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

Abstract

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 = 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.

Figure 1.. Schematic diagram of phase 1 GBM clinical trial.

The primary objective was to determine the safety and tolerability of escalating pharmacological ascorbate doses combined with therapeutic radiation therapy and temozolomide (radiation phase) followed by continued treatment with pharmacological ascorbate combined with temozolomide (adjuvant phase) in GBM subjects.

Figure 2.. Graphical depiction of dose escalation rules applied to the clinical trial.

The clinical trial utilized two design methods: Storer’s phase 1 two-stage design B/D (interpatient dose escalation) followed by an intra-patient dose escalation to achieve an ascorbate plasma concentration of 20 mM. Dose limiting toxicities were assessed clinically but also at pre-defined radiographic checkpoints (fraction 20 of radiation and one month post-radiation). These checkpoints determined cohort entry as well as stopping rules.

Figure 3.. Overall and progression free survival of phase 1 GBM clinical trial subjects.

Historical median progression free survival for GBM patients treated with radiation and temozolomide therapy is approximately 7 months and median overall survival is 14 – 16 months. (A) Kaplan-Meier progression free survival curve (orange line) and overall survival curve (gray line) of all subjects treated with pharmacological ascorbate in combination with therapeutic radiation and temozolomide. (B) Kaplan-Meier progression free survival curve of subjects without detection of MGMT promoter methylation (black line) and with MGMT promoter methylation (red line). Subjects were treated with pharmacological ascorbate in combination with therapeutic radiation and temozolomide. (C) Swimmers plot showing outcomes of the 11 evaluable subjects. Active ascorbate therapy is indicated by orange bars, progression free survival is indicated by green bars, and overall survival is indicated by grey bars. The radiation phase ascorbate dose cohort of each subject is indicated along the y-axis. Red bars indicate subjects who chose to terminate the trial prematurely for personal reasons. Death is indicated by a black line at the end of the bar. Subjects with undetectable MGMT promoter methylation are indicated with a minus sign while subjects with detectable MGMT promoter methylation are indicated with a plus sign. The 62.5 g dose cohort subject and 87.5 g dose cohort subject who remains alive had isocitrate dehydrogenase (IDH) mutations.