Levonorgestrel in Preventing Ovarian Cancer in Patients at High Risk for Ovarian Cancer

Study Overview
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Brief Summary
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This randomized phase II trial is studying how well levonorgestrel works in preventing ovarian cancer in patients at high risk for ovarian cancer. Chemoprevention is the use of certain drugs to keep cancer from forming. The use of levonorgestrel may prevent ovarian cancer.

Detailed Description
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PRIMARY OBJECTIVES: I. Determine the impact of levonorgestrel on the relative frequency of apoptosis in the ovarian epithelium of patients at high risk for ovarian cancer. SECONDARY OBJECTIVES: I. Estimate the impact of this drug on proliferation and transforming growth factor-beta (TGF-beta) expression in the ovarian epithelium of these patients. II. Assess the safety of this drug in these patients. OUTLINE: This is a prospective, randomized, placebo-controlled, double-blind study. Patients are stratified according to menopausal status (premenopausal vs postmenopausal). Patients are randomized to 1 of 2 treatment arms. ARM I: Patients receive oral levonorgestrel once daily. ARM II: Patients receive oral placebo once daily. In both arms, treatment continues for 4-6 weeks in the absence of disease progression or unacceptable toxicity, including on the day of surgery. Patients then undergo prophylactic salpingo-oophorectomy. After completion of study therapy, patients are followed at 1 year. NOTE: * Patients who are unable to have surgery completed during the expected 4-6 weeks, may continue levonorgestrel or placebo for a time period no > 5 months. Patients unable to undergo surgery within 5 months are removed from the study.

Official Title
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Phase II Double Blind Randomized Trial Evaluating the Biologic Effect of Levonorgestrel on the Double Blind Randomized Trial Evaluating the Biologic Effect of Levonorgestrel on the Ovarian Epithelium in Women at High Risk for Ovarian Cancer

Conditions
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Ovarian Carcinoma

Intervention / Treatment
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* Other: Laboratory Biomarker Analysis
* Drug: Levonorgestrel
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At increased genetic risk for ovarian cancer AND planning to undergo risk-reducing salpingo-oophorectomy (RRSO) Has ≥ 1 intact ovary Patients enrolled on clinical trial GOG-0199 and planning to undergo RRSO allowed Submission of fixed ovarian tissue (FN01) required Must meet 1 of the following additional criteria: Family of the patient has a documented deleterious BRCA1 or BRCA2 mutation and either the patient herself has tested positive for a deleterious BRCA1 or BRCA2 mutation or the patient has a first- or second-degree relative with a deleterious BRCA1 or BRCA2 mutation No patient with a deleterious BRCA1 or BRCA2 mutation whose first- or second-degree relative has tested negative for the exact same mutation The family contains members with ≥ 2 ovarian* and/or breast cancers among the first- or second-degree relatives (male relatives must be counted) of the patient within the same lineage (this condition may be satisfied by multiple primary cancers in the same person or, where breast cancer is required to meet this criterion, ≥ 1 breast cancer must have been diagnosed prior to menopause or at age ≤ 50 years if age at menopause is unknown) The patient is of Ashkenazi Jewish ethnicity (lineage via the mother) with one first- degree or two second-degree maternal relatives with breast and/or ovarian cancer* (where breast cancer is required to meet this criterion, ≥ 1 breast cancer must have been diagnosed prior to menopause or at age ≤ 50 years if age at menopause is unknown) The probability of carrying a BRCA1 or BRCA2 mutation, given the family pedigree of breast and ovarian cancers, exceeds 20%, as calculated by BRCAPRO No prior history of ovarian cancer, including low malignant potential cancers, or primary papillary serous carcinoma of the peritoneum No prior or concurrent history of breast cancer, including ductal carcinoma in situ (DCIS) of the breast Women with a history of hormone receptor-negative breast cancer (both estrogen receptor-negative and progesterone receptor-negative) are eligible Not pregnant or nursing Negative pregnancy test Fertile patients must use effective nonhormonal contraception prior to the prophylactic salpingo-oophorectomy No prior history of deep vein thrombosis, stroke, liver disease, or heart attack No prior history of myocardial infarction No known bleeding disorders or hypercoagulable states No other malignancy, including ductal carcinoma in situ, within 1 year of systemic therapy, except for nonmelanoma skin cancer No prior chemotherapy regimen lasting ≥ 12 months No oral or intrauterine hormonal contraception or hormonal replacement therapy within the past 3 months or injectable medroxyprogesterone within the past 12 months No intraperitoneal surgery within the past 3 months (including laparoscopy) No prior or concurrent radiotherapy to the pelvis No concurrent hormonal contraception No concurrent tamoxifen, raloxifene, estrogen, progesterone-like hormones, or other hormonal medication (including hormone replacement therapy)

Ages Eligible for Study
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Minimum Age: 30 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm I (levonorgestrel)<br>Patients receive oral levonorgestrel once daily. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Levonorgestrel<br>* Given orally<br>* Other names: Plan B;|
| Placebo Comparator: Arm II (placebo)<br>Patients receive oral placebo once daily. | Other: Laboratory Biomarker Analysis<br>* Correlative studies<br>Drug: Levonorgestrel<br>* Given orally<br>* Other names: Plan B;Other: Placebo<br>* Given orally<br>* Other names: sham therapy;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Proportion Cells That Are Apoptotic in Epithelial Ovarian Tissue | The median proportion of cells that are considered to be apoptotic are counted in the ovarian tissue sample, among the total number of cells available in the sample slide. | Surgical specimen (4 - 6 weeks after entry) | 
| Number of Participants With Adverse Events According to Grade as Determined by NCI CTCAE v.3.0 | Participants were graded using CTCAE v.30 criteria. Grade 1 is the least severe grade. Each adverse event lists criteria for grading, grade 1 being mild, up to grade 5. Grade 4 is generally life threatening. Grade 5 is death. | Up to 20 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Proliferation as Measured by Ki-67 |  | Time of surgery (4 to 6 weeks after entry) | 
| Patients With High Expression of Transforming Growth Factor-beta 1 |  | Baseline to time of surgery (4 to 6 weeks) |