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

  • STATUS
    Recruiting
  • days left to enroll
    37
  • participants needed
    50
  • sponsor
    National Cancer Institute (NCI)
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Updated on 19 August 2023
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insulin
cancer
hysterectomy
estrogen
megestrol
uterine disease
a hemoglobin
hyperplasia

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. 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.

Description

PRIMARY OBJECTIVE:

I. 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 hysterectomy.

SECONDARY OBJECTIVE:

I. 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.

i. 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:

I. 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 surgery, patients receive megestrol acetate orally (PO) twice daily (BID) for 21-35 days (up to and including the night before surgery) in the absence of disease progression or unacceptable toxicity. Patients also undergo biopsy on the day of surgery.

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

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

Details
Condition Endometrial Atypical Hyperplasia/Endometrioid Intraepithelial Neoplasia, Endometrial Carcinoma
Treatment questionnaire administration, biopsy, Megestrol Acetate, Extended Release Metformin Hydrochloride
Clinical Study IdentifierNCT04576104
SponsorNational Cancer Institute (NCI)
Last Modified on19 August 2023

Eligibility

 Yes No Not Sure

Inclusion Criteria

Participants with endometrial intraepithelial neoplasia (EIN) on an endometrial biopsy or dilation and curettage specimen will be eligible. 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
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 prior to hysterectomy. 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
Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial
Must be a candidate and accepting of surgical management of EIN with planned hysterectomy
For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
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
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
Ability to understand and the willingness to sign a written informed consent document
Patients on chronic suppressive antiviral therapy for herpes simplex virus (HSV) are eligible

Exclusion Criteria

Participants receiving any other investigational agents within 30 days of enrollment or during this study
Current hormonal therapy or 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
Pregnant women are excluded from this study because it requires hysterectomy 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
History of allergic reactions attributed to compounds of similar chemical or biologic composition to metformin or megestrol acetate
Norethindrone acetate up to and including 10 mg daily
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
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 oral contraceptives or hormonal replacement therapy is allowed, provided that it was discontinued > 3 months from current EIN diagnosis
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
Current use of metformin therapy (prior use of metformin therapy is allowed, provided
Women who are diabetics taking sulfonylureas and meglitinides will be excluded
that it was discontinued > 1 year from trial enrollment)
Women with an alcohol use or abuse disorder due to increased risk of lactic acidosis with metformin
Cancer survivors with evidence of active disease
Current use of dofetilide, ulipristal, or carbonic anhydrase inhibitors as well as drugs that reduce metformin clearance such as ranolazine, vandetanib, dolutegravir, or cimetidine
Uncontrolled intercurrent illness or psychiatric illness/social situations that would limit compliance with study requirements
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