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

Abstract

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 ≤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 ≥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.Research.

The Treatment of Advanced Melanoma: Therapeutic Update

“…Agonistic anti-OX40 antibodies showed an anti-tumor activity, associated with the infiltration and the proliferation of T cells and effector T cells at tumor sites, respectively [ 60 ]. A phase I trial evaluated the tolerability of ivuxolimab, a fully human immunoglobulin G2 agonistic monoclonal antibody specific for OX40, in a cohort of 52 patients with advanced cancer (melanoma: 2) [ 61 ]. A preliminary antitumor activity and the tolerability of ivuxolimab was reported.…”

Identification and validation a costimulatory molecule gene signature to predict the prognosis and immunotherapy response for hepatocellular carcinoma

“…In addition, TNFRSF4 was overexpressed in HCC, associated with a more aggressive phenotype and the activation of multiple immunosuppressive pathways [ 36 ]. A phase I clinical research also supported that Ivuxolimab (a TNFRSF4 agonist) showed well tolerance and effective anti-tumor capacity in locally advanced or metastatic cancers, including HCC [ 37 ]. Consequently, treatment targeting TNFRSF4-TNFSF4 should be considered in the future.…”

Tipping the scales: Immunotherapeutic strategies that disrupt immunosuppression and promote immune activation

“…The clinical efficacy of several agonists for 4-1BB and OX40 in combination with ICIs is currently under investigation. Recently published results from a clinical trial (NCT02315066) of OX40 agonist, alone or in combination with a 4-1BB agonist, have shown disease control in 56% of patients associated with an increase in CD4 + memory T cell proliferation and activation without dose-limiting toxicities ( 66 ). In a phase I study (NCT02554812), 26.1% of the patients who received combination treatment with the 4-1BB agonist utomilumab and pembrolizumab had complete or partial responses.…”