Preliminary Results of a Phase 1, Dose-Escalation Study of PRT2527, a Potent and Highly Selective CDK9 Inhibitor, As Monotherapy and in Combination with Zanubrutinib in Patients with Relapsed/Refractory Lymphoid Malignancies
Bibliographic record
Abstract
Introduction: Cyclin-dependent kinase 9 (CDK9), a key regulator of transcription elongation, is a potential target in transcriptionally addicted cancers dependent on oncogenic drivers with short half-lives such as MYC, MYB, and MCL1. PRT2527, an investigational, potent, and highly selective CDK9 inhibitor, is being developed for select relapsed/refractory (R/R) hematologic malignancies as monotherapy and in combination (combo) with targeted agents. Zanubrutinib (zanu) is a Bruton tyrosine kinase (BTK) inhibitor that upregulates BCL2 modifying factor (BMF), a proapoptotic molecule physiologically inhibited by BCL2, BCLXL, and BCLW (Kong, et al. ChemMedChem. 2018). The combo of CDK9 and BTK inhibition may lead to a synergistic effect by enhancing apoptotic priming and shifting dependency toward the CDK9 targets, MCL1 and BFL1. Methods: PRT2527-02 is a phase 1, multicenter, dose-escalation and dose-confirmation study evaluating safety and preliminary efficacy of PRT2527 as monotherapy and in combo with standard-dose zanu in patients (pts) with select R/R hematologic malignancies (NCT05665530). Pts must have relapsed or be refractory to or ineligible for standard-of-care therapy. PRT2527 was administered intravenously in escalating doses as a once weekly infusion, and zanu was administered orally. Treatment continued until disease progression or unacceptable toxicity. Dose escalation decisions were guided by the Bayesian optimal interval design method based on dose-limiting toxicities (DLTs) in cycle 1. Primary endpoints include safety, tolerability, DLTs, and recommended phase 2 dose of PRT2527 monotherapy and in combo with zanu. Secondary and exploratory endpoints include overall response rate and pharmacokinetic/pharmacodynamic profiles of PRT2527 monotherapy and in combo with zanu. Results: As of June 21, 2024, 31 pts (17 diffuse large B-cell lymphoma [DLBCL] not otherwise specified, 7 peripheral T-cell lymphoma [PTCL], 2 high-grade B-cell lymphoma, 2 mantle cell lymphoma [MCL], 2 chronic lymphocytic leukemia [CLL], and 1 Richter syndrome) were enrolled and treated with PRT2527. Median age was 64 (range, 27-94) years, 61% were male, and median prior lines of therapy was 3 (range, 1-7). Nineteen pts were treated with PRT2527 monotherapy (9 mg/m2, n=6; 15 mg/m2, n=5; 18 mg/m2, n=8) and 12 with PRT2527 and zanu combo (9 mg/m2, n=6; 15 mg/m2, n=6). Median duration of study treatment was 3.6 weeks (range, 0.7-30.4) for monotherapy and 6.8 weeks (range, 1.3-20.4) for combo. Most frequently reported (>20%) any-grade treatment-emergent adverse events (TEAEs) were neutropenia (53%), nausea (53%), and constipation (21%) with monotherapy and neutropenia, diarrhea, asthenia, hypokalemia, and vomiting (25% each) with combo. Overall, grade 3/4 TEAEs occurred in 18 (58%) pts, most frequently neutropenia (39%). Nine (29%) pts had a TEAE leading to dose hold: 6 (19%) due to grade 3/4 neutropenia that resolved with growth factor. No clinical tumor lysis syndrome was observed, and no DLTs were reported. Three pts achieved a response: a complete response in 1 non-GCB double-expressor DLBCL pt post-CAR T-cell therapy on monotherapy (9 mg/m2) and 1 MCL pt on combo (9 mg/m2), and a partial response in 1 PTCL pt on monotherapy (9 mg/m2). Eleven pts were on study and have not reached the first response assessment. Additional responders across tumor types have been seen after the data cut-off and will be presented. Fourteen (45%) pts remain on study (monotherapy [n=7], combo [n=7]), and 17 (55%) pts discontinued treatment: 14 (45%) due to PD, 2 (6%) due to TEAEs (supraventricular tachycardia [n=1], AML [n=1]), and 1 (3%) due to death (COVID-19). Whole blood expression of the CDK9 transcriptional targets MCL1 and MYC demonstrated target engagement at all dose levels, with a more prolonged transcriptional decrease at higher doses. At 18 mg/m2 (n=7), a median decrease of 80.5% in MCL1 and 82.4% in MYC messenger RNA (mRNA) was achieved 2 hours after the start of infusion. By 6 hours, median MCL1 mRNA returned to baseline levels while MYC levels remained suppressed with a median inhibition of 32.1%. Conclusions: PRT2527 as monotherapy and in combo with zanu had an acceptable safety profile and evidence of preliminary activity in pts with R/R lymphoid malignancies. Neutropenia was the most common TEAE, manageable with growth factor support. Dose finding with PRT2527 as monotherapy or in combo with zanu is ongoing.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
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 source (direct Gemma or distilled Codex), 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".