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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

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

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Temozolomide
* Radiation: radiation therapy
* Drug: Ascorbic Acid


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ascorbate, radiation, temozolomide<br>Concomitant therapy: Radiation therapy, oral temozolomide, and pharmacological ascorbate (ascorbic acid) infusions Adjuvant therapy: Oral temozolomide and pharmacological ascorbate (ascorbic acid) infusions | Drug: Temozolomide<br>* 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.<br>* Other names: Temodal;Radiation: radiation therapy<br>* Conformal radiation administered daily, M-F, to a total dose of 61.2 Gray in 34 fractions.<br>* Other names: external beam radiation therapy;Drug: Ascorbic Acid<br>* 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.<br>* Other names: 67457-118-50;|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ascorbic Acid, temozolomide, radiation