| Title: |
Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib |
| Authors: |
Coombes, RC; Howell, S; Lord, SR; Kenny, L; Mansi, J; Mitri, Z; Palmieri, C; Chap, LI; Richards, P; Gradishar, W; Sardesai, S; Melear, J; O’Shaughnessy, J; Ward, P; Chalasani, P; Arkenau, T; Baird, RD; Jeselsohn, R; Ali, S; Clack, G; Bahl, A; McIntosh, S; Krebs, MG |
| Publisher Information: |
Nature Research |
| Publication Year: |
2025 |
| Collection: |
Oxford University Research Archive (ORA) |
| Description: |
Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2− breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1038/s41467-023-40061-y |
| Availability: |
https://doi.org/10.1038/s41467-023-40061-y; https://ora.ox.ac.uk/objects/uuid:ce7730b0-fe87-4281-a4f1-8c9a43c3c7f0 |
| Rights: |
info:eu-repo/semantics/openAccess ; CC Attribution (CC BY) |
| Accession Number: |
edsbas.EEC74C50 |
| Database: |
BASE |