Temozolomide, Memantine Hydrochloride, Mefloquine, and Metformin Hydrochloride in Treating Patients With Glioblastoma Multiforme After Radiation Therapy

Sponsor

M.D. Anderson Cancer Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT01430351

Collaborator

National Cancer Institute (NCI) (NIH)

144

Enrollment

Location

Arms

132.5

Anticipated Duration (Months)

1.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This phase I trial studies the side effects and best dose of combination chemotherapy in treating patients with glioblastoma multiforme after radiation therapy. Drugs used in chemotherapy, such as temozolomide, memantine hydrochloride, and metformin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing them or stopping them from dividing. Mefloquine may help temozolomide, memantine hydrochloride, and metformin hydrochloride kill more cancer cells by making tumor cells more sensitive to the drug. Giving more than one drug (combination chemotherapy) may kill more tumor cells.

Condition or Disease	Intervention/Treatment	Phase
Glioblastoma Gliosarcoma Supratentorial Glioblastoma	Drug: Mefloquine Drug: Memantine Hydrochloride Drug: Metformin Hydrochloride Drug: Temozolomide	Phase 1

Detailed Description

PRIMARY OBJECTIVES:

To determine the safety and tolerability of temozolomide (TMZ) in combination with metformin (metformin hydrochloride) (MFRMN) and/or mefloquine (MFLOQ) and/or memantine (memantine hydrochloride) (MEMTN) in patients receiving adjuvant therapy after completing external beam radiotherapy (XRT) in combination with chemotherapy for newly diagnosed glioblastoma multiforme (GBM).

SECONDARY OBJECTIVES:

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.

OUTLINE: This is a dose-escalation study. Patients are randomized to 1 of 8 different treatment arms.

ARM 1: Patients receive temozolomide orally (PO) once daily (QD) on days 1-5.

ARM 2: Patients receive temozolomide PO as in Arm 1 and memantine hydrochloride PO twice daily (BID).

ARM 3: Patients receive temozolomide PO as in Arm 1 and 30 mg mefloquine PO QD on days 1-3 of week 1 and then days 2, 4, and 6 every other week.

ARM 4: Patients receive temozolomide PO as in Arm 1 and metformin hydrochloride PO BID.

ARM 5: Patients receive temozolomide PO and memantine hydrochloride PO BID as in Arm 2, and mefloquine PO QD as in Arm 3.

ARM 6: Patients receive temozolomide PO and memantine hydrochloride PO BID as in Arm 2, and metformin hydrochloride PO BID as in Arm 4.

ARM 7: Patients receive temozolomide PO as in Arm 1, mefloquine PO QD as in Arm 3, and metformin hydrochloride PO BID as in Arm 4.

ARM 8: Patients receive temozolomide PO and memantine hydrochloride PO BID as in Arm 2, metformin hydrochloride PO BID as in Arm 4, and mefloquine PO QD as in Arm 3.

In all arms, courses repeat every 28 days for up to 24 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

144 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel 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 :

Sep 14, 2011

Anticipated Primary Completion Date :

Sep 30, 2022

Anticipated Study Completion Date :

Sep 30, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 (temozolomide) Patients receive temozolomide PO QD on days 1-5.	Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 2 (temozolomide, memantine hydrochloride) Patients receive temozolomide PO as in Arm 1 and memantine hydrochloride PO BID.	Drug: Memantine Hydrochloride Given PO Other Names: Ebixia Namenda Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 3 (temozolomide, mefloquine) Patients receive temozolomide PO as in Arm 1 and 30 mg mefloquine PO QD on days 1-3 of week 1 and then days 2, 4, and 6 every other week.	Drug: Mefloquine Given PO Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 4 (temozolomide, metformin hydrochloride) Patients receive temozolomide PO as in Arm 1 and metformin hydrochloride PO BID.	Drug: Metformin Hydrochloride Given PO Other Names: APO-Metformin Cidophage Dimefor Glifage Glucoformin Glucophage Glucophage ER Metformin HCl Riomet Siofor Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 5 (temozolomide, memantine hydrochloride, mefloquine) Patients receive temozolomide PO and memantine hydrochloride PO BID as in Arm 2, and mefloquine PO QD as in Arm 3.	Drug: Mefloquine Given PO Drug: Memantine Hydrochloride Given PO Other Names: Ebixia Namenda Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 6 (temozolomide, memantine hydrochloride, metformin) Patients receive temozolomide PO and memantine hydrochloride PO BID as in Arm 2, and metformin hydrochloride PO BID as in Arm 4.	Drug: Memantine Hydrochloride Given PO Other Names: Ebixia Namenda Drug: Metformin Hydrochloride Given PO Other Names: APO-Metformin Cidophage Dimefor Glifage Glucoformin Glucophage Glucophage ER Metformin HCl Riomet Siofor Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 7 (temozolomide, mefloquine, metformin hydrochloride) Patients receive temozolomide PO as in Arm 1, mefloquine PO QD as in Arm 3, and metformin hydrochloride PO BID as in Arm 4.	Drug: Mefloquine Given PO Drug: Metformin Hydrochloride Given PO Other Names: APO-Metformin Cidophage Dimefor Glifage Glucoformin Glucophage Glucophage ER Metformin HCl Riomet Siofor Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac
Experimental: Arm 8 (TMZ, memantine hydrochloride, metformin, mefloquine) Patients receive temozolomide PO and memantine hydrochloride PO BID as in Arm 2, metformin hydrochloride PO BID as in Arm 4, and mefloquine PO QD as in Arm 3.	Drug: Mefloquine Given PO Drug: Memantine Hydrochloride Given PO Other Names: Ebixia Namenda Drug: Metformin Hydrochloride Given PO Other Names: APO-Metformin Cidophage Dimefor Glifage Glucoformin Glucophage Glucophage ER Metformin HCl Riomet Siofor Drug: Temozolomide Given PO Other Names: CCRG-81045 Imidazo[5,1-d]-1,2,3,5-tetrazine-8-carboxamide, 3, 4-dihydro-3-methyl-4-oxo- M & B 39831 M and B 39831 Methazolastone RP-46161 SCH 52365 Temcad Temodal Temodar Temomedac

Outcome Measures

Primary Outcome Measures

Incidence of toxicities graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [During first 28 days]

Secondary Outcome Measures

Median progression free survival (PFS) [Up to 4 years]
PFS [Up to 18 months]
Median overall survival (OS) [Up to 4 years]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Patients with histologically proven supratentorial glioblastoma or gliosarcoma (World Health Organization [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)
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
Patients must have a Karnofsky performance status (KPS) of >= 60
White blood cells (WBC) >= 3,000/ul (performed within 14 days prior to registration)
Absolute neutrophil count (ANC) >= 1,500/mm^3 (performed within 14 days prior to registration)
Platelet count of >= 100,000/mm^3 (performed within 14 days prior to registration)
Hemoglobin >= 10 gm/dl (eligibility level for hemoglobin may be reached by transfusion) (performed within 14 days prior to registration)
Serum glutamic oxaloacetic transaminase (SGOT) < 2 times upper limit of normal (ULN) (performed within 14 days prior to registration)
Bilirubin < 2 times ULN (performed within 14 days prior to registration)
Creatinine < 1.5 mg/dL (performed within 14 days prior to registration)
For patients on mefloquine arm, a baseline electrocardiogram (EKG) without evidence of prolonged corrected QT (QTc) interval > 450 ms or clinically significant arrhythmia must be obtained within 14 days prior to registration
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 magnetic resonance (MR)/computed tomography (CT) is required; the same type of scan, i.e., magnetic resonance imaging (MRI) or CT must be used throughout the period of protocol treatment for tumor measurement
Patients must have completed standard radiation therapy with concurrent TMZ and must not have evidence of progressive disease on post treatment imaging
Women of childbearing potential must have a negative serum or urine beta-human chorionic gonadotropin (B-HCG) pregnancy test documented within 72 hours of start of therapy
Patients must be registered on the study within 5 weeks of completion of concurrent chemoradiation

Exclusion Criteria:

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
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
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
Patients must not have active infection or serious intercurrent medical illness
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 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
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-week wash out period will be required after stopping EIAED prior to initiation of treatment