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

Primary Purpose

Glioblastoma, GBM, Glioblastoma Multiforme

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ascorbate
Temozolomide
Radiation therapy
Sponsored by
Joseph J. Cullen, MD, FACS
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Glioblastoma focused on measuring Ascorbate, Ascorbic acid, Vitamin C, Radiation, Temozolomide

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Holden Comprehensive Cancer Center at the University of Iowa

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

15g Ascorbate

25g Ascorbate

50g arm

62.5g

75g Ascorbate

87.5g Ascorbate

Arm Description

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.

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.

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.

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.

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.

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.

Outcomes

Primary Outcome Measures

Number of grade 3, 4, & 5 adverse events
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 Outcome Measures

Time to progression
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
From start of treatment (cycle 1, day 1) until the date of death from any cause.

Full Information

First Posted
December 14, 2012
Last Updated
October 18, 2023
Sponsor
Joseph J. Cullen, MD, FACS
Collaborators
National Institutes of Health (NIH), National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT01752491
Brief Title
A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Official Title
A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 1, 2013 (Actual)
Primary Completion Date
November 30, 2015 (Actual)
Study Completion Date
December 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Joseph J. Cullen, MD, FACS
Collaborators
National Institutes of Health (NIH), National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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).
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Glioblastoma, GBM, Glioblastoma Multiforme
Keywords
Ascorbate, Ascorbic acid, Vitamin C, Radiation, Temozolomide

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
15g Ascorbate
Arm Type
Experimental
Arm Description
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.
Arm Title
25g Ascorbate
Arm Type
Experimental
Arm Description
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.
Arm Title
50g arm
Arm Type
Experimental
Arm Description
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.
Arm Title
62.5g
Arm Type
Experimental
Arm Description
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.
Arm Title
75g Ascorbate
Arm Type
Experimental
Arm Description
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.
Arm Title
87.5g Ascorbate
Arm Type
Experimental
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Ascorbate
Other Intervention Name(s)
Ascorbic Acid, Vitamin C
Intervention Description
Intravenous infusion of high-dose ascorbate
Intervention Type
Drug
Intervention Name(s)
Temozolomide
Other Intervention Name(s)
Temodar
Intervention Description
Oral chemotherapeutic
Intervention Type
Radiation
Intervention Name(s)
Radiation therapy
Other Intervention Name(s)
External beam radiation therapy
Intervention Description
External beam radiation therapy
Primary Outcome Measure Information:
Title
Number of grade 3, 4, & 5 adverse events
Description
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).
Time Frame
Weekly during therapy for up to 10 months
Secondary Outcome Measure Information:
Title
Time to progression
Description
Time from the start of therapy (day 1, cycle 1) to documented disease progression in MRI imaging as described by MacDonald and colleagues.
Time Frame
monthly up to 5 years post treatment
Title
Overall survival
Description
From start of treatment (cycle 1, day 1) until the date of death from any cause.
Time Frame
Up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
John M. Buatti, MD
Organizational Affiliation
Department of Radiation Oncology, The University of Iowa
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Joseph J Cullen, MD
Organizational Affiliation
Professor of Surgery, The University of Iowa
Official's Role
Study Director
Facility Information:
Facility Name
Holden Comprehensive Cancer Center at the University of Iowa
City
Iowa City
State/Province
Iowa
ZIP/Postal Code
52242
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Individual participant data is shared through an NIH/NCI approved data sharing plan in compliance with subject's consent to sharing. Investigators interested in IPD should contact the sponsor, study PI, or study coordinator for more information.
IPD Sharing Time Frame
Study protocol, SAP, and ICF will be shared at conclusion of the study.
IPD Sharing Access Criteria
Investigators interested in IPD should contact the sponsor, study PI, or study coordinator for more information. IRB approval for the recipient investigator may be required, as determined by the individual data received.
Citations:
PubMed Identifier
22728050
Citation
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.
Results Reference
background
PubMed Identifier
20068072
Citation
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.
Results Reference
background
PubMed Identifier
28366679
Citation
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.
Results Reference
result

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

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