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Fluoxetine to Induce Cytotoxic Lysosomal Stress and Enhance Temozolomide Efficacy in Patients with Recurrent Malignant Gliomas, the FLIRT Trial
Trial Status: active
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.
Inclusion Criteria
Age ≥ 24 years of age
* Note: Fluoxetine has a warning about suicidal thoughts in children, adolescents, and young adults. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24
Patients with recurrent malignant glioma
Tumor volume ≥ 1 cm^3
Clinical indication for resection or biopsy, intended to take place after cycle 1 (note: a diagnostic tissue sample will be obtained 21 +/- 2 days after the start of TMZ for recurrence)
Clinical indication for repeat treatment with TMZ (Patients with recurrent malignant glioma who experience progression after a treatment-free interval of at least 6 months from prior TMZ)
Karnofsky performance status (KPS) ≥ 70%
Platelets ≥ 100,000/uL
Hemoglobin > 9 gm/dL
Absolute neutrophil count (ANC) ≥ 1000/uL
Creatinine =< 1.5 x upper limit of normal (ULN)
Total bilirubin =< 1.5 x ULN (Exception: Patient has known Gilbert’s syndrome or patient has suspected Gilbert’s syndrome for which additional lab testing of direct and/or indirect bilirubin supports this diagnosis. In these instances, a total bilirubin of ≤ 3.0 x ULN is acceptable.)
Able to undergo MRI brain with and without contrast
If the patient is a sexually active female of childbearing potential, whose partner is male, or if the patient is a sexually active male, whose partner is a female of childbearing potential, the patient must use appropriate contraceptive measures for the duration of the treatment and for 6 months afterwards. Female patients of childbearing potential must have a negative serum pregnancy test at the time of screening and prior to cycle 1 visit. Signed informed consent approved by the institutional review board
Exclusion Criteria
Patients who are currently taking or have taken in the past 2 months: monoamine oxidase inhibitors (MAOI), pimozide, thioridazine, drugs metabolized by the CYP2D6 pathway, tricyclic antidepressants, antipsychotics, serotonergic drugs, triptans, tryptophan, olanzapine
Patients on anticoagulant drugs (e.g., nonsteroidal antiinflammatory drugs [NSAIDs], aspirin, warfarin) that are unable to safely discontinue the medication for the duration of this trial will be excluded from this study. Patients on anticoagulant drugs (e.g., NSAIDs, aspirin, warfarin) that are able to safely discontinue the medication will need to stop the anti-coagulant prior to the optional biopsy per the recommendation of the neurosurgeon
Patients currently taking or who have taken any anti-depressant medication within the past year, including fluoxetine
Patients with any history of mood/psychotic/substance use/bipolar disorder/schizoaffective disorders. Note that situational depression due to recent recurrence is not an exclusion
Prior, unrelated malignancy requiring current active treatment except for cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the skin
Patients who are pregnant or breastfeeding
Patients with contrast-enhancing tumor crossing the midline, tumor in eloquent brain regions, extensive tumor dissemination (subependymal or leptomeningeal), or in unsafe brain regions per the opinion of the treating neurosurgeon
Patients with worsening neurologic deficits, clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement for immediate palliative treatment
Unstable systemic disease in the opinion of the treating physician
Treated with immunotherapeutic agents within 4 weeks, alkylating agents within 4 weeks, nitrosoureas within 6 weeks, or non-alkylating chemotherapy within 2 weeks before starting the first study drug or optional biopsy (whichever comes first), unless the patient has recovered from the expected toxic effects of such therapy
Treated with antiangiogenic agents (i.e., bevacizumab) within 4 weeks before pre-treatment optional biopsy. (Bevacizumab may interfere with wound healing.)
Patients with allergy to fluoxetine
Patients with known cardiac disease, predisposing to long QT syndrome
Patients with diabetes mellitus, epilepsy, history of bleeding disorders, history of mania or susceptibility to angle-closure glaucoma
Patients with a history of seizure disorder prior to onset of their primary glioma
Patients who demonstrated thrombocytopenia following prior treatment with TMZ (requiring platelet transfusion)
Additional locations may be listed on ClinicalTrials.gov for NCT05634707.
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.
