TY - JOUR
T1 - Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181)
AU - Powderly, John
AU - Spira, Alexander
AU - Kondo, Shunsuke
AU - Doi, Toshihiko
AU - Luke, Jason J.
AU - Rasco, Drew
AU - Gao, Bo
AU - Tanner, Minna
AU - Cassier, Philippe A.
AU - Gazzah, Anas
AU - Italiano, Antoine
AU - Tosi, Diego
AU - Afar, Daniel E.
AU - Parikh, Apurvasena
AU - Engelhardt, Benjamin
AU - Englert, Stefan
AU - Lambert, Stacie L.
AU - Kasichayanula, Sreeneeranj
AU - Mensing, Sven
AU - Menon, Rajeev
AU - Vosganian, Gregory
AU - Tolcher, Anthony
N1 - Funding Information:
This study was funded by AbbVie. AbbVie contributed to the study design, research, and interpretation of the data and the writing, review, and approval of the manuscript. AbbVie and the authors thank James Sheridan and Merriam McClellan from AbbVie Redwood City for development and providing in vitro evaluations of the PD-1 receptor saturation assay, Betty Wang for biomarker operations assistance, Kinjal Hew and Mary Saltarelli for assistance in biomarker data transfer, Yan Song and Chun Zhang for assistance in biomarker data reformatting, Nils Boehm for bioanalytical support, Markus Jaeger for CPPM programming support, and Bryan Horrigan for support with data analysis. Medical writing support was provided by Wesley Wayman, an employee of AbbVie.
Publisher Copyright:
© 2020 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics.
PY - 2021/1
Y1 - 2021/1
N2 - 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.
AB - 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.
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U2 - 10.1111/cts.12855
DO - 10.1111/cts.12855
M3 - Article
C2 - 32770720
AN - SCOPUS:85098063620
SN - 1752-8054
VL - 14
SP - 277
EP - 287
JO - Clinical and translational science
JF - Clinical and translational science
IS - 1
ER -