A Phase 1/2 Multi-Center, Dose-Finding Study to Assess Safety, Tolerability, PK and Efficacy of ZN-d5, a Novel BCL-2 Inhibitor, for Treatment of Subjects with Relapsed/Refractory AL Amyloidosis

Background: Light-chain (AL) amyloidosis arises from a plasma cell clone that overproduces immunoglobulin light chains which aggregate and deposit within tissues and organs, interfering with normal function. Commonly, cardiac, hepatic, and renal involvement produce the major morbidities observed in this rare disease. At present, treatment of AL amyloidosis aims at the elimination of the plasma cell clone to rapidly reduce the level of circulating light chains. Recently, the addition of subcutaneous daratumumab to the standard CyBorD (cyclophosphamide, bortezomib, and dexamethasone) as first-line regimen, was shown to significantly improve complete hematologic and organ response rates. However, the management of patients with relapsed or refractory disease remains challenging. Pre-clinical and clinical data have shown that BCL-2 inhibition is active against malignant plasma cells, and may be particularly effective against cells harboring the t(11;14) translocation, found in about half 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 BCL-2-selective BCL-2 inhibitor in clinical development for hematologic malignancies, which is active against multiple myeloma in preclinical models, and which may be useful in the treatment of AL amyloidosis.

Methods: ZN-d5-003 is a multicenter, international Phase 1/2 clinical trial evaluating single-agent oral ZN-d5 in relapsed or refractory AL amyloidosis subjects. In the Phase 1 part, the primary objectives are to determine the safety, tolerability and maximum tolerated dose of ZN-d5, and to determine the recommended Phase 2 dose. Cohorts of increasing doses (200mg; 400mg; 800mg; 1200mg; 1600mg QD) will enroll subjects based on Bayesian Optimum Interval (BOIN) design. In Phase 2, the primary objective is to assess the hematological response rate (HRR) among subjects with or without t(11;14) translocation. Bayesian Optimal Phase 2 (BOP2) design is implemented for interim efficacy monitoring. Key criteria for eligibility include the following: subjects must have a biopsy-confirmed diagnosis of AL amyloidosis, at least 1 and no more than 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 subjects are eligible for the study, however they will be separately analyzed for safety and efficacy. 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 subject at approximately 25 sites for phase 1, and at least 50 sites for phase 2.

Conclusion: This study will evaluate treatment of AL amyloidosis utilizing BCL-2 inhibition and will test the hypothesis of whether t(11;14) is a relevant predictive biomarker. Dose escalation cohorts are currently undergoing evaluation and the study is open to enrollment. Upon determination of a recommended phase 2 dose, the study will commence Phase 2. Clinical trial: NCT05199337.

Kastritis:Takeda: Honoraria; Janssen: Honoraria, Research Funding; Genesis Pharma: Honoraria; GSK: Honoraria; Pfizer: Honoraria, Research Funding; Amgen: Honoraria, Research Funding. Matous:BeiGene: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees. Eves:Zentalis: Current Employment, Current holder of stock options in a privately-held company; BMS: Ended employment in the past 24 months. Zheng:Zentalis Pharmaceuticals, Inc.: Current Employment, Current holder of stock options in a privately-held company. Fiorino:Zentalis: Current Employment. Berdeja:Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Sanofi: Consultancy, Research Funding; Bluebird bio: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy, Research Funding; Kite Pharma: Consultancy; Legend Biotech: Consultancy; SecuraBio: Consultancy; Takeda: Consultancy, Research Funding; Acetylon: Research Funding; Amgen: Research Funding; C4 Therapeutics: Research Funding; CARsgen: Research Funding; Cartesian Therapeutics: Research Funding; Celularity: Research Funding; EMD Sorono: Research Funding; Fate Therapeutics: Research Funding; GlaxoSmithKline: Research Funding; Ichnos Sciences: Research Funding; Incyte: Research Funding; Karyopharm: Research Funding; Lilly: Research Funding; Novartis: Research Funding; Poseida: Research Funding; Teva: Research Funding; Zentalis: Research Funding; 2Seventy bio: Research Funding.