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

  • STATUS
    Recruiting
  • End date
    Jun 24, 2023
  • participants needed
    30
  • sponsor
    UNC Lineberger Comprehensive Cancer Center
Updated on 24 January 2021
cancer
progestin
levonorgestrel
adenocarcinoma
hyperplasia
endometrial adenocarcinoma

Summary

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.

Description

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.

Details
Condition Endometrial Carcinoma, Uterine Cancer, Complex Atypical Hyperplasia, Endometrial Cancer
Treatment Metformin
Clinical Study IdentifierNCT02035787
SponsorUNC Lineberger Comprehensive Cancer Center
Last Modified on24 January 2021

Eligibility

Yes No Not Sure

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
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