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 in the absence of disease progression or unacceptable
toxicity.
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 in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed up for up to 30 days.
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 surgery. Other commonly used
pathologic terms for EIN, such as complex atypical hyperplasia and atypical
hyperplasia will also be eligible
- No prior therapy for EIN is permitted
- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
- 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])
=< 1.5 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
- Must be a candidate and accepting of surgical management of EIN with planned
hysterectomy
- 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
- Participants who are cancer survivors, provided they are without evidence of active
disease are eligible
- Participants who are human immunodeficiency virus (HIV)-positive will be eligible for
participation
Exclusion Criteria:
- No current hormonal therapy or hormone replacement therapy (prior use of oral
contraceptives or hormonal replacement therapy is allowed, provided that it was
discontinued > 3 months from trial enrollment). Vaginal estrogen use is permitted
- No current use of metformin therapy (prior use of metformin therapy is allowed,
provided that it was discontinued > 1 year from trial enrollment)
- Not currently breastfeeding or pregnant
- Participants may not be 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 including, but not limited to, ongoing or active
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements
- 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. Fertility and reproduction studies
with high doses of megestrol acetate have shown a reversible feminizing effect on some
male rat fetuses. 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 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
