This early phase I trial tests the safety and effectiveness of fluoxetine in cytotoxic lysosomal stress and in enhancing the effect of temozolomide in patients with malignant gliomas that has come back after a period of improvement (recurrent). Fluoxetine is in a class of medications called selective serotonin reuptake inhibitors. It works by increasing the amount of serotonin, a natural substance in the brain that helps maintain mental balance. Fluoxetine may also cause changes to structures in the cells called lysosomes. Lysosomes are structures in cells that contain digestive enzymes that help keep the cells free of extra or worn out cell parts. Temozolomide is in a class of medications called alkylating agents. It works by damaging the cell's DNA and may kill tumor cells and slow down or stop tumor growth. Giving fluoxetine may induce lysosomal stress and kill more tumor cells when given with temozolomide in patients with recurrent malignant gliomas.
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT05634707.
PRIMARY OBJECTIVE:
I. Determine if fluoxetine increases lysosomal stress in patients with recurrent malignant glioma by evaluating LAMP1 expression in tumor samples pre-resection via biopsy and during surgery.
SECONDARY OBJECTIVES:
I. Evaluate the safety of co-treatment of 40 mg/day and 60 mg/day fluoxetine alongside temozolomide in patients with malignant glioma (both before and after resection/biopsy).
II. Estimate objective response rate.
EXPLORATORY OBJECTIVES:
I. Determine intra-tumoral accumulation of fluoxetine and norfluoxetine levels in resected samples using liquid chromatography mass spectrometry (LC-MS)/mass spectrometry (MS) quantification in serum and tumor samples.
II. Determine if fluoxetine can enhance deoxyribonucleic acid (DNA) damage induced by temozolomide (TMZ) by evaluating gamma H2AX expression in tumor samples of patients with recurrent malignant glioma.
III. Assess anti-tumor effect by evaluated post-treatment tumor samples for presence or absence of viable tumor and necrosis.
IV. Assess internalization and downregulation of epidermal growth factor receptor (EGFR) through treatment with fluoxetine.
V. Overall survival (OS) and progression-free survival (PFS).
OUTLINE: This is a dose escalation study of fluoxetine. Patients are randomized to 1 of 2 arms.
ARM I: Patients receive TMZ orally (PO) once daily (QD) on days 1-7 and then undergo a surgical resection or biopsy on around day 21 of cycle 1. Treatment resumes after surgical resection or biopsy and cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients may optionally receive fluoxetine PO QD after resection in co-ordination with treating physician. Patients also undergo blood sample collection and magnetic resonance imaging (MRI) at screening and throughout study. Additionally, patients may undergo a tissue biopsy before randomization.
ARM II: Patients receive fluoxetine PO QD on days 1-28 and TMZ PO QD on days 6-12 and then undergo a surgical resection or biopsy on around 21 days after starting TMZ with cycle 1. Treatment resumes after surgical resection or biopsy and cycles repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo blood sample collection and MRI at screening and throughout study. Additionally, patients may undergo tissue biopsy before randomization.
Lead OrganizationDuke University Medical Center
Principal InvestigatorMustafa Khasraw
