Trial to Assess PRT2527 Plus Zanubrutinib for Hematologic Malignancies

Article

The combination of CDK9 plus BTK inhibition has already demonstrated synergistic clinical efficacy vs BTK inhibition alone. Now, a clinical trial collaboration will evaluate PRT2527 and zanubrutinib for patients with hematologic malignancies.

Jennifer R. Brown, MD, PhD

Jennifer R. Brown, MD, PhD

A clinical trial collaboration between Prelude Therapeutics Incorporated and BeiGene will evaluate the combination of the investigational CDK9 inhibitor, PRT2527, and Brutons kinase inhibitor (BTK), zanubrutinib (Brukinsa), for patients with hematologic malignancies.1

Data have shown inhibition of BTK is an active therapeutic approach in various B cell malignancies. The combination of CDK9 inhibition with BTK inhibition has already demonstrated synergistic clinical efficacy compared with BTK inhibition alone. As a result, investigators will further study the combination in patients with certain hematologic malignancies to improve patient outcomes.

About the Phase 1 Study

Trial Name: A Phase 1 Open-Label, Multi-Center, Safety and Efficacy Study of PRT2527 in Participants With Relapsed/Refractory Hematologic Malignancies

ClinicalTrials.gov Identifier: NCT05665530

Sponsor: Prelude Therapeutics

Recruitment Contact:
PRT2527-02IVStudy@preludetx.com

Completion Date: March 2025

"Zanubrutinib is a second generation covalent inhibitor of BTK, achieving very high levels of BTK occupancy continuously, and also maintaining continuous therapeutic drug levels throughout its dosing interval," Jennifer R. Brown, MD, PhD, from the Dana-Farber Cancer Institute, told Targeted OncologyTM. "It is important to continue evaluating combinations with zanubrutinib for patients with hematologic malignancies as we are not curing our patients with single agent BTK inhibitors, and combinations carry the promise of potential synergistic efficacy and the avoidance of resistance, as well as the potential for time-limited therapy."

PRT2527 is a potent and selective CDK9 inhibitor which reduced MCL1 and MYC protein levels and was highly active in preclinical studies and models at well-tolerated doses.

Treatment with PRT2527 has led to high potency and kinase selectivity. Experts are hopeful that this may improve efficacy and safety compared to less selective CDK9 inhibitors and allow for rapid development in combinations.

Currently, PRT2527 as a monotherapy is being evaluated in a phase 1 dose-escalation study for the treatment of patients with advanced solid tumors and relapsed/refractory hematologic malignancies.

In this phase 1 dose-escalation study, PRT2527 is being evaluated in patients with select relapsed or refractory hematologic malignancies to assess the safety, tolerability, recommended phase 2 dose (PR2D), and preliminary efficacy of the agent.2

The open-label, multicenter study will administer PRT2527 via intravenous infusion once a week on a 21-day treatment cycle to patients aged 18 years and older with a histologically or cytologically confirmed diagnosis of aggressive B-cell lymphoma subtypes, mantle cell lymphoma, chronic lymphocytic leukemia or small lymphocytic lymphoma, including Richter's syndrome, based on local testing that have relapsed, become refractory to, or are ineligible for standard-of-care therapy will be enrolled in the trial.

Additionally, patients must have an archival or fresh tumor tissue sample from a core or excisional/surgical biopsy, an ECOG performance status of 0 or 1, adequate organ function, and echocardiogram indicating a left ventricular ejection fraction of ≥ 50%.

Primary end points of the study are to assess the dose limiting toxicities, safety, tolerability and RP2D of PRT2527. Secondary end points are assessing the objective response rate, duration of response, complete response, and pharmacokinetics.

“The opportunity to combine Prelude’s potent, selective and potentially best-in-class CDK9 inhibitor with BeiGene’s next-generation highly efficacious and tolerable BTK inhibitor, zanubrutinib, reflects our commitment to bringing the most promising options to patients,” said Jane Huang, MD, president, and chief medical officer of Prelude Therapeutics, in the press release.

Under terms of the clinical trial collaboration agreement, zanubrutinib will be provided to Prelude, and Prelude will retain all global operational, development and commercialization rights and responsibilities for PRT2527.

REFERENCES:
1. Prelude Therapeutics announces clinical trial collaboration with BeiGene to evaluate PRT2527 in combination with zanubrutinib in hematologic cancers. News release. Prelude Therapeutics Incorporated. March 15, 2023. Accessed March 16, 2023. https://yhoo.it/409Yluc
2. A study of PRT2527 in participants with relapsed/refractory hematologic malignancies. ClinicalTrials.gov Updated February 23, 2023. Accessed March 16, 2023. https://clinicaltrials.gov/ct2/show/NCT05665530?term=PRT2527&draw=2&rank=1
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