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

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 (FL) and other CD20+ non-Hodgkin lymphomas (NHLs). Experimental Design: Primary objectives were to assess treatment safety and tolerability for estimating the maximum tolerated dose (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 [Q4W]) and rituximab (375 mg/m2 weekly) in the dose escalation groups or utomilumab (1.2 mg/kg Q4W) plus rituximab in the dose expansion cohort. No patient experienced DLTThe MTD for utomilumab in combination with rituximab was not reached and estimated to be ≥10 mg/kg Q4W. The majority of the utomilumab treatment-related adverse events (AEs) were grade 1-2; the most common AE was fatigue (16.4%). The pharmacokinetics of utomilumab in combination with rituximab was linear in the 0.03-10 mg/kg dose range. A low incidence (1.5%) of treatment-induced anti-drug antibodies against utomilumab was observed. The objective response rate was 21.2% (95% CI 12.1, 33.0%) in all patients with NHL, including 4 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.