A Randomized Surgical Window of Opportunity Study With Dose Escalation to Evaluate Whether Oral Fluoxetine Can Induce Cytotoxic Lysosomal Stress and Enhance Temozolomide Efficacy in Clinical Glioma

The purpose of this study is to determine whether oral fluoxetine can induce lysosomal stress and enhance Temozolomide (TMZ)-induced cell death in patients diagnosed with recurrent malignant glioma. The primary objective is to determine if fluoxetine increases lysosomal stress in patients with recurrent IDHwt glioma by evaluating LAMP1 expression in tumor samples obtained pre-resection via biopsy and during surgery. Following consent, an optional biopsy may be performed to confirm recurrence of high-grade glioma. Recurrent glioma patients for whom retreatment with TMZ is appropriate and who are able to undergo tumor resection after 1 cycle of temozolomide will be enrolled in this study. Following enrollment, patients will randomly be assigned to (1:2) a study arm: control (n=10) or experimental (n=20). Within the experimental arm, two maintenance dose levels of fluoxetine are planned - 40mg OD (n=10) and 60mg OD (n=10). Patients randomized to the control arm will receive only 50 mg/m2 TMZ daily for 7 days (Days 6-12), followed by resection 21 days after initiation of the TMZ cycle. Patients randomized to the experimental arm will receive fluoxetine at 20 mg/day for 5 days (loading initiation dose) followed by a maintenance dose of 40 mg/day starting on Day 6 (dose level 1) or 60 mg/day starting on Day 6 (dose level 2) This truncated initiation period of fluoxetine has been discussed with the psychiatry department at Duke University Hospital and has been judged to be safe given the additional monitoring precautions that are being included as part of this study. On Day 6, patients will start treatment with 50 mg/m2 TMZ daily for 7 days (Days 6-12). Resection will occur 21 days after initiation of the TMZ cycle on Day 27. Patients will remain on their assigned dose of fluoxetine through resection and follow-up, as long as the treatment regimen is tolerated. The change between baseline and post-resection will be computed to determine if co-administration of fluoxetine and TMZ will result in increased expression of LAMP1 on resected glioma cells. Within each group, a Wilcoxon signed-rank test will be conducted to determine if there are significant within group changes. A Kruskal-Wallis test will compare the three patient groups (Control Group, Fluoxetine Group \[low-dose\], Fluoxetine Group \[high-dose\]) with respect to these changes. If data suggests that parametric method are appropriate, then analysis of variance and a paired t-test will be conducted. Risks commonly associated with fluoxetine include nausea, diarrhea, lack of appetite, dry mouth, upset stomach or heartburn, constipation, insomnia, anxiety, nervousness, drowsiness, tremor, unusual dreams, headaches, dizziness, yawning, swelling of face, low body temperature, sexual dysfunction, rash, hives and itching, sweating, flu-like symptoms, sore throat, stuffy nose, and fever.