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Background: Primary immune thrombocytopenia (ITP) is characterized by increased platelet destruction and impaired platelet production, resulting in decreased platelet counts and increased bleeding risk. Spleen Tyrosine Kinase (Syk) plays a pivotal role in the regulation of downstream signals in immune receptors, including B cell receptors (BCRs) and has been implicated in autoantibody production. On the other hand, all activating Fc receptors signal via Syk, which has roles in cellular proliferation, differentiation, survival, immune regulation, and cytoskeletal rearrangements during phagocytosis. This randomized, double-blind, placebo-controlled phase 1b study (NCT03951623) aimed to assess the safety, pharmacokinetics (PK), determine the recommended phase 2 dose (RP2D) and evaluate preliminary efficacy of HMPL-523, a novel, potent and highly selective Syk inhibitor, in patients with ITP. Methods: Relapsed/refractory ITP patients with platelet counts less than 30×10 9/L were eligible for the study. This randomized study (3:1) consists of two stages with dose escalation (DES) and dose expansion (DEX). Four dose groups were set (100, 200, 300 and 400mg QD) and patients were randomized to either HMPL-523 or placebo in each dose group (n=8) to determine the RP2D in DES. Additional 12 patients were enrolled at RP2D to further assess the safety and efficacy in DEX. Each patient received an 8-week double blind treatment (8w-DB), followed by a 16-week, open-label HMPL-523 treatment (16w-OL), except for all patients of 100mg cohort and 2 patients of 200mg cohort (only received 8w-DB per protocol v1.0). Treatment-emergent adverse events were graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 5.0. The efficacy of overall response rate was defined as the proportion of patients with at least one platelet counts ≥50×10 9/L, and durable response rate was defined as the proportion of patients with platelet counts ≥50×10 9/L for at least 4 of the last 6 scheduled visits. Results: As of data cutoff (June 23, 2021), 33 patients (24:9) were enrolled in DES at 100-400mg. And 300mg QD was determined as RP2D. Additional 12 patients (10:2) were enrolled in DEX at 300mg QD. Main baseline patient characteristics are shown in Table 1. During 8-w DB treatment period, the overall response rate was 3 (50.0%), 2 (33.3%), 11 (68.8%) and 2 (33.3%) at 100-400mg dose cohorts, respectively, compared to 1 (9.1%) in the placebo. The durable response rate at 300mg was 5 (31.3%), compared to 1 (9.1%) in placebo. For all patients enrolled in 300mg cohort with at least one dose of HMPL-523 (n=20), including both 8w-DB and 16w-OL treatment period, the overall response rate was 80%; the durable response rate was 27.8% in the durable response-evaluable set (defined as patients received HMPL-523 treatment and completed at least 6 scheduled visits or discontinued during HMPL-523 treatment, n=18). No DLTs were observed at 100-400mg dose cohorts. The most common TEAEs (≥2 patients) related with HMPL-523 in 8w-DB were LDH increased (6 [17.6%]), ALT increased (5 [14.7%]), amylase increased (5 [14.7%]), AST increased (4 [11.8%]), neutrophil count decreased (3 [8.8%]), hypokalemia (3 [8.8%]), urine protein detection (3 [8.8%]), WBC count decreased (3 [8.8%]), gamma-glutamyl transferase (2 [5.9%]), asthenia (2 [5.9%]), dizziness (2 [5.9%]), total bile acid increased (2 [5.9%]), diarrhea (2 [5.9%]), abdominal pain (2 [5.9%]), hypertriglyceridemia (2 [5.9%]) and hyperlipidemia (2 [5.9%]). For all patients enrolled in 300mg cohort (n=20) throughout HMPL-523 treatment period (up to 24 weeks), ALT increased (5 [25.0%]), LDH increased (5 [25.0%]), AST increased (4 [20.0%]), total bile acid increased (4 [20.0%]), amylase increased (3 [15.0%]), TBiL increased (2 [10.0%]), hyperlipemia (2 [10.0%]) and hypertension (2 [10.0%]) were the most frequently reported HMPL-523-related TEAEs (≥2 patients). At the dose of 100-400mg QD, the exposure of HMPL-523 (C max and AUC tau) in plasma increased dose proportionally. Median T max was 4 h and mean T 1/2 was 11-13 h across all four dose levels. Conclusion: HMPL-523 was well tolerated at all dose levels within the range of 100 mg to 400 mg. HMPL-523 300mg QD for ITP treatment is an efficacious and safe dose and recommended as RP2D. A randomized phase 3 study will commence to further confirm the efficacy of HMPL-523 in primary ITP. Figure 1 Figure 1. Disclosures Shi: HUTCHMED: Current Employment. Yin: HUTCHMED: Current Employment. Fan: Hutchmed: Current Employment.

Introduction HMPL-689 is a potent and highly selective small molecule inhibitor of phosphoinositide 3-kinase-delta (PI3Kδ). Despite available agents targeting the B-cell receptor (BCR) pathway, there remains a need for alternative therapies in the relapsed/refractory (R/R) setting due to agent-specific toxicities and suboptimal efficacy among lymphoma subtypes. This study (NCT03128164) is a phase 1, open-label, dose escalation and expansion study in China to assess the safety, pharmacokinetics (PK), and preliminary efficacy of HMPL-689 as a monotherapy in patients with R/R lymphomas. Here we present the preliminary results of the dose-escalation phase of the study. Methods In this dose escalation phase, patients with R/R lymphoma failed of standard therapy, at least 1 prior therapy, were eligible. The dose-escalation study consisted of cohort A (BID) and cohort B (QD), in which HMPL-689 was orally administered continuously on a 28-day cycle. The modified toxicity probability interval scheme-2 (mTPI-2) design was applied for the dose escalation and maximum tolerated dose (MTD) determination. Blood samples for PK and pharmacodynamics (PD) analyses were collected during Cycle 1 and Day 1 of each subsequent cycle. Results A total of 56 patients were enrolled, with 5 chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), 23 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL), 9 mantle cell lymphoma (MCL), 9 diffuse large B cell lymphoma (DLBCL), and 3 Hodgkin's lymphoma (HL) patients (Table 1). The median age was 56 years (range 26-73). The median number of prior therapies was 3 (range 1-8), of which 39 patients had prior exposure to rituximab. 29 patients received HMPL-689 in cohort A (BID): 2.5 mg (n=3), 5 mg (n=9), 7.5 mg (n=8), and 10 mg (n=9), while 27 patients were in cohort B (QD): 5 mg (n=3), 10 mg (n=3), 20 mg (n=9), 30 mg (n=9), and 40 mg (n=3). Median duration of HMPL-689 therapy was 7.6 months (range 0.4 -Not reached [NR]). The most common Grade ≥3 non-hematologic treatment emergent adverse events (TEAEs) were pneumonia and hypertension. Grade ≥3 hematologic TEAEs were neutropenia (Table 2). No Grade 5 TEAE was reported. In cohort A, 4 dose limited toxicities (DLTs) were observed, including Grade 3 asymptomatic amylase (2 pts, 5 mg), Grade 4 hypercalcemia (1 pt, 10 mg), Grade 3 lipase increased (1 pt, 10 mg). In cohort B, 5 DLTs including Grade 3 skin maculopapular (1 pt, 20 mg), hypertriglyceridemia (1 pt, 30 mg), QT interval prolongation (1 pt, 30 mg) and rash (2 pts, 40 mg) were reported. Plasma PK data for the 5-30 mg QD and 2.5-10 mg BID multiple-dose regimens were determined. HMPL-689 drug exposures increased in a dose proportional fashion up to 30mg QD, as reflected in AUC and Cmax. The geometric mean AUCtau and Cmax at 30 mg QD in patients were approximately 2150 h•ng/mL and 260 ng/mL, respectively at steady state. The median Tmax was around 2 h and the arithmetic mean t1/2 was within the range of 5-10 hours, consistent across all dose levels. 51 out of the 56 patients had post-baseline tumor assessment, with 6 complete response (CR) (2 CLL/SLL, 4 FL), 21 partial responses (PR) (2 CLL/SLL, 5 MZL, 7 FL, 4 MCL, 3 DLBCL) and 18 stable disease (SD) (2 MZL, 9 FL, 4 MCL, 1 DLBCL, 2 HL). This resulted in 52.9% (27/51) objective response rate (ORR) in efficacy evaluable patients. The median time to response (TTR) and duration of response (DOR) were 3.5 months (1.8-8.4) and 6.4 months (0.7-NR), respectively (Table 3). One patient with FL who achieved CR (per post hoc independent radiologic review) was on treatment > 586 days. Final data quality control/verification is ongoing. As a result, 30 mg QD of HMPL-689 has been selected as recommended phase 2 dose (RP2D) based on overall safety and tolerability, PK/PD and preliminary efficacy data. Conclusions: HMPL-689 was well tolerated and the RP2D was determined to be 30 mg QD orally. It exhibited dose-proportional pharmacokinetics, a manageable toxicity profile, and promising single-agent clinical activity in R/R B-cell lymphoma patients. The dose expansion study is ongoing, evaluating the safety and efficacy of HMPL-689 in patients with R/R B-cell lymphoma. Acknowledgement 1. We would like to thank all patients and their families who participated in this trial; 2. We would like to thank all investigators, study coordinators and the entire project team. Disclosures Duan: Hutchison MediPharma Limitied: Current Employment. Yu:Hutchison MediPharma Limitied: Current Employment. Cai:Hutchison MediPharma Limitied: Current Employment. Su:Hutchison MediPharma Limited: Current Employment.

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. Disclosures 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.

Introduction: Spleen Tyrosine Kinase (SYK), a non-receptor type of tyrosine kinase, is a member of Syk/ZAP70 tyrosine kinase family. It plays a pivotal role in the regulation of B-cell receptor (BCR) signal pathway, which regulates proliferation, differentiation and survival of B lymphocytes. The abnormal activation of BCR singling is closely related to transformation and development of B cell lymphoma. Targeting BCR downstream molecules, such as Bruton' tyrosine kinase (BTK) and phosphoinositide-3-kinase δ (PI3Kδ) has emerged as new therapeutic approaches and inhibitors of BTK and PI3Kδ were approved recently by FDA for treatment of some subtypes of B-cell malignancies. Currently, a couple small molecular inhibitors against SYK, another BCR downstream molecule, are under the early clinical development and showed initial efficacy in B cell lymphomas. HMPL-523, discovered and currently being developed in Phase I clinical trial by Hutchison MediPharma, is a novel, highly potent and selective SYK inhibitor (IC50: 0.025 μM). The anti-tumor activity of HMPL-523 was evaluated in this study. Methods: Inhibitory effects of HMPL-523 on cell viability were investigated in a panel of B cell lymphoma cell lines with SYK/BCR dysregulation by CellTiter-Glo luminescent or CCK-8 assay. The effect of HMPL-523 on SYK signaling pathway was detected by western blot. Annexin-V- positive and PI-negative population was recognized as apoptotic cells by FACS. Nude mice bearing B cell lymphoma xenograft tumors with SYK/BCR dysregulation were used to determine anti-tumor activity of HMPL-523 in vivo. Result: HMPL-523 blocked phosphorylation of BLNK, downstream protein of Syk, in human mantle cell line REC-1 and human plasma cell line ARH-7777 with IC50 of 0.105 µM and 0.173 μM, respectively. HMPL-523 also inhibited cell viability of Ba/F3 Tel-Syk with IC50 of 0.033 μM. Furthermore, inhibitory effects of HMPL-523 on cell viability were evaluated in a panel of B -cell lymphoma cell lines with SYK/BCR deregulation. Results showed that HMPL- 523 potently inhibited cell survival with IC50s from 0.4 to 2 μM. Consistent with the effect on cell viability, HMPL-523 increased the apoptotic rate of REC-1 cells. Moreover, HMPL-523 showed the synergistic activities on killing human diffused large B cell lymphoma (DLBCL) in combination with other drugs such as BTK inhibitor, PI3Kδ inhibitors and Bcl2 family inhibitor. The detailed mechanisms underlying the synergism are still under investigation. Anti-tumor activity of HMPL-523 was determined in Syk dependent xenograft models. Daily oral administration of 100 mg/kg HMPL-523 showed potent anti-tumor activity in B cell lymphoma REC-1 (TGI: 59%). Conclusion:HMPL-523 is a highly potent SYK inhibitor with good activity against B-cell lymphoma in pre-clinical in vitro and in vivo models, supporting further clinical research for HMPL-523 as either single agent or combination drug with other agents to treat B-cell malignancies e.g. DLBCL Disclosures Yang: Hutchison MediPharma Ltd: Employment, Research Funding. Deng:Hutchison MediPharma Ltd: Employment, Research Funding. Sun:Hutchison MediPharma Ltd: Employment, Research Funding. Liang:Hutchison MediPharma Ltd: Employment, Research Funding. Wang:Hutchison MediPharma Ltd: Employment, Research Funding. Fan:Hutchison MediPharma Ltd: Employment, Research Funding. Tang:Hutchison MediPharma Ltd: Employment, Research Funding. Yu:Hutchison MediPharma Ltd: Employment, Research Funding. Sun:Hutchison MediPharma Ltd: Employment, Equity Ownership. Zhou:Hutchison MediPharma Ltd: Employment, Research Funding. Dai:Hutchison MediPharma Ltd: Employment, Research Funding. Qing:Hutchison MediPharma Ltd: Employment, Research Funding. Su:Hutchison MediPharma Ltd: Employment, Research Funding. Ren:Hutchison MediPharma Ltd: Employment, Research Funding.