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

Study Description

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Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Brain Cancer	Drug: Temozolomide; Drug: Memantine; Drug: Mefloquine; Drug: Metformin	Phase 1

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	144 participants
Allocation:	Non-Randomized
Intervention Model:	Factorial Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase I Lead-in to a 2x2x2 Factorial Trial of Temozolomide, Memantine, Mefloquine, and Metformin as Post-Radiation Adjuvant Therapy of Glioblastoma Multiforme
Actual Study Start Date :	September 2011
Estimated Primary Completion Date :	September 2019
Estimated Study Completion Date :	September 2019

Arms and Interventions

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Arm	Intervention/treatment
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.	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
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.	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: 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: Apo-Mefloquine; Lariam
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.	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: Metformin; 1000 mg by mouth twice a day for a 28 day cycle.
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.	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: Apo-Mefloquine; Lariam
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.	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: Metformin; 1000 mg by mouth twice a day for a 28 day cycle.
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.	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: 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: Apo-Mefloquine; Lariam; Drug: Metformin; 1000 mg by mouth twice a day for a 28 day cycle.
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.	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: Apo-Mefloquine; Lariam; Drug: Metformin; 1000 mg by mouth twice a day for a 28 day cycle.

Outcome Measures

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Primary Outcome Measures :

1. Maximum Tolerated Dose (MTD) Levels [ Time Frame: First 28 days of treatment only (cycle 1) ]
   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.
2. Progression Free Survival (PFS) [ Time Frame: 6 months ]
   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.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

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.

Contacts and Locations

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Locations

United States, Texas
University of Texas MD Anderson Cancer Center
Houston, Texas, United States, 77030

Sponsors and Collaborators

M.D. Anderson Cancer Center

Investigators

Principal Investigator:	John DeGroot, MD	M.D. Anderson Cancer Center

More Information

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Additional Information:

University of Texas MD Anderson Cancer Center Website 

Responsible Party:	M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:	NCT01430351 History of Changes
Other Study ID Numbers:	2011-0374; NCI-2011-03038 ( Registry Identifier: NCI CTRP )
First Posted:	September 8, 2011
Last Update Posted:	January 14, 2019
Last Verified:	January 2019

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by M.D. Anderson Cancer Center:

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

Additional relevant MeSH terms:

Glioblastoma; Brain Neoplasms; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases	Central Nervous System Diseases; Nervous System Diseases; Metformin; Temozolomide; Dacarbazine; Memantine; Mefloquine; Hypoglycemic Agents; Physiological Effects of Drugs; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiparkinson Agents; Anti-Dyskinesia Agents