Page 151 - Haematologica Vol. 109 - July 2024

ARTICLE - Non-Hodgkin Lymphoma
Phase I study of the Syk inhibitor sovleplenib in relapsed
or refractory mature B-cell tumors
Yuqin Song,1* Junning Cao,2* Qingyuan Zhang,3* Caixia Li,4 Lugui Qiu,5 Junyuan Qi,5 Huilai Zhang,6 Wenyu Li,7 Lihong Liu,8 Hongmei Jing,9 Keshu Zhou,10 Weijing Zhang,11 Liling Zhang,12 Daqi Li,13 Liqun Zou,14 Haiyan Yang,15 Wenbin Qian,16 Hui Zhou,17 Jianda Hu,18 Hongyan Yin,19 Sisi Fu,19 Songhua Fan,19 Qian Xu,19 Jian Wang,19 Xiaoyun Jia,19 Guangxiu Dai,19 Weiguo Su19 and Jun Zhu1
1Peking University Cancer Hospital & Institute, Beijing; 2Fudan University Shanghai Cancer Center, Shanghai; 3The Affiliated Tumor Hospital of Harbin Medical University, Harbin; 4The First Affiliated Hospital of Soochow University, Suzhou; 5Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin; 6Tianjin Medical University Cancer Institute & Hospital, Tianjin; 7Guangdong Provincial Peoples Hospital, Guangzhou; 8The Fourth Hospital of Hebei Medical University, Shijiazhuang; 9Peking University Third Hospital, Beijing; 10Henan Cancer Hospital, Zhengzhou; 11Beijing Shijitan Hospital Affiliated to Capital Medical University, Beijing; 12Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan; 13Jinan Central Hospital Affiliated to Shandong First Medical University, Jinan; 14West China Hospital of Sichuan University, Chengdu; 15Zhejiang Cancer Hospital, Hangzhou; 16The First Affiliated Hospital of School of Medicine, Zhejiang University, Hangzhou; 17Hunan Cancer Hospital, Changsha; 18Fujian Medical University Union Hospital, Fuzhou and 19HUTCHMED Limited, Shanghai, China
*YS, JC and QZ contributed equally as first authors.
Abstract
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-lim- iting 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/Waldenström 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.
Introduction
Non-Hodgkin lymphomas (NHL) are the 12th most com- mon cancer globally, with more than 544,000 diagnoses per annum.1,2 In China, approximately 92,800 NHL cases
are diagnosed annually, 64% of which are mature B-cell malignancies.1,3 A fraction of patients with mature B-cell tumors are resistant to or relapse after current first-line therapies; therefore, an unmet need exists for new treat- ment options.4,5
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Correspondence: J. Zhu zhujun@csco.org.cn
Received: Accepted: Early view:
November 9, 2022. January 4, 2024. January 18, 2024.
https://doi.org/10.3324/haematol.2022.282401
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