Coombes, R Charles, Howell, Sacha, Lord, Simon R, Kenny, Laura, Mansi, Janine, Mitri, Zahi, Palmieri, Carlo 
ORCID: 0000-0001-9496-2718, Chap, Linnea I, Richards, Paul, Gradishar, William et al (show 13 more authors)
(2023)
Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.
NATURE COMMUNICATIONS, 14 (1).
4444-.
Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | Humans, Cyclin-Dependent Kinases, Enzyme Inhibitors, Biopsy, Administration, Oral, Cyclin-Dependent Kinase Inhibitor Proteins, Triple Negative Breast Neoplasms, Fulvestrant |
| Divisions: | Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
| Depositing User: | Symplectic Admin |
| Date Deposited: | 27 Sep 2023 10:53 |
| Last Modified: | 27 Sep 2023 10:53 |
| DOI: | 10.1038/s41467-023-40061-y |
| Open Access URL: | https://doi.org/10.1038/s41467-023-40061-y |
| Related URLs: | |
| URI: | https://livrepository.liverpool.ac.uk/id/eprint/3173115 |
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