Acute Myeloid Leukemia (AML), Aggressive B-Cell Non-Hodgkin's Lymphoma (NHL), Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL), Chronic Myelomonocytic Leukemia (CMML), Diffuse Large B-cell Lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma, MDS/Myeloproliferative Neoplasm (MPN) Overlap Syndrome, Myelodysplastic Syndrome (MDS), Myeloid Malignancies, Richter's Syndrome, T-cell Lymphoma
Conditions
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
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.
Interventions
DRUGPRT2527
PRT2527 will be administered by intravenous infusion once weekly.
DRUGZanubrutinib
Zanubrutinib will be provided in capsules for oral administration once or twice daily.
DRUGVenetoclax
Venetoclax will be provided in tablet for oral administration once daily
Sponsors
Prelude Therapeutics
BeiGene
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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) |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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: Maximum observed plasma concentration | Baseline through approximately 2 years | PRT2527 pharmacokinetics will be calculated including the maximum observed plasma concentration (Cmax) |
| 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) |
Countries
Australia, Canada, France, Germany, Italy, Poland, South Korea, Switzerland, United Kingdom, United States
Outcome results
None listed