Using fluoxetine to enhance chemotherapy effects in recurrent glioma

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

This study is testing if adding the depression medication fluoxetine to chemotherapy can help people with recurrent glioma get better results from their treatment.

Quick facts

• Phase: EARLY_PHASE1
• Study type: Interventional
• Enrollment: 30 (estimated)
• Ages: 24 Years and up
• Sex: All
• Sponsor: Duke University (other)
• Drugs / interventions: bevacizumab, chemotherapy, radiation
• Locations: 3 sites (San Diego, California and 2 other locations)
• Trial ID: NCT05634707 on ClinicalTrials.gov

What this trial studies

This study evaluates whether fluoxetine, an FDA-approved medication for depression, can increase lysosomal stress in patients with recurrent IDHwt glioma, potentially enhancing the effectiveness of the chemotherapy drug temozolomide (TMZ). Patients will be randomly assigned to receive either fluoxetine in combination with TMZ or TMZ alone, with tumor samples collected before and during surgery to assess lysosomal changes. The study aims to determine the impact of fluoxetine on LAMP1 expression in tumor samples, which may indicate increased lysosomal stress and improved cancer cell death. The trial includes a loading dose of fluoxetine followed by two different maintenance doses.

Who should consider this trial

Good fit: Ideal candidates are adults aged 24 and older with recurrent glioma who are eligible for retreatment with temozolomide and can undergo tumor resection.

Not a fit: Patients with non-recurrent glioma or those who do not meet the eligibility criteria for surgery or chemotherapy may not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could improve treatment outcomes for patients with recurrent glioma by enhancing the efficacy of chemotherapy.

How similar studies have performed: While the use of fluoxetine in this context is novel, other studies have explored the role of lysosomal stress in cancer treatment, indicating potential for success.

Eligibility criteria

Inclusion Criteria:

1. 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.
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 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.
10. Signed informed consent approved by the Institutional Review Board

Exclusion Criteria:

1. Patients currently taking or who have taken any other anti-depressant medication within the past year
2. Patients currently taking psychotropic agents or who have taken other psychotropic agents 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 cervical carcinoma in situ and adequately treated basal cell or squamous cell carcinoma of the 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 the treating neurosurgeon
7. Patients with worsening neurologic deficits, clinically significant increased intracranial pressure (e.g., impending herniation), uncontrolled seizures, or requirement 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 the radiation field or 2 progressive scans at least 4 weeks apart or histopathologic confirmation of recurrent tumor
10. 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
11. Treated with antiangiogenic agents (i.e., bevacizumab) within 4 weeks before biopsy
12. Patients who have developed disease progression while receiving temozolomide treatment 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 of mania or susceptibility to angle-closure glaucoma
16. Patients with a history or who develop significant hyponatremia (serum sodium less than 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: Monoamine Oxidase Inhibitors (MAOI), Pimozide, Thioridazine, Drugs metabolized by the CYP2D6 pathway, 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)

Where this trial is running

San Diego, California and 2 other locations

• UC San Diego Moores Cancer Center — San Diego, California, United States (RECRUITING)
• NYU Langone Health — New York, New York, United States (RECRUITING)
• The Preston Robert Tisch Brain Tumor Center at Duke University — Durham, North Carolina, United States (RECRUITING)

Study contacts

• Principal investigator: Mustafa Khasraw, MBChB, MD, FRCP, FRACP — Duke University
• Study coordinator: Mustafa Khasraw, MBChB, MD, FRCP, FRACP

Conditions: Primary Brain Tumor, Brain Tumor, Recurrent, Brain tumor, Fluoxetine, Prozac, Recurrent, Glioma, Temozolomide