A Phase I Study of High-dose L-methylfolate in Combination With Temozolomide and Bevacizumab in Recurrent High Grade Glioma

The phase I part of the study will be completed to determine the Maximum Tolerated Dose (MTD)
of high-dose L-methylfolate in combination with bevacizumab at 10mg/kg IV every 14 days, a
5-day regimen per month of temozolomide at 150 mg/m2/day and a 250 mg tablet of vitamin C.
Dose escalation will involve 3 patients treated at each dose level of L-methylfolate (15mg,
30 mg, 60 mg or 90 mg), and the MTD will be confirmed by expansion of 3 additional patients.
It is anticipated that 6 to 15 patients will be enrolled in the phase 1 part of the study.
Patients will continue treatment until disease progression. Once the MTD of L-methylfolate
has been determined, patients enrolled at a lower dose level may increase L-methylfolate dose
to the MTD dose, per investigator discretion.

The phase II part of the study will consist of patients taking the MTD of L-methylfolate
daily in combination with bevacizumab at 10 mg/kg IV every 14 days, a 5-day regimen per month
of temozolomide at 150 mg/m2/day and a 250 mg tablet of vitamin C. There will be 32 patients
treated in the Phase II study and the patients will continue treatment until progression. The
6 patients treated at the MTD cohort in Phase

Inclusion Criteria:

- Patients must have histologically confirmed malignant glioma (anaplastic
oligodendroglioma, anaplastic astrocytoma, anaplastic oligoastroctyoma or
glioblastoma). Patients must have genetically confirmed Isocitrate dehydrogenase I
(IDH1) wild-type tumor.

- Patients must have measurable disease, defined as at least one lesion that can be
accurately measured in at least one dimension as greater than or equal to 5 mm.
Patients can have non-measurable disease if they have had recent surgery for
radiographic progression.

- Patients can have been treated with standard therapy for high grade glioma, including
surgical resection, chemoradiation with temozolomide, adjuvant temozolomide and
bevacizumab. Patients can have received experimental therapy for high grade glioma.

- Patients must be 18 years of age or older.

- Patients may not be breast-feeding a child.

- Patients must have a Karnofsky Performance Score of greater than or equal to 60
percent.

- Patients must have normal organ and marrow function as defined below:

leukocytes greater than or equal to 3,000/milliliter (mcL) absolute neutrophil count
greater than or equal to 1,500/mcL platelets greater than or equal to 100,000/mcL total
bilirubin within normal institutional limits Aspartate transaminase (serum glutamic
oxaloacetic transaminase)Alanine transaminase (Serum Glutamic Pyruvate Transaminase) less
than or equal to 2.5 times institutional upper limit of normal Creatinine within normal
institutional limits OR creatinine clearance greater than or equal to 60/mL/min 1.73 m2 for
patients with creatinine levels above institutional normal

- Patients must have no concurrent malignancy except curatively treated basal or
squamous cell carcinoma of the skin or carcinoma in situ of the cervix or breast.
Patients with prior malignancies must be disease-free for greater than or equal to 3
years.

- The effects of high-dose L-methylfolate on the developing human fetus at the
recommended therapeutic dose are unknown, but, there is evidence that folic acid can
be protective against neural tube defects. However, there is some concern that folate
supplementation can increase the incidence of autism, and thus women of child-bearing
potential and men must agree to use adequate contraception (hormonal or barrier method
of birth control; abstinence) prior to study entry and for the duration of study
participation. Should a woman become pregnant or suspect she is pregnant while she or
her partner is participating in this study, the patient should inform the treating
physician immediately. All women will have pregnancy testing performed prior to
entering the trial.

- Patients must have the ability to understand and the willingness to sign a written
informed consent document.

- Patients must be able to tolerate MRIs. CT scans can NOT be substituted for MRI in
this study.

- Patients on therapeutic warfarin or enoxaparin are eligible.

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 2 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events (greater than grade I) due to agents administered more
than 4 weeks earlier.

- Patients with genetically confirmed IDH1-mutated tumor.

- Patients may not be receiving any other investigational agents.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to folic acid.

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, stage II hypertension, or psychiatric illness/social situations that would
limit compliance with study requirements.

- Pregnant women are excluded from this study because high-dose folic acid has the
potential for teratogenic or abortifacient effects. Because there is an unknown but
potential risk for adverse events in nursing infants secondary to treatment of the
mother with high-dose folic acid breastfeeding should be discontinued if the mother is
treated with high-dose folic acid.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with high-dose folic acid. In addition,
these patients are at increased risk of lethal infections when treated with
marrow-suppressive therapy. Appropriate studies will be undertaken in patients
receiving combination antiretroviral therapy when indicated.