Evaluation of Fluoxetine and Cytotoxic Lysosomal Stress in Glioma (FLIRT)

Inclusion Criteria:

1. Age ≥ 24 years of age Note: Fluoxetine has a warning about suicidal thoughts inchildren, adolescents, and young adults. Short-term studies did not show an increasein the risk of suicidality with antidepressants compared to placebo in adults beyondage 24.

2. Patients with recurrent glioma

3. Tumor volume ≥ 1 cm3

4. Clinical indication for craniotomy for biopsy and resection of the lesion

5. Clinical indication for repeat treatment with Temozolomide

6. Karnofsky Performance Status (KPS) > 70%

7. Adequate organ function: platelets > 100,000/µL, hemoglobin >9 gm/dL, ANC > 1000/µL;creatinine < 1.5x upper limit of normal (ULN), total bilirubin < 1.5x ULN, AST/ALT < 2.5x ULN within 72 hours prior to first administration of Fluoxetine

8. Able to undergo MRI brain with and without contrast

9. If the patient is a sexually active female of childbearing potential, whose partneris male, or if the patient is a sexually active male, whose partner is a female ofchildbearing potential, the patient must use appropriate contraceptive measures forthe duration of the treatment and for 6 months afterwards. Female patients ofchildbearing potential must have a negative serum pregnancy test at the time ofscreening and within 48 hours of starting the infusion of the study drug.

10. Signed informed consent approved by the Institutional Review Board

Exclusion Criteria:

1. Patients currently taking or who have taken any other anti-depressant medicationwithin the past year

2. Patients currently taking psychotropic agents or who have taken other psychotropicagents within the past 7 days

3. Patients with any history of mood/psychotic/substance use disorders

4. Prior, unrelated malignancy requiring current active treatment except for cervicalcarcinoma in situ and adequately treated basal cell or squamous cell carcinoma ofthe skin

5. Patients who are pregnant or breastfeeding

6. Patients with contrast-enhancing tumor crossing the midline, multifocal tumor,infratentorial tumor, tumor in eloquent brain regions, extensive tumor dissemination (subependymal or leptomeningeal), or in unsafe brain regions per the opinion of thetreating neurosurgeon

7. Patients with worsening neurologic deficits, clinically significant increasedintracranial pressure (e.g., impending herniation), uncontrolled seizures, orrequirement for immediate palliative treatment

8. Unstable systemic disease in the opinion of the treating physician

9. Less than 12 weeks from radiation therapy, unless progressive disease outside of theradiation field or 2 progressive scans at least 4 weeks apart or histopathologicconfirmation of recurrent tumor

10. Treated with immunotherapeutic agents within 4 weeks, alkylating agents within 4weeks, nitrosoureas within 6 weeks, or non-alkylating chemotherapy within 2 weeksbefore enrollment, unless the patient has recovered from the expected toxic effectsof such therapy

11. Treated with antiangiogenic agents (i.e., bevacizumab) within 4 weeks before biopsy

12. Patients who have developed disease progression while receiving temozolomidetreatment are not eligible

13. Patients with allergy to fluoxetine

14. Patients with known cardiac disease, predisposing to long QT syndrome

15. Patients with diabetes mellitus, epilepsy, history of bleeding disorders, history ofmania or susceptibility to angle-closure glaucoma

16. Patients with a history or who develop significant hyponatremia (serum sodium lessthan 130mmol/L)

17. Patients with a history of bipolar disorder or schizoaffective disorder

18. Patients with a history of seizure disorder prior to onset of their primary glioma

19. Patients who are currently taking or have taken in the past 2 months: MonoamineOxidase Inhibitors (MAOI), Pimozide, Thioridazine, Drugs metabolized by the CYP2D6pathway, Tricyclic Antidepressants, Antipsychotics, Serotonergic Drugs, Triptans,Tryptophan, Anticoagulant drugs (e.g., NSAIDs, aspirin, warfarin), Olanzapine

20. Patients who demonstrated thrombocytopenia following prior treatment with TMZ (platelets < 50,000/µL)