2005 - A phase 1 study evaluating PRT2527, a potent and highly selective CDK9 inhibitor, in patients with select relapsed/refractory B-cell malignancies

PRT2527 is an investigational, potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. CDK9 is a key regulator of transcription elongation and has been studied as a potential target for therapy in transcriptionally addicted cancers that are dependent on oncogenic drivers with short half-lives. Although most of these drivers do not respond to direct inhibition, studies suggest that a subset of drivers with short half-lives such as MYC, MYB, and MCL-1 may be targeted indirectly through CDK9 inhibition in select hematological malignancies and solid tumors. Preclinical data with PRT2527 have demonstrated evidence of on-target inhibition of MYC, MYB, and MCL-1, as well as induced apoptosis, as measured by cleaved caspase 3 in cell lines and translational models (e.g., patient-derived xenograft models; Zhang Y, et al., AACR-NCI-EORTC 2021).

Methods: PRT2527-02 is a phase 1, open-label, multicenter, dose-finding study to evaluate the safety, tolerability, recommended phase 2 dose (R2PD), and preliminary efficacy of PRT2527 in patients with select B-cell malignancies such as aggressive B-cell lymphoma subtypes, mantle cell lymphoma, and chronic lymphocytic lymphoma/small lymphocytic lymphoma including Richter syndrome. Aggressive B-cell lymphoma subtypes, including diffuse large B-cell lymphoma not otherwise specified, gray zone lymphoma, follicular lymphoma grade 3b, high-grade B-cell lymphoma with or without translocations, and primary mediastinal large B-cell lymphoma or large B-cell lymphoma transformed from indolent B-cell lymphoma, are eligible to enroll. Patients must have relapsed or be refractory to or ineligible for standard-of-care therapy. Other key eligibility criteria include measurable disease or requirement for treatment in accordance with standard disease-specific criteria for the hematologic malignancies under study, Eastern Cooperative Oncology Group performance status of 0 to 1, and adequate bone marrow, renal, and liver function.

The study consists of dose escalation with successive cohorts of patients receiving escalating doses of intravenous PRT2527 once weekly in a 21-day cycle. PRT2527 treatment will continue until disease progression or unacceptable toxicity, whichever comes first. Dose escalation and de-escalation decisions will be guided by the Bayesian optimal interval design method based on the number of patients with dose-limiting toxicities (DLTs) observed at the dose level under evaluation until a maximum tolerated dose and R2PD have been determined. The primary endpoints include safety, tolerability, DLTs, and RP2D of PRT2527. Secondary endpoints include objective response rate, duration of response, duration of complete response, and pharmacokinetic profile of PRT2527. The study is open to enrollment and registered at ClinicalTrials.gov, NCT05665530.