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

Clin Cancer Res. 2020 Jun 1;26(11):2524-2534. doi: 10.1158/1078-0432.CCR-19-2973. Epub 2020 Mar 6.


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.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Follicular / drug therapy*
  • Adenocarcinoma, Follicular / immunology
  • Adenocarcinoma, Follicular / pathology
  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal, Humanized / administration & dosage
  • Antigens, CD20 / metabolism*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacokinetics*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoglobulin G / administration & dosage
  • Lymphoma, Non-Hodgkin / drug therapy*
  • Lymphoma, Non-Hodgkin / immunology
  • Lymphoma, Non-Hodgkin / pathology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Prognosis
  • Rituximab / administration & dosage
  • Tissue Distribution
  • Tumor Necrosis Factor Receptor Superfamily, Member 9 / agonists*


  • Antibodies, Monoclonal, Humanized
  • Antigens, CD20
  • Immunoglobulin G
  • TNFRSF9 protein, human
  • Tumor Necrosis Factor Receptor Superfamily, Member 9
  • Rituximab
  • utomilumab

Associated data