Journal Article

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

McIntosh, Stuart, Bahl, Ashwani, Jeselsohn, Rinath, Gradishar, William, Kenny, Laura, Chap, Linnea I., Mitri, Zahi, Richards, Paul, Lord, Simon R., Ward, Patrick, Baird, Richard D., Krebs, Matthew G., Clack, Glen, Arkenau, Tobias, Melear, Jason, Mansi, Janine, Palmieri, Carlo, Howell, Sacha, Chalasani, Pavani, Sardesai, Sagar, O’Shaughnessy, Joyce, Coombes, R. C., Ali, Simak

2023

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 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