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

Study Overview
=================
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.

Detailed Description
-----------------
This is an open-label, multi-center, dose-escalation, Phase 1 study of PRT2527, a CDK9 inhibitor, as monotherapy and in combination with zanubrutinib, a Bruton tyrosine kinase inhibitor (BTKi), evaluating participants with select R/R hematologic malignancies including aggressive B-cell lymphoma subtypes, mantle cell lymphoma (MCL), and chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), including Richter's syndrome and T-cell lymphoma (TCL) subtypes. 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 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 104 participants will be enrolled in the dose escalation and indication-specific, dose confirmation cohorts.

Official Title
-----------------
A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib in Participants With Relapsed/Refractory Hematologic Malignancies

Conditions
-----------------
Aggressive B-Cell Non-Hodgkin's Lymphoma, Aggressive B-Cell NHL, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Mantle Cell Lymphoma (MCL), Richter's Syndrome, T-cell Lymphoma

Intervention / Treatment
-----------------
* Drug: PRT2527
* Drug: Zanubrutinib


Participation Criteria
=================
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, CLL/SLL, including Richter's syndrome, based on local testing , or TCL (monotherapy only) that have relapsed or become refractory to or be ineligible for standard-of-care therapy Must provide either an archival or fresh tumor tissue sample from a core or excisional/surgical biopsy Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 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 Mean corrected QT interval of > 470 msec following triplicate ECG measurements or a history of long QT Syndrome 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 or inducers or use of moderate CYP3A4 inducers (for combination therapy only) 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PRT2527 Monotherapy<br>PRT2527 will be administered by intravenous infusion once weekly on a 21-day treatment cycle 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<br>* PRT2527 will be administered by intravenous infusion once weekly.<br>|
| Experimental: PRT2527/Zanubrutinib Combination<br>PRT2527 will be administered by intravenous infusion once weekly on a 35-day treatment cycle for Cycle 1 followed by 21-day treatment for subsequent treatment cycles 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 daily. | Drug: PRT2527<br>* PRT2527 will be administered by intravenous infusion once weekly.<br>Drug: Zanubrutinib<br>* Zanubrutinib will be provided in capsules for oral administration once daily.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) of PRT2527 | Dose limiting toxicities will be evaluated over the 21-day observation period for monotherapy and 35-day observation period for combination therapy. | Baseline through Day 21 for monotherapy, and baseline through Day 35 for combination therapy. | 
| Safety and tolerability of PRT2527 monotherapy and in combination with zanubrutinib: AEs, CTCAE Assessments | 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) | Baseline through approximately 2 years | 
| Maximum tolerated dose (MTD)/Recommended phase 2 dose (RP2D) of PRT2527 monotherapy and in combination with zanubrutinib | The MTD/RP2D will be established for further investigation in participants with relapsed or refractory hematologic malignancies | Baseline through approximately 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib: Objective response rate (ORR) | Best overall response of either complete response (CR) or partial response (PR), as assessed by the investigator in accordance with standard disease-specific criteria for the hematologic malignancies under study | Baseline through approximately 2 years | 
| Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib: Duration of response/Complete Response (DOR/DoCR) | Duration from time of first observed response (CR or PR) 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 | Baseline through approximately 2 years | 
| Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib: Maximum observed plasma concentration | PRT2527 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: Area under the curve | PRT2527 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: Time of maximum concentration | PRT2527 pharmacokinetics will be calculated including the time of maximum concentration (Tmax) | Baseline through approximately 2 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Aggressive B-Cell Non-Hodgkin's Lymphoma, Aggressive B-Cell NHL, Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, CDK9, CLL/SLL, Cyclin-Dependent Kinase 9, Hematologic Malignancies, Mantle Cell Lymphoma (MCL), PRT2527, Relapse/Refractory, Richter's Syndrome, T-cell Lymphoma (TCL), Zanubrutinib