A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial.
Biomarkers
Everolimus
PKPD modeling and simulation
Sorafenib
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
05 2023
05 2023
Historique:
received:
01
04
2022
accepted:
08
03
2023
medline:
5
5
2023
pubmed:
4
4
2023
entrez:
3
4
2023
Statut:
ppublish
Résumé
The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. Everolimus (5-10 mg once daily, qd) and sorafenib (200-400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6-14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7-4.2, n = 43). Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit. ClinicalTrials.gov Identifier: NCT01932177.
Identifiants
pubmed: 37010549
doi: 10.1007/s00280-023-04520-z
pii: 10.1007/s00280-023-04520-z
doi:
Substances chimiques
Sorafenib
9ZOQ3TZI87
Everolimus
9HW64Q8G6G
Vascular Endothelial Growth Factor A
0
Niacinamide
25X51I8RD4
Phenylurea Compounds
0
Biomarkers
0
Banques de données
ClinicalTrials.gov
['NCT01932177']
Types de publication
Clinical Trial, Phase I
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
413-425Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.
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