Brief Title
Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients
Official Title
Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients
Brief 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.
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
Primary Outcome
Response rate
Secondary Outcome
adverse event measurement
Condition
Complex Atypical Hyperplasia
Intervention
Metformin
Study Arms / Comparison Groups
Metformin
Description: Metformin, 850 mg. twice daily.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
30
Start Date
February 27, 2014
Completion Date
February 2029
Primary Completion Date
July 2028
Eligibility 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
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Victoria Bae-Jump, MD, PhD, 919-966-4432, [email protected]
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT02035787
Organization ID
LCCC 1326
Secondary IDs
12-0886
Responsible Party
Sponsor
Study Sponsor
UNC Lineberger Comprehensive Cancer Center
Study Sponsor
Victoria Bae-Jump, MD, PhD, Principal Investigator, UNC Lineberger Comprehensive Cancer Center
Verification Date
March 2023