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

This study is currently recruiting participants.
Verified March 2014 by M.D. Anderson Cancer Center
Sponsor:
Information provided by (Responsible Party):
M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier:
NCT01430351
First received: September 6, 2011
Last updated: March 7, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Brain Cancer
Drug: Temozolomide
Drug: Memantine
Drug: Mefloquine
Drug: Metformin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Factorial Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by M.D. Anderson Cancer Center:

Primary Outcome Measures:
  • 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.


Estimated Enrollment: 144
Study Start Date: September 2011
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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:
  • Mefloquine
  • 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:
  • Mefloquine
  • 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:
  • Mefloquine
  • 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:
  • Mefloquine
  • Apo-Mefloquine
  • Lariam
Drug: Metformin
1000 mg by mouth twice a day for a 28 day cycle.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
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
Please refer to this study by its ClinicalTrials.gov identifier: NCT01430351

Contacts
Contact: Marta Penas-Prado, MD 713-792-2883

Locations
United States, Texas
UT MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Sponsors and Collaborators
M.D. Anderson Cancer Center
Investigators
Principal Investigator: Marta Penas-Prado, MD UT MD Anderson Cancer Center
  More Information

Additional Information:
No publications provided

Responsible Party: M.D. Anderson Cancer Center
ClinicalTrials.gov Identifier: NCT01430351     History of Changes
Other Study ID Numbers: 2011-0374, NCI-2011-03038
Study First Received: September 6, 2011
Last Updated: March 7, 2014
Health Authority: United States: Institutional Review Board

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:
Brain Neoplasms
Glioblastoma
Central Nervous System Neoplasms
Nervous System Neoplasms
Neoplasms by Site
Neoplasms
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Mefloquine
Memantine
Metformin
Temozolomide
Dacarbazine
Antimalarials
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Dopamine Agents
Neurotransmitter Agents

ClinicalTrials.gov processed this record on April 15, 2014