metformin with the levonorgestrel-releasing intrauterine device for the treatment of complex atypical hyperplasia (cah) and endometrial cancer (ec) in non-surgical patients

Conditions: Complex Atypical Hyperplasia; Endometrial Cancer

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.

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.

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 \ 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

Keywords: metformin endometrial cancer lineberger comprehensive cancer center complex atypical hyperplasia