Convection-Enhanced Delivery of a First-in-Class Anti-β1 Integrin Antibody for the Treatment of High-Grade Glioma Utilizing Real-Time Imaging

• Type of Material: Article
• Authors: Chibueze D Nwagwu, Emory University; Amanda V Immidisetti, Rutgers Robert Wood Johnson Medical School; Gabriela Bukanowska, OncoSynergy, Inc.; Michael A Vogelbaum, H.Lee Moffitt Cancer Center and Research Institute; Anne-Marie Carbonell, OncoSynergy, Inc.
• Language: English
• Date: 2021-01-01
• Publisher: MDPI AG
• Publication Version: Final Published Version
• Copyright Statement: © 2020 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/pharmaceutics13010040
• Title of Journal or Parent Work: Pharmaceutics
• Volume: 13
• Issue: 1
• Grant/Funding Information: This research was in part funded by the Musella Foundation for Brain Tumor Research and Information. The APC was funded by OncoSynergy, Inc.
• Keywords: OS2966; convection enhanced delivery; β1 integrin; monoclonal antibody; ITGB1; clinical trial; CD29; high-grade glioma; glioblastoma
• Research Categories: Health Sciences, Oncology; Health Sciences, Medicine and Surgery

Abstract

Introduction: OS2966 is a first-in-class, humanized and de-immunized monoclonal antibody which targets the adhesion receptor subunit, CD29/β1 integrin. CD29 expression is highly upregulated in glioblastoma and has been shown to drive tumor progression, invasion, and resistance to multiple modalities of therapy. Here, we present a novel Phase I clinical trial design addressing several factors plaguing effective treatment of high-grade gliomas (HGG). Study Design: This 2-part, ascending-dose, Phase I clinical trial will enroll patients with recurrent/progressive HGG requiring a clinically indicated resection. In Study Part 1, patients will undergo stereotactic tumor biopsy followed by placement of a purpose-built catheter which will be used for the intratumoral, convection-enhanced delivery (CED) of OS2966. Gadolinium contrast will be added to OS2966 before each infusion, enabling the real-time visualization of therapeutic distribution via MRI. Subsequently, patients will undergo their clinically indicated tumor resection followed by CED of OS2966 to the surrounding tumor-infiltrated brain. Matched pre- and post-infusion tumor specimens will be utilized for biomarker development and validation of target engagement by receptor occupancy. Dose escalation will be achieved using a unique concentration-based accelerated titration design. Discussion: The present study design leverages multiple innovations including: (1) the latest CED technology, (2) 2-part design including neoadjuvant intratumoral administration, (3) a first-in-class investigational therapeutic, and (4) concentration-based dosing. Trial registration: A U.S. Food and Drug Administration (FDA) Investigational New Drug application (IND) for the above protocol is now active.