A Phase I, Open-Label, Dose-Escalation Study of the OX40 Agonist Ivuxolimab in Patients With Locally Advanced or Metastatic Cancers.

Purpose: Stimulation of effector T cells is an appealing immunotherapeutic approach in oncology. OX40 (CD134) is a co-stimulatory receptor expressed on activated CD4+ and CD8+ T cells. Induction of OX40 following antigen recognition results in enhanced T-cell activation, proliferation, and survival, and OX40 targeting shows therapeutic efficacy in preclinical studies. We report the monotherapy dose-escalation portion of a multicenter, phase I trial (NCT02315066) of ivuxolimab (PF-04518600), a fully human immunoglobulin G2 agonistic monoclonal antibody specific for human OX40. Experimental Design: Adult patients (N = 52) with selected locally advanced or metastatic cancers received ivuxolimab 0.01-10 mg/kg. Primary endpoints were safety and tolerability. Secondary/exploratory endpoints included preliminary assessment of antitumor activity, and biomarker analyses. Results: The most common all-causality adverse events were fatigue (46.2%), nausea (28.8%), and decreased appetite (25.0%). Of 31 treatment-related adverse events, 30 (96.8%) were grade {less than or equal to}2. No dose-limiting toxicities occurred. Ivuxolimab exposure increased in a dose-proportionate manner from 0.3 to 10 mg/kg. Full peripheral blood target engagement occurred at {greater than or equal to}0.3 mg/kg. Three (5.8%) patients achieved a partial response, and disease control was achieved in 56% of patients. Increased CD4+ central memory T-cell proliferation and activation, and clonal expansion of CD4+ and CD8+ T cells in peripheral blood were observed at 0.1 to 3.0 mg/kg. Increased immune cell infiltrate and OX40 expression were evident in on-treatment tumor biopsies. Conclusions: Ivuxolimab was generally well tolerated with on-target immune activation at clinically relevant doses, showed preliminary anti-tumor activity, and may serve as a partner for combination studies.