A PHASE 1 STUDY EVALUATING PRT2527, A POTENT AND HIGHLY SELECTIVE CDK9 INHIBITOR, IN PATIENTS WITH SELECT RELAPSED/REFRACTORY B‐CELL MALIGNANCIES

Introduction: PRT2527 is a potent, highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. CDK9 key regulator of transcription elongation and has been studied as potential target for therapy in transcriptionally addicted cancers, which are dependent on oncogenic drivers with short half-lives. Although most these do not respond to direct inhibition, studies suggest that subset half-lives such MYC, MYB, MCL1 may be targeted indirectly through inhibition select hematological malignancies solid tumors. Preclinical data have demonstrated evidence on-target MCL1, well induced apoptosis, measured by cleaved caspase 3 cell lines translational models (e.g., patient-derived xenograft [PDX] models) (Zhang Y et al., AACR-NCI-EORTC 2021). Methods: PRT2527-02 phase 1, open-label, multicenter, dose-finding study evaluate the safety, tolerability, recommended 2 dose (R2PD), preliminary efficacy patients B-cell aggressive lymphoma subtypes, mantle lymphoma, chronic lymphocytic lymphoma/small Richter syndrome). Aggressive including diffuse large otherwise specified, gray zone follicular grade 3b, high-grade primary mediastinal or transformed from indolent B-cell, eligible enroll. Patients must relapsed refractory ineligible standard-of-care therapy. Other eligibility criteria include measurable disease requirement treatment accordance standard disease-specific hematologic under study, Eastern Cooperative Oncology Group performance status 0–1, adequate bone marrow, renal, liver function. The consists escalation successive cohorts receiving escalating doses intravenous once weekly 21-day cycle. will continue until progression unacceptable toxicity, whichever comes first. Dose de-escalation decisions guided Bayesian optimal interval design method based number participants dose-limiting toxicities (DLTs) observed at level evaluation maximum tolerated R2PD determined. endpoints DLTs, RP2D PRT2527. Secondary objective response rate, duration response, complete pharmacokinetic profile open enrollment since February 2023. Clinical trial information: NCT05665530. research was funded by: Prelude Therapeutics Keywords: non-Hodgkin molecular therapies, ongoing trials Conflicts interests pertinent abstract. B. D. Cheson Employment leadership position: AON, Symbio (Japan) Consultant advisory role Abbvie, Pharmacyclics, Bristol Myers Squibb, ADC Therapeutics, AstraZeneca, Astellas, Tessa, Imaging Endpoints, Oncopeptides, Ascentage, Reddy Biosimilar Research funding: Lilly, Morphosys, Prelude, GenMab remuneration: Expert Testimony: Eagle Therapeutics; Speakers Bureau: BeiGene, Incyte, Lilly F. Morschhauser Roche/Gilead/Novartis/Genmab S. E. Assouline AbbVie, BMS, Janssen, Pfizer, Roche Novartis Canada W. Sun Honoraria: K. Atwal Stock ownership: Hong Imago BioSciences, Genentech BioSciences Patents, Royalties: Stanford University C. Sarkozy GSK, BMS Janssen Educational grants: Roche, Incyte