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

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests two treatments, etoposide (a chemotherapy drug) and tamoxifen (a hormone therapy), to determine which is more effective for people whose glioblastoma (a type of brain tumor) has recurred after initial treatment. Researchers aim to identify which drug better manages the cancer's return. Participants must have a confirmed case of glioblastoma that has progressed after initial chemoradiotherapy with temozolomide and must not have received radiation treatment in the past three months. As a Phase 2 trial, this research focuses on assessing the treatment's effectiveness in an initial, smaller group, offering participants a chance to contribute to important findings.

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.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

A study on tamoxifen found no harmful effects from the treatment, and no deaths resulted from its use. This suggests that tamoxifen is generally safe. For etoposide, a study examined real-world data for side effects. It found that while etoposide is used in treatment, some side effects can occur, though specific details were not provided in the sources. Both treatments have been used previously, which may reassure patients about their safety. Discuss any concerns or questions with the trial team or your doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about Tamoxifen and Etoposide for recurrent glioblastoma because these treatments offer unique approaches to tackling the cancer. Unlike standard therapies like Temozolomide, which is the typical chemotherapy drug used, Etoposide works by inhibiting an enzyme necessary for cancer cell division, potentially stopping tumor growth in its tracks. Tamoxifen, typically used for breast cancer, is being explored for its potential to block estrogen receptors, which might play a role in glioblastoma cell proliferation. These novel mechanisms of action could offer new hope for patients who have limited options after standard treatments.

What evidence suggests that this trial's treatments could be effective for recurrent glioblastoma?

This trial will compare Tamoxifen and Etoposide for treating recurrent glioblastoma. Research has shown that Tamoxifen, which participants in this trial may receive, can help treat recurrent gliomas by stabilizing the condition and slowing tumor growth. In some cases, patients who received high doses of Tamoxifen lived for about 10 months on average.

Etoposide is another treatment option in this trial. It is often used with other medications for recurrent glioblastoma, a severe form of brain tumor. Studies indicate that this combination can help patients live longer, with some having an average survival of about 11.7 months. However, limited evidence exists on Etoposide's effectiveness alone for recurrent gliomas. Both treatments show potential, but their effectiveness can vary depending on individual patient factors. ^{5 6 7 8 9}

Are You a Good Fit for This Trial?

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 for a Trial Participant

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

What Are the Treatments Tested in This Trial?

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.

How Is the Trial Designed?

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+

Published Research Related to This Trial

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]

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 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]

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 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]

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]

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 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]

Citations

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Phase II trial of carboplatin and etoposide for patients with ... We present the results of a phase II trial of carboplatin and etoposide (CE) combination as first-line chemotherapy in patients with recurrent glioblastoma ...

2. ar.iiarjournals.org ar.iiarjournals.org/content/33/8/3307

Etoposide Improves Survival in High-grade Glioma: A Meta ... Etoposide has shown synergistic activity with cisplatin in recurrent malignant glioma, with a partial response rate of 21% and mOS of 11.7 months (19).

3. ascopubs.org ascopubs.org/doi/10.1200/jco.2006.24.18_suppl.1565

A phase II study of temozolomide and oral VP-16 for adults ... The median progression-free survival (PFS) was 2 mo. (0–51+ mo), and the 6 mo. PFS was 19%. Of the 12 patients with anaplastic gliomas, 2 had a ...

4. cambridge.org cambridge.org/core/journals/canadian-journal-of-neurological-sciences/article/value-of-etoposide-for-recurrent-glioma/767A4417B96A171A3A364CD145A6A1F2

The Value of Etoposide for Recurrent Glioma There are no data available on the efficacy of oral etoposide monotherapy in recurrent glioma. This retrospective study evaluated the efficacy ...

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Feasibility and tolerability of trofosfamide and etoposide in ... The observed median overall survival (mOS) was in the range of 8–12 months. Due to the small sample sizes and the lack of control arm data in these pediatric ...

6. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10637489/

A pharmacovigilance study of etoposide in the FDA ... This study aimed to assess and evaluate etoposide-related adverse events in a real-world setting by using data mining method on the US Food and Drug ...

7. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11828300/

Etoposide-mediated glioblastoma cell death The relapsed lesion is typically refractory to further treatment and invariably leads to patient death. While the management of newly diagnosed GBM with ...

8. academic.oup.com academic.oup.com/neuro-oncology/article/25/Supplement_2/ii119/7264585

P17.13.A OUTCOME ANALYSIS OF PATIENTS WITH ... Tumour recurrence in patients with gliomas is associated with short survival and there is no standard second-line therapy. Etoposide (VP16) ...

9. go.drugbank.com go.drugbank.com/drugs/DB00773

Etoposide: Uses, Interactions, Mechanism of Action Improve decision support & research outcomes with our structured adverse effects data. See a data sample. Toxicity ... Recurrent Glioblastoma · 1, somestatus ...