Progesterone for Glioblastoma

Age: 18+

Sex: Any

Trial Phase: Phase < 1

Sponsor: Emory University

Must not be taking: Anticoagulants, Estrogen/Progesterone

Disqualifiers: Pacemakers, Severe hepatic dysfunction, others

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 24 weeks

32 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores how natural progesterone might help treat glioblastoma, a type of brain cancer that has returned after treatment. Researchers aim to determine the best dose and assess whether progesterone can slow the tumor's growth and spread. Individuals with glioblastoma or gliosarcoma who have tried up to two other treatments without success may be suitable candidates for this trial. Participants will receive daily progesterone injections for up to 24 weeks, provided the treatment remains effective and side effects are manageable. As an Early Phase 1 trial, this research focuses on understanding how progesterone works in people, offering participants the opportunity to be among the first to receive this promising treatment.

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

The trial requires you to stop any current estrogen or progesterone therapy, including hormonal contraceptives, at least 7 days before starting the study. If you are on anti-tumor agents, you must stop them 4 weeks prior to starting the trial. Other medications are not specified, so consult with the trial team for guidance.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research shows that progesterone might be a safe option for treating recurrent glioblastoma, a type of brain cancer. Some studies indicate that high doses of progesterone can slow the growth of cancer cells without affecting healthy cells. This suggests it could be safer than many traditional cancer treatments, which often have more severe side effects.

However, other findings are important to consider. Some studies have linked long-term use of certain progesterone-like drugs to a higher risk of developing another type of brain tumor called meningioma. This risk appears related to specific synthetic versions of progesterone, not the natural form tested in this trial.

Since this is an early study, researchers are still determining the best dose and monitoring for any possible side effects. The early phase of the trial means that while initial safety information might be limited, the treatment has shown enough promise for further testing. Participants should discuss potential risks and benefits with their healthcare providers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

Unlike the standard treatments for glioblastoma, which typically include surgery, radiation, and chemotherapy, therapeutic progesterone offers a unique approach by potentially targeting the hormonal pathways involved in cancer growth. Researchers are excited about this treatment because progesterone is administered subcutaneously, allowing for a steady release that may enhance its effectiveness while potentially reducing side effects. This method of delivery and the hormone-based mechanism of action present an innovative angle in the fight against this aggressive brain tumor, offering hope for improved outcomes.

What evidence suggests that progesterone might be an effective treatment for glioblastoma?

Research suggests that progesterone, which participants in this trial will receive, might help treat glioblastoma by slowing tumor growth. Studies have shown that high doses of progesterone can reduce the growth of certain glioblastoma cells. It seems to work by altering how the tumor obtains energy and grows. Additionally, progesterone may accelerate the aging of tumor cells, which can help slow their spread. While these findings are promising, most of the evidence comes from lab studies, not yet from human trials. ^{1 5 6 7 8}

Who Is on the Research Team?

Hui-Kuo G. Shu, MD, PhD, FASTRO

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Are You a Good Fit for This Trial?

This trial is for adults with recurrent glioblastoma who can undergo MRI scans, have certain blood cell counts within normal ranges, and a life expectancy of at least 12 weeks. Women must not be pregnant and agree to use contraception. Excluded are those with active infections, recent thromboembolic disease, incompatible implants for MRI, severe liver issues, history of breast or genital cancers (unless in remission for 3+ years), or on other anti-tumor therapies.

Inclusion Criteria

Bilirubin =< 2 x UNL (=< 14 days prior to registration)

I have had up to two treatments for my recurring brain tumor.

I am not currently participating in another cancer treatment trial.

Exclusion Criteria

I do not have any implants or conditions that make MRI unsafe for me.

I have not had a blood clot in the last 6 months.

I do not have a history of severe liver problems.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive progesterone subcutaneously once daily for up to 24 weeks

24 weeks

Daily visits for subcutaneous injections

Follow-up

Participants are monitored for safety and effectiveness after treatment

Up to 2 years

What Are the Treatments Tested in This Trial?

Interventions

• Therapeutic Progesterone

Trial Overview The trial is testing natural progesterone's effectiveness in controlling tumor growth in patients with recurrent glioblastoma. It involves determining the best dose and observing potential benefits or side effects while monitoring quality-of-life through assessments and questionnaires.

How Is the Trial Designed?

Group I: Treatment (progesterone) Experimental Treatment 3 Interventions

Patients receive progesterone SC QD for up to 24 weeks in the absence of disease progression or unacceptable toxicity.

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

Approved in United States as Progesterone for:

• Menopause management
• Premenstrual syndrome (PMS)
• Endometrial hyperplasia prevention
• Uterine bleeding
• Premature labor

Approved in European Union as Progesterone for:

• Menopause management
• Premenstrual syndrome (PMS)
• Endometrial hyperplasia prevention
• Uterine bleeding
• Premature labor
• Hormone replacement therapy

Approved in Canada as Progesterone for:

• Menopause management
• Premenstrual syndrome (PMS)
• Endometrial hyperplasia prevention
• Uterine bleeding
• Premature labor

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

5α-Dihydroprogesterone (5α-DHP) significantly promotes the proliferation and migration of human glioblastoma (GBM) cells, specifically the U87 and U251 cell lines, at a concentration of 10 nM, similar to the effects of progesterone.

The effects of 5α-DHP on GBM cell proliferation and migration are mediated through the activation of progesterone receptors, as demonstrated by the use of the PR antagonist RU486 (mifepristone), which blocked these effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

5alpha-dihydroprogesterone promotes proliferation and migration of human glioblastoma cells. Zamora-Sánchez, CJ., Hernández-Vega, AM., Gaona-Domínguez, S., et al.[2021]

In a study involving male rats with implanted human glioblastoma cells, progesterone significantly increased the tumor area and infiltration length, indicating its potential role in promoting tumor growth.

The effects of progesterone were mediated through its interaction with intracellular progesterone receptors, as silencing these receptors blocked the tumor-promoting effects of progesterone.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intracellular Progesterone Receptor Mediates the Increase in Glioblastoma Growth Induced by Progesterone in the Rat Brain. Germán-Castelán, L., Manjarrez-Marmolejo, J., González-Arenas, A., et al.[2018]

High doses of progesterone (P4) significantly reduced the viability of neuroblastoma cells in vitro and inhibited tumor growth by about 50% in a mouse model, demonstrating its potential as an effective treatment for this type of cancer.

P4 showed selective toxicity, as it did not harm healthy neurons or fibroblasts, and exhibited a high margin of safety, making it a promising candidate for further clinical studies in treating neuroblastoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progesterone inhibits the growth of human neuroblastoma: in vitro and in vivo evidence. Atif, F., Sayeed, I., Yousuf, S., et al.[2021]

High concentrations of progesterone (P4) significantly decreased the viability of human glioblastoma multiforme (GBM) cells in vitro, while low physiological concentrations promoted cell proliferation, indicating a dose-dependent effect.

In a mouse model, P4 treatment significantly inhibited tumor growth and extended survival by 60% without causing systemic toxicity, suggesting its potential as a safe therapeutic option for GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling. Atif, F., Yousuf, S., Stein, DG.[2022]

Mifepristone demonstrated significant growth suppression of glioma cell lines U257/7 and IN1265, with reductions of 36% and 11% respectively after 96 hours of treatment, suggesting its potential as a therapeutic option for glioblastoma multiforme.

The study found no significant expression of progesterone receptors in the cell lines, indicating that the mechanism of action for mifepristone's effects may not involve these receptors, and further research is needed to explore its use in clinical settings.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Study of effectiveness of mifepristone for glioma cell line growth suppression. Ramaswamy, R., Ashton, K., Lea, R., et al.[2013]

Medroxyprogesterone acetate (MPA) significantly reduced C6 glioma cell growth in vitro, decreasing the thymidine-labelling index by up to 73% and colony growth by 61%, suggesting its potential as a growth inhibitor for glial tumors.

MPA also appears to enhance the effectiveness of certain chemotherapy drugs like procarbazine and cisplatin, while reducing the effectiveness of methotrexate, indicating its role in drug sensitization for glioma treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Medroxyprogesterone acetate alone or synergistic with chemotherapy suppresses colony formation and DNA synthesis in C6 glioma in vitro. Altinoz, MA., Bilir, A., Ozar, E., et al.[2020]

Combining progesterone (PROG) with temozolomide (TMZ) significantly enhances the ability to kill glioblastoma multiforme (GBM) cells compared to TMZ alone, as shown in two human GBM cell lines over 3 and 6 days.

PROG not only increases the effectiveness of TMZ against GBM cells but also reduces the toxicity of TMZ in healthy cells, indicating a potential for safer treatment options for patients with GBM.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells. Atif, F., Patel, NR., Yousuf, S., et al.[2021]

Female hormones, particularly progesterone, are linked to an increased risk of meningiomas but a decreased risk of gliomas, suggesting that progesterone has complex effects on different types of brain tumors.

High-dose progestins like medroxyprogesterone acetate (MPA) may inhibit brain tumor growth by downregulating progesterone receptors, and further research is needed to explore their potential in treating glioblastoma, especially in combination with immunotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Reproductive epidemiology of glial tumors may reveal novel treatments: high-dose progestins or progesterone antagonists as endocrino-immune modifiers against glioma. Altinoz, MA., Ozpinar, A., Elmaci, I.[2020]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC10157356/

Progesterone and its metabolite allopregnanolone promote ... These results suggest that P4 and its metabolite 3α-THP induce the invasion of glioblastoma cells by increasing MMP-9 expression through the cSrc kinase family.

2. cancer.gov cancer.gov/clinicaltrials/NCI-2021-01498

Natural Progesterone for the Treatment of Recurrent ... This early phase I trial identifies the best dose, possible benefits and/or side effects of natural progesterone in treating patients with glioblastoma that ...

3. nature.com nature.com/articles/s41598-018-37399-5

Progesterone Treatment Attenuates Glycolytic Metabolism ... Progesterone inhibits the modulators of glycolytic metabolism and induces premature senescence in GBM cells and this can help to reduce/slow tumor progression.

4. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0024320520302848

Effects of progesterone on the cell number ... Progesterone (P) increases the proliferation, migration, and invasion of GBM cell lines through the interaction with its intracellular receptor (PR).

5. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7433824/

Progesterone at high doses reduces the growth of U87 and ... Progesterone at high doses reduces the growth of U87 and A172 glioblastoma cells: Proteomic changes regarding metabolism and immunity - PMC.

6. sciencemediacentre.es sciencemediacentre.es/en/reactions-some-progesterone-analogues-increase-risk-developing-type-brain-tumour-study-finds

Progesterone analogues increase risk of a type of brain ... Study has found a link between long-term use of some progesterone hormone analogues and an increased risk of developing meningioma.

7. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0960076014000934

Anti-tumor effects of progesterone in human glioblastoma ... High-dose progesterone induces cell death in human glioblastoma cell lines. · Progesterone is safe for normal healthy cells. · Progesterone inhibits the growth of ...

8. bmj.com bmj.com/content/384/bmj-2023-078078

Use of progestogens and the risk of intracranial meningioma Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma.