Format

Send to

Choose Destination
Clin Cancer Res. 2019 Aug 19. doi: 10.1158/1078-0432.CCR-19-0594. [Epub ahead of print]

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

Author information

1
Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, Iowa.
2
Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, Iowa.
3
Penn State Cancer Institute, Hershey, Pennsylvania.
4
Department of Neurosurgery, University of Iowa Hospitals & Clinics, Iowa City, Iowa.
5
Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City, Iowa.
6
Department of Biostatistics, The University of Iowa, Iowa City, Iowa.
7
Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, Iowa. john-buatti@uiowa.edu.

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center