Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib

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: M...

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Veröffentlicht in:Nature communications Jg. 14; H. 1; S. 4444 - 10
Hauptverfasser: Coombes, R. C., Howell, Sacha, Lord, Simon R., Kenny, Laura, Mansi, Janine, Mitri, Zahi, Palmieri, Carlo, Chap, Linnea I., Richards, Paul, Gradishar, William, Sardesai, Sagar, Melear, Jason, O’Shaughnessy, Joyce, Ward, Patrick, Chalasani, Pavani, Arkenau, Tobias, Baird, Richard D., Jeselsohn, Rinath, Ali, Simak, Clack, Glen, Bahl, Ashwani, McIntosh, Stuart, Krebs, Matthew G.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 24.07.2023
Nature Publishing Group
Nature Portfolio
Schlagworte:
13/95
38/23
631/67/1059/153
692/308/153
692/4028/67/1347
Administration, Oral
Anticancer properties
Antitumor agents
Biopsy
Breast cancer
Cancer therapies
Cyclin-dependent kinase 4
Cyclin-Dependent Kinase Inhibitor Proteins
Cyclin-Dependent Kinases
Diarrhea
Disease control
DNA-directed RNA polymerase
Enzyme Inhibitors
ErbB-2 protein
Fulvestrant
Humanities and Social Sciences
Humans
Inhibitors
Lymphocytes
Malignancy
Modules
multidisciplinary
Oral administration
Patients
Pharmacodynamics
Pharmacokinetics
RNA polymerase
RNA polymerase II
Safety
Science
Science (multidisciplinary)
Solid tumors
Substrates
Triple Negative Breast Neoplasms
Tumors
Vomiting
ISSN:2041-1723, 2041-1723
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Zusammenfassung: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. Pre-clinical studies have demonstrated the anti-tumor activity of selective inhibitors of CDK7, including samuraciclib. Here the authors report the results from dose escalation and two expansion cohorts in patients with breast cancer of a multi-modular Phase I clinical trial of samuraciclib as anti-cancer treatment.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-40061-y