Journal article
First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma
Clinical cancer research, Vol.25(22), pp.6590-6597
11/15/2019
DOI: 10.1158/1078-0432.CCR-19-0594
PMCID: PMC6858950
PMID: 31427282
Abstract
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.
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).
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.
P-AscH
/RT/TMZ is safe with promising clinical outcomes warranting further investigation.
Details
- Title: Subtitle
- First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma
- Creators
- Bryan G Allen - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaKellie L Bodeker - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaMark C Smith - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaVarun Monga - Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, IowaSonia Sandhu - Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, IowaRaymond Hohl - Penn State Cancer Institute, Hershey, PennsylvaniaThomas Carlisle - Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, IowaHeather Brown - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaNancy Hollenbeck - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaSandy Vollstedt - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaJeremy D Greenlee - Department of Neurosurgery, University of Iowa Hospitals & Clinics, Iowa City, IowaMatthew A Howard - Department of Neurosurgery, University of Iowa Hospitals & Clinics, Iowa City, IowaKranti A Mapuskar - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaSteven N Seyedin - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaJoseph M Caster - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaKarra A Jones - Department of Pathology, University of Iowa Hospitals & Clinics, Iowa City, IowaJoseph J Cullen - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaDaniel Berg - Division of Hematology and Oncology, Department of Internal Medicine, University of Iowa Hospitals & Clinics, Iowa City, IowaBrett A Wagner - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaGarry R Buettner - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaMindi J TenNapel - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaBrian J Smith - Department of Biostatistics, The University of Iowa, Iowa City, IowaDouglas R Spitz - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, IowaJohn M Buatti - Department of Radiation Oncology, University of Iowa Hospitals & Clinics, Iowa City, Iowa. john-buatti@uiowa.edu
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.25(22), pp.6590-6597
- Publisher
- United States
- DOI
- 10.1158/1078-0432.CCR-19-0594
- PMID
- 31427282
- PMCID
- PMC6858950
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Grant note
- P01 CA217797 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA182804 / NCI NIH HHS
- Language
- English
- Date published
- 11/15/2019
- Academic Unit
- Neurology; Hematology, Oncology, and Blood & Marrow Transplantation; Stead Family Department of Pediatrics; Pathology; Iowa Neuroscience Institute; Biostatistics; Surgery; Radiation Oncology; Neurosurgery; Otolaryngology; Holden Comprehensive Cancer Center; Internal Medicine
- Record Identifier
- 9984070362702771
Metrics
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