Metformin Hydrochloride and Levonorgestrel-Releasing Intrauterine System in Treating Patients with Atypical Endometrial Hyperplasia or Endometrial Cancer

Status: Active

Description

This early phase I trial studies how well metformin hydrochloride works when added to levonorgestrel-releasing intrauterine system in treating patients with atypical endometrial hyperplasia or endometrial cancer who cannot undergo surgery. Metformin hydrochloride is a widely-used type II diabetes drug that may also stop cancer cells from dividing. Estrogen may cause cancer. Levonorgestrel-releasing intrauterine system is a device placed in the uterus that reduces the level of estrogen in the body. Giving metformin hydrochloride in addition to treatment with levonorgestrel-releasing intrauterine system may be an effective alternative for patients with atypical endometrial hyperplasia or endometrial cancer who cannot undergo surgery.

Eligibility Criteria

Inclusion Criteria

  • Histologically confirmed CAH or grade 1 EC
  • 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% and/or perioperative respiratory failure risk > 5% AND ** Independent medicine or cardiology pre-op consultation concluding ‘high’ surgical risk * Patient determined to be a non-surgical candidate by the primary treating physician
  • Planned treatment with the LR-IUD for CAH or grade 1 EC by primary physician
  • Women of childbearing potential (WOCBP) must have negative urine pregnancy test within 7 days of day 1 (D1) of treatment
  • Understand study design, risks, and benefits and have signed informed consent

Exclusion Criteria

  • Creatinine (Cr) > 1.5 mg/dL or Cr clearance < 60 mL/m^2
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2 x 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 magnetic resonance imaging (MRI) (MRI only to be done for EC patients) or tumor size > 2 cm 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

Locations & Contacts

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: Active
Contact: Allison Staley
Phone: 919-966-5996
Email: astaley@unchealth.unc.edu

Ohio

Cincinnati
TriHealth Cancer Institute-Anderson
Status: Active
Contact: Diann Elizabeth Fischesser
Phone: 513-862-1892
Email: Diann_frischesser@trihealthcare.com

Virginia

Falls Church
Inova Fairfax Hospital
Status: Active
Contact: George Larry Maxwell
Phone: 703-776-6040

Trial Objectives and Outline

PRIMARY OBJECTIVES:

I. To compare the rate of complete response (CR) at 6 months in non-surgical grade 1 endometrial cancer (EC) and complex atypical hyperplasia (CAH) patients receiving metformin (metformin hydrochloride) + levonorgestrel-releasing intrauterine device (LR-IUD) to 50%.

SECONDARY OBJECTIVES:

I. To estimate the rate of CR at 6 months separately in grade 1 EC and CAH patients receiving metformin + LR-IUD.

II. To estimate the rate of CR at 12 months in non-surgical grade 1 EC and CAH patients receiving metformin + LR-IUD.

III. To document patient adherence to long-term (>= 3 months) metformin administration.

IV. To describe safety of metformin + LR-IUD treatment.

TERTIARY OBJECTIVES:

I. To explore changes in cellular proliferation as measured by the marker, marker of proliferation Ki-67 (Ki-67), from baseline to 6 months.

II. 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.

III. 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.

IV. To explore association between metabolic factors and metformin concentration levels in tumor tissue/blood/urine and CR at 6 months.

OUTLINE:

Beginning within 30 days of standard of care dilation and curettage (D & C) and levonorgestrel-releasing intrauterine system placement, patients receive metformin hydrochloride orally (PO) twice daily (BID) (titrated from once daily [QD] within the first 4 weeks) for 12 months in the absence in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at up to 30 days.

Trial Phase & Type

Trial Phase

No phase specified

Trial Type

Treatment

Lead Organization

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Allison Staley

Trial IDs

Primary ID LCCC 1326
Secondary IDs NCI-2014-00799, 13-3723, 12-0886
Clinicaltrials.gov ID NCT02035787