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Clinical Trial
. 2023 Jul 24;14(1):4444.
doi: 10.1038/s41467-023-40061-y.

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

R C Coombes  1 , Sacha Howell  2 , Simon R Lord  3 , Laura Kenny  1 , Janine Mansi  4 , Zahi Mitri  5 , Carlo Palmieri  6 , Linnea I Chap  7 , Paul Richards  8 , William Gradishar  9 , Sagar Sardesai  10 , Jason Melear  11 , Joyce O'Shaughnessy  11 , Patrick Ward  10 , Pavani Chalasani  12 , Tobias Arkenau  13 , Richard D Baird  14 , Rinath Jeselsohn  15 , Simak Ali  1 , Glen Clack  16 , Ashwani Bahl  16 , Stuart McIntosh  16 , Matthew G Krebs  17
Affiliations
Clinical Trial

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

R C Coombes et al. Nat Commun. .

Erratum in

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.

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Conflict of interest statement

R.C.C. has had a travel grant from Carrick Therapeutics and owns a patent on samuraciclib (patent number WO/2015/124941); he also has a grant from AstraZeneca. S.H. has received speaker fees Pfizer and advisory board and grant funding from Lilly. S.R.L. has received consulting fees from Sanofi, GLG consulting, Atheneum and Rejuversen. He has also received payment or honoraria for lectures, presentations, or educational events from Eisai, Prosigna, Roche, Pfizer, Novartis, Shionogi and Sanofi, and was previously employed by Pfizer. He has received travel, accommodation or expenses from Pfizer, Roche, Synthon and Piqur Therapeutics, and research funding from CRUK, Against Breast Cancer, Pathios Therapeutics and is cofounder of Mitox Therapeutics. His institution has received funding for clinical trials for which he was chief/principal investigator from CRUK, Boehringer Ingelheim, Piqur Therapeutics, Astra Zeneca, Carrick Therapeutics, Sanofi, Merck KGaA, Synthon, Roche and Prostate Cancer UK. J.O. has received honoraria for consulting and/or advisory boards from the following: AbbVie Inc., Agendia, Amgen Biotechnology, Aptitude Health, AstraZeneca, Bayer, Bristol-Myers Squibb, Carrick Therapeutics, Celgene Corporation, Clovis Oncology, Daiichi Sankyo, Eisai, G1 Therapeutics, Genentech, Gilead Sciences, GRAIL, Halozyme Therapeutics, Heron Therapeutics, Immunomedics, Ipsen Biopharmaceuticals, Lilly, Merck, Myriad, Nektar Therapeutics, Novartis, Ontada, Pfizer, Pharmacyclics, Pierre Fabre Pharmaceuticals, Puma Biotechnology, Prime Oncology, Roche, Samsung Bioepis, Sanofi, Seagen, Syndax Pharmaceuticals, Taiho Oncology, Takeda, and Synthon. ZM has a consulting/advisory role with AstraZeneca, Gilead Sciences and Daiichi Sankyo. He has also received research funding for his institution from Seattle Genetics, Novartis, AstraZeneca, Radius Health, Daiichi Sankyo, Lilly, GlaxoSmithKline, and Olema Oncology. CP acknowledges support from The Liverpool Experimental Cancer Medicine Centre [Grant Reference:C18616/A25153], The Clatterbridge Cancer Charity, North West Cancer and Make 2nds Count. CP reports grant funding support from Pfizer, Daiichi Sankyo, Exact Sciences, Gilead and Seagen. Honoraria for advisory boards have been received from Pfizer, Roche, Daiichi Sankyo, Novartis, Exact sciences, Gilead, SeaGen and Eli Lilly and support for travel and conferences from Roche, Novartis and Gilead. T.A. is employed by Sarah Cannon/HCA Healthcare UK and Ellipses Pharma and receives funding in an advisory capacity from iOnctura, Labgenius, and Servier. R.D.B. has a consulting/advisory role with Shionogi, Daiichi Sankyo, Molecular Partners, Roche/Genentech, Novartis, and AstraZeneca. He has also received research funding for his institution from AstraZeneca, Genentech, Shionogi, Molecular Partners, Sanofi, Boehringer Ingelheim, Roche, Biomarin, GI Therapeutics, and Carrick Therapeutics, and travel/accommodation/expenses from Shionogi, AstraZeneca, Molecular Partners, and Daiichi Sankyo. R.J. has received research funding from Pfizer and Lilly, and she serves on an advisory board for Carrick Therapeutics and Luminex. S.A. is a named inventor on patents describing CDK inhibitors, including samuraciclib, owns shares in Carrick Therapeutics and has been funded by Carrick Therapeutics; he also has grants from AstraZeneca. G.C., A.B., and S.M. are Carrick employees and shareholders. M.K. has received honoraria from Janssen, Roche; consulting/advisory fees from Achilles Therapeutics, Bayer, Guardant Health, Janssen, OM Pharma, Roche, Seattle Genetics; speakers fees from AstraZeneca, Janssen, Roche and research funding from Roche and Novartis for his institution. He has received travel, accommodation or expenses from AstraZeneca, BerGenBio, Immutep, Janssen and Roche. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Best RECIST response and time on study in Module 1A.
A Best response. Each bar represents the best percentage change from baseline for an individual patient and labels indicate the best objective response for the same patient. N = 30 (Note: only participants with measurable lesions at both baseline and post-baseline are included in this figure). BID = twice daily; OD = once daily; PD = progressive disease; PR=partial response; SD = stable disease. B Time on study. Each bar is annotated with the location of the primary malignancy for each participant.Only patients with measurable lesions at both baseline and post-baseline are included in the figure. N = 36. BID twice daily, CR complete response, OD once daily, PD progressive disease, PR partial response, SD stable disease.
Fig. 2
Fig. 2. Best RECIST response and time on study in Module 1B-1.
A Best response. Each bar represents the best percentage change from baseline for an individual patient. N = 19 (Note: only participants with at least one post-baseline value are included in this figure). * Lesion size increase from 12 to 15 mm was below the threshold for classification as progressive disease (minimum increase of 5 mm). B Time on study. Time on study for each patient (prior lines of chemotherapy for each patient indicated). N = 20.
Fig. 3
Fig. 3. Best RECIST response and time on study in Module 2A.
A Best response. Each bar represents the best percentage change from baseline for an individual patient. N = 25 (Note: only participants with at least one post-baseline value are included in this figure). B Time on study. Time on study for each patient (presence of liver metastases and mutation status for each patient also indicated). N = 25. CBR24 clinical benefit rate at 24 weeks, mt mutation detected.
Fig. 4
Fig. 4. Evidence of target engagement.
Reductions in CDK1/2/3 and pPolII levels in paired tumor biopsy samples demonstrates target engagement and proof of mechanism. Images are representative of two technical replicates from paired biopsies from a single patient. See Supplementary Table 11 for quantification and additional data from a further 5 patient paired biopsies. CDK cyclin-dependent kinase, OD once daily, pCDK phosphorylated cyclin-dependent kinase, pPolII phosphorylated RNA polymerase II.
See this image and copyright information in PMC

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