First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma

Abstract

Standard treatment for glioblastoma (GBM) includes surgery, radiation (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of ≈14 months. Preclinical models suggest pharmacological ascorbate (P-AscH − ) enhances RT/TMZ anti-tumor effect in GBM. We evaluated the safety of adding P-AscH − to standard RT/TMZ therapy. This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/ P-AscH − ) and adjuvant (ADJ) phase (post RT/TMZ/ P-AscH − phase). Eight P-AscH − dose cohorts were evaluated in the RT phase until targeted plasma ascorbate levels were achieved (≥ 20 mM). In the ADJ phase, P-AscH − doses were escalated in each subject at each cycle until plasma concentrations were ≥ 20 mM. P-AscH − was infused 3 times weekly during the RT-phase and 2 times weekly during the ADJ-phase continuing for 6 cycles or until disease progression. Adverse events (AEs) were quantified by CTCAE(v4.03). Eleven subjects were evaluable. No dose limiting toxicities occurred. Observed toxicities were consistent with historical controls. Adverse events related to study drug were dry mouth and chills. Targeted ascorbate plasma levels of 20 mM were achieved in the 87.5 g cohort; diminishing returns were realized in higher dose cohorts. Median progression free survival (PFS) was 9.4 months and median overall survival (OS) was 18 months. In subjects with undetectable MGMT promoter methylation ( n=8 ), median PFS was 10 months and median OS was 23 months. P-AscH − /RT/TMZ is safe with promising clinical outcomes warranting further investigation.