A first-in-human phase 1 study of oral LOXO-338, a selective BCL2 inhibitor, in patients with advanced hematologic malignancies (trial in progress).
Authors: Roeker Lindsey Elizabeth , Alencar Alvaro Jose , Guru Murthy Guru Subramanian , Hoffmann Marc Steven , Pagel John M. , Patel Vishalkumar , Pauff James Michael , Zinzani Pier Luigi , Le Gouill Steven , Mato Anthony , Jurczak Wojciech 
Published: June 2022

TPS7582 Background: B-cell lymphoma 2 (BCL2) is a key regulator of apoptosis and provides protection from cell death in many hematologic malignancies. LOXO-338 is an orally bioavailable small molecule inhibitor of BCL2, developed to achieve selectivity over BCL-xL and thus avoid dose-limiting thrombocytopenia associated with BCL-xL inhibition. In preclinical studies, LOXO-338 showed a favorable pharmacological profile, selectively inhibited BCL2, and was well-tolerated in vivo. LOXO-338 also demonstrated dose-dependent tumor growth inhibition in various murine xenograft models and showed improved efficacy in combination with pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor (Brandhuber et al. Cancer Res 2021 81 (13 Suppl) 1258). Methods: LOXO-BCL-20001 is a global open-label, first-in-human phase 1 study of oral LOXO-338 in patients (pts) with advanced hematologic malignancies who have received prior therapy. The study will be conducted in 2 parts. Part 1 will evaluate LOXO-338 as monotherapy and will explore different dosing strategies. Part 2 will evaluate LOXO-338 in combination with pirtobrutinib. Part 1 dose escalation will follow an i3+3 design. Each cycle will be 28 days. Eligible pts include those with CLL/SLL, mantle cell lymphoma, and Waldenström macroglobulinemia (WM) who received standard therapy. Pts with other B-cell non-Hodgkin lymphomas (NHL) who received standard therapy, are not candidates for available therapy, or have no options with proven benefit are also eligible. Pts with active or suspected Richter transformation, transformed low grade lymphoma, Burkitt or Burkitt-like lymphoma, and multiple myeloma are also eligible. Pts with AL amyloidosis are eligible in monotherapy dose expansion; all other pts are eligible in both monotherapy and combination dose expansion. Pts must not have progressed while receiving prior BCL2 inhibitor; those with WM or AL amyloidosis must not have received a prior BCL2 inhibitor. Key exclusion criteria include history of CNS involvement, stem cell transplant or CAR-T therapy <60 days, concurrent anticancer therapy, and clinically significant cardiovascular disease. Primary objective is to determine the recommended phase 2 dose of oral LOXO-338 in pts who were previously treated for CLL/SLL and other B-cell NHL, administered alone or in combination with pirtobrutinib. Determining anti-tumor activity in pts with WM and AL amyloidosis is an additional primary objective of part 1 monotherapy. Secondary objectives include determining the safety profile, PK, and preliminary efficacy of LOXO-338 administered alone and in combination with pirtobrutinib. Antitumor activity will be evaluated based on overall response rate (ORR), progression-free survival (PFS), time to progression (TTP) and duration of response (DOR) according to disease-specific response criteria. Clinical trial information: NCT05024045.