649TiP A phase I/Ib study evaluating the safety, pharmacokinetics, and preliminary efficacy of LP-118 in subjects with relapsed or refractory haematological malignancies

Abstract

Newave Pharmaceutical is developing an investigational compound LP-118, a next generation selective B-cell lymphoma 2 (BCL-2) inhibitor with tuned B-cell lymphoma extra-large (BCL-XL) activity to improve antitumor efficacy and reduce risk for thrombocytopenia. Clinical development of LP-118 includes targeting of relapsed or refractory hematological malignancies. BCL-2 and BCL-XL are important anti-apoptotic proteins in the intrinsic apoptotic pathway and are involved in the pathophysiology of many hematologic malignancies, including Non-Hodgkin’s Lymphoma (NHL), Richter transformation (RT), multiple myeloma (MM), acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), etc. (Valentin, Grabow et al. 2018). Considering that concern about acquired resistance to venetoclax (the first FDA-approved BCL-2 selective inhibitor indicated for the treatment of AML has been an obstacle in the treatment of AML patients, a promising strategy for overcoming BCL-2 acquired resistance mutation is urgently needed (Tahir, Smith et al. 2017) The inhibitory effect of LP-118 on the targets BCL-2 and BCL-XL is carefully adjusted to be between that of navitoclax and venetoclax with the aim of minimizing BCL-XL on-target platelet toxicity while retaining and improving antitumor efficacy. Newave Pharmaceutical, Inc. intends to conduct the first in human study of LP-118 in hematologic malignancies with a primary focus on relapsed or refractory NHL, RT, MM, T-PLL, AML, ALL, MDS, MDS/MPN, and MF. Phase Ia dose-escalation will begin with Group 1 until DLT is observed and MTD is established, or until an RP2D or OBD is established. Once the MTD, RP2D, or OBD is established for Group 1, the phase Ia dose escalation can proceed for Group 2 (hight risk). Group 1 relapsed/refractory: low risk tumor lysis CLL/SLL; MF, MDS/MPN, CMML-2, MPN-BP, MDS, AML; NHL, RT, MM, T-PLL; ALL A classic “3+3” design will be used in this study. The safe starting dose of LP-118 calculated from non-clinical toxicity studies is 50 mg/d. To mitigate risk of TLS, an accelerated step-up dosing schedule of LP-118 will be used to reach the target dose for each cohort. NCT04771572. Newave Pharmaceutical Inc.