Clinical Trials /

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

NCT02397083

Description:

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.

Related Conditions:
  • Endometrial Endometrioid Adenocarcinoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Levonorgestrel-Releasing Intrauterine System With or Without Everolimus in Treating Patients With Atypical Hyperplasia or Stage IA Grade 1 Endometrial Cancer
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 2014-0944
  • SECONDARY ID: NCI-2015-00919
  • SECONDARY ID: 2014-0944
  • SECONDARY ID: P30CA016672
  • SECONDARY ID: P50CA098258
  • NCT ID: NCT02397083

Conditions

  • Atypical Endometrial Hyperplasia
  • FIGO Grade 1 Endometrial Endometrioid Adenocarcinoma
  • FIGO Grade 2 Endometrial Endometrioid Adenocarcinoma

Interventions

DrugSynonymsArms
Everolimus42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, ZortressArm II (LIUD, everolimus)

Purpose

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.

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:

      Patients undergo placement of the LIUD on day 1. Patients achieving stable disease at 3
      months are randomized to 1 of 2 treatment arms. Patients with complete response may continue
      treatment with the LIUD.

      ARM I: Patients continue treatment with the LIUD for up to 9 months in the absence of disease
      progression or unacceptable toxicity.

      ARM II: Patients continue treatment with the LIUD and receive everolimus orally (PO) once
      daily (QD) on days 1-28. Treatment repeats every 28 days for up to 9 cycles in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 6, 9, and 12 months and then
      every 6 months thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (LIUD)ExperimentalPatients continue treatment with the LIUD for up to 9 months in the absence of disease progression or unacceptable toxicity.
    Arm II (LIUD, everolimus)ExperimentalPatients 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.
    • Everolimus

    Eligibility Criteria

            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
    
              -  Prior progesterone treatment is ALLOWED
    
              -  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 hemoglobin A1c (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
    
              -  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
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Response rate (levonorgestrel intrauterine device [LIUD] alone)
    Time Frame:At 3 months
    Safety Issue:
    Description:Estimated with a 2-sided 90% confidence interval.

    Secondary Outcome Measures

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

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:M.D. Anderson Cancer Center

    Last Updated