Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients

Study Overview
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Brief Summary
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Purpose: This is an open label, single-arm, single-center study of the addition of metformin to standard levonorgestrel-releasing intrauterine device (LR-IUD) treatment of 30 evaluable non-surgical patients with either complex atypical hyperplasia (CAH; n=15) or grade 1 endometrial adenocarcinoma (EC; n=15). Participants:Women, over the age of 18 years, with biopsy-proven CAH/EC who are not candidates for surgical management, and therefore are planned to start standard of care treatment with the LR-IUD Procedures (methods): subjects will be given oral metformin therapy for 12 months, or until disease progression occurs (whichever occurs first), in addition to LR-IUD treatment. Serial endometrial biopsies will be performed, as per standard of care, to assess disease status.

Detailed Description
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STUDY OBJECTIVES Primary Objective -To compare the rate of CR at 6 months in non-surgical grade 1 EC and CAH patients receiving metformin + LR-IUD to 50% Secondary Objectives to estimate the rate of CR at 6 months separately in grade 1 EC and CAH patients receiving metformin + LR-IUD to estimate the rate of CR at 12 months in non-surgical grade 1 EC and CAH patients receiving metformin + LR-IUD to document patient adherence to long-term (≥3 months) metformin administration To describe safety of metformin + LR-IUD treatment Exploratory Objectives To explore changes in cellular proliferation as measured by the marker, Ki-67, from baseline to 6 months To explore association between the level of expression of the metformin transporter proteins and key targets of the metformin/mammalian target of rapamycin (mTOR) signaling pathway and CR status at 6 months To perform a comprehensive unbiased profiling of metabolites by analyzing the metabolic fingerprints of the biofluids (i.e. serum and urine) and footprints of the tumor tissue pre- and post- 6 months of metformin treatment To explore association between metabolic factors and metformin concentration levels in tumor tissue/blood/urine and CR at 6 months This is an open label, single-arm, single-center study of the addition of metformin to standard levonorgestrel-releasing intrauterine device (LR-IUD) treatment of 30 evaluable non-surgical patients with either complex atypical hyperplasia (CAH; n=15) or grade 1 endometrial adenocarcinoma (EC; n=15). Women, over the age of 18 years, with biopsy-proven CAH/EC who are not candidates for surgical management, and therefore are planned to start standard of care treatment with the LR-IUD, will be given oral metformin therapy for 12 months, or until disease progression occurs (whichever occurs first), in addition to LR-IUD treatment. Serial endometrial biopsies will be performed, as per standard of care, to assess disease status. We hypothesize that the addition of metformin to standard LR-IUD treatment of CAH and grade 1 EC will result in a complete response (CR) rate at 6 months that is significantly higher than 50% in a population of non-surgical candidates. In addition, we plan to estimate CR rate at 6 months in CAH and EC separately, and in the group as a whole at 12 months. We will also document the rate of patient adherence to long-term metformin therapy.

Official Title
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Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients

Conditions
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Endometrial Cancer, Complex Atypical Hyperplasia

Intervention / Treatment
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* Drug: Metformin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects must meet all of the inclusion criteria to participate in this study: Histologically confirmed CAH or grade 1 EC Females age ≥ 18 years Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 4 Non-surgical candidates due to: Desire for fertility preserving treatment Unacceptable surgical risk as defined by: American Society of Anesthesiologists Physical Status (ASA) ≥ 4 and/or Perioperative Cardiac Risk > 5%(45) and/or Perioperative Respiratory Failure Risk > 5%(46) AND oIndependent medicine or cardiology pre-op consultation concluding 'high' surgical risk. Planned treatment with the LR-IUD for CAH or grade 1 EC by primary physician Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days of D1 of treatment Understand study design, risks, and benefits and have signed informed consent Exclusion Criteria Any patient meeting any of the exclusion criteria at baseline will be excluded from study participation. Evidence of renal dysfunction (Cr > 1.5mg/dL or Cr clearance < 60 mL/m2) or liver dysfunction (AST/alanine aminotransferase (ALT) > 2x upper limit of normal (ULN)) Currently receiving progestin therapy (local, topical, or systemic) Myometrial invasion >50% or evidence of nodal or metastatic disease on baseline MRI (MRI only to be done for EC patients) or tumor size > 2cm on MRI or pelvic ultrasound Mixed histology including clear cell, serous, undifferentiated or sarcomatous elements Prior or current use of metformin within the past 3 months History of hypersensitivity to metformin or history of discontinuation secondary to attributed adverse effects Chronic (daily use for > 1 month) use of cimetidine (significant increase in metformin concentration and risk of lactic acidosis) Iodinated contrast agents used in prior 48 hours (significant increase in metformin concentration and risk of lactic acidosis) Pregnant or lactating Recent (< 4 weeks) active, documented, cervical infection

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Metformin<br>Metformin, 850 mg. twice daily. | Drug: Metformin<br>* Metformin added to standard non-surgical treatment with levonorgestrel-Releasing Intrauterine Device.<br>* Other names: glucophage;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate | percent of individuals achieving complete disease regression as defined by no evidence of microscopic viable hyperplasia or carcinoma on endometrial biopsy after 6 months of treatment compared to a base rate of 50% | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| adverse event measurement | to categorize the type, severity and attribution of all recorded adverse events using CTCAE version 4.0. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metformin, endometrial cancer, Lineberger Comprehensive Cancer Center, complex atypical hyperplasia