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AzTrials

Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial NeoplasiaPhase 2NCT04576104

Megestrol Acetate Compared With Megestrol Acetate and Metformin to Prevent Endometrial Cancer

A Phase 2 study testing Biopsy Procedure, Extended Release Metformin Hydrochloride and Megestrol Acetate in people with Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia and Endometrial Carcinoma, run by Northwestern University at 8 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Biopsy Procedure, Extended Release Metformin Hydrochloride and Megestrol Acetate
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
51 participants
Where
8 sitesUnited States
Study dates
29 Nov 2021to 30 Jun 2026
Phase
Phase 2
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Participants with endometrial intraepithelial neoplasia (EIN) on an endometrial biopsy or dilation and curettage specimen will be eligible. Participants diagnosed with EIN bordering on, approaching or suspicious for endometrial adenocarcinoma are allowed. Participants can be diagnosed with EIN at any time in the three months prior to enrollment. Other commonly used pathologic terms for EIN, such as complex atypical hyperplasia and atypical hyperplasia will also be eligible
  • Age >= 18 years-old. EIN is almost exclusively an adult condition. Because no dosing or adverse event (AE) data are currently available on the use of megestrol acetate in participants < 18 years of age, children and adolescents are excluded from this study
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2 (Karnofsky >= 60%)
  • Total bilirubin =< 1.5 x institutional upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional upper limit of normal
  • Creatinine =< 1.5 x institutional upper limit of normal
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  • Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
  • For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  • Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  • Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible
  • If the participant is diabetic, blood glucose must be appropriately controlled as evidenced by a hemoglobin A1c of < 8.0 in the last three months prior to enrollment. If no A1c is available, it will be drawn with baseline laboratory parameters as is standard of care. For women who are diabetics who are on insulin, metformin can cause relative hypoglycemia. Women who are diabetic and receiving insulin will be allowed to participate, but will be asked to monitor their blood glucoses closely and alert the study team if persistent hypoglycemia is noted
  • Must be a candidate and accepting of surgical management of EIN with planned hysterectomy or non-surgical treatment with a progestin IUD
  • The effects of megestrol acetate on the developing human fetus at the recommended therapeutic dose are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately. For metformin, published studies with metformin use during pregnancy have not reported a clear association with metformin and major birth defect or miscarriage risk. Metformin can increase the potential for unintended pregnancy in premenopausal women as therapy with metformin may result in ovulation in some anovulatory women
  • Ability to understand and the willingness to sign a written informed consent document

Who cannot join

  • Current hormonal contraceptives or post-menopausal hormone replacement therapy, and uses of progestins (including progestin containing intrauterine device [IUD]) EXCEPT FOR:
  • Megestrol acetate up to and including 40 mg daily
  • Medroxyprogesterone acetate up to and including 10 mg daily
  • Norethindrone acetate up to and including 10 mg daily
  • Norethindrone up to and including 0.35 mg daily
  • Oral micronized progesterone up to and including 30 0mg daily These low potency and lower dose progestins are permitted provided they have been used for less than 8 weeks (56 days) prior to enrollment and were started after the pre-treatment biopsy (e.g. endometrial biopsy or dilation and curettage). Participants will discontinue these low potency and lower dose progestins at the time of enrollment NOTES: Vaginal estrogen use is permitted. Prior use of hormonal contraceptives or post-menopausal hormone therapy is allowed, provided that it was discontinued > 3 months from current EIN diagnosis.
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  • Current use of selective estrogen receptor modulators (SERMs) and aromatase inhibitors. Prior use of SERMs or aromatase inhibitors is allowed, provided that it was discontinued > 3 months from current EIN diagnosis
  • Current use of metformin therapy (prior use of metformin therapy is allowed, provided that it was discontinued > 1 year from trial enrollment)
  • Use of GLP-1 or dual GLP-1/GIP-1 receptor agonists within 6 weeks prior to the baseline diagnostic biopsy or randomization
  • Participants receiving any other investigational agents within 30 days of enrollment or during this study.
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or megestrol acetate
  • Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study because it requires hysterectomy or progestin IUD placement which is contraindicated in women who are pregnant and wish to continue the pregnancy. Additionally, megestrol acetate is a category D agent. Megestrol acetate may cause fetal harm when administered to a pregnant woman
  • Women who are breastfeeding are excluded because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with megestrol acetate. Breastfeeding should be discontinued if the mother is treated with megestrol acetate
  • Personal history of pulmonary embolism, thrombotic stroke, arterial thrombosis or deep vein thrombosis of the extremity or deep vein thrombosis
  • Women who are diabetics on insulin will be eligible to participate but they will be required to check their blood sugar regularly. Patients who are unable to check their blood sugar will be excluded from participation
  • Women who are diabetics taking sulfonylureas and meglitinides will be excluded
  • Women with an alcohol use or abuse disorder due to increased risk of lactic acidosis with metformin
  • Current use of dofetilide, ulipristal, or carbonic anhydrase inhibitors as well as drugs that reduce metformin clearance such as ranolazine, vandetanib, dolutegravir, or cimetidine
  • Cancer survivors with evidence of active disease

Trial locations and contacts

8 sites in 1 country.

8 sites in 1 country

United States8 sites

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • Northwestern University

    Chicago, Illinois, 60611

  • University of Colorado

    Denver, Colorado, 80217-3364

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • Cedars Sinai Medical Center

    Los Angeles, California, 90048

  • University of Minnesota/Masonic Cancer Center

    Minneapolis, Minnesota, 55455

  • Northwestern Medicine Central DuPage Hospital

    Winfield, Illinois, 60190

Other trials in United States

About this study

Official title: Surgical Window of Opportunity Study of Megestrol Acetate Compared With Megestrol Acetate and Metformin for Endometrial Intraepithelial Neoplasia

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. To compare the change in endometrial cell proliferation, as measured by the percentage (%) of Ki-67 positive cells, in participants with endometrial intraepithelial neoplasia who undergo 4 weeks of treatment with megestrol acetate + metformin or megestrol acetate alone prior to planned procedure (hysterectomy) or progestin intrauterine device [IUD] placement).

SECONDARY OBJECTIVE:

  1. To measure the changes in protein expression in the endometrial intraepithelial neoplasia lesion, using immunohistochemistry (i-vi) in subjects treated with megestrol acetate + metformin compared to those treated with megestrol acetate alone.
  2. Estrogen receptor (ER) and progesterone receptor (PR) ii. PTEN/PAX2 expression iii. Markers of the PI3K-Akt-mTOR pathway (phosphor-acetyl-CoA carboxylase (ACC), p(Ser473)-Akt, phosphor-S6K, p4EBP1) iv. Markers of cell death (TUNEL, cleaved caspase-3) v. Markers of intratumoral insulin signaling (Phosphorylated insulin receptor (pIR) and insulin-like growth factor-1 receptor (total and phosphorylated IGF1R), vi. Mismatch repair (MMR) deficiency (baseline only).

EXPLORATORY OBJECTIVE:

  1. To explore whether baseline Ki-67 expression and other clinical characteristics are associated with treatment response.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Prior to standard of care planned procedure, patients receive megestrol acetate orally (PO) twice daily (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.

ARM II: 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.

After completion of study treatment, patients are followed for up to 42 days.

Being tested
Biopsy Procedure, Extended Release Metformin Hydrochloride, Megestrol Acetate, Questionnaire Administration
Medical subject headings
Endometrial Hyperplasia, Endometrial Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Biopsy ProcedureProcedure or surgery

    Also called Biopsy, BIOPSY_TYPE, Bx

    Undergo biopsy

  • Extended Release Metformin HydrochlorideDrug

    Also called ER Metformin Hydrochloride, Extended-release Metformin Hydrochloride, Glucophage XR, Glumetza

    Given PO

  • Megestrol AcetateDrug

    Also called 17-Hydroxy-6-methylpregna-4,6-diene-3,20-dione acetate, 17.alpha.-Acetoxy-6-methylpregna-4,6-diene-3,20-dione, 6-Dehydro-6-methyl-17.alpha.-acetoxyprogesterone, 6-Methyl-6-dehydro-17.alpha.-acetoxyprogesterone

    Given PO

  • Questionnaire AdministrationOther

    Ancillary studies

Study groups in NCT04576104
Study groupRoleWhat they receive
Arm I (megestrol acetate)Active comparatorPrior 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.
Receives: Procedure: Biopsy Procedure; Drug: Megestrol Acetate; Other: Questionnaire Administration
Arm II (megestrol acetate, metformin hydrochloride)ExperimentalPrior 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.
Receives: Procedure: Biopsy Procedure; Drug: Extended Release Metformin Hydrochloride; Drug: Megestrol Acetate; Other: Questionnaire Administration

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Percentage of Ki-67 positive cells

    Will measure the change in endometrial cell proliferation, as measured by the percentage of Ki-67 positive cells, in subjects treated with megestrol acetate + metformin compared to those treated with megestrol acetate alone, in all evaluable participants, and following stratification by menopausal status, as well as use of low dose, low potency progestins (yes/no).

    Measured: Up to 42 days post planned procedure

Secondary outcomes (1)

  1. Changes in protein expression

    Measured by immunohistochemistry of samples in subjects treated with megestrol acetate + metformin compared to those treated with megestrol acetate alone. Additional analyses will be stratified for premenopausal and postmenopausal status, as well as use of low dose, low potency progestins (yes/no) to assess whether there are biologic differences in these two groups of women. i. Estrogen receptor and progesterone receptor; ii. PTEN/PAX2 expression; iii. Markers of the PI3K-Akt-mTOR pathway (phosphor-acetyl-CoA carboxylase, p(Ser473)-Akt, phosphor-S6K, p4EBP1);iv. Markers of cell death (TUNEL, cleaved caspase-3);v. Markers of intratumoral insulin signaling (Phosphorylated insulin receptor and insulin- like growth factor-1 receptor (total and phosphorylated IGF1R); vi. Mismatch repair deficiency (baseline only).

    Measured: Baseline up to 42 days post planned procedure

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Oct 2020
  2. Study start29 Nov 2021
  3. Primary completion28 Aug 2025
  4. Study completion30 Jun 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
51 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT04576104
Sponsor's protocol ID
NCI-2020-07529
Other IDs
NCI-2020-07529, NCI20-02-01, NWU20-02-01, P30CA060553, UG1CA242643
Status last verified
Jan 2026
First submitted
3 Oct 2020
Last updated
21 Jan 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Biopsy Procedure, Extended Release Metformin Hydrochloride and Megestrol Acetate in people with Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia and Endometrial Carcinoma, run by Northwestern University at 8 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 14 inclusion and 20 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 21 Jan 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 8 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Percentage of Ki-67 positive cells (time frame: Up to 42 days post planned procedure). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT04576104.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Jan 2026.

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