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

UNC Lineberger Comprehensive Cancer Center

Status and phase

Completed

Phase 2

Conditions

Endometrial Cancer

Complex Atypical Hyperplasia

Treatments

Drug: Metformin

Study type

Interventional

Funder types

Other

Identifiers

NCT02035787

12-0886 (Other Identifier)

LCCC1326

Details and patient eligibility

About

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.

Full 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.

Enrollment

20 patients

Sex

Female

Ages

18+ years old

Volunteers

No Healthy Volunteers

Inclusion and exclusion criteria

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