Fluoxetine + Chemotherapy for Brain Cancer

Recruiting at 2 trial locations

Overseen By Mustafa Khasraw, M.D.

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Duke University

Must be taking: Temozolomide

Must not be taking: Antidepressants, Psychotropics, Anticoagulants, others

Disqualifiers: Mood disorders, Cardiac disease, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Approved in 2 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 2

Duration: 4 weeks

30 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is testing whether fluoxetine, a common antidepressant, can help improve the effectiveness of a chemotherapy drug called temozolomide (TMZ) in patients with recurrent brain cancer. The study focuses on patients whose cancer has returned and who are undergoing surgery. Fluoxetine is thought to make certain cell parts work harder, which helps TMZ kill cancer cells more effectively. Fluoxetine (Prozac) is one of the most frequently prescribed antidepressants in the United States and has been studied for its effects on depression in cancer patients.

Will I have to stop taking my current medications?

Yes, you may need to stop taking certain medications. The trial excludes participants who are currently taking or have recently taken antidepressants, psychotropic agents, and several other specific drugs. It's important to discuss your current medications with the trial team to see if they are allowed.

Is the combination of Fluoxetine and Temozolomide safe for treating brain cancer?

Temozolomide is generally well tolerated and safe, with common side effects like fatigue, nausea, and mild blood-related issues. However, severe blood disorders like myelodysplastic syndrome and aplastic anemia have been reported, though they are rare. ^{1 2 3 4 5}

What makes the combination of fluoxetine and temozolomide unique for treating brain cancer?

The combination of fluoxetine (an antidepressant) and temozolomide (a chemotherapy drug) is unique because fluoxetine enhances the effectiveness of temozolomide by activating a specific cell death pathway in glioma cells, potentially overcoming resistance to chemotherapy. ^{2 6 7 8 9}

What data supports the effectiveness of the drug combination of Fluoxetine and Temozolomide for brain cancer?

Temozolomide (TMZ) is an effective drug for treating brain tumors like glioblastoma multiforme (GBM) and anaplastic astrocytoma, often used with radiotherapy to improve survival. It has a favorable safety profile and is being studied in combination with other treatments for various cancers. ^{2 9 10 11 12}

Who Is on the Research Team?

Mustafa Khasraw, MBChB, MD, FRCP, FRACP

Principal Investigator

Duke University

Are You a Good Fit for This Trial?

Adults over 24 with recurrent glioma brain tumors suitable for surgery and repeat chemo with Temozolomide can join. They must be fairly active (KPS > 70%), have good organ function, and agree to use contraception if needed. Excluded are those on antidepressants within a year, other psychotropics recently, history of mood disorders, certain cancers, pregnant or breastfeeding women, specific tumor locations or conditions deemed unsafe by surgeons.

Inclusion Criteria

I am using birth control and my pregnancy test was negative.

Able to undergo MRI brain with and without contrast

My brain tumor has come back after treatment.

Exclusion Criteria

Patients who are pregnant or breastfeeding

Patients with any history of mood/psychotic/substance use disorders

I am currently taking or have taken psychotropic medication in the last week.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive fluoxetine and temozolomide pre-surgery to evaluate lysosomal stress and enhance temozolomide efficacy

4 weeks

Weekly visits for monitoring and drug administration

Surgery

Tumor resection or biopsy is performed to obtain samples for LAMP1 expression analysis

1 day

In-person surgical visit

Follow-up

Participants are monitored for safety and effectiveness after treatment and surgery

4 weeks

2 visits (in-person)

What Are the Treatments Tested in This Trial?

Interventions

• Fluoxetine
• Temozolomide

Trial Overview The trial tests whether Fluoxetine causes stress in cell structures called lysosomes in the brain which might help Temozolomide work better against cancer cells. Participants will take Fluoxetine before their scheduled surgery where researchers will compare tissue samples from before and after starting the drug.

How Is the Trial Designed?

Group I: Fluoxetine pre-surgery Experimental Treatment 1 Intervention

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).

Group II: Temozolomide pre-surgery Active Control 1 Intervention

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.

Temozolomide is already approved in European Union, United States for the following indications:

Approved in European Union as Temodal for:

• Newly diagnosed glioblastoma multiforme concomitantly with radiotherapy and subsequently as monotherapy treatment
• Children from the age of three years, adolescents and adults with malignant glioma, such as glioblastoma multiforme or anaplastic astrocytoma, showing recurrence or progression after standard therapy

Approved in United States as Temodar for:

• Newly diagnosed glioblastoma concomitantly with radiotherapy and subsequently as monotherapy treatment
• Newly diagnosed or refractory anaplastic astrocytoma

Who Is Running the Clinical Trial?

Duke University

Lead Sponsor

Trials

2,495

Recruited

5,912,000+

Published Research Related to This Trial

In a phase II clinical trial involving 21 patients with newly diagnosed glioblastoma multiforme (GBM), the combination of temozolomide (TMZ) with radiotherapy resulted in a one-year survival rate of 58% and a median survival time of 15.7 months, indicating its efficacy in extending survival.

The treatment regimen was well-tolerated, with only mild to moderate non-hematological side effects and minimal severe hematological toxicity, suggesting that TMZ has a favorable safety profile compared to traditional chemotherapy agents.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. Lanzetta, G., Campanella, C., Rozzi, A., et al.[2018]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

Temozolomide (TMZ) is shown to be more cost-effective than the traditional PCV treatment for glioblastoma multiforme (GBM), with costs of €2367 per extra life-month and €32,471 per quality-adjusted life-year (QALY).

The analysis indicates that TMZ has a high probability (over 60%) of being the most cost-effective treatment option at various willingness-to-pay thresholds, especially when considering quality of life improvements.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. Martikainen, JA., Kivioja, A., Hallinen, T., et al.[2018]

Temozolomide (TMZ) is the only anticancer drug proven to improve survival in glioblastoma when used with radiotherapy, showing high concentrations in brain tumors and cerebrospinal fluid, which enhances its effectiveness.

Molecular markers like MGMT promoter methylation can predict better responses to TMZ treatment, but side effects such as myelosuppression and nausea are common, necessitating precautions like prophylaxis against Pneumocystis carinii pneumonia.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. Shinoura, N., Yamada, R., Tabei, Y., et al.[2018]

Naringenin (NGEN) significantly reduces the migration and invasion of drug-resistant glioma cells, suggesting it can enhance the effectiveness of temozolomide (TMZ) treatment.

The study provides evidence that NGEN can overcome TMZ resistance by modifying protein levels related to cell migration and invasion, making it a promising adjunct therapy for glioma patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. J, J., Vanisree, AJ.[2022]

Temozolomide (TMZ) is an effective oral treatment for malignant gliomas, providing significant survival benefits while being generally well tolerated by patients.

While most side effects of TMZ are mild to moderate, there is a risk of severe hematologic adverse events, such as myelodysplastic syndrome and aplastic anemia, which have been documented in the literature.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. Scaringi, C., De Sanctis, V., Minniti, G., et al.[2018]

Temozolomide (TMZ) is generally safe with mild to moderate side effects, but this case report highlights a rare instance of severe aplastic anemia (AA) in a 68-year-old female patient following treatment for glioblastoma, indicating a potential serious risk associated with the drug.

The patient's AA was managed successfully with supportive care, including platelet transfusions and growth factor treatment, and her blood counts returned to normal within 38 days, emphasizing the importance of monitoring blood parameters during and after TMZ treatment to detect such rare toxicities early.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. Gilbar, PJ., Pokharel, K., Mangos, HM.[2022]

The study confirmed that the generic temozolomide capsules (TOZ039) are bioequivalent to the brand Temodal® capsules, with pharmacokinetic parameters falling within the acceptable range for both 20-mg and 100-mg doses in 29 patients with brain tumors.

The treatment was found to be safe, with no treatment-related severe adverse events or mortality reported, although 82.8% of patients experienced some adverse effects, highlighting the importance of monitoring patient responses during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. Hu, C., Lin, Q., Liu, C., et al.[2021]

In a phase II trial involving 46 patients with progressive low-grade glioma, Temozolomide (Temodar) demonstrated a 61% objective response rate, with 24% achieving complete response and 37% achieving partial response.

The treatment showed promising safety, with limited toxicity observed; however, one patient experienced severe complications, highlighting the need for careful monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. Quinn, JA., Reardon, DA., Friedman, AH., et al.[2022]

Fluoxetine (FLT) significantly inhibits the growth of glioma cells and induces apoptosis, particularly in rat glioma C6 cells, by activating the CHOP-dependent apoptosis pathway.

The combination of FLT and temozolomide (TMZ) shows a synergistic effect, enhancing the cytotoxicity against glioma cells, suggesting that FLT can sensitize these cells to TMZ treatment, which may improve outcomes for patients with advanced glioma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Ma, J., Yang, YR., Chen, W., et al.[2022]

Temozolomide (TMZ) is an effective oral treatment for recurrent glioblastoma multiforme, showing nearly 100% bioavailability and a favorable safety profile, making it a promising option for patients with this aggressive brain cancer.

Research is ongoing to enhance the efficacy of TMZ by combining it with other treatments like chemotherapy, radiation, and immunotherapy, as well as exploring alternative dosing strategies to overcome resistance in gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of malignant gliomas with temozolomide. Prados, MD.[2018]

Temozolomide (TMZ) is commonly used as an adjuvant therapy for malignant glioma, but in this case study, a patient developed treatment-related acute myeloid leukemia (t-AML) after receiving 15 cycles of TMZ, highlighting a rare but serious complication.

The case raises questions about the duration of TMZ therapy, as the patient showed no tumor progression but still developed t-AML, suggesting a need for better guidelines to balance treatment benefits and risks in long-term TMZ use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. Kosugi, K., Saito, K., Takahashi, W., et al.[2018]

Citations

1. Greece pubmed.ncbi.nlm.nih.gov

Temozolomide in radio-chemotherapy combined treatment for newly-diagnosed glioblastoma multiforme: phase II clinical trial. [2018]

2. United States pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. [2019]

3. New Zealand pubmed.ncbi.nlm.nih.gov

Economic evaluation of temozolomide in the treatment of recurrent glioblastoma multiforme. [2018]

4. Japan pubmed.ncbi.nlm.nih.gov

[Temozolomide: Temodal]. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Naringenin Sensitizes Resistant C6 Glioma Cells with a Repressive Impact on the Migrating Ability. [2022]

6. Switzerland pubmed.ncbi.nlm.nih.gov

Temozolomide-related hematologic toxicity. [2018]

7. England pubmed.ncbi.nlm.nih.gov

Temozolomide-induced aplastic anaemia: Case report and review of the literature. [2022]

8. Germany pubmed.ncbi.nlm.nih.gov

Bioequivalence study of 20-mg and 100-mg temozolomide capsules (TOZ309 and Temodal&#174;) in glioma patients in China. [2021]

9. United States pubmed.ncbi.nlm.nih.gov

Phase II trial of temozolomide in patients with progressive low-grade glioma. [2022]

10. Greece pubmed.ncbi.nlm.nih.gov

Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. [2022]

11. United States pubmed.ncbi.nlm.nih.gov

Future directions in the treatment of malignant gliomas with temozolomide. [2018]

12. United States pubmed.ncbi.nlm.nih.gov

A Case of Therapy-Related Acute Myeloid Leukemia Associated with Adjuvant Temozolomide Chemotherapy for Anaplastic Astrocytoma. [2018]