Trial in Progress: Phase 1b/2 Open-Label Study of Lisaftoclax (APG-2575) Monotherapy or in Combination with Lenalidomide/Dexamethasone in Patients with Relapsed or Refractory Multiple Myeloma (R/R MM)

Background: Multiple myeloma (MM) is a hematologic malignancy (HM) caused by proliferation of plasma cells in bone and extramedullary sites, with frequent symptoms including hypercalcemia, renal impairment, anemia, and bone lesions. High-dose therapy and autologous hematopoietic stem cell transplantation have been treatment mainstays. More recent introduction of the proteasome inhibitor bortezomib and other agents offers promise. Bortezomib can prevent breakdown of proapoptotic factors by malignant cells, triggering apoptosis, and lenalidomide can stimulate programmed death of malignant cells both directly and indirectly. Despite these and other treatment advances, relapse is virtually inevitable, and MM remains incurable. Lisaftoclax is a novel, potent, selective BCL-2 inhibitor that is under clinical development for HMs. In chronic lymphocytic leukemia, lisaftoclax requires a short ramp-up to help mitigate tumor lysis syndrome and is associated with a potentially lower incidence of neutropenia (Ailawadhi et al. J Clin Oncol 2021;39: abstract 7502).

Methods: This open-label, multicenter study is assessing the safety, tolerability, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of lisaftoclax alone or combined with lenalidomide and dexamethasone. The primary aim is to determine dose-limiting toxicity (DLT), maximum tolerated dose, and recommended phase 2 dose (RP2D) of lisaftoclax when administered alone (Arm A) or in tandem with lenalidomide and dexamethasone (Rd; Arm B), each in 28-day cycles. The trial is enrolling adults who have (1) R/R MM with measurable sites and received ≥ 1 prior therapy; (2) ECOG performance status of 0 to 2; and (3) adequate hematologic, hepatic, renal, and coagulation function. Excluded were individuals with (1) lenalidomide intolerance; (2) recent monoclonal antibody (≤ 8 weeks before study onset), CAR-T (≤ 3 months), and other MM treatments (≤ 2 weeks); (3) history of allogenic stem cell transplantation or BCL-2 treatment; (4) other systemic conditions, including POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), amyloidosis, Fahrenheit macroglobulinemia, non-secretory MM, and plasma cell leukemia; (5) known CNS involvement; and (6) serious and potentially uncontrolled medical disorders, including cardiovascular disease, chronic inflammatory disorders, and active infection warranting systemic treatment (e.g. HIV, hepatitis). Lisaftoclax is administered as monotherapy orally once daily at 3 dose levels (400, 600, and 800 mg) without ramp-up, every 28 days as a cycle in a "3+3" dose escalation in Arm A and similarly in Arm B, which also includes Rd: lenalidomide 25 mg (10 mg for patients with baseline creatinine clearance ≥ 30 mL/min but < 60 mL/min) orally on Days 1 through 21 of each 28-day cycle and dexamethasone 40 mg (or 20 mg for patients aged > 75) orally on Days 1, 8, 15, and 22 of a repeated 28-day cycle. The primary outcome measure is DLT, defined by the rate of some predefined treatment-related adverse events (measured by NCI CTCAE v5) within the first 28 days of study treatment. As of July 19, 2021, three of fifty-seven patients have been enrolled. Internal study identifier APG2575MC101. Clinicaltrial.gov identifier: NCT04674514.