A PHASE 1 STUDY EVALUATING PRT2527, A POTENT AND HIGHLY SELECTIVE CDK9 INHIBITOR, IN PATIENTS WITH SELECT RELAPSED/REFRACTORY B‐CELL MALIGNANCIES
Bibliographic record
Abstract
Introduction: PRT2527 is a potent, 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, which 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 MCL1 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 MCL1, as well as induced apoptosis, as measured by cleaved caspase 3 in cell lines and translational models (e.g., patient-derived xenograft [PDX] 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 (e.g., 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, and primary mediastinal large B-cell lymphoma or large B-cell lymphoma transformed from indolent B-cell, 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 0–1, 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 participants 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 has been open to enrollment since February 2023. Clinical trial information: NCT05665530. The research was funded by: Prelude Therapeutics Keywords: aggressive B-cell non-Hodgkin lymphoma, molecular targeted therapies, ongoing trials Conflicts of interests pertinent to the abstract. B. D. Cheson Employment or leadership position: AON, Symbio (Japan) Consultant or advisory role Abbvie, Pharmacyclics, Bristol Myers Squibb, ADC Therapeutics, AstraZeneca, Astellas, Tessa, Imaging Endpoints, Oncopeptides, Ascentage, Reddy Biosimilar Research funding: Lilly, Morphosys, Prelude, GenMab Other remuneration: Expert Testimony: Eagle Therapeutics; Speakers Bureau: BeiGene, Morphosys, Incyte, Lilly F. Morschhauser Consultant or advisory role Roche/Gilead/Novartis/Genmab S. E. Assouline Consultant or advisory role AbbVie, BMS, AstraZeneca, Janssen, BeiGene, Pfizer, Roche Research funding: Novartis Canada W. Sun Honoraria: Prelude S. K. Atwal Employment or leadership position: Prelude Therapeutics Stock ownership: Prelude Therapeutics W. Hong Employment or leadership position: Prelude Therapeutics, Imago BioSciences, Genentech Stock ownership: Imago BioSciences Other remuneration: Patents, Royalties: Stanford University C. Sarkozy Consultant or advisory role Janssen, Incyte, GSK, BMS Honoraria: Janssen Research funding: Roche Educational grants: Roche, Incyte
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".