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J Clin Oncol. 2017 Jun 20;35(18):2028-2036. doi: 10.1200/JCO.2016.70.1508. Epub 2017 May 2.

Safety and Activity of Varlilumab, a Novel and First-in-Class Agonist Anti-CD27 Antibody, in Patients With Advanced Solid Tumors.

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Howard A. Burris and Jeffrey R. Infante, Sarah Cannon Research Institute, Tennessee Oncology, Nashville, TN; Stephen M. Ansell, Mayo Clinic, Rochester, MN; John J. Nemunaitis, Mary Crowley Cancer Research Center, Dallas, TX; Geoffrey R. Weiss and Timothy Bullock, University of Virginia, Charlottesville, VA; Victor M. Villalobos and Branimir I. Sikic, Stanford Cancer Institute, Stanford, CA; Matthew H. Taylor, Oregon Health & Science University, Portland, OR; Donald W. Northfelt, Mayo Clinic, Scottsdale, AZ; William E. Carson III, The Ohio State University, Columbus, OH; Thomas R. Hawthorne, Thomas A. Davis, Michael J. Yellin, and Tibor Keler, Celldex Therapeutics, Hampton, NJ.

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Purpose CD27, a costimulatory molecule on T cells, induces intracellular signals that mediate cellular activation, proliferation, effector function, and cell survival upon binding to its ligand, CD70. Varlilumab is a novel, first-in-class, agonist CD27 antibody that stimulates the CD27 pathway, which results in T-cell activation and antitumor activity in tumor models. This first-in-human, dose-escalation and expansion study evaluated the safety, pharmacology, and activity of varlilumab in patients with advanced solid tumors. Methods In a 3 + 3 dose-escalation design (n = 25), patients received a single dose of varlilumab (0.1, 0.3, 1.0, 3.0, or 10 mg/kg intravenously) with a 28-day observation, followed by up to five multidose cycles (one dose per week for 4 weeks), depending on tumor response. Expansion cohorts were initiated at 3.0 mg/kg in patients with melanoma (n = 16) and renal cell carcinoma (RCC; n = 15). Primary objectives were to assess the safety and the maximum tolerated and optimal biologic doses of varlilumab. Secondary objectives were to evaluate the pharmacokinetics, pharmacodynamics, and clinical antitumor activity of varlilumab. Results Exposure to varlilumab was linear and dose proportional across dose groups. Only one patient experienced a dose-limiting toxicity-grade 3 transient asymptomatic hyponatremia at the 1.0-mg/kg dose level. Treatment-related adverse events were generally grade 1 or 2 in severity. Evidence of biologic activity consistent with CD27 stimulation-chemokine induction, T-cell stimulation, regulatory T cell depletion-was observed at all dose levels. A patient with metastatic RCC experienced a partial response (78% shrinkage, progression-free survival > 2.3 years). Eight patients experienced stable disease > 3 months, including a patient with metastatic RCC with progression-free survival of > 3.9 years. Conclusion Dose escalation of varlilumab to 10 mg/kg was well tolerated without identification of a maximum tolerated dose. Varlilumab was biologically and clinically active.

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