Levonorgestrel-Releasing Intrauterine System With or Without Everolimus in Treating Patients With Atypical Hyperplasia or Stage IA Grade 1 Endometrial Cancer (LEVER)

Phase II Study of the Levonorgestrel Intrauterine Device Alone or in Combination With the mTORC1 Inhibitor, Everolimus, for the Treatment of Complex Atypical Hyperplasia and Stage Ia Grade 1 Endometrial Cancer

This randomized phase II trial studies how well levonorgestrel-releasing intrauterine system works when given alone or with everolimus in treating patients with atypical hyperplasia (a pre-cancerous growth of the lining of the uterus) or stage IA grade 1 endometrial cancer. The levonorgestrel-releasing intrauterine system is designed to prevent pregnancy by releasing a hormone called levonorgestrel, which is a type of progesterone. Progesterone is a common type of hormone that is used to prevent pregnancy and may prevent or slow tumor cell growth. Everolimus may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether the levonorgestrel-releasing intrauterine system works better with or without everolimus in treating patients with atypical hyperplasia or stage IA grade 1 endometrial cancer.

Study Overview

• Status: Active, not recruiting
• Conditions: Atypical Endometrial Hyperplasia; FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma; FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Everolimus; Device: Levonorgestrel-Releasing Intrauterine System

Detailed Description

PRIMARY OBJECTIVES:

I. Estimate the efficacy of the levonorgestrel intrauterine device (LIUD) (levonorgestrel-releasing intrauterine system) alone to treat complex atypical hyperplasia or stage Ia grade 1 endometrioid endometrial carcinoma with response rate.

II. Estimate the efficacy of the LIUD in combination with everolimus to treat LIUD-refractory complex atypical hyperplasia or stage Ia grade 1 endometrioid endometrial carcinoma with response rate.

SECONDARY OBJECTIVES:

I. Document the toxicity profile of the levonorgestrel intrauterine device alone or in combination with everolimus using the National Institutes of Health-National Cancer Institute (NIH-NCI) Common Terminology Criteria for Adverse Events version (v) 4.0.

II. Estimate overall survival (OS) and event-free survival (EFS) of patients with complex atypical hyperplasia or stage Ia grade 1 endometrioid endometrial cancer treated with the levonorgestrel IUD alone or in combination with everolimus.

III. Estimate the response duration associated with the levonorgestrel IUD alone or in combination with everolimus in patients with complex atypical hyperplasia or stage Ia grade 1 endometrioid endometrial cancer.

EXPLORATORY OBJECTIVE:

I. Determine if response to therapy can be predicted based on the molecular profile of the tumor, including estrogen-induced genes and relevant pathway members, or by change in gene expression after therapy.

OUTLINE:

First Stage

• If D&C confirms EEC grade 1 or CAH-patient enrolled
• If the patient is found to have stable disease at 3 months continue on to the second stage of the study to be randomized.
• If the patient has a complete response at 3 months; EMB 3 months later to confirm complete response.
• Once complete response confirmed, patient Continues EMB every 6-12 months until disease progression per provider.
• If the patient has progressive disease at 3 months- OFF STUDY Second Stage
• Patients with stable disease at and 3 month EMB, recurrent disease at a subsequent EMB, or entering protocol with outside IUD in place showing stable disease demonstrating progesterone resistance

LIUD Only Arm

• Visits every 3 months
• EMB at 6 months
• if regression/SD: continue on study
• EMB at 9 months and 1 year:
• Off study for PD or D&C at MD's discretion
• SD at 1 year: off study
• CR at 1 year: SOC EMB 3 months later then Q6 months if confirmed CR
• If continuing on study: Q6mo EMB until progression, D&C, or pt./provider decision

LIUD+Everolimus Arm

• If progression at cycle 3, 6, 9:
• Discontinue everolimus, patient taken off study
• CR at cycle 9:
• EMB to confirm response at cycle 12
• If response confirmed -EMB every 6 cycles (6 months)
• Continue evaluations on each cycle day 1
• SD at cycle 9:
• Discontinue everolimus, come off study

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Shannon Westin, MD; Phone Number: (713) 794-4314; Email: swestin@mdanderson.org

Study Locations

• United States
  • Colorado
    • Greeley, Colorado, United States, 80631
      • North Colorado Medical Center
    • Loveland, Colorado, United States, 80539
      • McKee Medical Center
  • Hawaii
    • Honolulu, Hawaii, United States, 96813
      • Queen's Medical Center
  • Michigan
    • Saginaw, Michigan, United States, 48604
      • Covenant HealthCare Mackinaw
  • New Jersey
    • Camden, New Jersey, United States, 08103
      • Cooper Hospital University Medical Center
    • Voorhees, New Jersey, United States, 08043
      • MD Anderson Cancer Center at Cooper-Voorhees
  • New York
    • New Hyde Park, New York, United States, 11042
      • Northwell Health
  • Ohio
    • Mansfield, Ohio, United States, 44903
      • OhioHealth Mansfield Hospital
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma Health Sciences Center
  • Texas
    • Conroe, Texas, United States, 77384
      • MD Anderson in The Woodlands
    • Houston, Texas, United States, 77030
      • M D Anderson Cancer Center
    • Houston, Texas, United States, 77026-1967
      • Lyndon Baines Johnson General Hospital
    • Houston, Texas, United States, 77054
      • The Woman's Hospital of Texas
    • Houston, Texas, United States, 77024
      • Memorial Hermann Memorial City Medical Center
    • Houston, Texas, United States, 77079
      • MD Anderson West Houston
    • League City, Texas, United States, 77573
      • MD Anderson League City
    • Sugar Land, Texas, United States, 77478
      • MD Anderson in Sugar Land
  • Virginia
    • Charlottesville, Virginia, United States, 22908
      • University of Virginia Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• All patients with a diagnosis of complex atypical hyperplasia OR, grade 1 endometrioid OR focal grade 2 adenocarcinoma in predominately grade 1 disease endometrial carcinoma on endometrial biopsy or dilation and curettage (D & C) within three months of study enrollment
• Patients with complex atypical hyperplasia OR grade 1 endometrioid adenocarcinoma with stable/persistent disease with LIUD already in place. LIUD must have been in place for at least 3 months
• Prior progesterone treatment is ALLOWED, but a 28 day washout period is required before LIUD placement. If archival tissue is available from prior to any progesterone treatment, the washout period is not needed
• Ability to comply with endometrial biopsies every 3 months
• Eastern Cooperative Oncology Group (ECOG) performance status =< 2
• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
• Platelets >= 100 x 10^9/L
• Hemoglobin (Hb) > 9 g/dL
• Total serum bilirubin =< 2.0 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) =< 2.5 x upper limit of normal (ULN)
• International normalized ratio (INR) =< 2; factor 10A drawn if patient on anticoagulant Eliquis
• Serum creatinine =< 1.5 x ULN
• Fasting serum cholesterol =< 300 mg/dL OR =< 7.75 mmol/L AND fasting triglycerides =< 2.5 x ULN; NOTE: in case one or both of these thresholds are exceeded, the patient can only be included after initiation of appropriate lipid lowering medication
• Signed informed consent obtained prior to any screening procedures

Exclusion Criteria:

• Patients with grade 2-3 endometrioid, uterine serous, clear cell, mucinous, squamous, transitional cell, sarcomas, or carcinosarcoma histology
• Evidence of extrauterine spread of disease on imaging or during surgical evaluation
• Patients who have prior therapy with everolimus or any other mammalian target of rapamycin (mTOR) inhibitor
• Patients currently receiving anticancer therapies (including chemotherapy, radiation therapy, hormonal, or antibody-based therapy); prior treatment should have a washout period of 28 days or 4 1/2 half-lives (7 days), whichever is shorter
• Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus)
• Known intolerance or hypersensitivity to progesterone or its excipients
• Known impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral everolimus (e.g., inability to take oral medication or a requirement for intravenous [IV] alimentation, prior surgical procedures affecting absorption, malabsorption syndrome, and active peptic ulcer disease) are excluded; subjects with ulcerative colitis, inflammatory bowel disease, or a partial or complete small bowel obstruction are also excluded, as are any patients who cannot swallow the capsule whole
• Uncontrolled diabetes mellitus as defined by glycosylated hemoglobin (HbA1c) > 8% despite adequate therapy; patients with a known history of impaired fasting glucose or diabetes mellitus (DM) may be included, however blood glucose and antidiabetic treatment must be monitored closely throughout the trial and adjusted as necessary
• Patients who have any severe and/or uncontrolled medical conditions such as: a) unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction =< 6 months prior to start of everolimus, serious uncontrolled cardiac arrhythmia, or any other clinically significant cardiac disease; b) symptomatic congestive heart failure of New York Heart Association class III or IV; c) active (acute or chronic) or uncontrolled severe infection (not responding to antibiotics), liver disease such as cirrhosis, decompensated liver disease, and active and chronic hepatitis (i.e. quantifiable hepatitis B virus-deoxyribonucleic acid [HBV-DNA] and/or positive hepatitis B surface antigen [HbsAg], quantifiable hepatitis C virus-ribonucleic acid [HCV-RNA]); d) known severely impaired lung function (spirometry and diffusing capacity of the lung for carbon monoxide [DLCO] 50% or less of normal and oxygen [O2] saturation 88% or less at rest on room air); e) active, bleeding diathesis
• Chronic treatment with corticosteroids or other immunosuppressive agents; topical or inhaled corticosteroids are allowed
• Patients who have a known history of human immunodeficiency virus (HIV) seropositivity
• Patients who have received live attenuated vaccines within 1 week of start of everolimus and during the study; patient should also avoid close contact with others who have received live attenuated vaccines; examples of live attenuated vaccines include intranasal influenza, measles, mumps, rubella, oral polio, Bacillus Calmette-Guerin (BCG), yellow fever, varicella and TY21a typhoid vaccines
• Other malignancies within the past 3 years except for basal or squamous cell carcinoma of the skin
• Active (acute or chronic) or uncontrolled severe infections (not responding to antibiotics), including acute pelvic inflammatory disease
• Congenital or acquired uterine anomaly which distorts the uterine cavity
• Genital actinomycosis
• Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
• Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing
• Women who are pregnant or nursing (lactating) women
• Women of child-bearing potential (WOCBP), defined as women physiologically capable of becoming pregnant, must use one additional highly effective methods of contraception in addition to the LIUD during the study and 8 weeks after; acceptable effective contraception methods include combo of the following: a) barrier methods of contraception: condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/ vaginal suppository; b) total abstinence or; c) male/female sterilization; women are considered post-menopausal and not of child-bearing potential if they have had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without hysterectomy) or tubal ligation > six weeks prior to randomization; in the case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment is she considered not of child-bearing potential
• Women who are on contraindicated medications to everolimus must have confirmation from their physician that they may change or discontinue the medication if randomized to the LIUD + everolimus arm

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm I (LIUD); Patients continue treatment with the LIUD for up to 9 months in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Device: Levonorgestrel-Releasing Intrauterine System; Placed in the uterus; Other Names: Mirena
Experimental: Arm II (LIUD, everolimus); Patients continue treatment with the LIUD and receive everolimus PO QD on days 1-28. Treatment repeats every 28 days for up to 9 cycles in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Everolimus; Given PO; Other Names: 42-O-(2-Hydroxy)ethyl Rapamycin; Afinitor; Certican; RAD 001; RAD001; Votubia; Zortress; Device: Levonorgestrel-Releasing Intrauterine System; Placed in the uterus; Other Names: Mirena

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate (levonorgestrel intrauterine device [LIUD] alone)	Estimated with a 2-sided 90% confidence interval.	At 3 months
Response rate (levonorgestrel intrauterine device [LIUD] alone)	Estimated with a 2-sided 90% confidence interval.	6 months
Response rate for levonorgestrel intrauterine device (LIUD) alone or in combination with everolimus after LIUD failure (i.e., failure to achieve complete response after initial 3 months of LIUD alone)	Fisher's exact test will be used to compare response rates by 6 months between the LIUD alone arm and the LIUD plus everolimus arm. Estimated on each arm with a 2-sided 90% confidence interval.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Tabulated by treatment arm, severity, and relationship to study drug.	Up to 11 years
Progression free survival	Estimated using the Kaplan-Meier product-limit estimator. The log-rank test will be used to compare treatment arms.	Up to 11 years
Overall survival	Estimated using the Kaplan-Meier product-limit estimator. The log-rank test will be used to compare treatment arms.	Up to 11 years
Response duration	Estimated using the Kaplan-Meier product-limit estimator. The log-rank test will be used to compare treatment arms.	Up to 4 weeks after completion of study treatment

Collaborators and Investigators

• Sponsor: M.D. Anderson Cancer Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Shannon N Westin, MD, M.D. Anderson Cancer Center

Publications and helpful links

Helpful Links

• M D Anderson Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): September 23, 2015
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): September 30, 2026

Study Registration Dates

• First Submitted: March 18, 2015
• First Submitted That Met QC Criteria: March 18, 2015
• First Posted (Estimated): March 24, 2015

Study Record Updates

• Last Update Posted (Estimated): February 21, 2024
• Last Update Submitted That Met QC Criteria: February 19, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Uterine Neoplasms; Genital Neoplasms, Female; Uterine Diseases; Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Ovarian Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Hyperplasia; Adenocarcinoma; Endometrial Hyperplasia; Endometrial Neoplasms; Carcinoma, Endometrioid; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protein Kinase Inhibitors; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; MTOR Inhibitors; Levonorgestrel; Everolimus
• Other Study ID Numbers: 2014-0944 (Other Identifier: M D Anderson Cancer Center); P50CA098258 (U.S. NIH Grant/Contract); NCI-2015-00919 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No