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.
| Original language | English (US) |
|---|---|
| Article number | 4444 |
| Journal | Nature communications |
| Volume | 14 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 2023 |
Funding
The authors would like to acknowledge the input from the following people: Ed Ainscow, Anthony Barrett, Paul Dickinson, Iain Macpherson, Kristine Pemberton and Manfred Lehnert. The study was designed and funded by Carrick Therapeutics. Carrick Therapeutics also provided funding to third party Contract Research Organisations for data collection and processing. Debbie Jordan Ltd provided medical writing services for this manuscript, with the cost of these services paid by Carrick Therapeutics. R.C.C. and S.A. would like to acknowledge Cancer Research UK for funding (C37/A18784). M.G.K. and S.H. acknowledge support from National Institute for Health Research (NIHR) Manchester Biomedical Research Centre, NIHR Manchester Clinical Research Facility at The Christie and Manchester Experimental Cancer Medicine Centre (Manchester, UK). S.R.L. acknowledges support from The Oxford Experimental Cancer Medicine Centre and National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. L.K. acknowledges infrastructure support from the Imperial Experimental Cancer Medicine Centre, Cancer Research UK Imperial Centre, National Institute for Health Research (NIHR), Imperial Biomedical Research Centre (BRC), Imperial College Healthcare NHS Trust Tissue Bank, and the NIHR Imperial Clinical Research Facility. C.P. acknowledges support from The Liverpool Experimental Cancer Medicine Centre [Grant Reference: C18616/A25153], Cancer Research UK. R.B. acknowledges support from the Cancer Research UK Cambridge Centre, Cambridge Experimental Cancer Medicine Centre and NIHR Cambridge Biomedical Research Centre including Cambridge Clinical Research Centre (grant #BRC-1215-20014). The views expressed in this paper are those of the authors and not necessarily those of the supporting bodies listed above.
ASJC Scopus subject areas
- General Chemistry
- General Biochemistry, Genetics and Molecular Biology
- General Physics and Astronomy
