PHASE 1 STUDY OF PRT1419 (MCL1 INHIBITOR) AS MONOTHERAPY OR IN COMBINATION WITH AZACITIDINE OR VENETOCLAX IN PATIENTS WITH RELAPSED/REFRACTORY MYELOID OR B‐CELL MALIGNANCIES

Introduction: PRT1419 is a potent and selective inhibitor of myeloid cell leukemia-1 (MCL-1). MCL-1 frequently amplified or overexpressed in hematologic malignancies associated with higher grade malignancy poor prognosis (Xiang et al., Onco Targets Ther 2018). Azacitidine (AZA) treatment was shown to induce several proapoptotic changes primary acute leukemia (AML) isolates, including decrease protein levels (Tsao al, Ann Hematol 2012; Jin Clin Cancer Res 2020). Several mechanisms acquired resistance have been described patients (pts) AML treated venetoclax (VEN)-based regimens, the loss dependence on BCL-2 upregulation (Saliba Drug Resist 2021; Pei Discov Considering that mediator VEN AZA downregulates MCL-1, may confer additive synergistic benefits treatment-resistant B-cell malignancies. Methods: PRT1419-03 phase 1, open-label, multicenter, dose-finding study evaluate safety, tolerability, recommended 2 dose (R2PD), preliminary efficacy as monotherapy combination pts selected relapsed/refractory Pts must progressed prior without access to, eligibility for, further approved therapies. Adult confirmed diagnosis AML, CMML, MDS, MDS/MPN Overlap Syndrome, CLL/SLL, NHLs (mantle lymphoma, follicular marginal zone lymphoma) are eligible for this study. Other key criteria include Eastern Cooperative Oncology Group performance status 0 adequate organ cardiac function assessed by echocardiogram biochemical markers damage. As monotherapy, will receive escalating doses intravenous once weekly 28-day cycle using 3 + escalation design until maximum tolerated (MTD) RP2D has reached. Once defined, (myeloid malignancies) malignancies; MTD/RP2D then be enrolled into indication-specific confirmation cohorts. continue relapse/disease progression, intolerance, pt withdrawal. The endpoints dose-limiting toxicities (DLTs), monotherapy. Secondary DLTs, research funded by: Prelude Therapeutics Keywords: therapies, molecular targeted ongoing trials Conflicts interests pertinent abstract. R. Zuniga Employment leadership position: New York & Blood Specialist - Port Jefferson Station, NY Consultant advisory role Mirati G. Keiffer Astellas Honoraria: Research funding: AbbVie, Therapeutics, Cyteir F. Ravandi-Kashani BMS/celgene, Novartis, Astellas, Abbvie, Jazz, Taiho, Syros Amgen, Astex, Prelude, Biomea A. D. Goldberg Daiichi Sankyo, Genentech Dava Aptose, Celularity, ADC Aprea, AROG, Pfizer, Trillium E. Traer Daiichi-Sankyo, Servier Schrodinger, Incyte, Astra-Zeneca remuneration: Patents, Royalties: Humarrow, Inc L. P. Frenzel Abbvie Educational grants: C. Röllig BMS, Pfizer W. Sun S. K. Atwal Stock ownership: Hong Imago BioSciences, BioSciences Stanford University Assouline AstraZeneca, Janssen, BeiGene, Roche Novartis Canada