Background: Spleen tyrosine kinase (Syk) is a key component of B-cell receptor (BCR) signaling and is an established therapeutic target in multiple subtypes of B-cell lymphomas. HMPL-523 is an oral, selective Syk inhibitor, and has shown strong anti-tumor efficacy in xenograft models of B-cell malignancies. Here we report the safety, pharmacokinetics (PK) and preliminary anti-tumor activity results of the dose escalation stage in a Phase 1 study in patients with relapsed/refractory (R/R) B-cell lymphomas treated with HMPL-523 monotherapy (NCT02857998).

Methods: This study comprised a dose escalation stage and a dose expansion stage. The primary objectives for the dose escalation stage were to evaluate the safety, tolerability, and to determine maximum tolerated dose (MTD) and /or recommended Phase 2 dose (RP2D) of HMPL-523. Secondary objectives were to assess the PK and preliminary anti-tumor activity. Treatment responses were assessed by the Lugano criteria, modified International Workshop on Chronic Lymphocytic Leukemia (CLL) guideline, or the consensus of international workshops on Waldenstrom Macroglobulinemia (WM), at weeks 8, 16, 24, and then every 12 weeks.

Results: As of May 3rd 2018, 27 patients had been enrolled and dosed with one of the five dose levels of 200-800 mg once daily (QD) or 200 mg twice daily (BID) under the conventional "3+3" dose escalation design. Baseline tumor subtypes included follicular lymphoma (FL; n=10), diffuse large B cell lymphoma (DLBCL; n=5), CLL / small lymphocytic lymphoma (SLL; n=4), mantle cell lymphoma (MCL; n=4), marginal zone lymphoma (MZL; n=3) and WM (n=1). All patients (median age was 57 years [range 31-73]) were Asian, and 55.6% of the patients were male, with a median prior lines of therapy of 3 (range 1-6). All patients had received prior systemic chemotherapies and/or antibodies, including alkylating agents (100%), anti-CD20 antibodies (75%), and anthracyclines (95.8%). Three patients (8.3%) had received prior ibrutinib/placebo from clinical trials.

Median follow-up time was 98 days (range, 8-427), and 70.4% of patients had discontinued therapy, mostly due to disease progression (25.9%) and adverse events (AEs) (14.8%). The AEs of any cause reported in more than 10% patients were leukopenia (44.4%), neutropenia (44.4%), alkaline phosphatase (ALT) increased (40.7%), aspartate aminotransferase (AST) increased (40.7%), thrombocytopenia (29.6%), blood bilirubin increased (29.6%), anaemia (25.9%), proteinuria (18.5%), amylases increased (18.5%), yellow skin (18.5%), hypokalaemia (14.8%), lung infection (14.8%), influenza syndrome (14.8%), hyperuricaemia (11.1%), cough (11.1%), and bilirubin conjugated increased (11.1%). The ≥ Grade 3 AEs of any cause reported in more than 5% patients were neutropenia (18.5%), lung infection (7.4%), and blood bilirubin increased (7.4%). Serious AEs were reported in 8 patients with 9 events, of which 5 events were considered to be related to HMPL-523 (i.e., interstitial pneumonia, febrile neutropenia, kidney failure, lung infection, and bilirubin conjugated increased). No fatal AE was reported. Five dose limiting toxicities (DLTs) were observed: 1 in the 200 mg QD cohort (Grade 3 amylase increased), 2 in the 800 mg QD cohort (Grade 3 febrile neutropenia; Grade 3 kidney failure), and 2 in the 200 mg BID cohort (Grade 3 bilirubin conjugated increased; Grade 4 hyperuricaemia and blood creatine phosphokinase increased). The MTD was reached at the 600 mg QD dose level which was determined as the RP2D.

Preliminary PK data indicated that the exposures of HMPL-523 increased with the increase in dose from 200 mg QD to 800 mg QD. The geometric mean exposures indicated as AUCtau and Cmax at 600 mg QD at steady state were approximately 4,000 h•ng/mL and 300 ng/mL, respectively, and the t1/2 was in the range of 7-15 hours across all dose levels.

Among 21 efficacy evaluable patients with at least one post treatment efficacy assessment, best tumor response was seen in 4 (19.0%) patients who achieved partial response (3/10 FL, and 1/3 CLL/SLL), and 9 (40%) patients who achieved stable disease (3/4 MCL, 3/10 FL, 1/3 CLL/SLL, 1/2 MZL, and 1/1 WM).

Conclusions: HMPL-523 is well tolerated as a single agent in Chinese patients with R/R B-cell lymphomas. MTD was reached and RP2D was determined to be 600 mg QD. Preliminary anti-tumor activity was observed in indolent lymphomas, including CLL/SLL and FL.


Zhu:Beijing Cancer Hospital: Employment. Song:Peking University Cancer Hospital (Beijing Cancer Hospital): Employment. Hua:Hutchison Medipharma: Employment. Yang:Hutchison Medipharma: Employment. Yu:Hutchison Medipharma: Employment. Wang:Hutchison Medipharma: Employment. Dai:Hutchison Medipharma: Employment. Su:Hutchison Medipharma: Employment.

Author notes


Asterisk with author names denotes non-ASH members.