A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies
- Conditions
- Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)Mantle Cell Lymphoma (MCL)Diffuse Large B-cell Lymphoma (DLBCL)Acute Myeloid Leukemia (AML)Myelodysplastic Syndrome (MDS)Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL)MDS/Myeloproliferative Neoplasm (MPN) Overlap SyndromeRichter's SyndromeT-cell LymphomaChronic Myelomonocytic Leukemia (CMML)
- Interventions
- Registration Number
- NCT05665530
- Lead Sponsor
- Prelude Therapeutics
- Brief Summary
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.
- 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.
Recruitment & Eligibility
- Status
- ACTIVE_NOT_RECRUITING
- Sex
- All
- Target Recruitment
- 86
- 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%
- 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 & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description PRT2527/Zanubrutinib Combination in Lymphoid Malignancies Zanubrutinib 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. PRT2527 Monotherapy in Lymphoid Malignancies PRT2527 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. PRT2527/Zanubrutinib Combination in Lymphoid Malignancies PRT2527 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. PRT2527 Monotherapy in Myeloid Malignancies PRT2527 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. PRT2527/Venetoclax Combination in Myeloid Malignancies PRT2527 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. PRT2527/Venetoclax Combination in Myeloid Malignancies Venetoclax 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.
- Primary Outcome Measures
Name Time Method Safety and tolerability of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: AEs, CTCAE Assessments Baseline through approximately 2 years 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)
Dose limiting toxicity (DLT) of PRT2527 Baseline through Day 21, 28, or 35 days. Dose limiting toxicities will be evaluated during Cycle 1 depending on the treatment arm and intrapatient ramp-up.
Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax Baseline through approximately 2 years The MTD/RP2D will be established for further investigation in participants with relapsed or refractory hematologic malignancies
- Secondary Outcome Measures
Name Time Method Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Maximum observed plasma concentration Baseline through approximately 2 years PRT2527 pharmacokinetics will be calculated including the maximum observed plasma concentration (Cmax)
Anti-tumor activity of PRT2527 as monotherapy and in combination with zanubrutinib or venetoclax: Objective response rate (ORR) Baseline through approximately 2 years Best overall response as assessed by the investigator in accordance with standard disease-specific criteria for the hematologic malignancies under study
Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Duration of response/Complete Response (DOR/DoCR) Baseline through approximately 2 years 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
Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Area under the curve Baseline through approximately 2 years PRT2527 pharmacokinetics will be calculated including the area under the plasma concentration versus time curve (AUC)
Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Time of maximum concentration Baseline through approximately 2 years PRT2527 pharmacokinetics will be calculated including the time of maximum concentration (Tmax)
Trial Locations
- Locations (24)
City of Hope
🇺🇸Duarte, California, United States
American Oncology Partners of Maryland, PA
🇺🇸Bethesda, Maryland, United States
Dana-Farber Cancer Institute
🇺🇸Boston, Massachusetts, United States
Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
🇺🇸New York, New York, United States
University of Virginia Comprehensive Cancer Center
🇺🇸Charlottesville, Virginia, United States
Austin Health
🇦🇺Heidelberg, Victoria, Australia
Alfred Health
🇦🇺Melbourne, Victoria, Australia
Monash Health
🇦🇺Melbourne, Victoria, Australia
Linear Clinical Research Ltd
🇦🇺Perth, Western Australia, Australia
Jewish General Hospital
🇨🇦Montreal, Quebec, Canada
Hopital Henri Mondor
🇫🇷Creteil, France
Claude Huriez Hospital
🇫🇷Lille, France
Centre Léon Bérard
🇫🇷Lyon, France
Institut Curie
🇫🇷Saint-Cloud, France
Universitatsklinikum Koln, Klinik I fur lnnere Medizin
🇩🇪Koln, North Rhine-Westphalia, Germany
lstituto Romagnolo per lo Studio dei Tumori "Dino Amadori" IRST
🇮🇹Meldola, FC, Italy
IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola
🇮🇹Bologna, Italy
Ospedale Santa Maria delle Croci - AUSL della Romagna
🇮🇹Ravenna, Italy
lnje University Busan Paik Hospital
🇰🇷Busan, Korea, Republic of
Keimyung_University Dongsan Hospital
🇰🇷Daegu, Korea, Republic of
Samsung Medical Center
🇰🇷Seoul, Korea, Republic of
Pratia MCM Krakow
🇵🇱Kraków, Malopolskie, Poland
Ente Ospedaliero Cantonale (EOC) lstituto Oncologico della Svizzera italiana (IOSl)- Ospedale San Giovanni (ORBV)
🇨🇭Bellinzona, Ticino, Switzerland
The Leeds Teaching Hospitals NHS Trust, St James University Hospital
🇬🇧Leeds, West Yorkshire, United Kingdom