Phase 1, open-label, multicenter study of sovleplenib (HMPL-523) in patients with relapsed or refractory lymphoma.

Relapsed or refractory lymphoma carries poor prognosis, with limited options after standard therapies. Spleen tyrosine kinase (SYK) mediates B-cell receptor and aberrant T-cell receptor signaling, promoting survival and proliferation. HMPL-523 (sovleplenib) is a novel, selective oral SYK inhibitor with preclinical activity in lymphoid malignancies. This Phase 1, open-label, multicenter study (NCT03779113) enrolled adult patients with relapsed/refractory lymphoma who had exhausted approved therapies. The trial included dose escalation (100-800 mg once daily) and expansion (700 mg once daily) stages across multiple lymphoma subtypes. Safety was assessed per NCI CTCAE v5.0; efficacy per Lugano 2014 and disease-specific criteria. Sixty-nine patients were treated (Stage 1: n=21; Stage 2: n=48). The recommended Phase 2 dose was 700 mg once daily; the maximum tolerated dose was not reached. Common grade ≥3 treatment-emergent adverse events included neutropenia, elevated liver enzymes, and thrombocytopenia; no treatment-related deaths occurred. Among 53 response-evaluable patients across stage 1 and stage 2 who were treated at the recommended Phase 2 dose or above, overall response rate (ORR) was 30.2%, including 5 complete responses. ORR by key cohort was 25.9% for Hodgkin lymphoma (n=27), 28.6% for chronic lymphocytic leukemia post-Bruton's tyrosine kinase inhibitor (n=7), and 33.3% for peripheral T-cell lymphoma (n=9), with a median duration of response ranging from 5.7 to 11.3 months. Pharmacokinetic analysis showed dose-proportional exposure and ~2-fold accumulation with daily dosing. Sovleplenib demonstrated a safety profile managed with supportive medications, predictable pharmacokinetics, and preliminary antitumor activity in heavily pretreated lymphoma patients, supporting further investigation in combination and earlier-line settings. ClinicalTrials.gov Identifier: NCT03779113.