Low Dose Naltrexone for Glioma Patients

The proposed study is a placebo-controlled, randomized clinical trial. Potential participants will be identified via clinical protocol chart review of patients scheduled to attend their predetermined follow-up consultations at The Preston Robert Tisch Brain Tumor Center (PRT-BTC) at Duke University Medical Center after evaluation of treatment for newly diagnosed high grade gliomas. We will identify high grade glioma patients that will receive standard chemoradiation (radiotherapy with daily temozolomide dosed at 75 mg/m2). After obtaining written informed consent, all participants will be scheduled for baseline study assessments before starting radiotherapy. Patients will be randomized to receive either placebo or low dose naltrexone (LDN) dosed at 4.5 mg orally to be taken every evening before going to bed. Patients will be assessed at the following time points: 1. Baseline (before chemoradiation), 2. After chemoradiation (approximately 8 weeks from initial assessment), 3. Two months after standard chemoradiation (approximately 16 weeks after initial assessment), and 4. Four months after standard chemoradiation (approximately 24 weeks after initial assessment). Treatment with LDN or placebo will begin on first day of chemoradiation and will be continued for a total of 16 weeks from initial assessment. Last assessment at 24 weeks will occur 8 weeks after discontinuation of LDN or placebo. All visits will be linked to patients' clinical management visits. All testing will be performed at PRT-BTC and at Duke University Medical Center.

The following procedures will be obtained at each assessment visit:

• Complete a six-minute walk test. The exercise test is designed to determine how far the subject can walk in six minutes. This test will take place at the PRT-BTC at Duke University Medical Center with appropriate medical supervision.
• Blood testing that will be performed as part of each clinic visit. Approximately 10 milliliters or 2 teaspoons of blood will be drawn at each visit. This will not be additional blood work, but rather the standardized blood work that the subject will need for evaluation associated with radiation and chemotherapy treatments.

We will ask the subject to complete the following tests/questionnaires:

• Neurocognitive testing: this testing will be performed using a computer program called CNS Vital Signs®. This program consists of verbal and visual memory tests, attention tests, reasoning tests, and speed of processing tests. The subject will use a laptop computer to complete these tests. No previous exposure to computers or computer testing is needed to complete the test.
• Computerized Questionnaires: Four questionnaires will be presented using a computerized program. These will include Medical Outcomes Survey (MOS), Epworth Sleepiness Scale (ESS), Pittsburgh Sleep Quality Index (PSQI), and Zung Self-Rating Depression Scale (ZSDS). MOS assesses general health, well-being, and quality of life. ESS asks about level of sleepiness while PSQI asks about sleep quality. Finally, ZSDS will evaluate feelings of depression and sadness.
• Beck depression inventory (BDI): This questionnaire asks questions about the subject's levels of sadness, changes in the subject's mood, sleeping and eating patterns, the subject's level of interest in activities, thoughts and feelings the subject is having and the subject's level of concentration. This is a pen and paper questionnaire.
• Functional Assessment of Cancer Therapy-Brain (FACT-BR) scale: This questionnaire asks questions about physical, function, emotional, and social well-being. This is a pen and paper questionnaire.
• Functional Assessment of Cancer Therapy-Fatigue (FACIT-F) scale: This questionnaire asks questions about fatigue. This is a pen and paper questionnaire.
• Functional Assessment of Cancer Therapy-Cognition (FACT-Cog) scale: This questionnaire asks questions about your thinking and ability to do memory, attention, and reasoning activities. This is a pen and paper questionnaire.

Inclusion criteria

• written informed consent prior to beginning specific protocol procedures
• histologically proven high-grade glioma
• planned treatment with concurrent radiotherapy and daily oral temozolomide (with or without Avastin)
• ≥ 18 years of age
• Karnofsky performance index ≥ 70%
• must be able to ambulate unassisted for 6 minutes safely
• The Preston Robert Tisch Brain Tumor Center (PRT-BTC) neuro-oncologist's approval
• hematocrit ≥ 29%, hemoglobin ≥ 9, absolute neutrophil count (ANC) ≥ 1,500 cells/microliter, platelets ≥ 100,000 cells/microliter
• serum creatinine < 1.5 times upper limit of normal, serum glutamic oxaloacetic transaminase (SGOT) < 2.5 times upper limit of normal and bilirubin < 2.0 times upper limit of normal
• if sexually active, patients will take contraceptive measures for the duration of the treatments
• Women of childbearing potential must have a negative serum pregnancy test within 48 hours prior to administration of study drug

Exclusion criteria

• prior therapy with naltrexone or naloxone
• co-medication that may interfere with study results, e.g. opioids,
• known hypersensitivity to any component of naltrexone
• pregnant (positive pregnancy test) or lactating