Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
24 07 2023
24 07 2023
Historique:
received:
27
09
2022
accepted:
11
07
2023
medline:
26
7
2023
pubmed:
25
7
2023
entrez:
24
7
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37488191
doi: 10.1038/s41467-023-40061-y
pii: 10.1038/s41467-023-40061-y
pmc: PMC10366102
doi:
Substances chimiques
Fulvestrant
22X328QOC4
Cyclin-Dependent Kinase Inhibitor Proteins
0
Cyclin-Dependent Kinases
EC 2.7.11.22
Enzyme Inhibitors
0
Banques de données
ClinicalTrials.gov
['NCT03363893']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4444Subventions
Organisme : Cancer Research UK
ID : C37/A18784
Pays : United Kingdom
Organisme : Department of Health
ID : BRC-1215-20014
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C18616/A25153
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2023. The Author(s).
Références
Malumbres, M. Cyclin-dependent kinases. Genome Biol. 15, 122 (2014).
doi: 10.1186/gb4184
pubmed: 25180339
pmcid: 4097832
Fisher, R. P. The CDK Network: linking cycles of cell division and gene expression. Genes Cancer. 3, 731–738 (2012).
doi: 10.1177/1947601912473308
pubmed: 23634260
pmcid: 3636752
Chymkowitch, P., Le May, N., Charneau, P., Compe, E. & Egly, J. M. The phosphorylation of the androgen receptor by TFIIH directs the ubiquitin/proteasome process. EMBO J. 30, 468–479 (2011).
doi: 10.1038/emboj.2010.337
pubmed: 21157430
Chen, D. et al. Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7. Mol Cell. 6, 127–137 (2000).
doi: 10.1016/S1097-2765(05)00004-3
pubmed: 10949034
Li, B. et al. Therapeutic rationale to target highly expressed CDK7 conferring poor outcomes in triple-negative breast cancer. Cancer Res. 77, 3834–3845 (2017).
doi: 10.1158/0008-5472.CAN-16-2546
pubmed: 28455421
Sava, G. P., Fan, H., Coombes, R. C., Buluwela, L. & Ali, S. CDK7 inhibitors as anticancer drugs. Cancer Metastasis Rev. 39, 805–823 (2020).
doi: 10.1007/s10555-020-09885-8
pubmed: 32385714
pmcid: 7497306
Wang, M., Wang, T., Zhang, X., Wu, X. & Jiang, S. Cyclin-dependent kinase 7 inhibitors in cancer therapy. Future Med. Chem. 12, 813–833 (2020).
doi: 10.4155/fmc-2019-0334
pubmed: 32208930
Patel, H. et al. ICEC0942, an orally bioavailable selective inhibitor of CDK7 for cancer treatment. Mol. Cancer Ther. 17, 1156–1166 (2018).
doi: 10.1158/1535-7163.MCT-16-0847
pubmed: 29545334
pmcid: 5985928
Guarducci, C. et al. Inhibition of CDK7 overcomes resistance to CDK4/6 inhibitors in hormone receptor positive breast cancer cells. Cancer Res. 79, PD7-12 (2019).
Ali, S. et al. The development of a selective cyclin-dependent kinase inhibitor that shows antitumor activity. Cancer Res. 69, 6208–6215 (2009).
doi: 10.1158/0008-5472.CAN-09-0301
pubmed: 19638587
pmcid: 2875168
Wang, Y. et al. Elevation of effective p53 expression sensitizes wild-type p53 breast cancer cells to CDK7 inhibitor THZ1. Cell Commun. Signal. 20, 96 (2022).
doi: 10.1186/s12964-022-00837-z
pubmed: 36058938
pmcid: 9442925
Tang, L. et al. SOX9 interacts with FOXC1 to activate MYC and regulate CDK7 inhibitor sensitivity in triple-negative breast cancer. Oncogenesis. 9, 47 (2020).
doi: 10.1038/s41389-020-0232-1
pubmed: 32398735
pmcid: 7217837
Webb, B. M. et al. TGF-β/activin signaling promotes CDK7 inhibitor resistance in triple-negative breast cancer cells through upregulation of multidrug transporters. J. Biol. Chem. 297, 101162 (2021).
doi: 10.1016/j.jbc.2021.101162
pubmed: 34481843
pmcid: 8498470
Bahl, AK et al. Activity of CT7001 an orally bio-available cyclin-dependent kinase 7 selective inhibitor in models of triple negative breast cancer. Cancer Res. 78. https://doi.org/10.1158/1538-7445.SABCS17-P1-09-04 (2018).
Lindeman, G. J. et al. Results from VERONICA: A randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC). J. Clin. Oncol. 39, 15 (2021).
doi: 10.1200/JCO.2021.39.15_suppl.1004
Papadopoulos, K. P. et al. First-in-human phase I study of SY-5609, an oral, potent, and selective noncovalent CDK7 inhibitor, in adult patients with select advanced solid tumors. J. Clin. Oncol. 38, TPS3662-TPS3662 (2020).
Datta, N. S. & Long, M. W. Modulation of MDM2/p53 and cyclin-activating kinase during the megakaryocyte differentiation of human erythroleukemia cells. Exp. Hematol. 30, 158–165 (2002).
doi: 10.1016/S0301-472X(01)00780-9
pubmed: 11823051
Rasool, R. U. et al. CDK7 inhibition suppresses castration-resistant prostate cancer through MED1 inactivation. Cancer Discov. 9, 1538–1555 (2019).
doi: 10.1158/2159-8290.CD-19-0189
pubmed: 31466944
Wang, J. et al. CDK7 inhibitor THZ1 enhances antiPD-1 therapy efficacy via the p38α/MYC/PD-L1 signaling in non-small cell lung cancer. J. Hematol. Oncol. 13, 99 (2020).
doi: 10.1186/s13045-020-00926-x
pubmed: 32690037
pmcid: 7370470
Kwiatkowski, N. et al. Targeting transcription regulation in cancer with a covalent CDK7 inhibitor. Nature. 511, 616–620 (2014).
doi: 10.1038/nature13393
pubmed: 25043025
pmcid: 4244910
Chipumuro, E. et al. CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer. Cell. 159, 1126–1139 (2014).
doi: 10.1016/j.cell.2014.10.024
pubmed: 25416950
pmcid: 4243043
Christensen, C. L. et al. Targeting transcriptional addictions in small cell lung cancer with a covalent CDK7 inhibitor. Cancer Cell. 26, 909–922 (2014).
doi: 10.1016/j.ccell.2014.10.019
pubmed: 25490451
pmcid: 4261156
Liu, H., Liu, K. & Dong, Z. Targeting CDK12 for cancer therapy: function, mechanism, and drug discovery. Cancer Res. 81, 18–26 (2021).
doi: 10.1158/0008-5472.CAN-20-2245
pubmed: 32958547
O’Leary, B. et al. Circulating tumor DNA markers for early progression on fulvestrant with or without palbociclib in ER+ advanced breast cancer. J. Natl. Cancer Inst. 113, 309–317 (2021).
doi: 10.1093/jnci/djaa087
pubmed: 32940689
Bardia, A. et al. Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial. SABCS Abstract GS3-02. Cancer Res. 82, GS2-02 (2022).
Cook, M. M. et al. Everolimus plus exemestane treatment in patients with metastatic hormone receptor-positive breast cancer previously treated with CDK4/6 inhibitor therapy. Oncologist. 26, 101–106 (2021).
doi: 10.1002/onco.13609
pubmed: 33230905
Rugo, H. S. et al. Alpelisib plus fulvestrant in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor (BYLieve): one cohort of a phase 2, multicentre, open-label, non-comparative study. Lancet Oncol. 22, 489–498 (2021).
doi: 10.1016/S1470-2045(21)00034-6
pubmed: 33794206
Juric, D. et al. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial. Cancer Res. 79, GS3–GS08 (2019).
doi: 10.1158/1538-7445.SABCS18-GS3-08
CEDR Faslodex Approval, 09 September 2010. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/021344Orig1s012.pdf .
Cristofanilli, M. et al. Overall survival (OS) with palbociclib (PAL) + fulvestrant (FUL) in women with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced breast cancer (ABC): Updated analyses from PALOMA-3. J. Clin. Oncol. 39, 15 (2021).
doi: 10.1200/JCO.2021.39.15_suppl.1000
Robertson, J. F. R. et al. Meta-analyses of visceral versus non-visceral metastatic hormone receptor-positive breast cancer treated by endocrine monotherapies. NPJ Breast Cancer 7, 11 (2021).
doi: 10.1038/s41523-021-00222-y
pubmed: 33579962
pmcid: 7881093
Eisenhauer, E. A. et al. New response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). Eur. J. Cancer. 45, 228–247 (2009).
doi: 10.1016/j.ejca.2008.10.026
pubmed: 19097774
Rothwell, D. G. et al. Utility of ctDNA to support patient selection for early phase clinical trials: the TARGET study. Nat. Med. 25, 738–743 (2019).
doi: 10.1038/s41591-019-0380-z
pubmed: 31011204