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

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.

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