Megestrol + Metformin for Endometrial Cancer Prevention

Not currently recruiting at 8 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: Northwestern University

Must not be taking: Hormonal contraceptives, SERMs, Metformin, others

Disqualifiers: Pregnancy, Breastfeeding, Active cancer, 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

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

Compensation: Varies

Number of Visits: 1

Duration: 3-5 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests whether megestrol acetate alone or combined with metformin can prevent a uterine pre-cancer condition (endometrial intraepithelial neoplasia) from developing into endometrial cancer. Megestrol acetate blocks estrogen, while metformin (also known as Glucophage, Glumetza, and other names) is typically used for diabetes but may also have anti-cancer effects. The trial aims to determine if the combination of these drugs is more effective than megestrol acetate alone. It is suitable for women diagnosed with endometrial intraepithelial neoplasia who are open to surgical or non-surgical treatment options. As a Phase 2 trial, the research focuses on evaluating the treatment's effectiveness in an initial, smaller group, allowing participants to contribute to significant medical advancements.

Will I have to stop taking my current medications?

The trial requires participants to stop using certain medications, such as current hormonal contraceptives, post-menopausal hormone replacement therapy, selective estrogen receptor modulators, aromatase inhibitors, and metformin. If you are taking any of these, you will need to discontinue them before enrolling in the study. Other medications may also need to be reviewed by the study team.

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

Research has shown that megestrol acetate is generally well-tolerated for its intended uses. It is already approved for treating advanced breast and uterine cancers, indicating reasonable safety. Some side effects may include weight gain, increased appetite, and fluid retention, but these are usually manageable.

Studies have found that adding metformin, a drug often used for diabetes, may enhance the effectiveness of megestrol acetate. Researchers are also studying metformin for its potential to fight cancer. Although there is limited evidence on this specific combination, metformin is widely used and has a known safety record in other conditions.

Overall, both drugs are considered safe based on their current uses, but as with any trial, there are some risks of side effects. Participants should discuss these with their healthcare provider. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Unlike the standard treatment options for endometrial cancer, which typically involve surgery or radiation, the combination of megestrol acetate and metformin is unique because it targets cancer prevention in a non-invasive way. Megestrol acetate is a hormone therapy that can help regulate the growth of cancer cells, while metformin, commonly used for diabetes, may reduce cancer risk through its impact on metabolism and insulin levels. Researchers are excited about this combination because it offers a potentially safer and less invasive approach to managing endometrial cancer risk, with the added benefit of metformin's metabolic effects, which could enhance the overall effectiveness of the treatment.

What evidence suggests that this trial's treatments could be effective for preventing endometrial cancer?

Research has shown that megestrol acetate, which participants in this trial may receive, yields promising results in treating endometrial cancer. In some studies, up to 85.71% of patients responded well, with some experiencing long-term benefits. This drug blocks hormones that help cancer grow, effectively slowing the progression of pre-cancerous conditions.

In this trial, one group of participants will receive megestrol acetate alone, while another group will receive a combination of megestrol acetate and metformin. Metformin is known for its potential anti-cancer effects. Some research suggests this combination could be more effective in slowing the growth of endometrial pre-cancer than megestrol alone. However, other studies have found no significant difference between using megestrol by itself and the combination. ^{4 6 7 8 9}

Who Is on the Research Team?

Emma Barber

Principal Investigator

Northwestern University

Are You a Good Fit for This Trial?

This trial is for adults with a pre-cancerous condition of the uterus called endometrial intraepithelial neoplasia (EIN), who are planning to have a hysterectomy. They must be in good health, not pregnant, and willing to use birth control if they can have children. People with certain viral infections must be on treatment with an undetectable viral load.

Inclusion Criteria

I am on long-term antiviral treatment for herpes.

I am willing to undergo a hysterectomy for my endometrial condition.

I am HIV positive, on treatment, and my viral load has been undetectable for the last 6 months.

Exclusion Criteria

I am not a diabetic woman taking sulfonylureas or meglitinides.

I am not pregnant as the study requires surgery and medication that could harm a fetus.

I am not breastfeeding as it may harm my nursing infant due to my treatment.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive megestrol acetate alone or in combination with metformin for 21-35 days prior to a planned procedure

3-5 weeks

Daily oral administration

Procedure and Biopsy

Participants undergo a planned procedure (hysterectomy or IUD placement) and biopsy on the day of the procedure

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

6 weeks

Follow-up visits as needed

What Are the Treatments Tested in This Trial?

Interventions

• Extended Release Metformin Hydrochloride
• Megestrol Acetate

Trial Overview The study is testing whether taking megestrol acetate alone or combined with metformin prevents EIN from turning into uterine cancer better than just megestrol acetate. Participants will receive these medications before their planned surgery to remove the uterus.

How Is the Trial Designed?

Group I: Arm II (megestrol acetate, metformin hydrochloride) Experimental Treatment 4 Interventions

Prior to standard of care planned procedure, patients receive megestrol acetate PO BID and metformin hydrochloride extended-release PO BID for 21-35 days (up to and including the night before planned procedure) in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on the day of planned procedure.

Group II: Arm I (megestrol acetate) Active Control 3 Interventions

Prior to standard of care planned procedure, patients receive megestrol acetate PO BID for 21-35 days (up to and including the night before planned procedure) in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on the day of planned procedure.

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

Approved in United States as Megace for:

• Breast cancer
• Endometrial cancer
• Prostate cancer
• Appetite stimulation

Approved in European Union as Megestrol for:

• Breast cancer
• Endometrial cancer
• Prostate cancer
• Appetite stimulation

Approved in Canada as Megace for:

• Breast cancer
• Endometrial cancer
• Prostate cancer
• Appetite stimulation

Who Is Running the Clinical Trial?

Northwestern University

Lead Sponsor

Trials

1,674

Recruited

989,000+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

Megestrol acetate has been shown to effectively inhibit the recurrence of endometrial hyperplasia and adenocarcinoma, which are conditions that can progress to invasive cancer if untreated.

In patients with inoperable endometrial adenocarcinoma, megestrol acetate not only treats the cancer but also increases survival rates in those with recurrent cases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Progestin therapy in lesions of the endometrium. Wentz, WB.[2013]

High-dose megestrol acetate (160-320 mg/d) effectively treats endometrial pathology in 27 women over 3 months, showing significant reductions in HDL-cholesterol, total cholesterol, and apolipoprotein A-I levels.

While megestrol acetate did not adversely affect serum glucose levels, it was associated with a significant weight gain in patients, indicating a need for monitoring weight during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metabolic effects associated with high-dose continuous megestrol acetate administration in the treatment of endometrial pathology. Güven, M., Dikmen, Y., Terek, MC., et al.[2019]

In a pilot study of 16 patients with endometrial atypical hyperplasia, the combination of metformin and megestrol acetate (MA) showed a higher complete response rate of 75% compared to 25% for MA alone, suggesting that metformin may enhance treatment efficacy.

The presence of metabolic syndrome did not significantly impact the treatment response, indicating that metformin plus MA could be a viable option for patients regardless of their metabolic status, with no irreversible toxicities reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conservative therapy with metformin plus megestrol acetate for endometrial atypical hyperplasia. Shan, W., Wang, C., Zhang, Z., et al.[2021]

In a clinical trial involving 60 women with endometrial hyperplasia (EH) without atypia, the combination of metformin and megestrol acetate led to a significantly higher treatment response, with 93.1% of participants showing no signs of EH after 3 months compared to 70.4% in the megestrol-only group.

The study suggests that adding metformin to megestrol acetate improves treatment outcomes for EH without atypia, indicating its potential as an effective adjuvant therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The impact of adjunctive metformin to progesterone for the treatment of non-atypical endometrial hyperplasia in a randomized fashion, a placebo-controlled, double blind clinical trial. Tehranian, A., Ghahghaei-Nezamabadi, A., Arab, M., et al.[2021]

In a 14-year study involving 70 postmenopausal women, continuous treatment with megestrol acetate (20 to 40 mg/d) effectively prevented the need for surgery in 93% of patients with endometrial hyperplasia.

The treatment was safe, with no cases of endometrial carcinoma reported and no major side effects, making it a viable option for patients at surgical risk.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hormonal therapy for lesions of the endometrium. Gal, D.[2018]

Two patients with endometrial neoplasia experienced severe hyperglycemia as a side effect of megestrol acetate treatment, highlighting a significant risk associated with this medication.

It is crucial for patients receiving megestrol acetate, particularly those with a history of glucose metabolism issues, to be closely monitored for hyperglycemia during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hyperglycemia secondary to megestrol acetate for endometrial neoplasia. Rose, PG.[2013]

In a study of 150 patients with atypical endometrial hyperplasia (AEH) or endometrioid endometrial cancer (EEC), the combination of metformin and megestrol acetate (MA) showed a higher complete response rate at 16 weeks compared to MA alone, particularly in AEH patients (39.6% vs. 20.4%).

The combination treatment was especially effective in non-obese and insulin-sensitive AEH patients, suggesting that metformin may enhance the efficacy of MA in fertility-sparing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Metformin plus megestrol acetate compared with megestrol acetate alone as fertility-sparing treatment in patients with atypical endometrial hyperplasia and well-differentiated endometrial cancer: a randomised controlled trial. Yang, BY., Gulinazi, Y., Du, Y., et al.[2020]

In a study of 4 young women with stage IA grade 2 endometrial carcinoma seeking to preserve fertility, 75% achieved a complete response to treatment with megestrol acetate, and some received metformin for metabolic syndrome.

The results suggest that megestrol acetate, with or without metformin, combined with regular hysteroscopic examinations, may be an effective fertility-sparing treatment option for this type of cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Conservative management of grade 2 stage IA endometrial carcinoma and literature review. Shan, W., Wu, P., Yang, B., et al.[2021]

In a study of 27 obese women (median BMI of 37.3 kg/m2) with suspected early stage endometrial cancer who declined non-surgical treatment, 41% experienced significant adverse surgical events after undergoing hysterectomy, highlighting the risks associated with surgery in this population.

Despite most surgeries being planned laparoscopically, 7% required conversion to an open approach, indicating potential complications in surgical management for patients with multiple medical co-morbidities.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Surgical safety and personal costs in morbidly obese, multimorbid patients diagnosed with early-stage endometrial cancer having a hysterectomy. Obermair, A., Brennan, DJ., Baxter, E., et al.[2020]

In a study of 79 women with atypical endometrial hyperplasia (AEH) and early endometrioid endometrial carcinoma (EEC), 96.2% achieved complete response (CR) after treatment with hysteroscopic curettage followed by megestrol acetate and metformin, indicating high efficacy of this conservative treatment.

A longer treatment duration of 9 months or more was linked to a lower recurrence rate after achieving CR, suggesting that extending treatment may enhance long-term outcomes despite a quicker initial response.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Hysteroscopic Curettage Followed by Megestrol Acetate Plus Metformin as a Fertility-Sparing Treatment for Women with Atypical Endometrial Hyperplasia or Well-Differentiated Endometrioid Endometrial Carcinoma. Jing, CY., Li, SN., Shan, BE., et al.[2022]

Citations

1. ascopubs.org ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.5585

Outcomes of recurrent and metastatic endometrial cancer ... Overall response rates have been reported in the range of 20-25% with responses up to 25-35% in ER+/PR+ve tumors. Despite comparative response ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8581832/

Megestrol acetate drives endometrial carcinoma cell ... This study demonstrates that megestrol acetate could induce irreversible G1 arrest and cellular senescence, affect the survival and growth of endometrial cancer ...

3. sciencedirect.com sciencedirect.com/science/article/pii/S1048891X24026781

Efficacy of Megestrol Acetate (Megace) in the Treatment ... Results: Our results showed a response rate of 85.71% (18 patients), and 3 patients underwent hysterectomy. The mean (SD) treatment duration was 8.85 (2.00) ...

4. clinicaltrials.gov clinicaltrials.gov/study/NCT04576104

Study Details | NCT04576104 | Megestrol Acetate ... This phase II trial studies the effect of megestrol acetate alone or in combination with metformin in preventing the progression of uterine pre-cancer ...

5. obgyn.onlinelibrary.wiley.com obgyn.onlinelibrary.wiley.com/doi/10.1111/aogs.70028

Long‐term outcomes of fertility‐sparing treatment in ... Nine patients (22.5%) achieved pregnancy, with three successfully conceiving after achieving complete response following retreatment.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/anda/98/74745ap.pdf

Megesterol Acetate Tablets USP 40mg - accessdata.fda.gov Megestrol acetate has not been tested for dialyzability, however, due to its low solubility it is postulated that this would not be an effective.

7. mayoclinic.org mayoclinic.org/drugs-supplements/megestrol-oral-route/description/drg-20528334

Megestrol (oral route) - Side effects & dosage Megestrol tablet is used to treat advanced cancer of the breast or uterus in patients whose cancer has already spread, come back, or cannot be treated with ...

8. dailymed.nlm.nih.gov dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=2c755c6b-32e9-4029-8b70-855007f7375b

Label: MEGESTROL ACETATE tablet - DailyMed Megestrol acetate tablets are indicated for the palliative treatment of advanced carcinoma of the breast or endometrium (ie, recurrent, inoperable, or ...

9. go.drugbank.com go.drugbank.com/drugs/DB00351

Megestrol acetate: Uses, Interactions, Mechanism of Action Also used for the palliative management of recurrent, inoperable, or metastatic breast cancer, endometrial cancer, and prostate cancer in Canada and some other ...