@article{0f9a9b206d604e958cb2a7c6b41b0690,
title = "First-in-Human Study of Utomilumab, a 4-1BB/CD137 Agonist, in Combination with Rituximab in Patients with Follicular and Other CD20+ Non-Hodgkin Lymphomas",
abstract = "Purpose: In this phase I study (NCT01307267), we evaluated safety, pharmacokinetics, clinical activity, and pharmacodynamics of treatment with utomilumab plus rituximab in patients with relapsed/refractory follicular lymphoma (FL) and other CD20+ non-Hodgkin lymphomas (NHL). Patients and Methods: Primary objectives were to assess treatment safety and tolerability for estimating the MTD, using a modified time-to-event continual reassessment method, and selecting the recommended phase II dose (RP2D). Results: Sixty-seven patients received utomilumab (0.03–10.0 mg/kg every 4 weeks) and rituximab (375 mg/m2 weekly) in the dose-escalation groups or utomilumab (1.2 mg/kg every 4 weeks) plus rituximab in the dose-expansion cohort. No patient experienced dose-limiting toxicity. The MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg every 4 weeks. The majority of the utomilumab treatment-related adverse events (AE) were grade 1 to 2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03 to 10 mg/kg dose range. A low incidence (1.5%) of treatment-induced antidrug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI, 12.1%–33.0%) in all patients with NHL, including four complete and 10 partial responses. Analysis of paired biopsies from a relapsed/refractory FL patient with complete response showed increased T-cell infiltration and cytotoxic activity in tumors. Biomarker correlations with outcomes suggested that clinical benefit may be contingent on patient immune function. Conclusions: Utomilumab in combination with rituximab demonstrated clinical activity and a favorable safety profile in patients with CD20+ NHLs.",
author = "Gopal, {Ajay K.} and Ronald Levy and Roch Houot and Patel, {Sandip P.} and Leslie Popplewell and Caron Jacobson and Mu, {Xinmeng J.} and Shibing Deng and Ching, {Keith A.} and Ying Chen and Davis, {Craig B.} and Bo Huang and Fly, {Kolette D.} and Aron Thall and Adrian Woolfson and Bartlett, {Nancy L.}",
note = "Funding Information: A.K. Gopal is an employee/paid consultant for Actinium, I-MAB, Asana, Bristol-Myers Squibb, Amgen, Takeda, BRIM bio, Seattle Genetics, Janssen, Aptevo, Gilead, Incite, Bayer, Pharmacyclics, and Astra Zeneca, and reports receiving other commercial research support from Merck, Seattle Genetics, Takeda, Janssen, Pfizer, Agios, IgM, Teva, Gilead, and Bristol-Myers Squibb. R. Levy is an employee/paid consultant for Five Prime, BeiGene, Teneobio, Sutro, Checkmate, Nurix, Dragonfly, Abpro, Apexigen, Viracta, Forty Seven Inc., Spotlight, XCella, Immunocore, and Walking Fish, and reports receiving commercial research grants from Bristol-Myers Squibb and Janssen. S.P. Patel is an employee/paid consultant for AstraZeneca, Bristol-Myers Squibb, Lilly, Illumina, Rakuten, Paradigm, and Tempus. C. Jacobson is an employee/ paid consultant for Kite, Novartis, Celgene, Bristol-Myers Squibb, Precision Biosciences, Nkarta, and Humanigen, reports receiving other commercial research support from Pfizer, speakers bureau honoraria from AXIS and Clinical Care Options, and other remuneration from Weitz Lux. X.J. Mu is an employee/paid consultant for and reports receiving commercial research grants from Pfizer Inc. K.A. Ching, C.B. Davis, B. Huang, and A. Thall are employees/paid consultants for Pfizer Inc. S. Deng, Y. Chen, and K.D. Fly are employees/paid consultants for and hold ownership interest (including patents) in Pfizer Inc. No potential conflicts of interest were disclosed by the other authors. Funding Information: The study was approved by the institutional review board or independent ethics committee of the participating institutions and followed the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. All subjects provided written informed consent. The study was sponsored by Pfizer and registered at ClinicalTrials.gov (NCT01307267). Publisher Copyright: {\textcopyright} 2020 American Association for Cancer Research.",
year = "2020",
month = jun,
day = "1",
doi = "10.1158/1078-0432.CCR-19-2973",
language = "English",
volume = "26",
pages = "2524--2534",
journal = "Clinical Cancer Research",
issn = "1078-0432",
number = "11",
}