A Phase I Lead-in to a 2x2x2 Factorial Trial of Temozolomide, Memantine, Mefloquine, and Metformin as Post-Radiation Adjuvant Therapy of Glioblastoma Multiforme

Inclusion Criteria:

1. Patients with histologically proven supratentorial glioblastoma or gliosarcoma (WHO
grade IV astrocytoma) will be eligible for this protocol. Patients will be eligible if
the original histology was low-grade glioma and a subsequent histological diagnosis of
glioblastoma or gliosarcoma is made prior to any definitive treatment (radiotherapy,
chemotherapy).

2. All patients must sign an informed consent indicating that they are aware of the
investigational nature of this study. Patients must be registered prior to treatment
with study drug.

3. Patients must be >/= 18 years old.

4. Patients must have a Karnofsky performance status(KPS) of >/= 60.

5. Patients must have adequate bone marrow function (WBC >/= 3,000/µl, ANC >/=
1,500/mm^3, platelet count of >/= 100,000/mm^3, and hemoglobin >/= 10 gm/dl), adequate
liver function (SGOT and bilirubin < 2 times ULN), and adequate renal function
(creatinine < 1.5 mg/dL) before starting therapy. These tests must be performed within
14 days prior to registration. Eligibility level for hemoglobin may be reached by
transfusion.

6. For patients on Mefloquine arm, a baseline EKG without evidence of prolonged QTc
interval >450 ms or clinically significant arrhythmia must be obtained within 14 days
prior to registration.

7. A brain scan should be performed within 14 days prior to registration and steroid
dosing should be stable or decreasing for at least 5 days. If the steroid dose is
increased between the date of imaging and registration a new baseline MR/CT is
required. The same type of scan, i.e., MRI or CT must be used throughout the period of
protocol treatment for tumor measurement.

8. Patients must have completed standard radiation therapy with concurrent TMZ and must
not have evidence of progressive disease on post treatment imaging.

9. Women of childbearing potential must have a negative serum or urine B-HCG pregnancy
test documented within 72 hours of start of therapy.

10. Patients must be registered on the study within 5 weeks of completion of concurrent
chemoradiation.

Exclusion Criteria:

1. Patients must not have any significant medical illnesses that in the investigator's
opinion cannot be adequately controlled with appropriate therapy or would compromise
the patient's ability to tolerate this therapy.

2. For Mefloquine arm, patients with evidence of QTc interval >450 ms or clinically
significant arrhythmia on baseline EKG obtained within 14 days of registration will be
ineligible for protocol enrollment.

3. Patients with a history of any other cancer (except non-melanoma skin cancer or
carcinoma in-situ of the cervix), unless in complete remission and off of all therapy
for that disease for a minimum of 3 years, are ineligible.

4. Patients must not have active infection or serious intercurrent medical illness.

5. Patients must not be pregnant/breast feeding and must agree to practice adequate
contraception(Acceptable forms of birth control include condom with spermicide and/or
diaphragm with spermicide, and non-barrier contraception such as tubal ligation,
vasectomy, oral contraceptives, implanted levonorgestrel, vaginal hormonal
contraceptive ring). Patients must not be pregnant because animal studies show that
both TMZ and MFLOQ are teratogenic, or there is insufficient information to estimate
risk.

6. Patients must not have any disease that will obscure toxicity or dangerously alter
drug metabolism. Patients with a history of psychosis/schizophrenia or cardiac disease
requiring beta-blocker treatment (unable to change medication to non-beta blocker),
anti-malarial drugs, or quinine or quinidine will not be eligible for enrollment to a
mefloquine containing arm. Patients who are on active treatment with one of the study
drugs at the time of evaluation will not be eligible for enrollment to an arm
containing that study drug.

7. For Mefloquine arm, patients must not be on enzyme inducing anticonvulsants (EIAED);
if the treating physician elects to change the medication to a non-enzyme inducing
agent, a 2-weeks wash out period will be required after stopping EIAED prior to
initiation of treatment.