Abstract. Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally‐administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma

Improving overall survival in recurrent glioblastoma remains a challenge, and drugs acting by unique mechanisms are urgently required. Ixazomib is an orally‐administered proteasome inhibitor used in combination with lenalidomide and dexamethasone to treat patients with multiple myeloma who have received at least one prior therapy. However, ixazo‐ mib's ability to reach brain tumors has not been studied during its development. The aim of the present study (ClinicalTrials. gov, NCT02630030) was to establish and quantify ixazomib's presence in glioblastoma. The present study investigated 3 patients with recurrent glioblastoma after administration of oral ixazomib citrate (MLN 9708) at a fixed 4.0 mg dose within a 3‐hpreoperative window. A total of 2 blood samples were taken from each patient at the time of incision, tumor sampling and closure. Brain tumor samples were collected during tumor resection. These samples were then used to measure the plasma and brain tumor tissue concentration of the biologically‐active form of ixazomib (MLN 2238). Patient 1 had plasma concen‐ trations of ixazomib averaging 26.2, 21.8 and 15.3 ng/ml at incision, tumor sampling and closure, respectively. The brain tumor tissue concentration was 7.88 ng/g. Patient 2 had the same interval and brain tumor tissue measurements of 19.0, 18.0 and 8.93 ng/ml, and 2.03 ng/g. Patient 3 had plasma concentration interval measurements of 25.6, 36.2 and 28.7 ng/ml. Multiple brain tumor tissue samples were taken in patient 3, with an average tissue ixazomib concentration of 3.37 ng/g. Ixazomib was found at plasma concentrations commensurate with its previously established pharmacokinetic profile without clini‐ cally relevant drug‐related adverse events. Ixazomib reaches glioblastoma tissues at measurable concentrations at the time of tumor resection, confirming target tissue delivery. This justifies the phase I study of ixazomib in recurrent glioblas‐ toma currently in development. Introduction Glioblastoma (GBM) is the most common primary glial malig‐ nancy (1). Despite its prevalence, and the resultant abundance of organized clinical investigation over several decades, GBM remains a challenging therapeutic entity from its initial diag‐ nosis to its nearly inevitable recurrence. Multiple treatment modalities are under active investigation, offering limited promise to improving overall survival in this patient popula‐ tion (2). Drugs treating this disease through novel mechanisms are urgently needed. Recently, proteasome inhibitors have been developed as an additional treatment option for recurrent and, given their measured success, newly diagnosed multiple myeloma. The proteasome is responsible for degrading damaged and ubiqui‐ nated proteins integral to normal cellular functioning (3). Selectively preventing cellular maintenance in relatively rapidly dividing neoplastic cells has proven an effective strategy. Bortezomib, an intravenous agent of this drug class, has been approved in the US for treatment of multiple myeloma since 2003 (4). Initial studies of bortezomib in mouse models demonstrated a lack of penetration of the blood brain barrier (5). Despite this, the effective anti‐neoplastic characteristics of proteasome inhibitors were recognized, and bortezomib has since been investigated in GBM with good reported response (6‐9). Ixazomib (MLN2238) is a second generation, orally administered proteasome inhibitor. Following the trail blazed by the investigation of bortezomib, ixazomib has recently proven effective against multiple myeloma, offering the prac‐ tical advantage of its oral bioavailability (10‐12). In murine xenograft models of lymphoma, ixazomib was found to be a potent and reversible proteasome inhibitor. These murine xenograft model investigations explored the pharmacokinetic profiles of these two drugs and found them comparable. Additionally, ixazomib administration resulted in more tumor volume improvement compared with bortezomib (13). It was further demonstrated to have effect against human multiple myeloma cell lines with in vitro and in vivo studies (14‐16). Despite its promise, ixazomib activity against glioblastoma was not tested during its development. This phase 0 clinical trial utilized a new assay to identify and quantify ixazomib after pre‐operative administration in human brain specimens during recurrent glioblastoma resection. A phase 0 analysis of ixazomib in patients with glioblastoma JOSEPH QUILLIN1, RIKESH PATEL2, ERIC HERZBERG3, DENNY ALTON3, GALINA BIKZHANOVA3, LISA GEISLER3 and JEFFREY OLSON1 1Department of Neurosurgery; 2Winship Cancer Institute, Emory University, Atlanta, GA 30322; 3Covance Laboratories, Inc., Madison, WI 53704, USA Received June 5, 2020; Accepted July 8, 2020 DOI: 10.3892/mco.2020.2114 Correspondence to: Dr Joseph Quillin, Department of Neurosurgery, Emory University, 1365 Clifton Road NE, Atlanta,