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

March 18, 2024 updated by: UNC Lineberger Comprehensive Cancer Center

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.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed 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.

Study Type

Interventional

Enrollment (Actual)

21

Phase

  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

Study Locations

  • United States
    • North Carolina
      • Chapel Hill, North Carolina, United States, 27599
        • Lineberger Comprehensive Cancer Center
    • Ohio
      • Cincinnati, Ohio, United States, 45220
        • TriHealth

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Description

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

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Metformin
Metformin, 850 mg. twice daily.
Drug: Metformin
Metformin added to standard non-surgical treatment with levonorgestrel-Releasing Intrauterine Device.
Other Names:
  • glucophage

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Response rate
Time Frame: 6 months
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
Time Frame: 12 months
to categorize the type, severity and attribution of all recorded adverse events using CTCAE version 4.0.
12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

UNC Lineberger Comprehensive Cancer Center

Collaborators

Golfers Against Cancer Grant

Investigators

  • Principal Investigator: Victoria Bae-Jump, MD, PhD, UNC Lineberger Comprehensive Cancer Center

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 27, 2014

Primary Completion (Estimated)

April 12, 2024

Study Completion (Estimated)

October 1, 2024

Study Registration Dates

First Submitted

January 10, 2014

First Submitted That Met QC Criteria

January 10, 2014

First Posted (Estimated)

January 14, 2014

Study Record Updates

Last Update Posted (Actual)

March 19, 2024

Last Update Submitted That Met QC Criteria

March 18, 2024

Last Verified

March 1, 2024

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • LCCC1326
  • 12-0886 (Other Identifier: IRB)

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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