Model-informed approach for risk management of bleeding toxicities for bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1.
Clinical pharmacokinetics
Exposure–response relationship
Immune checkpoint inhibitor
Phase 1, 2, 3 trials
Solid tumors
Journal
Cancer chemotherapy and pharmacology
ISSN: 1432-0843
Titre abrégé: Cancer Chemother Pharmacol
Pays: Germany
ID NLM: 7806519
Informations de publication
Date de publication:
10 2022
10 2022
Historique:
received:
05
04
2022
accepted:
17
08
2022
pubmed:
7
9
2022
medline:
17
9
2022
entrez:
6
9
2022
Statut:
ppublish
Résumé
Bintrafusp alfa (BA) is a bifunctional fusion protein composed of the extracellular domain of the transforming growth factor-β (TGF-β) receptor II fused to a human immunoglobulin G1 antibody blocking programmed death ligand 1 (PD-L1). The recommended phase 2 dose (RP2D) was selected based on phase 1 efficacy, safety, and pharmacokinetic (PK)-pharmacodynamic data, assuming continuous inhibition of PD-L1 and TGF-β is required. Here, we describe a model-informed dose modification approach for risk management of BA-associated bleeding adverse events (AEs). The PK and AE data from studies NCT02517398, NCT02699515, NCT03840915, and NCT04246489 (n = 936) were used. Logistic regression analyses were conducted to evaluate potential relationships between bleeding AEs and BA time-averaged concentration (C The probability of bleeding AEs increased with increasing C A pragmatic model-informed approach for management of bleeding AEs was implemented in ongoing clinical trials of BA. This approach is expected to improve benefit-risk profile; however, its effectiveness will need to be evaluated based on safety data generated after implementation.
Identifiants
pubmed: 36066618
doi: 10.1007/s00280-022-04468-6
pii: 10.1007/s00280-022-04468-6
pmc: PMC9474582
doi:
Substances chimiques
B7-H1 Antigen
0
Immunologic Factors
0
Transforming Growth Factor beta
0
Banques de données
ClinicalTrials.gov
['NCT02517398', 'NCT02699515', 'NCT03840915', 'NCT04246489', 'NCT02517398']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
369-379Informations de copyright
© 2022. The Author(s).
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