A phase 0 analysis of ixazomib in patients with glioblastoma

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 who have received at least one prior therapy. However, ixazomib'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 concentrations 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 clinically 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 glioblastoma currently in development.

Glioma targeted therapy: insight into future of molecular approaches

“…Marizomib combined with TMZ is ongoing a phase III trial (NCT03345095), and Marizomib combined with Bevacizumab is ongoing a phase I/II trial (NCT02330562). Ixazomib has distinct permeability to tumor tissues preclinically with its efficacy trials to be further verified [ 120 ].…”

Brain-Permeable Immunoproteasome-Targeting Macrocyclic Peptide Epoxyketones for Alzheimer’s Disease

“…The most challenging endeavor in the design of CNS drugs is to overcome the BBB. Although several linear peptide-based cP inhibitors, including two peptide epoxyketones (carfilzomib-injectable and oprozomib-oral), are in the clinic or under clinical development, they are shown to be marginally brain permeable or impermeable. − Likewise, KZR-504, a linear peptide epoxyketone-based LMP2 inhibitor, is reported to have poor brain permeability in mice . The poor brain permeability may be attributed to rapid metabolism and the activity of the efflux transporters present in the BBB.…”

The Future Glioblastoma Clinical Trials Landscape: Early Phase 0, Window of Opportunity, and Adaptive Phase I–III Studies

“…In practice, however, phase 0 studies on patients with GBM are often deemed as exploratory analyses, so there is often a lack of a priori power analysis to determine sample sizes [ 15 •, 22 , 26 – 28 ], and low sample sizes are justified based on feasibility [ 15 •, 28 ]. Response criteria may be determined based on prior pre-/clinical data [ 26 ] or simply assessing if there is a relative change compared to archived tissue without a threshold (one-fold difference) [ 27 ].…”