PMID- 32770720 OWN - NLM STAT- MEDLINE DCOM- 20211025 LR - 20211025 IS - 1752-8062 (Electronic) IS - 1752-8054 (Print) IS - 1752-8054 (Linking) VI - 14 IP - 1 DP - 2021 Jan TI - Model Informed Dosing Regimen and Phase I Results of the Anti-PD-1 Antibody Budigalimab (ABBV-181). PG - 277-287 LID - 10.1111/cts.12855 [doi] 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. CI - (c) 2020 AbbVie Inc. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of the American Society for Clinical Pharmacology and Therapeutics. FAU - Powderly, John AU - Powderly J AD - Carolina BioOncology Institute, Huntersville, North Carolina, USA. FAU - Spira, Alexander AU - Spira A AD - Virginia Cancer Specialists, Fairfax, Virginia, USA. AD - Johns Hopkins School of Medicine, Baltimore, Maryland, USA. FAU - Kondo, Shunsuke AU - Kondo S AD - Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan. FAU - Doi, Toshihiko AU - Doi T AD - Department of Experimental Therapeutics, National Cancer Center Hospital East, Kashiwa, Japan. FAU - Luke, Jason J AU - Luke JJ AUID- ORCID: 0000-0002-1182-4908 AD - Division of Hematology/Oncology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA. FAU - Rasco, Drew AU - Rasco D AD - START Center for Cancer Care, San Antonio, Texas, USA. FAU - Gao, Bo AU - Gao B AD - Blacktown Cancer and Haematology Centre, Blacktown, Australia. FAU - Tanner, Minna AU - Tanner M AD - Department of Oncology, Tampere University Hospital, Tampere, Finland. FAU - Cassier, Philippe A AU - Cassier PA AD - Department of Medical Oncology, Centre Leon Berard, Lyon, France. FAU - Gazzah, Anas AU - Gazzah A AD - Drug Development Department, Gustave Roussy Universite Paris-Saclay, Villejuif, France. FAU - Italiano, Antoine AU - Italiano A AD - Department of Medical Oncology, Institut Bergonie, Bordeaux, France. FAU - Tosi, Diego AU - Tosi D AD - Department of Medical Oncology, Institut Regional du Cancer de Montpellier, Montpellier, France. FAU - Afar, Daniel E AU - Afar DE AD - Oncology Early Development, AbbVie, Inc., Redwood City, California, USA. FAU - Parikh, Apurvasena AU - Parikh A AD - Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Redwood City, California, USA. FAU - Engelhardt, Benjamin AU - Engelhardt B AD - Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany. FAU - Englert, Stefan AU - Englert S AD - Data and Statistical Sciences, AbbVie Deutschland GmbH & Co KG, Ludwigshafen, Germany. FAU - Lambert, Stacie L AU - Lambert SL AD - Oncology Early Development, AbbVie, Inc., Redwood City, California, USA. FAU - Kasichayanula, Sreeneeranj AU - Kasichayanula S AD - Clinical Pharmacology and Pharmacometrics, AbbVie, Inc., Redwood City, California, USA. FAU - Mensing, Sven AU - Mensing S AD - Clinical Pharmacology and Pharmacometrics, AbbVie Deutschland GmbH & Co. KG, Ludwigshafen am Rhein, Germany. FAU - Menon, Rajeev AU - Menon R AD - Clinical Pharmacology and Pharmacometrics, AbbVie Inc., North Chicago, Illinois, USA. FAU - Vosganian, Gregory AU - Vosganian G AD - Oncology Early Development, AbbVie, Inc., Redwood City, California, USA. FAU - Tolcher, Anthony AU - Tolcher A AD - Next Oncology, San Antonio, Texas, USA. LA - eng SI - ClinicalTrials.gov/NCT03000257 PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study PT - Research Support, Non-U.S. Gov't DEP - 20201226 PL - United States TA - Clin Transl Sci JT - Clinical and translational science JID - 101474067 RN - 0 (Antibodies, Monoclonal, Humanized) RN - 0 (Immune Checkpoint Inhibitors) RN - 0 (PDCD1 protein, human) RN - 0 (Programmed Cell Death 1 Receptor) RN - 0 (Recombinant Proteins) SB - IM MH - Administration, Intravenous MH - Adult MH - Aged MH - Aged, 80 and over MH - Antibodies, Monoclonal, Humanized/administration & dosage/adverse effects MH - Dose-Response Relationship, Drug MH - Drug Administration Schedule MH - Female MH - Humans MH - Immune Checkpoint Inhibitors/*administration & dosage/adverse effects/pharmacokinetics MH - Male MH - Middle Aged MH - *Models, Biological MH - Neoplasms/blood/*drug therapy/pathology MH - Programmed Cell Death 1 Receptor/*antagonists & inhibitors/metabolism MH - Recombinant Proteins/administration & dosage/adverse effects/pharmacokinetics MH - Response Evaluation Criteria in Solid Tumors PMC - PMC7877859 COIS- AbbVie provided financial support for the study and participated in the design, study conduct, analysis and interpretation of data, as well as the writing, review, and approval of the abstract. J.P.: Honoraria: BMS, Genentech, Merck; Financial Compensation: Carolina BioOncology Institute, PLLC, BioCytics Inc.; Stock: Iovance, BlueBird, Juno, Kite Pharma, BioCytics. Ownership: Carolina BioOncology Institute (principal owner). Research Funding: BMS, Genentech, EMD Serono, AstraZeneca, InCyte, Arcus, FLX BioSciences, Alkermes, Tempest, Curis, Corvus, AbbVie, and Sequenom. Institutional Funding Support: Nucleus. Non-Financial: BioCytics Inc. is developing immune cellular therapies and is collaborating with multiple biotech and biopharma companies, including Arcus, Nucleus, Terumo, and Miltenyi. Submitted investigator-initiated trial proposals for developing future cellular therapies with BMS, EMD Serono, Genentech, and AstraZeneca. Other: Developing intellectual property for autologous immune cellular therapies, and actively discussing potential collaboration projects with multiple biotech and biopharma companies. A.S.: Research Funding AbbVie, Consulting Amgen, AstraZeneca/Medimmune, Novartis. S.K.: Research funding, Pfizer (Inst), Merck Serono (Inst), AstraZeneca (Inst), Bayer (Inst), and Eli Lilly (Inst). T.D.: Consulting or Advisory Role: MSD, Daiichi Sankyo, Amgen, Sumitomo Dainippon, Taiho Pharmaceutical, Takeda, AbbVie, Novartis, Bayer, Boehringer Ingelheim, and Rakuten Medical. Research Funding: Taiho Pharmaceutical (Inst), Novartis (Inst), Merck Serono (Inst), MSD (Inst), Boehringer Ingelheim (Inst), Pfizer (Inst), Eli Lilly (Inst), Sumitomo Group (Inst), Kyowa Hakko Kirin (Inst), Daiichi Sankyo (Inst), Bristol-Myers Squibb (Inst), AbbVie (Inst), Quintiles (Inst), and Eisai (Inst). Honoraria: BMS, Ono Pharmaceutical, AbbVie, Astellas Pharma, Oncolys BioPharma, and Taiho Pharmaceutical. J.J.L.: Data and Safety Monitoring Board: TTC Oncology; Scientific Advisory Board: 7 Hills, Actym, Alphamab Oncology, Mavu (now part of AbbVie), Pyxis, Springbank, and Tempest. Consultancy: AbbVie, Akrevia, Algios, Array, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Compugen, Eisai, EMD Serono, Ideaya, Immunocore, Incyte, Janssen, Leap, Merck, Mersana, Novartis, RefleXion, Silicon, Tesaro, and Vividion. Research Support: (all to institution for clinical trials unless noted) AbbVie, Agios (IIT), Array (IIT), Astellas, Boston Biomedical, Bristol-Myers Squibb, CheckMate (SRA), Compugen, Corvus, EMD Serono, Evelo (SRA), Five Prime, FLX Bio, Genentech, Immatics, Immunocore, Incyte, Leap, MedImmune, Macrogenics, Necktar, Novartis, Palleon (SRA), Merck, Springbank, Tesaro, Tizona, and Xencor. Travel: Akrevia, AstraZeneca, Bayer, Bristol-Myers Squibb, EMD Serono, Immunocore, Incyte, Janssen, Merck, Mersana, Novartis, and RefleXion. Patents: (both provisional) Serial #15/612,657 (Cancer Immunotherapy), PCT/US18/36052 (Microbiome Biomarkers for Anti-PD-1/PD-L1 Responsiveness: Diagnostic, Prognostic and Therapeutic Uses Thereof). D.R.: Research funding from AbbVie. B.G.: Advisory Board MSD. M.T.: Consulting or Advisory role: Roche Finland, Pfizer, Novartis, Lilly, and AstraZeneca. Data and Safety Monitoring Board: Orion Corporation Orion Pharma. Honoraria: Novartis, Roche Finland, AstraZeneca, Teva, Novartis, Pfizer, Lilly, and MSD. Research support (institution) from Novartis, Roche, Genentech, MacroGenics, and AbbVie. P.A.C.: Received honorarium from Amgen, AstraZeneca, Blueprint Medicines, Novartis, Roche/Genentech, and Merck KGaA/Serono. Research support (institution) from Amgen, AstraZeneca, AbbVie, Blueprint Medicines, BMS, Celgene, GSK, Janssen, Lilly, MSD, Merck Serono, Novartis, and Roche/Genentech. A.G.: no conflicts of interest to declare. A.I.: Research grant: BMS, MSD, Bayer, Roche, PharmaMar, and AstraZeneca. Advisory board: Bayer, Roche, Epizyme, Springworks, and IPSEN. D.T.: Consultant: BioMarin, and Actelion. Preclinical research support (to institution): Astellas, Janssen, and Ipsen. Patent: "Association of actives for treating prostate cancer," #EP17306576.4 (pending). Travel, Accommodations, Expenses: Nutricia, Amicus Therapeutics, BioMarin, Astellas Pharma, MSD, and AstraZeneca. D.E.A., A.P., B.E., S.E., S.L.L., S.K., S.M., R.M., and G.V. are AbbVie employees and may own stock. A.T.: Consultant AbbVie, Adagene, Agenus, Aro Biotherapeutics, Ascentage, Aximmune, Bayer, Boston Bio, Cello Health, EMD Serono, Elucida Oncology, Forbius (formerly Formation Biologics), Genentech/Roche IDMC, Gilde Healthcare Partners, HBM, Immunomet, Ignyta, Mekanistic Therapeutics, Menarini Researche, Mirati IDMC, Nanobiotix, Nuvalent, Inc., OSI Pharmaceuticals, Partner Therapeutics, Pfizer, Pieris Pharmaceuticals, Pierre Fabre, Seattle Genetics, and Symphogen. Advisory Board ADC Therapeutics, Abgenomics, Aro Biotherapeutics, BioInvent International, Immunome, Jazz, Mirati, Sesen (formerly Eleven Bio), NBE Therapeutics, Pelican, PSI Pharma Support America, Inc. (Innate Pharma), TFS Trial Form Support International, and Zymeworks. Research Support: (all to institution for clinical trials) AbbVie, ADC Therapeutics, Adagene, Aminex, Ascentage, Asana, Birdie, CStone, Arrys, Deciphera GlaxoSmithKline, Inhibrx, Innate, Kiromic, Mersana, NatureWise, NextCure, Nitto BioPharma, Pfizer, Pieris, Syndax, Symphogen, Tizona, and Zymeworks. EDAT- 2020/08/10 06:00 MHDA- 2021/10/26 06:00 PMCR- 2021/01/01 CRDT- 2020/08/10 06:00 PHST- 2020/04/09 00:00 [received] PHST- 2020/06/22 00:00 [accepted] PHST- 2020/08/10 06:00 [pubmed] PHST- 2021/10/26 06:00 [medline] PHST- 2020/08/10 06:00 [entrez] PHST- 2021/01/01 00:00 [pmc-release] AID - CTS12855 [pii] AID - 10.1111/cts.12855 [doi] PST - ppublish SO - Clin Transl Sci. 2021 Jan;14(1):277-287. doi: 10.1111/cts.12855. Epub 2020 Dec 26.