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 promoter methylation (), 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.