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ARTICLE - Sovleplenib Syk inhibitor in R/R B-cell tumors Spleen tyrosine kinase (Syk) is a cytoplasmic protein tyro-
sine kinase that is ubiquitously expressed in hematopoi- etic cells, including B cells.6 Syk mediates B-cell receptor (BCR) signaling, which is pivotal in the pathogenesis of B-cell lymphoma7,8 and has been identified as an oncogen- ic driver in B-cell malignancies.8 Targeting Syk signaling, which is upstream of both Bruton tyrosine kinase (BTK) and phosphoinositide 3-kinase (PI3Kδ), may overcome drug resistance to BTK inhibitors (BTKi) or PI3Kδ inhibi- tors in chronic lymphocytic leukemia (CLL).9 Blocking Syk activity, using either small interfering RNA or a chemical inhibitor, leads to cell cycle arrest in diffuse large B-cell lymphoma (DLBCL) cells.10 Syk inhibition also blocks cel- lular proliferation in follicular lymphoma (FL), mantle cell lymphoma (MCL) and Burkitt lymphoma.11 Targeting the Syk pathway has demonstrated promise in the treatment of B-cell malignancies given the clinical activities of several Syk inhibitors in clinical trials;9,12-22 however, to date, no Syk inhibitors are approved for lymphoma.
Sovleplenib (HMPL-523) is a novel, small-molecule, po- tent and highly selective oral Syk inhibitor.23 Sovleplenib demonstrated a superior selectivity compared to R406 (the active metabolite of fostamatinib), especially against KDR and RET. In vitro, sovleplenib could effectively inhibit the phosphorylation of Syk and its downstream signaling molecule BLNK, ERK, AKT, PLCγ 1 and P38. Sovleplenib potently inhibited B-cell activation in human whole blood with a half maximal effective concentration (EC50) of 0.157 μM and anti-IgD antibody induced B-cell activation in rat and mouse whole blood with EC50 of 0.546 and 1.000 μM, respectively. Moreover, sovleplenib inhibited cell survival in a panel of B-cell lymphoma cell lines, with a lower half maximal inhibitory concentration (IC50) and an increased apoptotic rate in REC-1 cells compared with other Syk inhibitors.24 We conducted a phase I study to determine the safety, tolerability, efficacy and pharmacokinetics of sovleplenib in patients with relapsed/refractory mature B-cell malignancies in China.
Methods
Study design
This multicenter, open-label phase I study with dose- escalation and dose-expansion phases was conducted in China between December 2016 and April 2021. Dose escala- tion employed a conventional 3+3 study design with doses from 200-800 mg once daily (q.d.). One additional regimen with a 200 mg twice-daily (b.i.d.) starting dose was explored. Dose expansion at the recommended phase II dose (RP2D) was conducted using a basket design for four cohorts: (A) CLL/small lymphocytic lymphoma (SLL), (B) aggressive B-cell lymphoma, (C) MCL and (D) indolent B-cell lympho- ma. Patients received oral sovleplenib in 28-day cycles until progressive disease (PD), intolerable toxicity or consent
Y. Song et al.
withdrawal. Prophylactic antibiotics were not permitted. The primary objective of the dose-escalation phase was to evaluate safety and determine the RP2D by the safe- ty review committee (SRC). The primary objective of the dose-expansion phase was to evaluate safety and prelim- inary efficacy.
The study was conducted in accordance with the Dec- laration of Helsinki and Good Clinical Practice. Ethical approval was obtained by the ethics committees. A list of ethics committees that approved the study is included in the Online Supplementary Appendix. All patients provided written informed consent.
Patients
Eligible adult patients had pathologically confirmed ma- ture B-cell tumors that progressed or were ineligible for standard treatment (see Online Supplementary Appendix), including CLL/SLL, aggressive B-cell lymphoma (DLBCL, Richter syndrome and grade 3b FL), MCL or indolent B-cell lymphoma (marginal zone lymphoma [MZL], lymphoplas- macytic lymphoma/Waldenström macroglobulinemia [LPL/ WM], grades 1, 2, 3a FL) in dose expansion; an Eastern Co- operative Oncology Group performance status of 0-1; and bidimensionally measurable disease at baseline in dose expansion (except CLL or LPL/WM patients). Patients with protocol-defined laboratory abnormalities or a history of clinically significant liver disease were excluded. Detailed eligibility criteria are listed in the Online Supplementary Appendix.
Assessments
Treatment-emergent adverse events (TEAE) were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03. Tumor response was as- sessed according to modified IWCLL 2008 criteria for CLL/ SLL, IWM-7 for LPL/WM and modified Cheson 2014 criteria for other B-cell lymphomas. Responses were assessed with enhanced computed tomography (CT) every 8 weeks for the first 24 weeks, and every 12 weeks thereafter. For DLBCL, MCL, FL, and other fluorodeoxyglucose-sensitive lymphoma, responses were assessed by positron emission tomography-computed tomography (PET-CT) with enhanced CT according to Cheson 2014 criteria. For pharmacokinetic analyses, plasma samples were collected at multiple time points (Online Supplementary Appendix). Plasma concen- trations of sovleplenib and its metabolites were assessed using liquid chromatography-tandem mass spectrometry (LabCorp Drug Development, Shanghai, China), and bio- marker concentrations were measured by MILLIPLEX human cytokine/chemokine panel assay (Millipore).
Statistical analysis
The study planned to enroll 217-232 patients, with 27-42 during dose escalation and 190 during dose expansion based on adverse event (AE) assumptions (Online Supple-
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