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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Glioblastoma, GBM, Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Ascorbate
* Drug: Temozolomide
* Radiation: Radiation therapy


Participation Criteria
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Eligibility Criteria
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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

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
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 15g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Temozolomide<br>* Oral chemotherapeutic<br>* Other names: Temodar;Radiation: Radiation therapy<br>* External beam radiation therapy<br>* Other names: External beam radiation therapy;|
| Experimental: 25g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Temozolomide<br>* Oral chemotherapeutic<br>* Other names: Temodar;Radiation: Radiation therapy<br>* External beam radiation therapy<br>* Other names: External beam radiation therapy;|
| Experimental: 50g arm<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Temozolomide<br>* Oral chemotherapeutic<br>* Other names: Temodar;Radiation: Radiation therapy<br>* External beam radiation therapy<br>* Other names: External beam radiation therapy;|
| Experimental: 62.5g<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Temozolomide<br>* Oral chemotherapeutic<br>* Other names: Temodar;Radiation: Radiation therapy<br>* External beam radiation therapy<br>* Other names: External beam radiation therapy;|
| Experimental: 75g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Temozolomide<br>* Oral chemotherapeutic<br>* Other names: Temodar;Radiation: Radiation therapy<br>* External beam radiation therapy<br>* Other names: External beam radiation therapy;|
| Experimental: 87.5g Ascorbate<br>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<br>* Intravenous infusion of high-dose ascorbate<br>* Other names: Vitamin C;Drug: Temozolomide<br>* Oral chemotherapeutic<br>* Other names: Temodar;Radiation: Radiation therapy<br>* External beam radiation therapy<br>* Other names: External beam radiation therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | monthly up to 5 years post treatment | 
| Overall survival | From start of treatment (cycle 1, day 1) until the date of death from any cause. | Up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ascorbate, Ascorbic acid, Vitamin C, Radiation, Temozolomide