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

NCT05634707 | Active Not Recruiting Early Phase 1 DMC FDA Drug

• 1 other identifier: Pro00110628
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 4

Brief Summary

The purpose of this research study 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. Lysosomes are organelles (structures in cells) that contain digestive enzymes (substances that break down chemicals) that help keep the cells free of extra or worn out cell parts. Fluoxetine, a drug approved by the FDA to treat problems like depression and anxiety, can cause changes to structures in cells called lysosomes that then improve how well the chemotherapy drug temozolomide (TMZ) kills cancer cells in the brain.

Conditions

Primary Brain Tumor; Brain Tumor, Recurrent

Keywords

Brain tumor; Fluoxetine; Prozac; Recurrent; Glioma; Temozolomide; Tumor resection; Tumor biopsy; Mustafa Khasraw; Pro00110628

Outcome Measures

Primary Outcomes (1)

• Change in LAMP1 expression in tumor samples obtained pre-resection via biopsy and during surgery

  Determine if fluoxetine increases lysosomal stress in patients with recurrent IDHwt glioma by evaluating LAMP1 expression in tumor samples obtained during surgery or biopsy

  baseline, 1 month

Secondary Outcomes (5)

• Proportion of patients with partial or complete response at the time of surgical resection

  1 month

• Serum levels of fluoxetine using LC-MS/MS quantification

  1 month

• Serum levels of norfluoxetine using LC-MS/MS quantification

  1 month

• Intra-tumoral levels of fluoxetine using LC-MS/MS quantification

  1 month

• Intra-tumoral levels of norfluoxetine using LC-MS/MS quantification

  1 month

Study Arms (2)

Fluoxetine pre-surgery

EXPERIMENTAL

Patients randomized to the experimental arm will receive fluoxetine at 20 mg/day for 5 days (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).

Drug: Fluoxetine

Temozolomide pre-surgery

ACTIVE COMPARATOR

Temozolomide pre-surgery (control) arm will receive 50 mg/m2 temozolomide daily for 7 days (Days 1-7), followed by resection or biopsy 21 days after initiation of the temozolomide cycle.

Drug: Temozolomide

Interventions

Fluoxetine DRUG

Patients randomized to the experimental arm will receive fluoxetine 20mg/day for 5 days before escalation to a maintenance dose at day 6. On day 6, patients will start treatment with 50 mg/m2 TMZ daily for 7 days (Days 6-12) * Arm 2A (n=10) - Escalate to maintenance 40mg/day fluoxetine on day 6 * Arm 2B (n=10) - This arm will be opened as long as there are less than 3/10 dose limiting toxicities in Arm 2A. Patients will escalate to maintenance 60mg/day fluoxetine on day 6

Fluoxetine pre-surgery

Temozolomide DRUG

Patients randomized to the control arm will receive 50 mg/m2 temozolomide daily for 7 days (Days 1-7), followed by resection or biopsy 21 days after initiation of the temozolomide cycle.

Temozolomide pre-surgery

Eligibility Criteria

• Age: 24 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 glioma
• Tumor volume ≥ 1 cm3
• Clinical indication for craniotomy for biopsy and resection of the lesion
• Clinical indication for repeat treatment with Temozolomide
• Karnofsky Performance Status (KPS) \> 70%
• 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
• 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 within 48 hours of starting the infusion of the study drug.
• Signed informed consent approved by the Institutional Review Board

You may not qualify if:

• Patients currently taking or who have taken any other anti-depressant medication within the past year
• Patients currently taking psychotropic agents or who have taken other psychotropic agents within the past 7 days
• Patients with any history of mood/psychotic/substance use disorders
• 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, multifocal tumor, infratentorial tumor, 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
• Less than 12 weeks from radiation therapy, unless progressive disease outside of the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation of recurrent tumor
• Treated with immunotherapeutic agents within 4 weeks, alkylating agents within 4 weeks, nitrosoureas within 6 weeks, or non-alkylating chemotherapy within 2 weeks before enrollment, unless the patient has recovered from the expected toxic effects of such therapy
• Treated with antiangiogenic agents (i.e., bevacizumab) within 4 weeks before biopsy
• Patients who have developed disease progression while receiving temozolomide treatment are not eligible
• 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

Sponsors & Collaborators

• Duke University: lead

Study Sites (4)

UC San Diego Moores Cancer Center

San Diego, California, 90074-1539, United States

Location

Stanford Cancer Institute

Stanford, California, 94305, United States

Location

NYU Langone Health

New York, New York, 10016, United States

Location

The Preston Robert Tisch Brain Tumor Center at Duke University

Durham, North Carolina, 27710, United States

Location

Related Links

• The Preston Robert Tisch Brain Center at Duke University
• Duke Health

MeSH Terms

Conditions

Brain Neoplasms; Recurrence; Glioma

Interventions

Fluoxetine; Temozolomide

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue

Intervention Hierarchy (Ancestors)

Propylamines; Amines; Organic Chemicals; Dacarbazine; Triazenes; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Mustafa Khasraw, MBChB, MD, FRCP, FRACP

  Duke University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 22, 2022
• First Posted: December 2, 2022
• Study Start: August 5, 2023
• Primary Completion (Estimated): December 5, 2026
• Study Completion (Estimated): June 5, 2027
• Last Updated: September 22, 2025

Record last verified: 2025-09

Data Sharing

• IPD Sharing: Will not share

Locations

US (4)