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

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

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).

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.

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