ;
Ren, Yongxin ;
Wang, Guanglin ;
Wang, Jian ;
Sai, Yang ;
Jia, Hong ;
Dai, Guangxiu ;
Li, Xiong ;
Su, Weiguo .
JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, 2024, 388 (01) :156-170
[9]   Unmet needs in the first-line treatment of follicular lymphoma [J].
Casulo, C. ;
Nastoupil, L. ;
Fowler, N. H. ;
Friedberg, J. W. ;
Flowers, C. R. .
ANNALS OF ONCOLOGY, 2017, 28 (09) :2094-2106
[10]   SYK-dependent tonic B-cell receptor signaling is a rational treatment target in diffuse large B-cell lymphoma [J].
Chen, Linfeng ;
Monti, Stefano ;
Juszczynski, Przemyslaw ;
Daley, John ;
Chen, Wen ;
Witzig, Thomas E. ;
Habermann, Thomas M. ;
Kutok, Jeffery L. ;
Shipp, Margaret A. .
BLOOD, 2008, 111 (04) :2230-2237