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

• ClinicalTrials.gov Identifier: NCT05665530
• Recruitment Status: Recruiting
• First Posted: December 27, 2022
• Last Update Posted: May 2, 2024
• Sponsor: Prelude Therapeutics
• Collaborator: BeiGene
• Information provided by (Responsible Party): Prelude Therapeutics

Tracking Information

• First Submitted Date: December 16, 2022
• First Posted Date: December 27, 2022
• Last Update Posted Date: May 2, 2024
• Actual Study Start Date: September 12, 2023
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 1, 2023)

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

Original Primary Outcome Measures (submitted: December 16, 2022)

• Dose limiting toxicity (DLT) of PRT2527 [ Time Frame: Baseline through Day 21 ]
  Dose limiting toxicities will be evaluated over the 21-day observation period
• Safety and tolerability of PRT2527: AEs, CTCAE Assessments [ Time Frame: 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 [ Time Frame: Baseline through approximately 2 years ]
  The MTD/RP2D will be established for further investigation in participants with relapsed or refractory hematologic malignancies

Current Secondary Outcome Measures (submitted: September 1, 2023)

• Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib: Objective response rate (ORR) [ Time Frame: Baseline through approximately 2 years ]
  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
• Anti-tumor activity of PRT2527 monotherapy and in combination with zanubrutinib: Duration of response/Complete Response (DOR/DoCR) [ Time Frame: Baseline through approximately 2 years ]
  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
• Pharmacokinetic profile of PRT2527 monotherapy and in combination with zanubrutinib: Maximum observed plasma concentration [ Time Frame: 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: Area under the curve [ Time Frame: 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: Time of maximum concentration [ Time Frame: Baseline through approximately 2 years ]
  PRT2527 pharmacokinetics will be calculated including the time of maximum concentration (Tmax)

Original Secondary Outcome Measures (submitted: December 16, 2022)

• Anti-tumor activity of PRT2527: Objective response rate (ORR) [ Time Frame: Baseline through approximately 2 years ]
  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
• Anti-tumor activity of PRT2527: Duration of response/Complete Response (DOR/DoCR) [ Time Frame: Baseline through approximately 2 years ]
  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
• Pharmacokinetic profile of PRT2527: Maximum observed plasma concentration [ Time Frame: Baseline through approximately 2 years ]
  PRT2527 pharmacokinetics will be calculated including the maximum observed plasma concentration (Cmax)
• Pharmacokinetic profile of PRT2527: Area under the curve [ Time Frame: 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: Time of maximum concentration [ Time Frame: Baseline through approximately 2 years ]
  PRT2527 pharmacokinetics will be calculated including the time of maximum concentration (Tmax)

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of PRT2527 as Monotherapy and in Combination With Zanubrutinib 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 in Participants With Relapsed/Refractory Hematologic Malignancies
• 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.
• Study Type: Interventional
• Study Phase: Phase 1
• Study Design: Allocation: Non-Randomized; Intervention Model: Sequential Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• 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

• Drug: PRT2527
  PRT2527 will be administered by intravenous infusion once weekly.
• Drug: Zanubrutinib
  Zanubrutinib will be provided in capsules for oral administration once daily.

Study Arms

• Experimental: PRT2527 Monotherapy
  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.
  Intervention: Drug: PRT2527
• Experimental: PRT2527/Zanubrutinib Combination

  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.

  Interventions:

  • Drug: PRT2527
  • Drug: Zanubrutinib

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 1, 2023): 104
• Original Estimated Enrollment (submitted: December 16, 2022): 51
• Estimated Study Completion Date: April 2025
• Estimated Primary Completion Date: April 2025 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Study Contact (Please Do Not Disclose Personal Information); See Email; clinicaltrials@preludetx.com

• Listed Location Countries: Australia, Canada, France, Germany, Italy, Korea, Republic of, Poland, Switzerland, United Kingdom, United States

Administrative Information

• NCT Number: NCT05665530
• Other Study ID Numbers: PRT2527-02
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Prelude Therapeutics
• Original Responsible Party: Same as current
• Current Study Sponsor: Prelude Therapeutics
• Original Study Sponsor: Same as current
• Collaborators: BeiGene
• Investigators: Not Provided
• PRS Account: Prelude Therapeutics
• Verification Date: May 2024