The IRX-2 regimen combined with nivolumab in recurrent/metastatic solid tumors: A phase 1b study to evaluate the safety, determine recommended phase 2 dose (RP2D), and investigate the biologic and clinical activity

Background: IRX-2 is a biologic immunotherapeutic containing a mixture of cytokines including IL-2, IL-1β IL-6, IL-8, TNFα, GM-CSF, and IFN-γ. It is derived from stimulating human PBMCs with phytohemagglutinin. Preclinical studies have shown that IRX-2 enhances dendritic cell maturation, T cell activation, and NK cell stimulation. In a Phase 2 trial of head and neck squamous cell carcinoma (HNSCC) patients, IRX-2 increased immune activation in the tumor microenvironment and was correlated with greater progression free survival and overall survival. Moreover, it has been shown that the degree of lymphocyte infiltration is an important prognostic factor for treatment with anti-programmed cell death protein 1 (PD-1) monoclonal antibodies. These data provide a compelling rationale for incorporating IRX-2 regimen into anti-PD-1 treatment strategies to increase the level of lymphocyte infiltration in the TME and improve immune response. Methods: This is a phase Ib trial exploring safety and tolerability of IRX-2 regimen in combination with nivolumab. Patients with recurrent or metastatic renal cell carcinoma, urothelial carcinoma, non-small cell lung cancer, HNSCC and melanoma are eligible. Patients who have received prior anti-PD-1/PD-L1 antibodies are eligible. IRX-2 regimen consists of cyclophosphamide 300mg/m2 (Day 1) and subcutaneous IRX-2 injections in 2 or 4 lymph nodebearing regions (based on dose level) for 10 days every 3 months. Two dose levels of IRX-2 regimen will be studied. Nivolumab is administered at 240 mg Q2W. Once the RP2D is determined, an additional 88 pts will be enrolled in an expansion phase, for a planned total enrollment of approximately 100 pts. Dose expansion phase will include cohorts of the 5 different diseases. Each cohort will include two groups: 1) anti-PD-1/PD-L1 antibody naïve tumors, and 2) progressed during or after anti-PD-1/PD-L1 antibodies. The primary study objective is to determine safety and tolerability of combination therapy. Secondary objectives are to evaluate the objective response rate, progression-free survival, and overall survival. Study Progress: Study is actively accruing.