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 M. 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: Research - peer-reviewArticle

    • 1 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.

    LanguageEnglish (US)
    Pages2028-2036
    Number of pages9
    JournalJournal of Clinical Oncology
    Volume35
    Issue number18
    DOIs
    StatePublished - Jun 20 2017

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    Anti-Idiotypic Antibodies
    Safety
    Neoplasms
    T-Lymphocytes
    Disease-Free Survival
    Maximum Tolerated Dose
    Hyponatremia
    Regulatory T-Lymphocytes
    Chemokines
    Renal Cell Carcinoma
    Melanoma
    Cell Survival
    Pharmacokinetics
    Cell Proliferation
    Observation
    Pharmacology
    Ligands
    Antibodies
    Therapeutics

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Burris, H. A., Infante, J. R., Ansell, S. M., Nemunaitis, J. J., Weiss, G. R., Villalobos, V. M., ... 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. DOI: 10.1200/JCO.2016.70.1508

    Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. / Burris, Howard A.; Infante, Jeffrey R.; Ansell, Stephen M.; Nemunaitis, John J.; Weiss, Geoffrey R.; Villalobos, Victor M.; Sikic, Branimir I.; Taylor, Matthew H.; Northfelt, Donald W.; Carson, William E.; Hawthorne, Thomas R.; Davis, Thomas A.; Yellin, Michael J.; Keler, Tibor; Bullock, Timothy.

    In: Journal of Clinical Oncology, Vol. 35, No. 18, 20.06.2017, p. 2028-2036.

    Research output: Research - peer-reviewArticle

    Burris, HA, Infante, JR, Ansell, SM, Nemunaitis, JJ, Weiss, GR, Villalobos, VM, Sikic, BI, Taylor, MH, Northfelt, DW, Carson, WE, Hawthorne, TR, Davis, TA, Yellin, MJ, 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, vol 35, no. 18, pp. 2028-2036. DOI: 10.1200/JCO.2016.70.1508
    Burris HA, Infante JR, Ansell SM, Nemunaitis JJ, Weiss GR, Villalobos VM et al. 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. 2017 Jun 20;35(18):2028-2036. Available from, DOI: 10.1200/JCO.2016.70.1508
    Burris, Howard A. ; Infante, Jeffrey R. ; Ansell, Stephen M. ; Nemunaitis, John J. ; Weiss, Geoffrey R. ; Villalobos, Victor M. ; Sikic, Branimir I. ; Taylor, Matthew H. ; Northfelt, Donald W. ; Carson, William E. ; Hawthorne, Thomas R. ; Davis, Thomas A. ; Yellin, Michael J. ; Keler, Tibor ; Bullock, Timothy. / Safety and activity of varlilumab, a novel and first-in-class agonist anti-CD27 antibody, in patients with advanced solid tumors. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 18. pp. 2028-2036
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    author = "Burris, {Howard A.} and Infante, {Jeffrey R.} and Ansell, {Stephen M.} and Nemunaitis, {John J.} and Weiss, {Geoffrey R.} and Villalobos, {Victor M.} and Sikic, {Branimir I.} and Taylor, {Matthew H.} and Northfelt, {Donald W.} and Carson, {William E.} and Hawthorne, {Thomas R.} and Davis, {Thomas A.} and Yellin, {Michael J.} and Tibor Keler and Timothy Bullock",
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    AU - Infante,Jeffrey R.

    AU - Ansell,Stephen M.

    AU - Nemunaitis,John J.

    AU - Weiss,Geoffrey R.

    AU - Villalobos,Victor M.

    AU - Sikic,Branimir I.

    AU - Taylor,Matthew H.

    AU - Northfelt,Donald W.

    AU - Carson,William E.

    AU - Hawthorne,Thomas R.

    AU - Davis,Thomas A.

    AU - Yellin,Michael J.

    AU - Keler,Tibor

    AU - Bullock,Timothy

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    N2 - 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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