A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies

A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With Relapsed/Refractory Hematologic Malignancies

This is a Phase 1 dose-escalation study of PRT2527, a potent and highly selective cyclin-dependent kinase (CDK) 9 inhibitor, in participants with select relapsed or refractory (R/R) hematologic malignancies. The purpose of this study is to evaluate the safety, tolerability, recommended phase 2 dose (PR2D), and preliminary efficacy of PRT2527 as a monotherapy and in combination with zanubrutinib or venetoclax.

Study Overview

• Status: Completed
• Conditions: Marginal Zone Lymphoma; Acute Myeloid Leukemia (AML); Chronic Myelomonocytic Leukemia (CMML); Myelodysplastic Syndrome (MDS); T-cell Lymphoma; Mantle Cell Lymphoma (MCL); Diffuse Large B-cell Lymphoma (DLBCL); Richter's Syndrome; Myeloid Malignancies; Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL); Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL); MDS/Myeloproliferative Neoplasm (MPN) Overlap Syndrome
• Intervention / Treatment: Drug: PRT2527; Drug: Zanubrutinib; Drug: Venetoclax

Detailed Description

This is an open-label, multi-center, dose-escalation, Phase 1 study of PRT2527, a CDK9 inhibitor, as monotherapy for participants with relapsed and refractory lymphoid and myeloid malignancies, in combination with zanubrutinib, a Bruton tyrosine kinase inhibitor (BTKi) for participants with lymphoid malignancies, or in combination with venetoclax, a B-cell lymphoma 2 inhibitor (BCL-2i) in participants with myeloid malignancies. The study will be conducted in two parts, the dose escalation phase and the dose confirmation phase for both monotherapy and combination therapy. The dose escalation phase will evaluate escalating doses of PRT2527 as a monotherapy and in combination with zanubrutinib or venetoclax until MTD is identified or when the RP2D is determined. The dose confirmation phase will evaluate indication-specific cohorts at the RP2D to confirm the dose.

Approximately 274 participants will be enrolled in the dose escalation and indication-specific, dose confirmation cohorts.

• Study Type: Interventional
• Enrollment (Actual): 86
• Phase: Phase 1

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
    • Melbourne, Victoria, Australia, 3168
      • Monash Health
    • Melbourne, Victoria, Australia, 3004
      • Alfred Health
  • Western Australia
    • Perth, Western Australia, Australia, 6009
      • Linear Clinical Research Ltd
• Canada
  • Quebec
    • Montreal, Quebec, Canada, H3T 1E2
      • Jewish General Hospital
• France
  • Créteil, France, 94010
    • Hopital Henri Mondor
  • Lille, France, 59000
    • Claude Huriez hospital
  • Lyon, France, 69373 Cedex 08
    • Centre léon bérard
  • Saint-Cloud, France, 92210
    • Institut Curie
• Germany
  • North Rhine-Westphalia
    • Cologne, North Rhine-Westphalia, Germany, 50937
      • Universitatsklinikum Koln, Klinik I fur lnnere Medizin
• Italy
  • Bologna, Italy, 40138
    • IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola
  • Ravenna, Italy, 48121
    • Ospedale Santa Maria delle Croci - AUSL della Romagna
  • FC
    • Meldola, FC, Italy, 47014
      • lstituto Romagnolo per lo Studio dei Tumori "Dino Amadori" IRST
• Poland
  • Lesser Poland Voivodeship
    • Krakow, Lesser Poland Voivodeship, Poland, 30-727
      • Pratia MCM Krakow
• South Korea
  • Busan, South Korea, 47392
    • lnje University Busan Paik Hospital
  • Daegu, South Korea, 42601
    • Keimyung_University Dongsan Hospital
  • Seoul, South Korea, 06351
    • Samsung Medical Center
• Switzerland
  • Canton Ticino
    • Bellinzona, Canton Ticino, Switzerland, 6500
      • Ente Ospedaliero Cantonale (EOC) lstituto Oncologico della Svizzera italiana (IOSl)- Ospedale San Giovanni (ORBV)
• United Kingdom
  • West Yorkshire
    • Leeds, West Yorkshire, United Kingdom, LS9 7TF
      • The Leeds Teaching Hospitals NHS Trust, St James University Hospital
• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope
  • Maryland
    • Bethesda, Maryland, United States, 20817
      • American Oncology Partners of Maryland, PA
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Dana-Farber Cancer Institute
  • New York
    • New York, New York, United States, 10016
      • Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures
• Histologically or cytologically confirmed diagnosis of aggressive B-cell lymphoma subtypes, MCL, MZL, or CLL/SLL (including Richter's syndrome) based on local testing, or TCL (monotherapy only), AML, CMML, MDS, or MDS/MPN overlap syndrome that have relapsed or become refractory to or be ineligible for standard-of-care therapy
• Eastern Cooperative Oncology Group (ECOG) Performance Status of < 2.
• Adequate organ function (hematology, renal, and hepatic)
• Echocardiogram (or multigated acquisition [MUGA] scan) indicating a left ventricular ejection fraction of ≥ 50%

Exclusion Criteria:

• Have active central nervous system involvement by malignancy, uncontrolled intercurrent illnesses, and active infections requiring systemic therapy
• Have undergone HSCT within the last 90 days or have graft versus host disease (GvHD) Grade > 1 at study entry
• Have severe pulmonary disease with hypoxemia
• History of another malignancy except for adequately treated non-melanoma skin cancer or lentigo maligna, superficial bladder cancer, and carcinoma in situ of the cervix without evidence of disease, and asymptomatic prostate cancer without known metastatic disease and no requirement for therapy
• Concurrent treatment or within 15 days of starting study treatment with strong CYP3A4 inhibitors
• Prior exposure to a CDK9 inhibitor
• Wait at least 5 half-lives of the agent or 14 days after their investigational or approved therapies before start of study treatment, whichever is shorter
• Mean corrected QT interval of > 470 msec following triplicate ECG measurement or history of long QT syndrome
• T-Cell leukemias

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: PRT2527 Monotherapy in Lymphoid Malignancies; PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication-specific cohorts during the dose confirmation phase.	Drug: PRT2527; PRT2527 will be administered by intravenous infusion once weekly.
Experimental: PRT2527/Zanubrutinib Combination in Lymphoid Malignancies; PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase. Zanubrutinib will be administered orally as combination therapy once or twice daily.	Drug: PRT2527; PRT2527 will be administered by intravenous infusion once weekly.; Drug: Zanubrutinib; Zanubrutinib will be provided in capsules for oral administration once or twice daily.
Experimental: PRT2527 Monotherapy in Myeloid Malignancies; PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication-specific cohorts during the dose confirmation phase.	Drug: PRT2527; PRT2527 will be administered by intravenous infusion once weekly.
Experimental: PRT2527/Venetoclax Combination in Myeloid Malignancies; PRT2527 will be administered by intravenous infusion once weekly at the dose level assigned during the dose escalation phase and at the defined RP2D dose for indication specific cohort during the dose confirmation phase. Venetoclax will be administered orally as a combination therapy once daily.	Drug: PRT2527; PRT2527 will be administered by intravenous infusion once weekly.; Drug: Venetoclax; Venetoclax will be provided in tablet for oral administration once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose limiting toxicity (DLT) of PRT2527	Dose limiting toxicities will be evaluated during Cycle 1 depending on the treatment arm and intrapatient ramp-up.	Baseline through Day 21, 28, or 35 days.
Safety and tolerability of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: AEs, CTCAE Assessments	Safety and tolerability will be evaluated by incidence of DLTs, dose interruption, modification, and discontinuation due to adverse events (AEs) according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE)	Baseline through approximately 2 years
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax	The MTD/RP2D will be established for further investigation in participants with relapsed or refractory hematologic malignancies	Baseline through approximately 2 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Anti-tumor activity of PRT2527 as monotherapy and in combination with zanubrutinib or venetoclax: Objective response rate (ORR)	Best overall response as assessed by the investigator in accordance with standard disease-specific criteria for the hematologic malignancies under study	Baseline through approximately 2 years
Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Duration of response/Complete Response (DOR/DoCR)	Duration from time of first observed response to the earliest date of disease progression, as assessed by the investigator in accordance with standard disease-specific criteria for the hematologic malignancies under study, or death due to any cause, whichever occurs first	Baseline through approximately 2 years
Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Maximum observed plasma concentration	PRT2527 pharmacokinetics will be calculated including the maximum observed plasma concentration (Cmax)	Baseline through approximately 2 years
Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Area under the curve	PRT2527 pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC)	Baseline through approximately 2 years
Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Time of maximum concentration	PRT2527 pharmacokinetics will be calculated including the time of maximum concentration (Tmax)	Baseline through approximately 2 years

Collaborators and Investigators

• Sponsor: Prelude Therapeutics
• Collaborators: BeiGene

Study record dates

Study Major Dates

• Study Start (Actual): September 12, 2023
• Primary Completion (Actual): June 12, 2025
• Study Completion (Actual): January 21, 2026

Study Registration Dates

• First Submitted: December 16, 2022
• First Submitted That Met QC Criteria: December 16, 2022
• First Posted (Actual): December 27, 2022

Study Record Updates

• Last Update Posted (Actual): January 26, 2026
• Last Update Submitted That Met QC Criteria: January 23, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: Venetoclax; Myelodysplastic Syndrome (MDS); Acute Myeloid Leukemia (AML); Hematologic Malignancies; Myeloid Malignancies; Zanubrutinib; Mantle Cell Lymphoma (MCL); Marginal Zone Lymphoma (MZL); Richter's Syndrome; Relapse/Refractory; Chronic Myelomonocytic Leukemia (CMML); PRT2527; Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma; CDK9; Cyclin-Dependent Kinase 9; T-cell Lymphoma (TCL); Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL); Diffuse Large B-cell lymphoma (DLBCL); MDS/Myeloproliferative Neoplasm (MPN) Overlap Syndrome
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Site; Neoplasms; Chronic Disease; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Leukemia, B-Cell; Lymphoma, B-Cell; Lymphoma; Leukemia, Myeloid; Myelodysplastic-Myeloproliferative Diseases; Bone Marrow Diseases; Leukemia, Lymphoid; Leukemia; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Recurrence; Leukemia, Myeloid, Acute; Hematologic Neoplasms; Lymphoma, Large B-Cell, Diffuse; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelomonocytic, Chronic; Myelodysplastic Syndromes; Lymphoma, T-Cell; Lymphoma, Mantle-Cell; Lymphoma, B-Cell, Marginal Zone; Tyrosine Kinase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; zanubrutinib; venetoclax
• Other Study ID Numbers: PRT2527-02

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No