Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors

Howard A. Burris, Jeffrey R. Infante, Stephen Maxted Ansell, John J. Nemunaitis, Geoffrey R. Weiss, Victor M. Villalobos, Branimir I. Sikic, Matthew H. Taylor, Donald W Northfelt, William E. Carson, Thomas R. Hawthorne, Thomas A. Davis, Michael J. Yellin, Tibor Keler, Timothy Bullock

Research output: Contribution to journalArticle

46 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)2028-2036
Number of pages9
JournalJournal of Clinical Oncology
Volume35
Issue number18
DOIs
StatePublished - Jun 20 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Burris, H. A., Infante, J. R., Ansell, S. M., Nemunaitis, J. J., Weiss, G. R., Villalobos, V. M., Sikic, B. I., Taylor, M. H., Northfelt, D. W., Carson, W. E., Hawthorne, T. R., Davis, T. A., Yellin, M. J., Keler, T., & Bullock, T. (2017). Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. Journal of Clinical Oncology, 35(18), 2028-2036. https://doi.org/10.1200/JCO.2016.70.1508