Trial Title:
Evaluation of Fluoxetine and Cytotoxic Lysosomal Stress in Glioma (FLIRT)
NCT ID:
NCT05634707
Condition:
Primary Brain Tumor
Brain Tumor, Recurrent
Conditions: Official terms:
Neoplasms
Glioma
Brain Neoplasms
Temozolomide
Fluoxetine
Conditions: Keywords:
Brain tumor
Fluoxetine
Prozac
Recurrent
Glioma
Temozolomide
Tumor resection
Tumor biopsy
Mustafa Khasraw
Pro00110628
Study type:
Interventional
Study phase:
Early Phase 1
Overall status:
Recruiting
Study design:
Allocation:
Randomized
Intervention model:
Parallel Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Fluoxetine
Description:
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
Arm group label:
Fluoxetine pre-surgery
Intervention type:
Drug
Intervention name:
Temozolomide
Description:
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.
Arm group label:
Temozolomide pre-surgery
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.
Detailed description:
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.
Criteria for 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)
Gender:
All
Minimum age:
24 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
UC San Diego Moores Cancer Center
Address:
City:
San Diego
Zip:
90074-1539
Country:
United States
Status:
Recruiting
Contact:
Last name:
David Piccioni, MD
Phone:
858-534-0244
Email:
dpiccioni@ucsd.edu
Facility:
Name:
NYU Langone Health
Address:
City:
New York
Zip:
10016
Country:
United States
Status:
Recruiting
Contact:
Last name:
Erik Sulman
Phone:
646-501-6153
Email:
Erik.Sulman@nyulangone.org
Contact backup:
Last name:
Keith Kallas
Phone:
929-455-2433
Email:
keith.kallas@nyulangone.org
Facility:
Name:
The Preston Robert Tisch Brain Tumor Center at Duke University
Address:
City:
Durham
Zip:
27710
Country:
United States
Status:
Recruiting
Contact:
Last name:
Mustafa Khasraw, MBChB, MD, FRCP, FRACP
Phone:
919-684-5301
Email:
dukebrain1@dm.duke.edu
Contact backup:
Last name:
Stevie Threatt
Phone:
919-684-5301
Email:
dukebrain1@dm.duke.edu
Start date:
August 5, 2023
Completion date:
June 5, 2027
Lead sponsor:
Agency:
Duke University
Agency class:
Other
Source:
Duke University
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05634707
https://tischbraintumorcenter.duke.edu/
http://www.dukehealth.org/clinical-trials
