A Phase 0 Window of Opportunity Trial of LB100, a Protein Phosphatase 2A Inhibitor, in Patients with Recurrent Gliomas

BackgroundLB100 is a protein phosphatase 2A (PP2A) inhibitor. Glioma models show inhibition of PP2A by LB100 causes cell death. Whether LB100 crosses the human blood brain barrier (BBB) is unknown. We sought to determine the pharmacokinetic (PK) properties of LB100 in human subject gliomas. MethodsA two-stage, phase 0 trial was done. Eligibility required a recurrent adult diffuse type of glioma deemed surgically resectable. In the first stage, 5 patients were pre-surgically dosed with LB100. Resected tumor then underwent PK analysis by LC-MS/MS. If one of five tumors demonstrated a PK response three additional subjects would be enrolled. Pharmacokinetic effect would be declared significant if at least 2 of 8 patients demonstrated a PK response and pharmacodynamic studies would then be performed. ResultsFive patients were evaluable. Glioblastoma, (n=2), Astrocytoma IDH-mutant grade 3-4 (n=2), and Oligodendroglioma IDH-mutant, grade 2 (n=1). Mean Cmax was 146 ng/mL (range: 95-179 ng/mL). Mean plasma half-life (T1/2) was 1.2 hours (range: 1.09-1.46 hours). Mean plasma drug exposure (AUCINF) was 414 hr*ng/mL (range: 325 to 468 ng*hr/mL. Average concentration of LB100 in tumor was 0.19 nM (range: 0 to 0.67 nM). Average plasma concentration of LB100 was 77.26 nM (range: 30.81 to 132.26 nM). The percent of drug penetration into the brain was 0.31% (range: 0% to 1.04%). The IC50 of PP2A is 0.2-0.4 uM; showing drug penetration was inadequate. ConclusionIn this first PK analysis of LB100 in human gliomas there was poor penetration of LB100 into glial tumors. Statement of Translational RelevanceThis phase 0 study represents the first pharmacokinetic (PK) analysis of LB100 in human brain cancers. It demonstrates there is poor penetration of LB100 crossing the blood brain barrier (BBB) into central nervous system (CNS) tumors. The ratio of the LB100 concentration in tumor to plasma tissue was much less than one percent, which resulted in a median LB100 tumor tissue concentration of 0.19 nM or 1000-fold less than a previously established minimum IC50 of 0.2uM, targeting the enzyme protein phosphatase 2A. This study highlights the importance of phase 0 studies as a component of new drug development for patients with CNS tumors. The poor brain tumor penetration demonstrated in this investigation will inform decision making regarding future LB100 clinical trials. Unless efforts are successful to reengineer LB100 to increase BBB permeability, upcoming trials will focus on non-CNS tumors.