Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib
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Authors
Charles Coombes, R.Howell, Sacha J
Lord, S. R.
Kenny, L.
Mansi, J.
Mitri, Z.
Palmieri, C.
Chap, L. I.
Richards, P.
Gradishar, W.
Sardesai, S.
Melear, J.
O'Shaughnessy, J.
Ward, P.
Chalasani, P.
Arkenau, T.
Baird, R. D.
Jeselsohn, R.
Ali, S.
Clack, G.
Bahl, A.
McIntosh, S.
Krebs, Matthew G
Affiliation
Imperial College, South Kensington, London, UKIssue Date
2023
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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.Citation
Charles Coombes R, Howell S, Lord SR, Kenny L, Mansi J, Mitri Z, et al. Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib. Nature communications. 2023 Jul 24;14(1):4444. PubMed PMID: 37488191. Epub 2023/07/25. eng.Journal
Nature CommunicationsDOI
10.1038/s41467-023-40061-yPubMed ID
37488191Additional Links
https://dx.doi.org/10.1038/s41467-023-40061-yType
ArticleLanguage
enae974a485f413a2113503eed53cd6c53
10.1038/s41467-023-40061-y
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