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

PHASE1RECRUITING

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.

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Study details:

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.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

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
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2023-09-12

    Primary completion: 2025-11-01

    Study completion finish: 2026-03-01

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE1

    trial

    Trial ID

    NCT05665530

    Intervention or treatment

    DRUG: PRT2527

    DRUG: Zanubrutinib

    DRUG: Venetoclax

    Conditions

    • Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL)
    • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)
    • Mantle Cell Lymphoma (MCL)
    • Richter's Syndrome
    • T-cell Lymphoma
    • Diffuse Large B-cell Lymphoma (DLBCL)
    • Marginal Zone Lymphoma
    • Myeloid Malignancies
    • Acute Myeloid Leukemia (AML)
    • Chronic Myelomonocytic Leukemia (CMML)
    • Myelodysplastic Syndrome (MDS)
    • MDS/Myeloproliferative Neoplasm (MPN) Overlap Syndrome
    Image related to Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL)
    • Condition: Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) and more

    • DRUG: PRT2527 and other drugs

    • Heidelberg, Victoria, Australia and more

    • Sponsor: Prelude Therapeutics

    Find a site

    Closest Location:

    Austin Health

    Research sites nearby

    Select from list below to view details:

    • Austin Health

      Heidelberg, Victoria, Australia

    • Alfred Health

      Melbourne, Victoria, Australia

    • Monash Health

      Melbourne, Victoria, Australia

    • Linear Clinical Research Ltd

      Perth, Western Australia, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/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.
    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.

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Dose limiting toxicity (DLT) of PRT2527Dose 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 AssessmentsSafety 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 venetoclaxThe MTD/RP2D will be established for further investigation in participants with relapsed or refractory hematologic malignanciesBaseline through approximately 2 years

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome 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 studyBaseline 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 firstBaseline through approximately 2 years
    Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Maximum observed plasma concentrationPRT2527 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 curvePRT2527 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 concentrationPRT2527 pharmacokinetics will be calculated including the time of maximum concentration (Tmax)Baseline through approximately 2 years

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    References

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

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