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

NCT01752491 | Completed Phase 1 DMC FDA Drug

• 3 other identifiers: 201211713P30CA086862U01CA140206
• Study Type: interventional
• Target: 13
• Locations: 1 country
• Sites: 1

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).

Conditions

Glioblastoma; GBM; Glioblastoma Multiforme

Keywords

Ascorbate; Ascorbic acid; Vitamin C; Radiation; Temozolomide

Outcome Measures

Primary Outcomes (1)

• 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).

  Weekly during therapy for up to 10 months

Secondary Outcomes (2)

• Time to progression

  monthly up to 5 years post treatment

• Overall survival

  Up to 5 years

Study Arms (6)

15g Ascorbate

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy

25g Ascorbate

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy

50g arm

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy

62.5g

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy

75g Ascorbate

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy

87.5g Ascorbate

EXPERIMENTAL

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; Drug: Temozolomide; Radiation: Radiation therapy

Interventions

Ascorbate DRUG

Intravenous infusion of high-dose ascorbate

Also known as: Ascorbic Acid, Vitamin C

15g Ascorbate; 25g Ascorbate; 50g arm; 62.5g; 75g Ascorbate; 87.5g Ascorbate

Temozolomide DRUG

Oral chemotherapeutic

Also known as: Temodar

15g Ascorbate; 25g Ascorbate; 50g arm; 62.5g; 75g Ascorbate; 87.5g Ascorbate

Radiation therapy RADIATION

External beam radiation therapy

Also known as: External beam radiation therapy

15g Ascorbate; 25g Ascorbate; 50g arm; 62.5g; 75g Ascorbate; 87.5g Ascorbate

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Joseph J. Cullen, MD, FACS: lead
• National Institutes of Health (NIH): collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

Holden Comprehensive Cancer Center at the University of Iowa

Iowa City, Iowa, 52242, United States

Location

Related Publications (3)

• 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.

  PMID: 22728050 BACKGROUND

• 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.

  PMID: 20068072 BACKGROUND

• 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.

  PMID: 28366679 RESULT

MeSH Terms

Conditions

Glioblastoma

Interventions

Ascorbic Acid; Temozolomide; Radiotherapy

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Sugar Acids; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Hydroxy Acids; Carbohydrates; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics

Study Officials

• John M. Buatti, MD

  Department of Radiation Oncology, The University of Iowa

  PRINCIPAL INVESTIGATOR

• Joseph J Cullen, MD

  Professor of Surgery, The University of Iowa

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor and Chair, Department of Radiation Oncology

Study Record Dates

• First Submitted: December 14, 2012
• First Posted: December 19, 2012
• Study Start: April 1, 2013
• Primary Completion: November 30, 2015
• Study Completion: November 15, 2019
• Last Updated: December 20, 2024

Record last verified: 2024-12

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, 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.

Locations

US (1)