A Phase I Lead-in to a 2x2x2 Factorial Trial of Temozolomide, Memantine, Mefloquine, and Metformin as Post-Radiation Adjuvant Therapy of Glioblastoma Multiforme
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.
Disease Group: Brain
Treatment Agent: Mefloquine
Treatment Location: Only at MD Anderson
Primary Objective To determine the safety and tolerability of temozolomide (TMZ) in combination with Metformin(MFRMN) and/or Mefloquine(MFLOQ) and/or Memantine(MEMTN) in patients receiving adjuvant therapy after completing external beam radiotherapy(XRT) in combination with chemotherapy for newly diagnosed glioblastoma multiforme(GBM). Secondary Objective To determine the median progression free survival (PFS) 6, 12, and 18 month PFS and median overall survival (OS) in patients treated with temozolomide and a combination of metformin and/or mefloquine and/or memantine.
IRB Review and Approval Date: 09/14/2011
Recruitment Status: Closed
Projected Accrual: N/A
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.
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 durgs, 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.