A Phase 2 Trial of High-Dose Ascorbate in Glioblastoma Multiforme

Pharmacological Ascorbate Combined With Radiation and Temozolomide in Glioblastoma Multiforme: A Phase 2 Trial

This clinical trial evaluates adding high-dose ascorbate (vitamin C) to standard of care treatment of glioblastoma multiforme (a type of brain tumor) in adults. All subjects will receive high-dose ascorbate in addition to the standard treatment.

Study Overview

• Status: Active, not recruiting
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Drug: Temozolomide; Radiation: radiation therapy; Drug: Ascorbic Acid

Detailed Description

Standard treatment for glioblastoma multiforme (GBM) involves maximum safe surgical resection followed by radiation combined with temozolomide (a chemotherapy pill you take by mouth). After radiation, patients receive additional cycles of temozolomide (adjuvant chemotherapy).

Participants will:

• receive high doses of intravenous (IV) ascorbate three times a week during the combined radiation and chemotherapy phase
• receive high doses of intravenous (IV) ascorbate twice a week during adjuvant chemotherapy (after radiation)
• complete health-related quality of life questionnaires pre-radiation, 4 weeks into radiation, 4 weeks after radiation, and then every 3 months. In addition, patients will complete neurocognitive testing pre-radiation, 4 weeks into radiation, 4 weeks after radiation, and approximately 9 months after initiating radiation therapy.

The adjuvant chemotherapy portion of this study lasts for 6 months. After that is completed, participants will go back to standard therapy for their cancer. Participants will continue to have life-long follow-up for this study.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Iowa
    • Iowa City, Iowa, United States, 52242
      • Holden Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Ability to understand and willingness to sign informed consent (power of attorney and/or legally authorized representatives cannot sign on behalf of the patient)
• 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 or biopsy
• Age ≥ 18 years
• ECOG performance status 0-2. (KPS > 50)
• Absolute neutrophil count (ANC) ≥ 1500 cells per mm3
• Platelets ≥ 100,000 per mm3
• Hemoglobin ≥ 8 g/dL
• Creatinine ≤ 2.0 mg
• Total bilirubin ≤ 1.5 mg/dL
• ALT ≤ 3 times the institutional upper limit of normal
• AST ≤ 3 times the institutional upper limit of normal
• Tolerate one test dose (15g) of ascorbate.
• Not pregnant.

Exclusion Criteria:

• Recurrent high grade glioma
• G6PD (glucose-6-phosphate dehydrogenase) deficiency.
• Patients actively receiving insulin or using a finger-stick glucometer daily for blood glucose measurements
• 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: warfarin, flecainide, methadone, amphetamines, quinidine, and chlorpropamide.
• Known active concurrent malignancy, as determined by treating physicians.
• Patients who have received prior chemotherapy (including Gliadel wafers) for the current glioma.
• Prior radiation therapy to the head or neck resulting in overlap of RT fields.
• Patients receiving any other investigational agents (imaging agents are acceptable)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection that would result in a hospital stay or delay of treatment, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements or impact patient safety.
• Pregnant women.
• Breastfeeding women.
• Known HIV-positive individuals. High-dose ascorbate acid is a known CYP450 3A4 inducer, which results in lower serum levels of antiretroviral drugs.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: ascorbate, radiation, temozolomide; Concomitant therapy: Radiation therapy, oral temozolomide, and pharmacological ascorbate (ascorbic acid) infusions Adjuvant therapy: Oral temozolomide and pharmacological ascorbate (ascorbic acid) infusions

Drug: Temozolomide; oral temozolomide (75 mg/m2), given 7 days per week, for a maximum of 49 days during radiation therapy. Starting 1 month after radiation therapy, additional temozolomide will be given as chemotherapy cycles. Each cycle is 28 days. For the first cycle, temozolomide will be administered (150 mg/m2) once per day for 5 days. If the subject tolerates the first cycle well, temozolomide will be prescribed at 200 mg/m2 for cycles 2 through 6. Each cycle is 28 days.; Other Names: Temodar; Temodal; Radiation: radiation therapy; Conformal radiation administered daily, M-F, to a total dose of 61.2 Gray in 34 fractions.; Other Names: EBRT; XRT; external beam radiation therapy; Drug: Ascorbic Acid; Intravenous infusions of 87.5g of ascorbate administered three times weekly during radiation. After radiation, ascorbate is administered twice weekly through the end of cycle 6 of temozolomide.; Other Names: Vitamin C; Ascorbate; Pharmacological Ascorbate; 67457-118-50

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	From radiation day 1 until date of death from any cause.	monthly up to 5 years post treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS)	From radiation day 1 to documented disease progression in MRI imaging as described by the RANO criteria	monthly up to 5 years post treatment
Adverse Event Frequency	Categorize and quantify using the Common Terminology Criteria for Adverse Events (CTCAE) v. 4 from radiation day 1 through 7 months post-radiation.	monthly through 7 months post-radiation

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Health-related Quality of Life (HRQOL)	Measure health-related outcomes using the validated EORTC (European Organization for Research and Treatment of Cancer) questionnaires QLQ-C30 and BN-20.	monthly for 3 months, then every 3 months up to 5 years post treatment

Collaborators and Investigators

• Sponsor: Bryan Allen
• Collaborators: National Cancer Institute (NCI); Gateway for Cancer Research; Holden Comprehensive Cancer Center
• Investigators: Principal Investigator: Bryan G. Allen, MD, PhD, Assistant Professor, Department of Radiation Oncology, The University of Iowa

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 13, 2017
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): December 1, 2027

Study Registration Dates

• First Submitted: January 16, 2015
• First Submitted That Met QC Criteria: January 16, 2015
• First Posted (Estimated): January 22, 2015

Study Record Updates

• Last Update Posted (Actual): November 7, 2023
• Last Update Submitted That Met QC Criteria: November 2, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Ascorbic Acid; radiation; temozolomide
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Micronutrients; Vitamins; Antioxidants; Temozolomide; Ascorbic Acid
• Other Study ID Numbers: 201504786

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data will be released publicly as per participant consent and IRB approval. Individual researchers should contact the research team for data sharing.
• IPD Sharing Time Frame: Study protocol and informed consent will be shared after primary completion. Statistical analysis plan will be shared with results reporting.
• IPD Sharing Access Criteria: An IRB-stamped signed usage agreement will be required in addition to a data sharing agreement between the academic centers.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No