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

Prelude Therapeutics

Status and phase: Enrolling; Phase 1

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

Treatments: Drug: Zanubrutinib; Drug: PRT2527; Drug: Venetoclax

Study type: Interventional

Funder types: Industry

Identifiers

NCT05665530

PRT2527-02

Details and patient eligibility

About

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.

Full 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.

Enrollment: 274 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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274 participants in 4 patient groups

PRT2527 Monotherapy in Lymphoid Malignancies

Experimental group

Description:

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.

Treatment:

Drug: PRT2527

PRT2527/Zanubrutinib Combination in Lymphoid Malignancies

Experimental group

Description:

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.

Treatment:

Drug: PRT2527

Drug: Zanubrutinib

PRT2527 Monotherapy in Myeloid Malignancies

Experimental group

Description:

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.

Treatment:

Drug: PRT2527

PRT2527/Venetoclax Combination in Myeloid Malignancies

Experimental group

Description:

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.

Treatment:

Drug: Venetoclax

Drug: PRT2527