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

Publication ,  Journal Article
Allen, BG; Bodeker, KL; Smith, MC; Monga, V; Sandhu, S; Hohl, R; Carlisle, T; Brown, H; Hollenbeck, N; Vollstedt, S; Greenlee, JD; Howard, MA ...
Published in: Clin Cancer Res
November 15, 2019

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.

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Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 15, 2019

Volume

25

Issue

22

Start / End Page

6590 / 6597

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Temozolomide
  • Radiotherapy
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Middle Aged
  • Male
  • Kaplan-Meier Estimate
  • Humans
  • Glioblastoma
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Allen, B. G., Bodeker, K. L., Smith, M. C., Monga, V., Sandhu, S., Hohl, R., … Buatti, J. M. (2019). First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clin Cancer Res, 25(22), 6590–6597. https://doi.org/10.1158/1078-0432.CCR-19-0594
Allen, Bryan G., Kellie L. Bodeker, Mark C. Smith, Varun Monga, Sonia Sandhu, Raymond Hohl, Thomas Carlisle, et al. “First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.Clin Cancer Res 25, no. 22 (November 15, 2019): 6590–97. https://doi.org/10.1158/1078-0432.CCR-19-0594.
Allen BG, Bodeker KL, Smith MC, Monga V, Sandhu S, Hohl R, et al. First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clin Cancer Res. 2019 Nov 15;25(22):6590–7.
Allen, Bryan G., et al. “First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma.Clin Cancer Res, vol. 25, no. 22, Nov. 2019, pp. 6590–97. Pubmed, doi:10.1158/1078-0432.CCR-19-0594.
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. First-in-Human Phase I Clinical Trial of Pharmacologic Ascorbate Combined with Radiation and Temozolomide for Newly Diagnosed Glioblastoma. Clin Cancer Res. 2019 Nov 15;25(22):6590–6597.

Published In

Clin Cancer Res

DOI

EISSN

1557-3265

Publication Date

November 15, 2019

Volume

25

Issue

22

Start / End Page

6590 / 6597

Location

United States

Related Subject Headings

  • Treatment Outcome
  • Temozolomide
  • Radiotherapy
  • Oncology & Carcinogenesis
  • Neoplasm Staging
  • Middle Aged
  • Male
  • Kaplan-Meier Estimate
  • Humans
  • Glioblastoma