Clinical trial NCT05665530: A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib or Venetoclax in Participants With R/R Hematologic Malignancies
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
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
Keywords: Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL)
Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
CDK9
Cyclin-Dependent Kinase 9
Hematologic Malignancies
Mantle Cell Lymphoma (MCL)
PRT2527
Relapse/Refractory
Richter's Syndrome
T-cell Lymphoma (TCL)
Zanubrutinib
Diffuse Large B-cell lymphoma (DLBCL)
Venetoclax
Marginal Zone Lymphoma (MZL)
Myeloid Malignancies
Acute Myeloid Leukemia (AML)
Chronic Myelomonocytic Leukemia (CMML)
Myelodysplastic Syndrome (MDS)
MDS/Myeloproliferative Neoplasm (MPN) Overlap Syndrome
Lead sponsor: Prelude Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: BeiGene
First posted: 2022-12-27
Enrollment: 86
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Dose limiting toxicity (DLT) of PRT2527
timeFrame: Baseline through Day 21, 28, or 35 days.
measure: Safety and tolerability of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: AEs, CTCAE Assessments
timeFrame: Baseline through approximately 2 years
measure: Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax
timeFrame: Baseline through approximately 2 years
Secondary outcomes:
measure: Anti-tumor activity of PRT2527 as monotherapy and in combination with zanubrutinib or venetoclax: Objective response rate (ORR)
timeFrame: Baseline through approximately 2 years
measure: Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Duration of response/Complete Response (DOR/DoCR)
timeFrame: Baseline through approximately 2 years
measure: Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Maximum observed plasma concentration
timeFrame: Baseline through approximately 2 years
measure: Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Area under the curve
timeFrame: Baseline through approximately 2 years
measure: Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib or venetoclax: Time of maximum concentration
timeFrame: Baseline through approximately 2 years
Other outcomes:
Locations:
city: Duarte
country: United States
facility: City of Hope
state: California
city: Bethesda
country: United States
facility: American Oncology Partners of Maryland, PA
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center at NYU Langone Health
state: New York
city: Charlottesville
country: United States
facility: University of Virginia Comprehensive Cancer Center
state: Virginia
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Melbourne
country: Australia
facility: Alfred Health
state: Victoria
city: Melbourne
country: Australia
facility: Monash Health
state: Victoria
city: Perth
country: Australia
facility: Linear Clinical Research Ltd
state: Western Australia
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Creteil
country: France
facility: Hopital Henri Mondor
city: Lille
country: France
facility: Claude Huriez Hospital
city: Lyon
country: France
facility: Centre Léon Bérard
city: Saint-Cloud
country: France
facility: Institut Curie
city: Koln
country: Germany
facility: Universitatsklinikum Koln, Klinik I fur lnnere Medizin
state: North Rhine-Westphalia
city: Meldola
country: Italy
facility: lstituto Romagnolo per lo Studio dei Tumori "Dino Amadori" IRST
state: FC
city: Bologna
country: Italy
facility: IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola
city: Ravenna
country: Italy
facility: Ospedale Santa Maria delle Croci - AUSL della Romagna
city: Busan
country: Korea, Republic of
facility: lnje University Busan Paik Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung_University Dongsan Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Kraków
country: Poland
facility: Pratia MCM Krakow
state: Malopolskie
city: Bellinzona
country: Switzerland
facility: Ente Ospedaliero Cantonale (EOC) lstituto Oncologico della Svizzera italiana (IOSl)- Ospedale San Giovanni (ORBV)
state: Ticino
city: Leeds
country: United Kingdom
facility: The Leeds Teaching Hospitals NHS Trust, St James University Hospital
state: West Yorkshire
Study officials:
References: