Megestrol + Metformin for Endometrial Cancer Prevention

Recruiting at 8 trial locations

Age: 18+

Sex: Any

Trial Phase: Phase 2

Sponsor: National Cancer Institute (NCI)

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

50 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This phase II trial studies the effect of megestrol acetate alone or in combination with metformin in preventing the progression of uterine pre-cancer (endometrial intraepithelial neoplasia) to endometrial cancer. Megestrol acetate is a drug used to block estrogen and suppress the effects of estrogen and androgens. It is the current non-surgical treatment of endometrial intraepithelial neoplasia. Metformin is a drug that has been found to have anti-cancer properties. Giving metformin and megestrol acetate together may decrease the growth of endometrial intraepithelial neoplasia in the uterus better than megestrol alone.

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 the combination of Megestrol and Metformin safe for humans?

Megestrol acetate has been used in postmenopausal women for endometrial conditions with no major side effects reported, but it can cause severe high blood sugar in some cases. Metformin is generally used for diabetes and has been suggested to have anticancer properties, but specific safety data for the combination with Megestrol is limited. ^{1 2 3 4 5}

How is the drug Megestrol + Metformin unique for endometrial cancer prevention?

The combination of Megestrol Acetate and Metformin is unique because it combines a hormone therapy with a drug that has anticancer properties, potentially enhancing the treatment's effectiveness in preventing endometrial cancer. This approach is different from using Megestrol Acetate alone, as Metformin may help inhibit cell growth and tumor development. ^{1 2 3 6 7}

What data supports the effectiveness of the drug Megestrol + Metformin for Endometrial Cancer Prevention?

Research shows that combining metformin with megestrol acetate can be more effective than using megestrol acetate alone for treating conditions like atypical endometrial hyperplasia and well-differentiated endometrial cancer, which are related to endometrial cancer. ^{2 4 8 9 10}

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?

National Cancer Institute (NCI)

Lead Sponsor

Trials

14,080

Recruited

41,180,000+

Published Research Related to This Trial

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 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 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]

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 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]

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]

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]

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]

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. England 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. [2020]

2. Korea (South) pubmed.ncbi.nlm.nih.gov

Conservative therapy with metformin plus megestrol acetate for endometrial atypical hyperplasia. [2021]

3. Australia pubmed.ncbi.nlm.nih.gov

Conservative management of grade 2 stage IA endometrial carcinoma and literature review. [2021]

4. England pubmed.ncbi.nlm.nih.gov

Surgical safety and personal costs in morbidly obese, multimorbid patients diagnosed with early-stage endometrial cancer having a hysterectomy. [2020]

5. Germany pubmed.ncbi.nlm.nih.gov

Metabolic effects associated with high-dose continuous megestrol acetate administration in the treatment of endometrial pathology. [2019]

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

Hormonal therapy for lesions of the endometrium. [2018]

7. France 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. [2021]

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

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

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

Progestin therapy in lesions of the endometrium. [2013]

10. United States 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. [2022]