Metformin With the Levonorgestrel-Releasing Intrauterine Device for the Treatment of Complex Atypical Hyperplasia (CAH) and Endometrial Cancer (EC) in Non-surgical Patients
Study Details
Study Description
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.
Condition or Disease | Intervention/Treatment | Phase |
---|---|---|
N/A |
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
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to estimate the rate of CR at 6 months separately in grade 1 EC and CAH patients receiving metformin + LR-IUD
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to estimate the rate of CR at 12 months in non-surgical grade 1 EC and CAH patients receiving metformin + LR-IUD
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to document patient adherence to long-term (≥3 months) metformin administration
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To describe safety of metformin + LR-IUD treatment
Exploratory Objectives
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To explore changes in cellular proliferation as measured by the marker, Ki-67, from baseline to 6 months
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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
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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
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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 Design
Arms and Interventions
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:
|
Outcome Measures
Primary Outcome Measures
- Response rate [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%
Secondary Outcome Measures
- adverse event measurement [12 months]
to categorize the type, severity and attribution of all recorded adverse events using CTCAE version 4.0.
Eligibility Criteria
Criteria
Inclusion Criteria:
Subjects must meet all of the inclusion criteria to participate in this study:
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Histologically confirmed CAH or grade 1 EC
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Females age ≥ 18 years
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Eastern Cooperative Oncology Group (ECOG) Performance Status 0 - 4
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Non-surgical candidates due to:
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Desire for fertility preserving treatment
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Unacceptable surgical risk as defined by:
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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.
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Planned treatment with the LR-IUD for CAH or grade 1 EC by primary physician
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Women of childbearing potential (WOCBP) must have negative pregnancy test within 7 days of D1 of treatment
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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.
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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))
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Currently receiving progestin therapy (local, topical, or systemic)
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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
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Mixed histology including clear cell, serous, undifferentiated or sarcomatous elements
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Prior or current use of metformin within the past 3 months
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History of hypersensitivity to metformin or history of discontinuation secondary to attributed adverse effects
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Chronic (daily use for > 1 month) use of cimetidine (significant increase in metformin concentration and risk of lactic acidosis)
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Iodinated contrast agents used in prior 48 hours (significant increase in metformin concentration and risk of lactic acidosis)
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Pregnant or lactating
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Recent (< 4 weeks) active, documented, cervical infection
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
---|---|---|---|---|---|
1 | Lineberger Comprehensive Cancer Center | Chapel Hill | North Carolina | United States | 27599 |
2 | TriHealth | Cincinnati | Ohio | United States | 45220 |
Sponsors and Collaborators
- UNC Lineberger Comprehensive Cancer Center
Investigators
- Principal Investigator: Victoria Bae-Jump, MD, PhD, UNC Lineberger Comprehensive Cancer Center
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- LCCC 1326
- 12-0886