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

Bryan G. Allen, Kellie L. Bodeker, Mark C. Smith, Varun Monga, Sonia Sandhu, Raymond Hohl, Thomas Carlisle, Heather Brown, Nancy Hollenbeck, Sandy Vollstedt, Jeremy D. Greenlee, Matthew A. Howard, Kranti A. Mapuskar, Steven N. Seyedin, Joseph M. Caster, Karra A. Jones, Joseph J. Cullen, Daniel Berg, Brett A. Wagner, Garry R. BuettnerMindi J. TenNapel, Brian J. Smith, Douglas R. Spitz, John M. Buatti

Research output: Contribution to journalArticle

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 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.

Original languageEnglish (US)
Pages (from-to)6590-6597
Number of pages8
JournalClinical Cancer Research
Volume25
Issue number22
DOIs
StatePublished - Nov 15 2019

Fingerprint

temozolomide
Clinical Trials, Phase I
Glioblastoma
Radiotherapy
Radiation
Disease-Free Survival
Survival
Chills

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Allen, Bryan G. ; Bodeker, Kellie L. ; Smith, Mark C. ; Monga, Varun ; Sandhu, Sonia ; Hohl, Raymond ; Carlisle, Thomas ; Brown, Heather ; Hollenbeck, Nancy ; Vollstedt, Sandy ; Greenlee, Jeremy D. ; Howard, Matthew A. ; Mapuskar, Kranti A. ; Seyedin, Steven N. ; Caster, Joseph M. ; Jones, Karra A. ; Cullen, Joseph J. ; Berg, Daniel ; Wagner, Brett A. ; Buettner, Garry R. ; TenNapel, Mindi J. ; Smith, Brian J. ; Spitz, Douglas R. ; Buatti, John M. / First-in-human phase I clinical trial of pharmacologic ascorbate combined with radiation and temozolomide for newly diagnosed glioblastoma. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 22. pp. 6590-6597.
@article{6e435591b09341a4b7f6d0aa06a0c0ce,
title = "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 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.",
author = "Allen, {Bryan G.} and Bodeker, {Kellie L.} and Smith, {Mark C.} and Varun Monga and Sonia Sandhu and Raymond Hohl and Thomas Carlisle and Heather Brown and Nancy Hollenbeck and Sandy Vollstedt and Greenlee, {Jeremy D.} and Howard, {Matthew A.} and Mapuskar, {Kranti A.} and Seyedin, {Steven N.} and Caster, {Joseph M.} and Jones, {Karra A.} and Cullen, {Joseph J.} and Daniel Berg and Wagner, {Brett A.} and Buettner, {Garry R.} and TenNapel, {Mindi J.} and Smith, {Brian J.} and Spitz, {Douglas R.} and Buatti, {John M.}",
year = "2019",
month = "11",
day = "15",
doi = "10.1158/1078-0432.CCR-19-0594",
language = "English (US)",
volume = "25",
pages = "6590--6597",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "22",

}

Allen, BG, Bodeker, KL, Smith, MC, Monga, V, Sandhu, S, Hohl, R, Carlisle, T, Brown, H, Hollenbeck, N, Vollstedt, S, Greenlee, JD, Howard, MA, Mapuskar, KA, Seyedin, SN, Caster, JM, Jones, KA, Cullen, JJ, Berg, D, Wagner, BA, Buettner, GR, TenNapel, MJ, Smith, BJ, Spitz, DR & Buatti, JM 2019, 'First-in-human phase I clinical trial of pharmacologic ascorbate combined with radiation and temozolomide for newly diagnosed glioblastoma', Clinical Cancer Research, vol. 25, no. 22, pp. 6590-6597. https://doi.org/10.1158/1078-0432.CCR-19-0594

First-in-human phase I clinical trial of pharmacologic ascorbate combined with radiation and temozolomide for newly diagnosed glioblastoma. / Allen, Bryan G.; Bodeker, Kellie L.; Smith, Mark C.; Monga, Varun; Sandhu, Sonia; Hohl, Raymond; Carlisle, Thomas; Brown, Heather; Hollenbeck, Nancy; Vollstedt, Sandy; Greenlee, Jeremy D.; Howard, Matthew A.; Mapuskar, Kranti A.; Seyedin, Steven N.; Caster, Joseph M.; Jones, Karra A.; Cullen, Joseph J.; Berg, Daniel; Wagner, Brett A.; Buettner, Garry R.; TenNapel, Mindi J.; Smith, Brian J.; Spitz, Douglas R.; Buatti, John M.

In: Clinical Cancer Research, Vol. 25, No. 22, 15.11.2019, p. 6590-6597.

Research output: Contribution to journalArticle

TY - JOUR

T1 - First-in-human phase I clinical trial of pharmacologic ascorbate combined with radiation and temozolomide for newly diagnosed glioblastoma

AU - Allen, Bryan G.

AU - Bodeker, Kellie L.

AU - Smith, Mark C.

AU - Monga, Varun

AU - Sandhu, Sonia

AU - Hohl, Raymond

AU - Carlisle, Thomas

AU - Brown, Heather

AU - Hollenbeck, Nancy

AU - Vollstedt, Sandy

AU - Greenlee, Jeremy D.

AU - Howard, Matthew A.

AU - Mapuskar, Kranti A.

AU - Seyedin, Steven N.

AU - Caster, Joseph M.

AU - Jones, Karra A.

AU - Cullen, Joseph J.

AU - Berg, Daniel

AU - Wagner, Brett A.

AU - Buettner, Garry R.

AU - TenNapel, Mindi J.

AU - Smith, Brian J.

AU - Spitz, Douglas R.

AU - Buatti, John M.

PY - 2019/11/15

Y1 - 2019/11/15

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85075062632&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85075062632&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-19-0594

DO - 10.1158/1078-0432.CCR-19-0594

M3 - Article

C2 - 31427282

AN - SCOPUS:85075062632

VL - 25

SP - 6590

EP - 6597

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 22

ER -