Clinical Trials /

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

NCT04576104

Description:

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.

Related Conditions:
  • Endometrial Intraepithelial Neoplasia
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Megestrol Acetate Compared With Megestrol Acetate and Metformin to Prevent Endometrial Cancer
  • Official Title: Surgical Window of Opportunity Study of Megestrol Acetate Compared With Megestrol Acetate and Metformin for Endometrial Intraepithelial Neoplasia

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-07529
  • SECONDARY ID: NCI-2020-07529
  • SECONDARY ID: NCI20-02-01
  • SECONDARY ID: NWU20-02-01
  • SECONDARY ID: P30CA060553
  • SECONDARY ID: UG1CA242643
  • NCT ID: NCT04576104

Conditions

  • Endometrial Intraepithelial Neoplasia

Interventions

DrugSynonymsArms
Extended Release Metformin HydrochlorideER Metformin Hydrochloride, Extended-release Metformin Hydrochloride, Glucophage XR, Glumetza, Metformin Hydrochloride Extended ReleaseArm II (megestrol acetate, metformin hydrochloride)
Megestrol Acetate17-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, BDH 1298, BDH-1298, Maygace, Megace, Megestat, Megestil, Niagestin, Ovaban, Pallace, SC-10363Arm I (megestrol acetate)

Purpose

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.

Detailed 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 insulinlike 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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (megestrol acetate)Active ComparatorPrior to standard of care surgery, patients receive megestrol acetate PO BID for 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Megestrol Acetate
Arm II (megestrol acetate, metformin hydrochloride)ExperimentalPrior to standard of care surgery, patients receive megestrol acetate PO BID and metformin hydrochloride extended-release PO BID for 4 weeks in the absence of disease progression or unacceptable toxicity.
  • Extended Release Metformin Hydrochloride
  • Megestrol Acetate

Eligibility Criteria

        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 taking insulin secretagogues will be excluded
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percentage of Ki-67 positive cells
Time Frame:Up to 30 days post surgery
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Changes in protein expression
Time Frame:Baseline up to 30 days post surgery
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 23, 2020