A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme

Overview

This is a phase 1 (first in man) study testing the safety of adding high dose ascorbate (vitamin C) to standard radiation and chemotherapy for initial treatment of glioblastoma multiforme (GBM).

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Non-Randomized
    • Intervention Model: Single Group Assignment
    • Primary Purpose: Treatment
    • Masking: None (Open Label)
  • Study Primary Completion Date: November 30, 2015

Detailed Description

This phase 1 study will test the safety of adding high dose ascorbate (vitamin C) to standard chemoradiation and, after the radiation is completed, during 6 cycles of temozolomide. Standard treatment for glioblastoma multiforme (GBM) involves surgery followed by radiation combined with temozolomide (a chemotherapy). After radiation, patients receive cycles of temozolomide (adjuvant chemotherapy) Participants will: – receive high doses of intravenous (IV) ascorbate three times a week during chemoradiation – receive high doses of intravenous (IV) ascorbate twice a week during adjuvant chemotherapy (after radiation) This is a phase 1 study will evaluate the side effects of adding this drug to the standard therapy. The dose given to a participant will be determined by how well other participants have tolerated the drug.

Interventions

  • Drug: Ascorbate
    • Intravenous infusion of high-dose ascorbate
  • Drug: Temozolomide
    • Oral chemotherapeutic
  • Radiation: Radiation therapy
    • External beam radiation therapy

Arms, Groups and Cohorts

  • Experimental: 15g Ascorbate
    • During radiation therapy: Radiation: 61.2 Gray (1.8 Gray / fraction / day), 5 days/week, for approximately 8 weeks. Temozolomide: 75 mg/m2, taken orally, once daily, every day, until radiation is completed. Ascorbate: 15 g administered by IV three times a week until 1 month after radiation is completed (approximately 12 weeks). After radiation therapy: Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
  • Experimental: 25g Ascorbate
    • If the 15g arm is tolerated, the study opens the 25g arm. During radiation therapy: Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. Ascorbate: 25 g administered by IV three times/wk until 1 month after radiation is completed (about 12 weeks). After radiation therapy: Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
  • Experimental: 50g arm
    • If the 25g arm is tolerated, the study opens the 50g arm. During radiation therapy: Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. Ascorbate: 50 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
  • Experimental: 62.5g
    • If the 50g arm is tolerated, the study opens the 62.5g arm. During radiation therapy: Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. Ascorbate: 62.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
  • Experimental: 75g Ascorbate
    • If the 62.5g arm is tolerated, the study opens the 75g arm. During radiation therapy: Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. Ascorbate: 75 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.
  • Experimental: 87.5g Ascorbate
    • If the 75g arm is tolerated, the study opens the 87.5g arm. During radiation therapy: Radiation: 61.2 Gray (1.8 Gy/fraction/day), 5 days/wk, for about 8 weeks. Temozolomide: 75 mg/m2, taken orally, once every day, until radiation is completed. Ascorbate: 87.5 g administered by IV three times a week until 1 month after radiation is completed (about 12 weeks). After radiation therapy: Temozolomide: Starting 1 month after radiation. 150 mg/m2 and then 200 mg/m2 daily. Starting 28 days after the completion of radiation therapy. Taken for 5 days followed by 23 days of rest for 6 cycles. Ascorbate: escalating weekly doses of ascorbate (up to 125 grams) to target a serum level of 350 mg/dL (20 mM). Ascorbate is administered twice weekly, each week, for up to 6 months.

Clinical Trial Outcome Measures

Primary Measures

  • Number of grade 3, 4, & 5 adverse events
    • Time Frame: Weekly during therapy for up to 10 months
    • Assess grade 3 and higher adverse events. Evaluate the frequency and severity against the published literature to determine the likely causality between ascorbate and the adverse event(s).

Secondary Measures

  • Time to progression
    • Time Frame: monthly up to 5 years post treatment
    • Time from the start of therapy (day 1, cycle 1) to documented disease progression in MRI imaging as described by MacDonald and colleagues.
  • Overall survival
    • Time Frame: Up to 5 years
    • From start of treatment (cycle 1, day 1) until the date of death from any cause.

Participating in This Clinical Trial

Inclusion Criteria

  • Patients must have newly diagnosed (i.e., within 5 weeks), histologically or cytologically confirmed glioblastoma multiforme. – Diagnosis must be made by surgical biopsy or excision. – Therapy must begin ≤ 5 weeks after surgery. – Age ≥ 18 years – ECOG performance status 0-2 (Karnofsky > 50%). – A complete blood count and differential must be obtained within 21 days prior to the first dose of radiation, with adequate bone marrow functions as defined below: – Absolute neutrophil count (ANC) ≥ 1500 cells per mm3 – Platelets ≥ 100,000 per mm3 – Hemoglobin ≥ 8 g/dL – Serum blood chemistries within 21 days before the first day of radiation, as defined below: – Creatinine ≤ 2.0 mg – Total bilirubin ≤ 1.5 mg/dL – ALT (Alanine Aminotransferase)≤ 3 times the institutional upper limit of normal – AST (Aspartate Aminotransferase) ≤ 3 times the institutional upper limit of normal – Tolerate one text dose (15g) of ascorbate – Not pregnant – Ability to understand and willingness to sign a written informed consent document Exclusion Criteria:

  • Recurrent high grade glioma – G6PD (glucose-6-phosphate dehydrogenase) deficiency – Patients actively receiving insulin unless approved by the study medical monitor, study sponsor, and the study principal investigator. – History of allergic reactions attributed to compounds of similar chemical or biologic composition to temozolomide. – Significant co-morbid central nervous system disease, including but not limited to, multiple sclerosis. – Patients who are on the following drugs and cannot have a drug substitution: flecainide, methadone, amphetamines, quinidine, and chlorpropamide. High dose ascorbic acid may affect urine acidification and, as a result, may affect clearance rates of these drugs. – Prior invasive malignancies (except non-melanomatous skin cancers and carcinoma in situ of the cervix or bladder) unless disease free for ≥ 5 years. – Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma. – Prior radiation therapy to the head or neck, which would result in overlap of radiation therapy fields. – Patients may not be receiving any other investigational agents. – Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. – Pregnant women are excluded from this study because ionizing radiation is a known teratogen, and temozolomide is a Class D agent with the potential for teratogenic or abortifacient effects. – Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 (an enzyme pathway) inducer, which results in lower serum levels of antiretroviral drugs

Gender Eligibility: All

Minimum Age: 18 Years

Maximum Age: N/A

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Joseph J. Cullen, MD, FACS
  • Collaborator
    • National Institutes of Health (NIH)
  • Provider of Information About this Clinical Study
    • Principal Investigator: John M. Buatti, Professor and Chair, Department of Radiation Oncology – University of Iowa
  • Overall Official(s)
    • John M. Buatti, MD, Principal Investigator, Department of Radiation Oncology, The University of Iowa
    • Joseph J Cullen, MD, Study Director, Professor of Surgery, The University of Iowa

References

Du J, Cullen JJ, Buettner GR. Ascorbic acid: chemistry, biology and the treatment of cancer. Biochim Biophys Acta. 2012 Dec;1826(2):443-57. doi: 10.1016/j.bbcan.2012.06.003. Epub 2012 Jun 20.

Du J, Martin SM, Levine M, Wagner BA, Buettner GR, Wang SH, Taghiyev AF, Du C, Knudson CM, Cullen JJ. Mechanisms of ascorbate-induced cytotoxicity in pancreatic cancer. Clin Cancer Res. 2010 Jan 15;16(2):509-20. doi: 10.1158/1078-0432.CCR-09-1713. Epub 2010 Jan 12.

Citations Reporting on Results

Schoenfeld JD, Sibenaller ZA, Mapuskar KA, Wagner BA, Cramer-Morales KL, Furqan M, Sandhu S, Carlisle TL, Smith MC, Abu Hejleh T, Berg DJ, Zhang J, Keech J, Parekh KR, Bhatia S, Monga V, Bodeker KL, Ahmann L, Vollstedt S, Brown H, Shanahan Kauffman EP, Schall ME, Hohl RJ, Clamon GH, Greenlee JD, Howard MA, Schultz MK, Smith BJ, Riley DP, Domann FE, Cullen JJ, Buettner GR, Buatti JM, Spitz DR, Allen BG. O2⋅- and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate. Cancer Cell. 2017 Apr 10;31(4):487-500.e8. doi: 10.1016/j.ccell.2017.02.018. Epub 2017 Mar 30. Erratum In: Cancer Cell. 2017 Aug 14;32(2):268.

Clinical trials entries are delivered from the US National Institutes of Health and are not reviewed separately by this site. Please see the identifier information above for retrieving further details from the government database.

At TrialBulletin.com, we keep tabs on over 200,000 clinical trials in the US and abroad, using medical data supplied directly by the US National Institutes of Health. Please see the About and Contact page for details.