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

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ClinicalTrials.gov Identifier: NCT01752491

Recruitment Status : Active, not recruiting

First Posted : December 19, 2012

Last Update Posted : July 26, 2022

View this study on Beta.ClinicalTrials.gov

Sponsor:

Collaborators:

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Information provided by (Responsible Party):

John M. Buatti, University of Iowa

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).

Condition or disease	Intervention/treatment	Phase
Glioblastoma GBM Glioblastoma Multiforme	Drug: Ascorbate Drug: Temozolomide Radiation: Radiation therapy	Phase 1

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.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	13 participants
Allocation:	Non-Randomized
Intervention Model:	Single Group Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I Trial of High-Dose Ascorbate in Glioblastoma Multiforme
Actual Study Start Date :	April 1, 2013
Actual Primary Completion Date :	November 30, 2015
Estimated Study Completion Date :	December 31, 2024

Resource links provided by the National Library of Medicine

Drug Information available for: Temozolomide

Genetic and Rare Diseases Information Center resources: Glioblastoma Glioma Neuroepithelioma

U.S. FDA Resources

Arms and Interventions

Arm	Intervention/treatment
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.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Temozolomide Oral chemotherapeutic Other Name: Temodar Radiation: Radiation therapy External beam radiation therapy Other Name: External beam radiation therapy
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.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Temozolomide Oral chemotherapeutic Other Name: Temodar Radiation: Radiation therapy External beam radiation therapy Other Name: External beam radiation therapy
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.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Temozolomide Oral chemotherapeutic Other Name: Temodar Radiation: Radiation therapy External beam radiation therapy Other Name: External beam radiation therapy
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.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Temozolomide Oral chemotherapeutic Other Name: Temodar Radiation: Radiation therapy External beam radiation therapy Other Name: External beam radiation therapy
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.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Temozolomide Oral chemotherapeutic Other Name: Temodar Radiation: Radiation therapy External beam radiation therapy Other Name: External beam radiation therapy
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.	Drug: Ascorbate Intravenous infusion of high-dose ascorbate Other Names: Ascorbic Acid Vitamin C Drug: Temozolomide Oral chemotherapeutic Other Name: Temodar Radiation: Radiation therapy External beam radiation therapy Other Name: External beam radiation therapy

Outcome Measures

Primary Outcome 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 Outcome 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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

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

Contacts and Locations

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01752491

Locations

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United States, Iowa
Holden Comprehensive Cancer Center at the University of Iowa
Iowa City, Iowa, United States, 52242

Sponsors and Collaborators

Joseph J. Cullen, MD, FACS

National Institutes of Health (NIH)

National Cancer Institute (NCI)

Investigators

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Principal Investigator:	John M. Buatti, MD	Department of Radiation Oncology, The University of Iowa
Study Director:	Joseph J Cullen, MD	Professor of Surgery, The University of Iowa

More Information

Publications of 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.

Other Publications:

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.

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Responsible Party:	John M. Buatti, Professor and Chair, Department of Radiation Oncology, University of Iowa
ClinicalTrials.gov Identifier:	NCT01752491
Other Study ID Numbers:	201211713 P30CA086862 ( U.S. NIH Grant/Contract ) U01CA140206 ( U.S. NIH Grant/Contract )
First Posted:	December 19, 2012 Key Record Dates
Last Update Posted:	July 26, 2022
Last Verified:	July 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Yes
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.
Supporting Materials:	Study Protocol Statistical Analysis Plan (SAP) Informed Consent Form (ICF)
Time Frame:	Study protocol, SAP, and ICF will be shared at conclusion of the study.
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.

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Studies a U.S. FDA-regulated Drug Product:	Yes
Studies a U.S. FDA-regulated Device Product:	No

Keywords provided by John M. Buatti, University of Iowa:


Ascorbate Ascorbic acid Vitamin C Radiation Temozolomide

Additional relevant MeSH terms:

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Glioblastoma Astrocytoma Glioma Neoplasms, Neuroepithelial Neuroectodermal Tumors Neoplasms, Germ Cell and Embryonal Neoplasms by Histologic Type Neoplasms Neoplasms, Glandular and Epithelial Neoplasms, Nerve Tissue Ascorbic Acid	Temozolomide Vitamins Micronutrients Physiological Effects of Drugs Antineoplastic Agents, Alkylating Alkylating Agents Molecular Mechanisms of Pharmacological Action Antineoplastic Agents Antioxidants Protective Agents

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