Comparing megestrol acetate alone or with metformin to prevent endometrial cancer

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

This study is testing if taking megestrol acetate alone or with metformin can help prevent pre-cancerous changes in the uterus from turning into endometrial cancer in women diagnosed with endometrial intraepithelial neoplasia.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 50 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: National Cancer Institute (NCI) (NIH)
• Locations: 8 sites (Los Angeles, California and 7 other locations)
• Trial ID: NCT04576104 on ClinicalTrials.gov

What this trial studies

This phase II trial investigates the effectiveness of megestrol acetate, both alone and in combination with metformin, in preventing the progression of endometrial intraepithelial neoplasia (EIN) to endometrial cancer. Participants diagnosed with EIN will be randomized to receive either treatment for 4 weeks before a planned procedure. The primary objective is to measure changes in endometrial cell proliferation, while secondary objectives include assessing protein expression changes in the lesions. The study aims to determine if the combination therapy is more effective than megestrol acetate alone in reducing the growth of pre-cancerous cells.

Who should consider this trial

Good fit: Ideal candidates are adults aged 18 and older diagnosed with endometrial intraepithelial neoplasia or similar conditions.

Not a fit: Patients under 18 years old or those without a diagnosis of endometrial intraepithelial neoplasia will not benefit from this study.

Why it matters

Potential benefit: If successful, this approach could provide a non-surgical treatment option that effectively prevents the progression of pre-cancerous conditions to endometrial cancer.

How similar studies have performed: While the combination of megestrol acetate and metformin is a novel approach, previous studies have shown promise in using metformin for cancer prevention.

Eligibility criteria

Inclusion Criteria:

* 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
* 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

Exclusion Criteria:

* 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.
* 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

Where this trial is running

Los Angeles, California and 7 other locations

• Cedars Sinai Medical Center — Los Angeles, California, United States (Active_not_recruiting)
• University of Colorado — Denver, Colorado, United States (Recruiting)
• Northwestern University — Chicago, Illinois, United States (Recruiting)
• Northwestern Medicine Central DuPage Hospital — Winfield, Illinois, United States (Recruiting)
• Dana-Farber Cancer Institute — Boston, Massachusetts, United States (Recruiting)
• University of Minnesota/Masonic Cancer Center — Minneapolis, Minnesota, United States (Recruiting)
• UNC Lineberger Comprehensive Cancer Center — Chapel Hill, North Carolina, United States (Recruiting)
• Duke University Medical Center — Durham, North Carolina, United States (Recruiting)

Study contacts

• Principal investigator: Emma Barber — Northwestern University

Conditions Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia; Endometrial Carcinoma