Abstract 31: The INSPIRE trial: A randomized trial of neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with newly diagnosed stage II, III, or IVa squamous cell carcinoma of the oral cavity
Authors: Wolf Gregory T. , Patel Mihir , Erman Audrey , Newman Jason G. , Krempl Greg , Nieva Jorge , Bell R. Bryan , Kaplan Michael , Kraus Dennis , Moyer Jeffrey , Panwar Aru , Valentino Joseph 
Published: December 2017

Abstract
Introduction: IRX-2 is a primary-cell-derived immune-restorative biologic consisting of a well-defined set of human cytokines that act on multiple immune system cell types to overcome tumor-mediated immunosuppression. The IRX-2 biologic stimulates T cells and natural killer cells and turns immature or defective dendritic cells into mature antigen-presenting cells. The IRX-2 biologic is provided as part of the IRX-2 regimen, which contains cyclophosphamide, indomethacin, and zinc to support an anticancer immune response. In a phase 2a clinical trial in 27 patients with therapy-naïve head and neck squamous cell carcinoma (HNSCC), treatment with the IRX-2 regimen was well tolerated and associated with immunologically mediated antitumor effects. The new multicenter randomized IRX-2 Neoadjuvant Therapy in Head and Neck SCC to Provide Immune Response Enhancement (INSPIRE) trial (NCT02609386) is designed to evaluate the safety and effectiveness of combined neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with oral cavity HNSCC, a disease known to have a disordered immune function.
Study Design: Patients enrolled in INSPIRE must be at least 18 years of age; have previously untreated Stage II, III, or IVa SCC of the oral cavity that is surgically resectable with curative intent; and have a Karnofsky Performance status ≥70%. Up to 200 patients will be randomized 2:1 to either the IRX-2 biologic regimen arm or the IRX-2 regimen control arm (the IRX regimen minus the IRX-2 biologic).
The neoadjuvant stage of INSPIRE begins 21 days before resection, when patients in both treatment arms will receive the IRX-2 regimen each day until resection. This regimen consists of the immunomodulatory chemotherapeutic agent cyclophosphamide, provided as a low-dose intravenous infusion, as well as two oral drugs, a zinc-containing multivitamin and indomethacin, a nonselective COX-1/COX-2 inhibitor. During this period, patients in the IRX-2 biologic regimen arm will also receive 10 days of the IRX-2 biologic subcutaneously injected into their bilateral sternocleidomastoid insertion regions.
After resection, patients receive standard adjuvant radiation or chemoradiation therapy followed by adjuvant IRX-2 booster regimens at 3, 6, 9, and 12 months. During each 10-day booster period, patients in the IRX-2 biologic regimen arm also receive, for 5 consecutive days, the IRX-2 biologic subcutaneously injected into their bilateral deltoid regions.
Study Endpoints: INSPIRE is now enrolling patients at 12 selected institutions in the United States. The primary endpoint of INSPIRE is event-free survival (EFS). Secondary endpoints include overall survival (OS) and safety as assessed by the incidence and severity of adverse events. Exploratory endpoints include changes in tumor size and histologic differences between pre- and post-treatment specimens in lymphocytic infiltration, assessed by both cell-surface marker expression (Perkin Elmer multiplex IHC) and immune cell gene signatures (NanoString).
Conclusion: With enrollment of up to 200 patients, the randomized INSPIRE trial provides the opportunity to assess the ability of the IRX-2 regimen to improve EFS and OS by inhibiting tumor-mediated immunosuppression. Analysis of the exploratory endpoints will generate data to better describe the mechanism of action of the IRX-2 regimen and provide insight into the differences between inflammatory and non-inflammatory responses to SCCs of the oral cavity.
Citation Format: Gregory T. Wolf, Mihir Patel, Audrey Erman, Jason G. Newman, Greg Krempl, Jorge Nieva, R. Bryan Bell, Michael Kaplan, Dennis Kraus, Jeffrey Moyer, Aru Panwar, Joseph Valentino. The INSPIRE trial: A randomized trial of neoadjuvant and adjuvant therapy with the IRX-2 regimen in patients with newly diagnosed stage II, III, or IVa squamous cell carcinoma of the oral cavity [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 31.