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

Trial Summary

What is the purpose of this trial?

This early phase I trial identifies the best dose, possible benefits and/or side effects of natural progesterone in treating patients with glioblastoma that has come back (recurrent). Progesterone is a type of hormone made by the body that plays a role in the menstrual cycle and pregnancy. Progesterone may help control tumor growth and spread in patients with glioblastoma.

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.

What evidence supports the effectiveness of the drug progesterone for treating glioblastoma?

Research shows that progesterone, when used in high doses, can significantly reduce the growth of glioblastoma cells and enhance the effects of the standard chemotherapy drug temozolomide, leading to increased tumor cell death and reduced side effects in healthy cells. ^{1 2 3 4 5}

Is progesterone generally safe for use in humans?

Progesterone has been studied in various contexts and is generally considered safe for humans, even at high doses, as it did not reduce the viability of healthy cells in studies. However, its effects can vary depending on the dose, with high doses potentially inhibiting tumor growth and low doses potentially stimulating it. ^{1 2 4 6 7}

How is the drug progesterone unique in treating glioblastoma?

Progesterone is unique in treating glioblastoma because it can enhance the effects of the standard chemotherapy drug temozolomide, leading to increased tumor cell death and reduced side effects on healthy cells. It works by suppressing specific signaling pathways (EGFR/PI3K/Akt/mTOR) that are involved in tumor growth. ^{1 2 3 4 8}

Research Team

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

Principal Investigator

Emory University Hospital/Winship Cancer Institute

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Anti-tumor effects of progesterone in human glioblastoma multiforme: role of PI3K/Akt/mTOR signaling. [2022]

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

5alpha-dihydroprogesterone promotes proliferation and migration of human glioblastoma cells. [2021]

3. England pubmed.ncbi.nlm.nih.gov

Study of effectiveness of mifepristone for glioma cell line growth suppression. [2013]

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

The Synergistic Effect of Combination Progesterone and Temozolomide on Human Glioblastoma Cells. [2021]

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

Medroxyprogesterone acetate alone or synergistic with chemotherapy suppresses colony formation and DNA synthesis in C6 glioma in vitro. [2020]

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

Progesterone inhibits the growth of human neuroblastoma: in vitro and in vivo evidence. [2021]

7. Germany 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. [2020]

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

Intracellular Progesterone Receptor Mediates the Increase in Glioblastoma Growth Induced by Progesterone in the Rat Brain. [2018]