A Phase I Study of sequences of the CDK4/6 Inhibitor, Ribociclib Combined with Gemcitabine in Patients with Advanced Solid Tumors.
Journal
Research square
Titre abrégé: Res Sq
Pays: United States
ID NLM: 101768035
Informations de publication
Date de publication:
25 Apr 2024
25 Apr 2024
Historique:
pubmed:
15
5
2024
medline:
15
5
2024
entrez:
15
5
2024
Statut:
epublish
Résumé
Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT). In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks. The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease. The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination. NCT03237390.
Sections du résumé
Background
UNASSIGNED
Based on preclinical data showing addition of CDK4/6 inhibitors to gemcitabine is synergistic, ribociclib was evaluated in combination with gemcitabine to determine the maximum tolerated dose (MTD) and dose limiting toxicities (DLT).
Methods
UNASSIGNED
In this single arm multicohort phase I trial, we evaluated the safety and efficacy of Ribociclib plus Gemcitabine in patients with advanced solid tumors. Patients received Gemcitabine intravenously on days 1 and 8 followed by Ribociclib days 8-14, with treatment repeated every 3 weeks.
Results
UNASSIGNED
The study enrolled 43 patients between October 2017 and September 2019. The escalation phase (19 patients) determined the MTD and recommended phase II dose (RP2D) to be ribociclib 800mg daily and gemcitabine 1000mg/m2 for the expansion phase (24 patients). One patient experienced Grade 4 thrombocytopenia. Eleven patients experienced Grade 3 adverse events (AE), the most common being neutropenia, thrombocytopenia, and anemia. No partial or complete responses were observed. 15/22 (68%) of efficacy evaluable patients who received the MTD achieved best response of stable disease.
Conclusions
UNASSIGNED
The addition of Ribociclib to Gemcitabine was tolerated well and yielded stability of tumors in both cohorts. Ribociclib and gemcitabine could have synergistic activity in certain tumor types, and our data provides support for the combination.
Clinical Trial Registration
UNASSIGNED
NCT03237390.
Identifiants
pubmed: 38746220
doi: 10.21203/rs.3.rs-4261257/v1
pmc: PMC11092794
pii:
doi:
Banques de données
ClinicalTrials.gov
['NCT03237390']
Types de publication
Preprint
Langues
eng
Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM008685
Pays : United States
Déclaration de conflit d'intérêts
Competing interests: The authors declare no conflict of interest.
Références
Oncotarget. 2018 Oct 16;9(81):35226-35240
pubmed: 30443290
Oncogene. 2020 Feb;39(9):1831-1845
pubmed: 31745297
N Engl J Med. 2016 Nov 3;375(18):1738-1748
pubmed: 27717303
Breast. 2016 Aug;28:191-8
pubmed: 27336726
Clin Cancer Res. 2018 Dec 1;24(23):6028-6039
pubmed: 30131386
Ann Oncol. 2019 Oct 1;30(10):1613-1621
pubmed: 31504118
Lancet Oncol. 2019 Nov;20(11):1587-1601
pubmed: 31575503
Cancer Sci. 2018 Jan;109(1):193-198
pubmed: 29059492
Clin Cancer Res. 2016 Dec 1;22(23):5696-5705
pubmed: 27542767
JCO Precis Oncol. 2020 Nov;4:498-504
pubmed: 35050742
Clin Cancer Res. 2020 Feb 1;26(3):566-580
pubmed: 31615937
Cell Cycle. 2011 Aug 1;10(15):2497-503
pubmed: 21775818
Oncogene. 2019 May;38(21):4125-4141
pubmed: 30700828
J Clin Oncol. 2018 Aug 20;36(24):2465-2472
pubmed: 29860922
Cancer Res. 2006 Nov 1;66(21):10258-63
pubmed: 17079443
Cancer Discov. 2016 Apr;6(4):353-67
pubmed: 26658964
Lancet Oncol. 2018 Jul;19(7):904-915
pubmed: 29804902
N Engl J Med. 2019 Jul 25;381(4):307-316
pubmed: 31166679
Mol Cancer Ther. 2020 Aug;19(8):1575-1588
pubmed: 32546660
Cell. 1995 May 5;81(3):323-30
pubmed: 7736585
Clin Cancer Res. 2017 May 15;23(10):2433-2441
pubmed: 28432176
Sci Rep. 2019 Sep 10;9(1):13014
pubmed: 31506466
Clin Cancer Res. 2019 Apr 1;25(7):2072-2079
pubmed: 30635336
Ther Adv Med Oncol. 2018 Jul 17;10:1758835918786451
pubmed: 30038670