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

• DOI: 10.1097/01.hs9.0000975252.55444.26
• Publication Date: 2023-08-09T14:37:05Z
• Authors: Efstathios Kastritis; Jeffrey Matous; Jesus Berdeja; Emad Abro; Bradley Augustson; Valentin Cabañas ...; M. Theresa Cibeira; Yael Cohen; Michael Fong; Moshe Gatt; Veronica Gonzalez...; Fiona Kwok; Noa Lavi; Hila Magen; Albert Oriol; Giovanni Palladini; Keith Stockerl-Go...; Taylor Eves; Cheng Zheng; Anthony Fiorino
• Keywords: AL amyloidosis; Daratumumab; Tolerability; Regimen

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