-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

4501 Preliminary Results of a Phase 1, Dose-Escalation Study of PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Relapsed/Refractory Lymphoid Malignancies

Program: Oral and Poster Abstracts
Session: 627. Aggressive Lymphomas: Pharmacologic Therapies: Poster III
Hematology Disease Topics & Pathways:
Research, Clinical trials, Clinical Research, Diseases, Lymphoid Malignancies
Monday, December 9, 2024, 6:00 PM-8:00 PM

Katharine L. Lewis1,2,3, Wojciech Jurczak, MD, PhD4, Gareth P. Gregory, MBBS(Hons), PhD, FRACP, FRCPA5, Constantine S. Tam6*, Won Seog Kim7*, Eliza A. Hawkes, MD8, Franck Morschhauser9, Sarit E. Assouline, MD10, Geoffrey Shouse, PhD, DO11, Petra Langerbeins12*, Monica Tani13*, Young Rok Do, MD, PhD14, Bruce D. Cheson15, Catherine S. Diefenbach, MD16, Craig A. Portell17*, Jennifer Xavier18*, Muhtarjan Osman18*, Siminder K. Atwal18*, Wan-Jen Hong18 and Clémentine Sarkozy19*

1Sir Charles Gairdner Hospital, Perth, Western Australia, Australia
2University of Western Australia, Perth, Western Australia, Australia
3WA Linear Clinical Research, Nedlands, Western Australia, Australia
4Maria Skłodowska – Curie National Research Institute of Oncology, Kraków, Poland
5School of Clinical Sciences at Monash Health, Monash University, Melbourne, Australia
6Alfred Hospital and Monash University, Melbourne, VIC, Australia
7Samsung Medical Center, Seoul, Korea, Republic of (South)
8Olivia Newton John Cancer Research Institute at Austin Health and Monash University, Melbourne, VIC, Australia
9CHU de Lille - Hôpital Claude Huriez, Universitaire de Lille, Lille, France
10McGill University, Jewish General Hospital, Montreal, QC, Canada
11City of Hope National Medical Center, Duarte, CA
12Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, Cologne, Germany
13Ospedale Santa Maria delle Croci, Ravenna, Italy
14Keimyung University Dongsan Hospital, Daegu, Korea, Republic of (South)
15American Oncology Partners PA, Bethesda, MD
16New York University, Perlmutter Cancer Center at NYU Langone Health, New York, NY
17University of Virgina, Charlottesville, VA
18Prelude Therapeutics Incorporated, Wilmington, DE
19Institut Curie, Saint-Cloud Hospital, Saint-Cloud, France

Introduction: Cyclin-dependent kinase 9 (CDK9), a key regulator of transcription elongation, is a potential target in transcriptionally addicted cancers dependent on oncogenic drivers with short half-lives such as MYC, MYB, and MCL1. PRT2527, an investigational, potent, and highly selective CDK9 inhibitor, is being developed for select relapsed/refractory (R/R) hematologic malignancies as monotherapy and in combination (combo) with targeted agents. Zanubrutinib (zanu) is a Bruton tyrosine kinase (BTK) inhibitor that upregulates BCL2 modifying factor (BMF), a proapoptotic molecule physiologically inhibited by BCL2, BCLXL, and BCLW (Kong, et al. ChemMedChem. 2018). The combo of CDK9 and BTK inhibition may lead to a synergistic effect by enhancing apoptotic priming and shifting dependency toward the CDK9 targets, MCL1 and BFL1.

Methods: PRT2527-02 is a phase 1, multicenter, dose-escalation and dose-confirmation study evaluating safety and preliminary efficacy of PRT2527 as monotherapy and in combo with standard-dose zanu in patients (pts) with select R/R hematologic malignancies (NCT05665530). Pts must have relapsed or be refractory to or ineligible for standard-of-care therapy. PRT2527 was administered intravenously in escalating doses as a once weekly infusion, and zanu was administered orally. Treatment continued until disease progression or unacceptable toxicity. Dose escalation decisions were guided by the Bayesian optimal interval design method based on dose-limiting toxicities (DLTs) in cycle 1. Primary endpoints include safety, tolerability, DLTs, and recommended phase 2 dose of PRT2527 monotherapy and in combo with zanu. Secondary and exploratory endpoints include overall response rate and pharmacokinetic/pharmacodynamic profiles of PRT2527 monotherapy and in combo with zanu.

Results: As of June 21, 2024, 31 pts (17 diffuse large B-cell lymphoma [DLBCL] not otherwise specified, 7 peripheral T-cell lymphoma [PTCL], 2 high-grade B-cell lymphoma, 2 mantle cell lymphoma [MCL], 2 chronic lymphocytic leukemia [CLL], and 1 Richter syndrome) were enrolled and treated with PRT2527. Median age was 64 (range, 27-94) years, 61% were male, and median prior lines of therapy was 3 (range, 1-7). Nineteen pts were treated with PRT2527 monotherapy (9 mg/m2, n=6; 15 mg/m2, n=5; 18 mg/m2, n=8) and 12 with PRT2527 and zanu combo (9 mg/m2, n=6; 15 mg/m2, n=6). Median duration of study treatment was 3.6 weeks (range, 0.7-30.4) for monotherapy and 6.8 weeks (range, 1.3-20.4) for combo.

Most frequently reported (>20%) any-grade treatment-emergent adverse events (TEAEs) were neutropenia (53%), nausea (53%), and constipation (21%) with monotherapy and neutropenia, diarrhea, asthenia, hypokalemia, and vomiting (25% each) with combo. Overall, grade 3/4 TEAEs occurred in 18 (58%) pts, most frequently neutropenia (39%). Nine (29%) pts had a TEAE leading to dose hold: 6 (19%) due to grade 3/4 neutropenia that resolved with growth factor. No clinical tumor lysis syndrome was observed, and no DLTs were reported. Three pts achieved a response: a complete response in 1 non-GCB double-expressor DLBCL pt post-CAR T-cell therapy on monotherapy (9 mg/m2) and 1 MCL pt on combo (9 mg/m2), and a partial response in 1 PTCL pt on monotherapy (9 mg/m2). Eleven pts were on study and have not reached the first response assessment. Additional responders across tumor types have been seen after the data cut-off and will be presented. Fourteen (45%) pts remain on study (monotherapy [n=7], combo [n=7]), and 17 (55%) pts discontinued treatment: 14 (45%) due to PD, 2 (6%) due to TEAEs (supraventricular tachycardia [n=1], AML [n=1]), and 1 (3%) due to death (COVID-19).

Whole blood expression of the CDK9 transcriptional targets MCL1 and MYC demonstrated target engagement at all dose levels, with a more prolonged transcriptional decrease at higher doses. At 18 mg/m2 (n=7), a median decrease of 80.5% in MCL1 and 82.4% in MYC messenger RNA (mRNA) was achieved 2 hours after the start of infusion. By 6 hours, median MCL1 mRNA returned to baseline levels while MYC levels remained suppressed with a median inhibition of 32.1%.

Conclusions: PRT2527 as monotherapy and in combo with zanu had an acceptable safety profile and evidence of preliminary activity in pts with R/R lymphoid malignancies. Neutropenia was the most common TEAE, manageable with growth factor support. Dose finding with PRT2527 as monotherapy or in combo with zanu is ongoing.

Disclosures: Lewis: Merck/MSD: Consultancy, Other: Advisory Board; AbbVie: Consultancy, Other: Advisory Board; Janssen: Honoraria; Gilead/Kite: Honoraria; Loxo/Lilly: Other: Trial steering committee, Patents & Royalties: Travel and accommodation for educational events/conferences; IQVIA: Other: Advisory Board; Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria, Patents & Royalties: Travel and accommodation for educational events/conferences. Jurczak: AstraZeneca: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Lilly: Consultancy, Research Funding; Regeneron: Consultancy, Research Funding; Janssen Cilag: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; MSD: Research Funding; Merck: Research Funding. Gregory: Merck, Amgen, Roche, Novartis, BMS, Clinigen, Gilead, Prelude Therapeutics: Membership on an entity's Board of Directors or advisory committees; Roche, Merck: Speakers Bureau; Merck, BeiGene (to institute, not individual): Research Funding. Tam: Janssen: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Loxo: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; Gilead: Honoraria; Lilly: Honoraria. Kim: Roche: Research Funding; Boryong: Research Funding; Kyowa-Kirin: Research Funding; Donga: Research Funding; Sanofi: Research Funding; BeiGene: Research Funding. Hawkes: Novartis: Membership on an entity's Board of Directors or advisory committees; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharpe and Dohme: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Research Funding, Speakers Bureau; Merck KGaA: Research Funding; Bristol Myer Squibb: Membership on an entity's Board of Directors or advisory committees, Other: Trial Steering Committee, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Morschhauser: Janssen: Honoraria; AbbVie: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Novartis: Consultancy; Takeda: Honoraria; Chugai: Honoraria; BMS: Consultancy; Kite/Gilead: Consultancy. Assouline: Janssen: Consultancy, Honoraria; BeiGene: Consultancy, Honoraria; F. Hoffman-La Roche Ltd.: Consultancy, Honoraria; Gilead: Honoraria; Pfizer: Consultancy; Ipsen: Consultancy; Novartis Canada Inc.: Research Funding; BMS: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Genentech/Roche: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria. Shouse: Beigene, Inc: Consultancy, Honoraria, Speakers Bureau; Astra Zeneca: Honoraria; Abbvie: Consultancy; Kite Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau. Langerbeins: AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants, Research Funding; BeiGene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel grants; Hoffmann-La Roche: Membership on an entity's Board of Directors or advisory committees, Other: Travel grants. Tani: Roche, Abbvie, Jansen-Cilag, Incyte, BeiGene, Takeda: Membership on an entity's Board of Directors or advisory committees; AstraZeneca SpA: Membership on an entity's Board of Directors or advisory committees. Cheson: Symbio Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Imaging Endpoints: Consultancy; Adaptive Biotechnologies: Consultancy; Merck: Consultancy; Regeneron: Consultancy; Lilly: Speakers Bureau; Beigene: Consultancy, Speakers Bureau; Calyx: Consultancy; AbbVie: Consultancy; Genmab: Consultancy; Ipsen: Consultancy; Clearview: Consultancy; Incyte: Speakers Bureau; Center for Cancer and Blood Disorders: Current Employment. Diefenbach: AstraZeneca: Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche: Consultancy, Research Funding; Genmab: Consultancy, Research Funding; Gilead: Current equity holder in publicly-traded company, Research Funding; Merck: Consultancy, Research Funding; Millenium: Research Funding; Morphosys: Consultancy, Research Funding; FATE Therapeutics: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; MEI Pharma: Consultancy, Research Funding; I MAB: Consultancy, Current equity holder in private company; NYU Grossman School of Medicine/Perlmutter Cancer Center at NYU Langone Health: Current Employment; OverT Therapeutics: Current equity holder in private company; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Research Funding. Portell: Merck: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Janssen: Consultancy; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy; Prelude: Research Funding; SeaGen/Pfizer: Research Funding; Infinity: Research Funding; Genentech/Roche: Research Funding; Kite: Research Funding. Xavier: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company, Current holder of stock options in a privately-held company. Osman: Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company. Atwal: Prelude Therapeutics: Current Employment, Current equity holder in private company, Other: Travel, Accommodations, Expenses; Fate Therapeutics: Ended employment in the past 24 months. Hong: Imago Biosciences: Divested equity in a private or publicly-traded company in the past 24 months, Ended employment in the past 24 months; Prelude Therapeutics: Current Employment, Current equity holder in publicly-traded company. Sarkozy: AstraZeneca: Honoraria; Roche: Research Funding; Prelude: Consultancy; BeiGene: Consultancy, Honoraria.

*signifies non-member of ASH