Pb2122: a phase 1/2 multi-center, dose-finding study investigating the safety, tolerability, pk and efficacy of zn-d5, a novel bcl-2 inhibitor, in patients with relapsed/refractory al amyloidosis

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Light-chain (AL) amyloidosis arises from a plasma cell clone that overproduces immunoglobulin light chains. These light chains deposit within tissues and organs and interfere with normal function. Frequently, cardiac, hepatic, and renal involvement contribute to the major morbidities observed in this rare disease. Current treatment of AL amyloidosis targets the plasma cell clone to rapidly reduce the level of circulating light chains. Recently, the addition of subcutaneous daratumumab to the standard first-line regimen of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) was shown to significantly improve complete hematologic and organ response rates. However, management of patients with relapsed or refractory (R/R) disease remains challenging. Pre-clinical and clinical data have shown that targeted inhibition of BCL-2 is active against malignant plasma cells and may be particularly effective against cells harboring the t(11;14) translocation which is found in ~50% of AL amyloidosis patients. Interestingly, small, retrospective studies have shown that BCL-2 inhibition may be an effective treatment option for patients with AL amyloidosis, particularly those with t(11;14). ZN-d5 is a novel, highly selective BCL-2 inhibitor in clinical development for hematologic malignancies that has demonstrated activity against multiple myeloma in preclinical models and may be useful in the treatment of AL amyloidosis. Aims: Investigate the safety and efficacy of ZN-d5 and establish the recommended Phase 2 dose (RP2D) of ZN-d5 in patients with R/R AL Amyloidosis. Methods: ZN-d5-003 is a multicenter, international Phase 1/2 clinical trial evaluating single-agent oral ZN-d5 in patients with R/R AL amyloidosis. In Phase 1, the primary objectives are to determine the safety, tolerability and maximum tolerated dose of ZN-d5, and to identify the RP2D. Cohorts of increasing doses (200mg; 400mg; 800mg; 1200mg; 1600mg daily) are enrolling patients based on the Bayesian Optimum Interval (BOIN) design. In Phase 2, the primary objective is to assess the hematological response rate (HRR) among patients with or without t(11;14) translocation. Bayesian Optimal Phase 2 (BOP2) design will be implemented for interim efficacy monitoring. Key eligibility criteria include: biopsy-confirmed diagnosis of AL amyloidosis, 1-3 prior lines of therapy (including HSCT), adequate organ function, and ECOG performance status of 0-2. All subjects must have measurable disease defined as dFLC of at least 20 mg/L; those considered for the trial will undergo bone marrow aspiration for assessment of t(11;14) status by FISH. Both t(11;14)-positive and -negative patients are eligible for the study, however they will be analyzed separately for safety and efficacy initially and then may be combined if deemed appropriate. Subjects must have a history of organ involvement (current measurable organ disease is not required). Exclusion criteria include: non-AL amyloidosis, diagnosis of multiple myeloma per 2014 IMWG criteria, or Mayo 2012 Stage IV disease. The study is expected to enroll up to approximately 140 subjects at approximately 25 sites for phase 1, and at least 50 sites for phase 2. Results: Enrollment for ZN-d5-003 began in March, 2022 and is ongoing in 7 countries. Summary/Conclusion: This study will evaluate treatment of AL amyloidosis utilizing BCL-2 inhibition. Dose escalation cohorts are currently undergoing evaluation and the study is open to enrollment. Upon determination of the RP2D, the study will commence Phase 2. Clinical trial registration: NCT05199337. Keywords: “t(11;14)”, Amyloidosis, BCL2, Phase I/II