Phase I Factorial Trial of Temozolomide, Memantine, Mefloquine, and Metformin for Post-Radiation Therapy (RT) Glioblastoma Multiforme (GBM)

• Maximum Tolerated Dose (MTD) Levels [ Time Frame: First 28 days of treatment only (cycle 1) ] [ Designated as safety issue: Yes ]
  MTD defined as dose where Dose Limiting Toxicity (DLT) fewer than one-third of participants experience a DLT to Metformin (MFRMN) and/or Mefloquine (MFLOQ) and/or Memantine (MEMTN) alone or in combination. MTD is dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT.
• Progression Free Survival (PFS) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  A brain MRI/CT will be done prior to every other cycle. A scan done at 6 months from initiation of therapy will be performed to ensure assessment of the primary endpoint.

• Maximum Tolerated Dose (MTD) Levels [ Time Frame: First 28 days of treatment only (cycle 1) ] [ Designated as safety issue: Yes ]
  MTD defined as dose where Dose Limiting Toxcity (DLT) fewer than one-third of participants experience a DLT to Metformin (MFRMN) and/or Mefloquine (MFLOQ) and/or Memantine (MEMTN) alone or in combination. MTD is dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT.
• Progression Free Survival (PFS) [ Time Frame: 6 months ] [ Designated as safety issue: Yes ]
  A brain MRI/CT will be done prior to every other cycle. A scan done at 6 months from initiation of therapy will be performed to ensure assessment of the primary endpoint. Films on participants achieving 6 months progression free survival or a response of partial response (PR) or complete response (CR) will be evaluated by a Central Film review.

The goal of this clinical research study is to find the highest tolerable dose of temozolomide in combination with memantine, mefloquine, and/or metformin that can be given to patients with glioblastoma who have already been given radiation and chemotherapy in combination. The safety of these drug combinations will also be studied.

Temozolomide is designed to kill cancer cells by damaging DNA (the genetic material of cells). The damaged DNA may cause tumor cell death.

Memantine is designed to block the activity of a protein found on the surface of cells that may control tumor growth and survival. This may stop further spread of tumor cells.

Mefloquine is designed to block a protein that helps to clean the waste in the cells and to destabilize the cell membrane. Blocking this protein may cause tumor cell death.

Metformin is designed to block a protein in tumor cells that is important in tumor growth and blood vessel development. This may cause cell death or reduce the spread of the disease.

Study Groups:

If you are found to be eligible to take part in this study, you will be assigned to a study group based on when you join this study. Three (3) to 6 participants will be enrolled in each group.

• If you are in Group 1, you will take temozolomide and memantine.
• If you are in Group 2, you will take temozolomide and mefloquine.
• If you are in Group 3, you will take temozolomide and metformin.

If no intolerable side effects are seen in Groups 1-3, the next participants will be enrolled in Groups 4-6. You will also be enrolled in a study group based on when you join the study.

• If you are in Group 4, you will take temozolomide, memantine, and mefloquine.
• If you are in Group 5, you will take temozolomide, memantine, and metformin.
• If you are in Group 6, you will take temozolomide, mefloquine, and metformin.

If no intolerable side effects are seen in Groups 4-6, the next 12 participants will be enrolled in Group 7. If you are in Group 7, you will take temozolomide, memantine, mefloquine, and metformin.

The study drug doses may vary from group to group. The study doctor will discuss this with you.

Study Drug Administration:

Each cycle is 28 days. Unless you have side effects, you will receive the same dose level of each drug for the entire study. If you do have side effects, your dose and the doses received by later study groups may be lowered.

You will take temozolomide by mouth 1 time each day on Days 1-5 of every cycle. You should swallow the temozolomide capsules whole, one right after the other, without chewing them. They should be taken on an empty stomach (at least 2 hours after and 1 hour before eating) with about 1 cup (8 ounces) of water.

If you are in Groups 1, 4, 5, or 7, you will take memantine by mouth 2 times each day while you are on study. It should be taken about 12 hours apart. You should swallow the memantine capsules whole, one right after the other, without chewing them. They should be taken on an empty stomach (at least 2 hours after and 1 hour before eating) with about 1 cup of water.

If you are in Groups 2, 4, 6, or 7, you will take mefloquine by mouth 1 time a day on Days 1-3 of the first week, then on Monday, Wednesday, and Friday of every week after that while you are on study. You should take mefloquine with food and about 1 cup of water.

If you are in Groups 3, 5, 6, or 7, you will take metformin by mouth 2 times a day every day while you are on study. It should be taken about 12 hours apart. You should swallow the metformin tablets whole, one right after the other, without chewing them. They should be taken with food and with about 1 cup of water.

While taking multiple study drugs, you can take mefloquine and metformin together. You can take temozolomide and memantine together. You should take mefloquine and/or metformin about 2-4 hours apart from temozolomide and/or memantine.

If you vomit while taking the study drugs, you should not make up the dose or take any more before the next scheduled dose.

Study Visits:

Every week for the first cycle, then every 4 weeks, you will be asked about any drugs you may be taking and if you have had any side effects.

Every week during Cycle 1, then every 2 weeks, blood (about 1-2 teaspoons) will be drawn for routine tests.

Every 4 week during Cycles 1 and 2, then every 8 weeks:

• You will have a physical exam, including measurement of your vital signs.
• You will have a neurologic exam.
• Your performance status will be recorded.

Every 8 weeks:

-You will have an MRI scan or CT scans of the brain to check the status of the disease.

If you are in Groups 2, 4, 6, or 7, on Day 1 of Cycles 3 and 7, you will have an ECG.

At any time during the study, extra tests may be performed if the doctor thinks they are needed for your safety. The study doctor will tell you more about any extra tests.

Length of Study:

You may take the study drugs for up to 24 cycles, as long as the doctor thinks it is in your best interest. You will no longer be able to take the study drug if the disease gets worse, if intolerable side effects occur, or if you are unable to follow study directions.

Long-Term Follow-Up:

After you stop taking the study drugs, the study staff will call you every 3 months to check how you are doing. Each phone call will take about 5 minutes.

This is an investigational study. Each study drug is FDA approved and commercially available for different uses:

• Temozolomide for the treatment of some types of brain cancer
• Memantine for the treatment of Alzheimer's disease
• Mefloquine for the treatment of malaria
• Metformin for the treatment of diabetes

The use of these drugs in combination is investigational.

Up to 144 patients will take part in this study. All will be enrolled at MD Anderson.

• Drug: Temozolomide
  150 m/m2 by mouth 1 time each day on alternate weeks on Days 1-7 and Days 15-21 of every 28 day cycle.
  Other Name: Temodar
• Drug: Memantine
  30 mg by mouth twice a day for a 28 day cycle.
  Other Name: Namenda
• Drug: Mefloquine
  250 mg by mouth 1 time a day on Days 1-3 of the first week, then on Monday, Wednesday, and Friday of every week after that for a 28 day cycle.
  Other Names:

  • Mefloquine
  • Apo-Mefloquine
  • Lariam
• Drug: Metformin
  1000 mg by mouth twice a day for a 28 day cycle.

• Experimental: Arm 1: TMZ + MEMTN
  Temozolomide 150 m/m2 by mouth 1 time each day on alternate weeks on Days 1-7 and Days 15-21 of every 28 day cycle. Memantine 30 mg by mouth twice a day for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Memantine
• Experimental: Arm 2: TMZ + MFLOQ
  Temozolomide 150 m/m2 by mouth on alternate weeks days 1-7, 15-21 of a 28 day cycle. Mefloquine 250 mg by mouth 1 time a day on Days 1-3 of the first week, then on Monday, Wednesday, and Friday of every week after that for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Mefloquine
• Experimental: Arm 3: TMZ + MFRMN
  Temozolomide 150 m/m2 by mouth on alternate weeks days 1-7, 15-21 of a 28 day cycle. Metformin 1000 mg by mouth twice a day for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Metformin
• Experimental: Arm 4: TMZ + MEMTN + MFLOQ
  Temozolomide 150 m/m2 by mouth on alternate weeks days 1-7, 15-21 of a 28 day cycle. Memantine 30 mg by mouth twice a day for a 28 day cycle. Mefloquine 250 mg by mouth 1 time a day on Days 1-3 of the first week, then on Monday, Wednesday, and Friday of every week after that for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Memantine
  • Drug: Mefloquine
• Experimental: Arm 5: TMZ + MEMTN + MFRMN
  Temozolomide 150m/m2 by mouth 1 time each day on alternate weeks on Days 1-7 and Days 15-21 of every 28 day cycle. Memantine 30 mg by mouth twice a day for a 28 day cycle. Metformin 1000 mg by mouth twice a day for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Memantine
  • Drug: Metformin
• Experimental: Arm 6: TMZ + MFLOQ + MFRMN
  Temozolomide 150 m/m2 by mouth 1 time each day on alternate weeks on Days 1-7 and Days 15-21 of every 28 day cycle. Mefloquine 250 mg by mouth 1 time a day on Days 1-3 of the first week, then on Monday, Wednesday, and Friday of every week after that for a 28 day cycle. Metformin 1000mg by mouth twice a day for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Mefloquine
  • Drug: Metformin
• Experimental: Arm 7: TMZ + MEMTN + MFRMN + MFLOQ
  Temozolomide 150 m/m2 by mouth 1 time each day on alternate weeks on Days 1-7 and Days 15-21 of every 28 day cycle. Memantine 30 mg by mouth twice a day for a 28 day cycle. Metformin 1000 mg by mouth twice a day for a 28 day cycle. Mefloquine 250 mg by mouth 1 time a day on Days 1-3 of the first week, then on Monday, Wednesday, and Friday of every week after that for a 28 day cycle.
  Interventions:

  • Drug: Temozolomide
  • Drug: Memantine
  • Drug: Mefloquine
  • Drug: Metformin

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.