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


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Brain Cancer

Thank you

Trial Information

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


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.


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/┬Ál, 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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Maximum Tolerated Dose (MTD) Levels

Outcome Description:

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.

Outcome Time Frame:

First 28 days of treatment only (cycle 1)

Safety Issue:

Yes

Principal Investigator

Marta Penas-Prado, MD

Investigator Role:

Principal Investigator

Investigator Affiliation:

UT MD Anderson Cancer Center

Authority:

United States: Institutional Review Board

Study ID:

2011-0374

NCT ID:

NCT01430351

Start Date:

September 2011

Completion Date:

Related Keywords:

  • Brain Cancer
  • Brain cancer
  • Central nervous system
  • Glioblastoma Multiforme
  • GBM
  • Post Radiation Therapy
  • Post-RT
  • External beam radiotherapy
  • XRT
  • Supratentorial glioblastoma
  • Gliosarcoma
  • Grade IV astrocytoma
  • Temozolomide
  • Temodar
  • Memantine
  • Namenda
  • Mefloquine
  • Apo-Mefloquine
  • Lariam
  • Metformin
  • Brain Neoplasms
  • Glioblastoma

Name

Location

UT MD Anderson Cancer Center Houston, Texas  77030