Model Informed Dosing Regimen and Phase I Results of the Anti‐PD‐1 Antibody Budigalimab (ABBV‐181)

Autor: Antoine Italiano, Minna Tanner, Gregory Vosganian, Philippe A. Cassier, Stacie Lambert, Rajeev M. Menon, Sven Mensing, Benjamin Engelhardt, Apurvasena Parikh, Drew W. Rasco, Stefan Englert, Anthony W. Tolcher, Bo Gao, Shunsuke Kondo, Sreeneeranj Kasichayanula, John D. Powderly, Daniel E. H. Afar, Anas Gazzah, Alexander I. Spira, Toshihiko Doi, Jason J. Luke, Diego Tosi
Rok vydání: 2020
Předmět:
Adult
Male
Oncology
030213 general clinical medicine
medicine.medical_specialty
Programmed Cell Death 1 Receptor
Antibodies
Monoclonal
Humanized
Models
Biological
030226 pharmacology & pharmacy
Drug Administration Schedule
Article
General Biochemistry
Genetics and Molecular Biology
03 medical and health sciences
0302 clinical medicine
Pharmacokinetics
Neoplasms
Internal medicine
medicine
Humans
Dosing
General Pharmacology
Toxicology and Pharmaceutics
Adverse effect
Immune Checkpoint Inhibitors
Response Evaluation Criteria in Solid Tumors
Aged
Aged
80 and over
Dose-Response Relationship
Drug
business.industry
Research
lcsh:Public aspects of medicine
General Neuroscience
lcsh:RM1-950
lcsh:RA1-1270
Articles
General Medicine
Middle Aged
Recombinant Proteins
Clinical trial
Regimen
lcsh:Therapeutics. Pharmacology
Pharmacodynamics
Cohort
Administration
Intravenous
Female
business
Zdroj: Clinical and Translational Science, Vol 14, Iss 1, Pp 277-287 (2021)
Clinical and Translational Science
ISSN: 1752-8062
1752-8054
DOI: 10.1111/cts.12855
Popis: Budigalimab is a humanized, recombinant, Fc mutated IgG1 monoclonal antibody targeting programmed cell death 1 (PD‐1) receptor, currently in phase I clinical trials. The safety, efficacy, pharmacokinetics (PKs), pharmacodynamics (PDs), and budigalimab dose selection from monotherapy dose escalation and multihistology expansion cohorts were evaluated in patients with previously treated advanced solid tumors who received budigalimab at 1, 3, or 10 mg/kg intravenously every 2 weeks (Q2W) in dose escalation, including Japanese patients that received 3 and 10 mg/kg Q2W. PK modeling and PK/PD assessments informed the dosing regimen in expansion phase using data from body‐weight‐based dosing in the escalation phase, based on which patients in the multihistology expansion cohort received flat doses of 250 mg Q2W or 500 mg every four weeks (Q4W). Immune‐related adverse events (AEs) were reported in 11 of 59 patients (18.6%), of which 1 of 59 (1.7%) was considered grade ≥ 3 and the safety profile of budigalimab was consistent with other PD‐1 targeting agents. No treatment‐related grade 5 AEs were reported. Four responses per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 were reported in the dose escalation cohort and none in the multihistology expansion cohort. PK of budigalimab was approximately dose proportional and sustained > 99% peripheral PD‐1 receptor saturation was observed by 2 hours postdosing, across doses. PK/PD and safety profiles were comparable between Japanese and Western patients, and exposure‐safety analyses did not indicate any trends. Observed PK and PD‐1 receptor saturation were consistent with model predictions for flat doses and less frequent regimens, validating the early application of PK modeling and PK/PD assessments to inform the recommended dose and regimen, following dose escalation.
Databáze: OpenAIRE
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