Bevacizumab and Ascorbic Acid in Patients Treating With Recurrent High Grade Glioma

PRIMARY OBJECTIVES:

I. To evaluate the toxicities and determine the recommended dose of intravenous ascorbic acid
given three times weekly in combination with intravenous bevacizumab every two weeks in
patients with recurrent high grade glioma.

SECONDARY OBJECTIVES:

I. To evaluate changes in the levels of serum ascorbic acid (using high performance liquid
chromatography [HPLC] with coulometric electrochemical detection) during therapy with
ascorbic acid and bevacizumab.

II. Radiographic assessment of disease status after 2 cycles of therapy with ascorbic acid
and bevacizumab.

III. To evaluate progression-free and overall survival of patients with recurrent high grade
glioma treated with therapy with ascorbic acid and bevacizumab. Patients with stable or
responsive disease after every 2 cycles will continue on therapy with ascorbic acid and
bevacizumab until intolerance or progressive disease.

IV. To descriptively examine quality of life (QOL) using European Organization for Research
and Treatment of Cancer (EORTC) Quality-of-Life Questionnaire QLQ-C30 during treatment.

OUTLINE: This is a dose-escalation study of ascorbic acid.

Patients receive ascorbic acid intravenously (IV) over 90-120 minutes three times per week
(at least 24 hours apart) and bevacizumab IV over 30-90 minutes on days 1 and 15. Treatment
repeats every 28 days for up to 12 courses in the absence of disease progression or
unacceptable toxicity.

After completion of study treatment, patients are followed up every 2 months for 1 year.

Inclusion Criteria:

- Patients must have pathologically proven diagnosis of high grade glioma

- Patients must have received prior radiation therapy and standard temozolomide;
patients who have received additional therapies for previous progressions will be
considered eligible

- Patients must be three or more months from the end of chemoradiotherapy or have biopsy
or imaging consistent with disease progression

- Patients must have recovered from toxicity of prior therapy

- Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 or better

- Absolute neutrophil count (ANC) >= 1,500/mm^3

- Hemoglobin >= 8 g/dL

- Platelet count >= 100,000/mm^3

- Serum creatinine that is at or below 2.0 mg/dL

- Serum aspartate transaminase (AST) and alanine transaminase (ALT) less than 1.5 times
the upper limits of normal

- Serum alkaline phosphatase less than 2.5 times the upper limits of normal

- The patient must be aware of the neoplastic nature of his/her disease and willingly
provide written, informed consent after being informed of the procedure to be
followed, the experimental nature of the therapy, alternatives, potential benefits,
side-effects, risks, and discomforts

- Women of reproductive potential must be non-pregnant and non-nursing and must agree to
employ an effective barrier method of birth control throughout the study and for up to
6 months following treatment

- Women of child-bearing potential must have a negative pregnancy test within 7 days of
initiating study; (no childbearing potential is defined as age 55 years or older and
no menses for two years or any age with surgical removal of the uterus and/or both
ovaries)

Exclusion Criteria:

- History of uncontrollable allergic reactions to bevacizumab or ascorbic acid

- Known human immunodeficiency virus (HIV)-positivity AND actively being treated with
highly active antiretroviral therapy (HAART)

- History of glucose-6-phosphate dehydrogenase deficiency

- History of oxalate nephrolithiasis or urine oxalate >60 mg/dL

- Anuria, dehydration, severe pulmonary congestion or pulmonary edema or fixed low
cardiac input

- Prior hypersensitivity to bevacizumab or toxicity requiring discontinuation of
bevacizumab

- Clinically significant cardiovascular disease defined as follows:

- Inadequately controlled hypertension (i.e., systolic blood pressure [SBP] > 160
mm Hg and/or diastolic pressure [DBP] > 90 mm Hg despite antihypertensive
therapy)

- History of cerebrovascular accident (CVA) within 6 months

- Myocardial infarction or unstable angina within 6 months

- Evidence or history of bleeding diathesis (greater than normal risk of bleeding, i.e.,
Hereditary Hemorrhagic Telangiectasia type I or HHT-1) or coagulopathy in the absence
of therapeutic anti-coagulation or any hemorrhage/bleeding event > grade 3 within 4
weeks prior to registration; note: patients with full-dose anticoagulants are eligible
provided the patient has been on a stable dose for at least 2 weeks of low molecular
weight heparin; therapeutic Coumadin and aspirin doses > 325 mg daily are not allowed

- Active wound, a serious or non-healing wound, an active ulcer or untreated bone
fracture

- History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
=< 6 months prior to registration

- Major surgical procedure, open biopsy or significant traumatic injury =< 28 days prior
to registration

- Any other clinically significant medical disease or condition laboratory abnormality
or psychiatric illness that, in the Investigator's opinion, may interfere with
protocol adherence or a subject's ability to give informed consent

- Patients who are on the following drugs and cannot have a drug substitution:
flecainide, methadone, amphetamines, quinidine, and chlorpropamide; Note: high dose
ascorbic acid may affect urine acidification and, as a result, may affect clearance
rates of these drugs

- Simultaneous participation in other therapeutic clinical trials will not be allowed

- Inability to co-operate with the requirements of the protocol

- Pregnant and nursing women are excluded from this study