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

T-cell Lymphoma Clinical Trial

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05665530
• Other study ID #: PRT2527-02
• Status: Recruiting
• Phase: Phase 1
• Start date: September 12, 2023
• Est. completion date: April 2025

Study information

• Verified date: May 2024
• Source: Prelude Therapeutics
• Contact: Study Contact (Please Do Not Disclose Personal Information)
• Phone: See Email
• Email: clinicaltrials[@]preludetx.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 104
• Est. completion date: April 2025
• Est. primary completion date: April 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Aggression
• Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
• Hematologic Neoplasms
• Leukemia, Lymphocytic, Chronic, B-Cell
• Leukemia, Lymphoid
• Lymphoma
• Lymphoma, B-Cell
• Lymphoma, Mantle-Cell
• Lymphoma, Non-Hodgkin
• Lymphoma, T-Cell
• Lymphoma, T-Cell, Peripheral
• Mantle Cell Lymphoma (MCL)
• Neoplasms
• Richter's Syndrome
• T-cell Lymphoma

Intervention

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

Locations

Country	Name	City	State
Australia	Austin Health	Heidelberg	Victoria
Australia	Alfred Health	Melbourne	Victoria
Australia	Monash Health	Melbourne	Victoria
Australia	Linear Clinical Research Ltd	Perth	Western Australia
Canada	Jewish General Hospital	Montreal	Quebec
France	Hopital Henri Mondor	Creteil
France	Claude Huriez Hospital	Lille
France	Centre Léon Bérard	Lyon
France	Institut Curie	Saint-Cloud
Germany	Universitatsklinikum Koln, Klinik I fur lnnere Medizin	Koln	North Rhine-Westphalia
Italy	IRCCS Azienda Ospedaliero-Universitaria di Bologna Policlinico Sant'Orsola	Bologna
Italy	lstituto Romagnolo per lo Studio dei Tumori "Dino Amadori" IRST	Meldola	FC
Italy	Ospedale Santa Maria delle Croci - AUSL della Romagna	Ravenna
Korea, Republic of	lnje University Busan Paik Hospital	Busan
Korea, Republic of	Keimyung_University Dongsan Hospital	Daegu
Korea, Republic of	Samsung Medical Center	Seoul
Poland	Pratia MCM Krakow	Kraków	Malopolskie
Switzerland	Ente Ospedaliero Cantonale (EOC) lstituto Oncologico della Svizzera italiana (IOSl)- Ospedale San Giovanni (ORBV)	Bellinzona	Ticino
United Kingdom	The Leeds Teaching Hospitals NHS Trust, St James University Hospital	Leeds	West Yorkshire
United States	American Oncology Partners of Maryland, PA	Bethesda	Maryland
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	University of Virginia Comprehensive Cancer Center	Charlottesville	Virginia
United States	City of Hope	Duarte	California
United States	Laura and Isaac Perlmutter Cancer Center at NYU Langone Health	New York	New York

Sponsors (2)

Lead Sponsor	Collaborator
Prelude Therapeutics	BeiGene

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Italy,  Korea, Republic of,  Poland,  Switzerland,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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.
Primary	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
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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