Tamoxifen vs Etoposide for Recurrent Glioblastoma

Overseen By Jacob Easaw, MD, PhD, FRCPC

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: AHS Cancer Control Alberta

Disqualifiers: Concurrent malignancy, Hypertension, Thrombosis, others

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

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

Duration: 3 months

60 Participants Needed

Trial Summary

Do I need to stop taking my current medications for the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, it mentions that corticosteroids should be given at the lowest dose needed to control symptoms.

What data supports the effectiveness of the drug Tamoxifen for treating recurrent glioblastoma?

Some studies suggest that Tamoxifen might help stabilize the condition in certain patients with recurrent glioma, potentially slowing down the tumor's growth and prolonging survival in selected cases. ^{1 2 3 4 5}

Is the combination of Tamoxifen and Etoposide safe for treating glioblastoma?

The combination of Tamoxifen and Etoposide has been studied for safety in treating glioblastoma. Some studies reported low rates of severe side effects, mainly nausea and vomiting, but there were deaths possibly related to high-dose Tamoxifen. High-dose Tamoxifen should not be used with primary chemotherapy due to safety concerns. ^{1 6 7 8 9}

How does the drug combination of Tamoxifen and Etoposide differ from other treatments for recurrent glioblastoma?

The combination of Tamoxifen and Etoposide is unique because Tamoxifen may help overcome resistance to chemotherapy by affecting P-glycoprotein, potentially enhancing the effectiveness of Etoposide. This approach is different from standard treatments, which often do not include Tamoxifen's potential to stabilize tumor growth in glioblastoma. ^{2 3 4 6 9}

What is the purpose of this trial?

The investigator propose a single-center randomized phase II controlled study designed to compare the management of first recurrence of GBM using etoposide versus tamoxifen.

Eligibility Criteria

This trial is for adults aged 18-65 with confirmed GBM that's worsened after initial treatment. They must have a measurable tumor on MRI, stable or reduced steroid use, and be in fair to good health (ECOG 0-2). Women who can bear children need a recent negative pregnancy test and agree to effective birth control during the study.

Inclusion Criteria

Progression documented by MRI with at least one bi-dimensionally measurable target lesion with one diameter of at least 10 mm, visible on two or more axial slices 5 mm apart

I am a woman who can have children and have a recent negative pregnancy test.

Laboratory evaluation obtained within 7 days prior to randomization, with adequate function as defined below: ANC ≥ 1.5 x 109/L, Platelets ≥ 100 x 109/L, Serum creatinine ≤ 1.5 times ULN, Total serum bilirubin ≤ 1.5 times ULN, ALT < 3 times ULN, AST < 3 times ULN, Alkaline phosphatase < 3 times ULN, Patient must understand and sign an informed consent prior to study registration

Exclusion Criteria

I have not had any blood clots in the last 6 months.

I've been cancer-free for 3 years, or had non-melanoma skin cancer or in situ carcinoma treated successfully.

I have not had major heart or stroke issues in the last 6 months.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either etoposide or tamoxifen for the management of first recurrence of GBM

3 months

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 5 years

Treatment Details

Interventions

• Etoposide
• Tamoxifen

Trial Overview The study compares two drugs, etoposide and tamoxifen, for treating first recurrence of GBM. It's a phase II trial where patients are randomly assigned to receive one of these treatments at a single center.

Participant Groups

Group I: Tamoxifen Experimental Treatment 1 Intervention

Group II: Etoposide Active Control 1 Intervention

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

Approved in United States as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Approved in European Union as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Approved in Canada as Etoposide for:

• Testicular cancer
• Small cell lung cancer
• Non-Hodgkin lymphoma
• Acute myeloid leukemia

Who Is Running the Clinical Trial?

AHS Cancer Control Alberta

Lead Sponsor

Trials

188

Recruited

26,900+

Findings from Research

In a phase 2 study involving 24 young adults with recurrent anaplastic astrocytomas, tamoxifen citrate showed modest efficacy, with 17% of patients experiencing a partial response and 46% achieving stable disease after treatment.

Tamoxifen was well-tolerated, with no reported toxic effects or treatment-related deaths, suggesting it may be a safe option for this heavily pretreated patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Salvage chemotherapy with tamoxifen for recurrent anaplastic astrocytomas. Chamberlain, MC., Kormanik, PA.[2022]

Tamoxifen (TAM) has shown promise in inhibiting the growth of human glioma cell lines and stabilizing the condition of some patients with recurrent gliomas, suggesting a potential role in treatment.

Despite various treatment approaches, the survival time for patients with cerebral gliomas remains generally less than 12 months, highlighting the need for effective therapies like TAM in multimodal postoperative care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen as a potential treatment of glioma. Mastronardi, L., Puzzilli, F., Ruggeri, A.[2019]

In a study of 50 newly diagnosed glioblastoma patients treated with high-dose tamoxifen, 33% experienced multifocal tumor recurrences, indicating a significant concern with this treatment approach.

Multifocal recurrences were linked to a longer median time to tumor progression compared to local recurrences, suggesting that initial responses to tamoxifen may lead to acquired resistance, contributing to the development of multifocal disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High-dose tamoxifen treatment increases the incidence of multifocal tumor recurrences in glioblastoma patients. Puchner, MJ., Giese, A., Lohmann, F., et al.[2021]

A patient with a left temporal-parietal glioblastoma showed clinical stabilization and improved CT results two years after receiving a combination of surgery, radiotherapy, chemotherapy, and tamoxifen.

The case suggests that tamoxifen, when used alongside standard treatments, may play a role in prolonging survival in patients with high-grade gliomas, although further research is needed to confirm its efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical and radiographic stabilization of intracranial glioblastoma. Report of a case treated after surgery with tamoxifen. Mastronardi, L., Farah, JO., Puzzilli, F., et al.[2017]

In a phase II trial involving 27 patients with recurrent malignant gliomas, treatment with intravenous carboplatin and high-dose oral tamoxifen resulted in a partial response in 15% of patients and stable disease in 52%, with a median overall survival of 14.09 months.

Some patients experienced long-lasting disease-free survival, particularly those with malignant mixed oligoastrocytomas, indicating that this treatment combination may offer significant benefits for certain subtypes of gliomas.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma. Tang, P., Roldan, G., Brasher, PM., et al.[2022]

Neoadjuvant chemotherapy with cisplatin and etoposide in 44 patients with high-grade gliomas showed a modest response rate of 12.5% and a median overall survival of 11.3 months, indicating it is a feasible treatment option.

The addition of high-dose tamoxifen did not demonstrate a clear benefit and was associated with potential risks, suggesting it should not be used alongside primary chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant cisplatin and etoposide, with or without tamoxifen, prior to radiotherapy in high-grade gliomas: a single-center experience. Díaz, R., Jordá, MV., Reynés, G., et al.[2019]

Tamoxifen effectively inhibits the growth of human glioblastoma cell lines (U-373, U-138, and U-87) at concentrations around 15 microM, showing a dose-dependent effect on cell proliferation and protein kinase C (PKC) activity.

Tamoxifen enhances the cytotoxic effects of gamma-radiation and BCNU, acting synergistically with gamma-radiation (4- to 6-fold increase) and additively with BCNU (approximately 2-fold), but does not affect the efficacy of etoposide, suggesting its potential as a treatment option for glioblastoma in combination therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tamoxifen inhibits particulate-associated protein kinase C activity, and sensitises cultured human glioblastoma cells not to etoposide but to gamma-radiation and BCNU. da Rocha, AB., Mans, DR., Bernard, EA., et al.[2019]

In a study of 12 patients with newly-diagnosed glioblastoma multiforme, high dose tamoxifen (TAM) was found to be feasible and relatively well-tolerated, with manageable toxicity, although one patient experienced significant vomiting and another had a potential adverse event of deep venous thrombosis.

Despite the safety of combining high dose TAM with postoperative brain irradiation, the treatment did not show any significant improvement in radiological responses or overall survival outcomes, with a median survival time of 33.4 weeks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

High dose tamoxifen and radiotherapy in patients with glioblastoma multiforme: a phase IB study. Muanza, T., Shenouda, G., Souhami, L., et al.[2021]

In a study of 70 patients with glioblastoma multiforme, adding tamoxifen to standard treatment did not improve median time to tumor progression or overall survival compared to BCNU alone.

However, patients receiving tamoxifen experienced a higher rate of blood toxicity and an increased risk of deep venous thrombosis, indicating potential safety concerns with this combination therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of supratentorial glioblastoma multiforme with radiotherapy and a combination of BCNU and tamoxifen: a phase II study. Napolitano, M., Keime-Guibert, F., Monjour, A., et al.[2019]

References

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

Salvage chemotherapy with tamoxifen for recurrent anaplastic astrocytomas. [2022]

2. England pubmed.ncbi.nlm.nih.gov

Tamoxifen as a potential treatment of glioma. [2019]

3. Greece pubmed.ncbi.nlm.nih.gov

High-dose tamoxifen treatment increases the incidence of multifocal tumor recurrences in glioblastoma patients. [2021]

4. Italy pubmed.ncbi.nlm.nih.gov

Clinical and radiographic stabilization of intracranial glioblastoma. Report of a case treated after surgery with tamoxifen. [2017]

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

A phase II study of carboplatin and chronic high-dose tamoxifen in patients with recurrent malignant glioma. [2022]

6. England pubmed.ncbi.nlm.nih.gov

Neoadjuvant cisplatin and etoposide, with or without tamoxifen, prior to radiotherapy in high-grade gliomas: a single-center experience. [2019]

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

Tamoxifen inhibits particulate-associated protein kinase C activity, and sensitises cultured human glioblastoma cells not to etoposide but to gamma-radiation and BCNU. [2019]

8. England pubmed.ncbi.nlm.nih.gov

High dose tamoxifen and radiotherapy in patients with glioblastoma multiforme: a phase IB study. [2021]

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

Treatment of supratentorial glioblastoma multiforme with radiotherapy and a combination of BCNU and tamoxifen: a phase II study. [2019]