First-in-human phase I clinical trial of pharmacologic ascorbate combined with radiation and temozolomide for newly diagnosed glioblastoma

Purpose: Standard treatment for glioblastoma (GBM) includes surgery, radiation therapy (RT), and temozolomide (TMZ), yielding a median overall survival (OS) of approximately 14 months. Preclinical models suggest that pharmacologic ascorbate (P-AscH^-) enhances RT/TMZ antitumor effect in GBM. We evaluated the safety of adding P-AscH^- to standard RT/TMZ therapy. Patients and Methods: This first-in-human trial was divided into an RT phase (concurrent RT/TMZ/P-AscH^-) and an 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 mmol/L). In the ADJ phase, P-AscH^- doses were escalated in each subject at each cycle until plasma concentrations were ≥20 mmol/L. P-AscH^- was infused 3 times weekly during the RT phase and 2 times weekly during the ADJ phase continuing for six cycles or until disease progression. Adverse events were quantified by CTCAE (v4.03). Results: 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 mmol/L 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 OS was 18 months. In subjects with undetectable MGMT promoter methylation (n ¼ 8), median PFS was 10 months and median OS was 23 months. Conclusions: P-AscH^-/RT/TMZ is safe with promising clinical outcomes warranting further investigation.