P684: PHASE 1 STUDY OF LP-108, A SELECTIVE BCL-2 INHIBITOR, IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA

Abstract

Background: Targeting BCL-2 family proteins is a well-recognized therapeutic approach. Globally approved BCL-2 inhibitor venetoclax has shown efficacies in certain hematologic malignancies (HMs) but requires weekly ramp-up to the target dose to mitigate the risk of tumor lysis syndrome (TLS). LP-108 is a novel, highly potent, orally bioavailable, and selective BCL-2 inhibitor that has shown promising preclinical antitumor activity in various HMs. Aims: To present preliminary results from an ongoing phase 1 study of LP-108 under daily dose ramp-up in patients with relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (NHL) (NCT04356846). Methods: This is an open-label, multicenter, phase I study to assess the safety, pharmacokinetics (PK) and preliminary efficacy of LP-108 in Chinese patients with r/r B-cell NHL, consisting of a dose-escalation phase and a dose-expansion phase. Adult r/r B-cell NHL patients requiring therapy are eligible if they had received at least one prior line of treatment (except BCL-2i). LP-108 is orally administered once daily in 28-day cycles until disease progression, unacceptable toxicity, or per investigator discretion. All patients provided and signed informed consent. Results: As of February 18, 2022, 19 patients have been enrolled and were evaluable for safety, with disease types of MCL (n = 7), CLL/SLL (n = 7), DLBCL (n = 2), FL, WM, and MALT (n = 1 each), and median age of 61 years (range, 39 to 83). Patients had received a median of 3 prior lines of therapy (range, 1~6), of which 13 (68%) patients were previously BTKi exposed. No dose-limiting toxicity (DLT) has been observed in patients who were treated with LP-108 up to 600 mg, thus the maximum tolerated dose (MTD) was not identified. With median duration of treatment of 55 days (range, 4~472), treatment-related adverse events (TRAEs) were reported in 17 patients (89.4%), most of which were grade 1 to 2 in severity. TRAEs of any grade occurred ≥20% of patients were neutropenia (36.8%), leukopenia (31.5%), ALT elevation (31.5%), AST elevation (26.3%), hyperphosphatemia (21%), hyperuricemia (21%), and diarrhea (21%). Grade 3 or 4 TRAEs were reported in 7 patients (36.8%), including neutropenia, thrombocytopenia, lymphopenia, laboratory TLS, and rash. Serious TRAEs included rash, thrombocytopenia, and laboratory TLS, each occurring in 1 patient. No patient discontinued treatment due to toxicity, and no clinical TLS was observed. No deaths occurred during treatment or within 28 days of the end of treatment. At doses ≥200 mg, 3 of 10 efficacy evaluable patients achieved an objective response (1 CR and 2 PR), 4 patients had stable disease (2 with substantially reduced lymphomegaly), and 3 patients had progressive disease. Rapid reduction in ALC was observed in CLL patients (pending imaging assessment) during ramp-up and the first cycle of treatment at doses as low as 20mg. At data cutoff, 11 patients remain on treatment and 8 patients discontinued treatment due to disease progression or patient decision. The PK profile showed that plasma exposure proportionally increased with doses ranging from 20 to 600 mg (mean AUC24h range, 1.26~46.5 h*μg/ml, mean Cmax range, 0.087~2.67 μg/ml). Plasma concentrations peaked approximately 4 to 10 hours after dosing, and the average terminal half-life of LP-108 was approximately 11.8 hours (range, 6.9~16.6). Image:Summary/Conclusion: LP-108 showed favorable safety profile up to 600 mg with daily dose ramp-up schedule, and antitumor activity in patients with r/r B-cell NHL. Dose escalation beyond 600 mg and further dose expansion are ongoing.