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

R. C. Coombes, Sacha Howell, Simon R. Lord, Laura Kenny, Janine Mansi, Zahi Mitri, Carlo Palmieri, Linnea I. Chap, Paul Richards, William Gradishar, Sagar Sardesai, Jason Melear, Joyce O’Shaughnessy, Patrick Ward, Pavani Chalasani, Tobias Arkenau, Richard D. Baird, Rinath Jeselsohn, Simak Ali, Glen Clack, Ashwani Bahl, Stuart McIntosh and Matthew G. Krebs ()
Additional contact information
R. C. Coombes: South Kensington
Sacha Howell: The University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Science Centre
Simon R. Lord: University of Oxford
Laura Kenny: South Kensington
Janine Mansi: Guy’s and St Thomas’ NHS Foundation Trust
Zahi Mitri: OHSU Knight Cancer Institute
Carlo Palmieri: University of Liverpool
Linnea I. Chap: University of California
Paul Richards: Blue Ridge Cancer Center
William Gradishar: Northwestern University
Sagar Sardesai: US Oncology Research, OHC
Jason Melear: Baylor University Medical Center, Texas Oncology
Joyce O’Shaughnessy: Baylor University Medical Center, Texas Oncology
Patrick Ward: US Oncology Research, OHC
Pavani Chalasani: University of Arizona Cancer Center
Tobias Arkenau: Sarah Cannon Research Institute
Richard D. Baird: Cancer Research UK Cambridge Centre
Rinath Jeselsohn: Dana-Farber Cancer Institute
Simak Ali: South Kensington
Glen Clack: Carrick Therapeutics
Ashwani Bahl: Carrick Therapeutics
Stuart McIntosh: Carrick Therapeutics
Matthew G. Krebs: The University of Manchester and The Christie NHS Foundation Trust, Manchester Academic Health Science Centre

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-40061-y

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