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
Everolimus,Levonorgestrel Intrauterine Device
The goal of this clinical research study is to learn if the Mirena intrauterine device (levonorgestrel IUD), alone or in combination with everolimus, is effective for the treatment of endometrial hyperplasia and/or early-stage endometrial cancer.
Disease Group: Endometrium
Treatment Agent: Everolimus,Levonorgestrel Intrauterine Device
Treatment Location: Both at MDACC & and Other Sites
Sponsor: Novartis - Supporter
Primary 1. Estimate the efficacy of the Levonorgestrel Intrauterine Device (LIUD) alone to treat complex atypical hyperplasia or stage Ia grade 1 endometrioid endometrial carcinoma with response rate. 2. 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 1. 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 v4.0 2. 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 3. 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 1. 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
IRB Review and Approval Date: 09/23/2015
Recruitment Status: Open
Projected Accrual: 270
1) All patients with a diagnosis of complex atypical hyperplasia OR
grade 1 endometrioid endometrial carcinoma on endometrial biopsy or D
& C within three months of study enrollment
2) Prior progesterone treatment for either diagnosis is ALLOWED.
3) Ability to comply with endometrial biopsies every 3 months
4) Age >/= 18 years
5) ECOG performance status </= 2
6) Adequate bone marrow function as shown by: absolute neutrophil count (ANC) >/= 1.5 x 10^9/L; Platelets >/=100 x 10^9/L; Hb >9 g/dL;
7) Adequate liver function as shown by: a) Total serum bilirubin </= 2.0 mg/dL; b) Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) </= 2.5x Upper Limit of Normal (ULN); c) International Normalized Ratio (INR) </= 2; factor 10A drawn if patient on anticoagulant Eliquis
8) Adequate renal function: serum creatinine </=1.5x ULN
9) Fasting serum cholesterol </= 300 mg/dL OR </= 7.75 mmol/L AND fasting triglycerides </= 2.5x 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;
10) Signed informed consent obtained prior to any screening procedures.
1) Patients with grade 2-3 endometrioid, uterine serous, clear cell,
mucinous, squamous, transitional cell, sarcomas, or carcinosarcoma histology
2) Evidence of extrauterine spread of disease on imaging or during surgical evaluation.
3) Patients who have prior therapy with everolimus or any other mTOR inhibitor.
4) 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;
5) Known intolerance or hypersensitivity to everolimus or other rapamycin analogs (e.g. sirolimus, temsirolimus);
6) Known intolerance or hypersensitivity to progesterone or its excipients
7) 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 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.
8) Uncontrolled diabetes mellitus as defined by 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;
9) 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 O2 saturation 88% or less at rest on room air), e. active, bleeding diathesis;
10) Chronic treatment with corticosteroids or other immunosuppressive agents. Topical or inhaled corticosteroids are allowed
11) Patients who have a known history of human immunodeficiency virus (HIV) seropositivity
12) 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-Guérin (BCG), yellow fever, varicella and TY21a typhoid vaccines
13) Other malignancies within the past 3 years except for basal or squamous cell carcinoma of the skin
14) Active (acute or chronic) or uncontrolled severe infections (not responding to antibiotics), including acute pelvic inflammatory disease
15) Congenital or acquired uterine anomaly which distorts the uterine cavity
16) Genital actinomycosis
17) 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
18) Patients who are currently part of or have participated in any clinical investigation with an investigational drug within 1 month prior to dosing.
19) Women who are pregnant or nursing (lactating) women
20) 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.
Information and next steps
For general questions about clinical trials: