This randomized pilot early phase I trial studies how well denosumab works in BRCA1/2 mutations carriers scheduled for risk-reducing salpingo-oophorectomy. Denosumab is a monoclonal antibody that may interfere with the ability of tumor cells to grow and spread.
PRIMARY OBJECTIVE: I. To compare the effect of denosumab 120 mg subcutaneously every 4 weeks for 1-2 doses to no treatment in the pre-surgical setting on Ki67 proliferation index by immunohistochemistry (IHC) in the fimbrial end of the fallopian tube of premenopausal BRCA1/2 mutation carriers undergoing risk-reducing salpingo-oophorectomy, with or without hysterectomy. SECONDARY OBJECTIVES: I. To assess Ki67 proliferation index by immunohistochemistry (IHC) in ovarian surface epithelium and endometrium (if also undergoing a hysterectomy, \~20% of participants) after exposure to denosumab compared to no treatment. II. To investigate other tissue-based biomarkers in the fimbrial end of the fallopian tube, ovarian surface epithelium, and endometrium (if also undergoing hysterectomy) after exposure to denosumab compared to no treatment, including: IIa. Apoptosis with cleaved caspase-3 by IHC. IIb. Receptor activator of NF-KB (RANK) and RANK ligand (RANKL) expression by IHC. IIc. Estrogen receptor (ER) and progesterone receptor (PR) expression by IHC. IId. CD44 and p53 expression by IHC. IIe. Signal transducer and activator of transcription 3 (STAT3) and phosphorylated-STAT3 (pSTAT3) expression by IHC. III. To analyze gene expression profiling in the fimbrial end of the fallopian tube and ovarian surface epithelium after exposure to denosumab compared to no treatment. IV. To investigate serum biomarkers at baseline (pre-treatment) and time of surgery (post-treatment) with denosumab compared to no treatment, including: IVa. Progesterone. IVb. Estradiol. IVc. Denosumab drug levels. V. To investigate serial serum C-terminal telopeptide (CTX) levels from baseline (pre-treatment) to time of surgery to 9 months and 12 months after start of intervention with denosumab compared to no treatment. VI. To monitor safety and adverse effects of denosumab compared to no treatment. OUTLINE: Patients are randomized 1 of 2 arms. ARM I: Beginning within 3 days of menstrual cycle, patients receive denosumab subcutaneously (SC) every 4 weeks for 1-2 doses and undergo risk-reducing salpingo-oophorectomy 14-28 days after last dose. ARM II: Patients receive no treatment for 2-8 weeks and then undergo risk-reducing salpingo-oophorectomy. After completion of study treatment, patients are followed up at 6, 9, and 12 months.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
PREVENTION
Masking
NONE
Enrollment
2
Given SC
Undergo risk-reducing salpingo-oophorectomy
Dana-Farber Cancer Institute
Boston, Massachusetts, United States
NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
New York, New York, United States
NYP/Weill Cornell Medical Center
New York, New York, United States
M D Anderson Cancer Center
Houston, Texas, United States
Ki67 Proliferation Index Fallopian Tube Fimbrial Epithelial Cells
Will be assessed using immunohistochemistry (IHC). Quantitative measures of the expression of Ki67 based upon percentage of positive cells will be scored by a pathologist blinded to treatment assignment. In order to evaluate the difference of Ki67 expression between the two arms, 2-sample t-test will be considered.
Time frame: Up to 12 months
Ki67 Proliferation Index in Ovarian Surface Epithelium and Endometrium
Will be assessed using IHC. In order to evaluate the difference of Ki67 expression between the two arms, 2-sample t-test will be considered.
Time frame: Up to 12 months
Other Tissue-based Biomarkers in the Fimbrial End of the Fallopian Tube, Ovarian Surface Epithelium, and Endometrium
Will be assessed using IHC. Including: apoptosis with cleaved caspase-3 (IHC), RANK/RANKL (IHC), estrogen receptor (ER)/progesterone receptor (PR) (IHC), CD44 and p53 (IHC), and STAT3 and pSTAT3 (IHC). Values of tissue-based biomarkers measurements such as tissue Ki67 proliferation index, serum progesterone, etc., which are continuous variables, will be summarized by descriptive statistics including mean, standard deviation, median and range. For tissue biomarkers, linear regression models will be employed to investigate the association of treatment while adjusting for possible confounders (i.e., age, race, etc.). Normality, homoscedasticity, independence of errors, and lack of multicollinearity in the covariates will be evaluated; if needed, proper transformation will be considered.
Time frame: Up to 12 months
Gene Expression Profiling of RANK, Cell Proliferation, Cell Cycle Progression, and Inflammation Pathways
For gene expression profiling analysis, nSolver Analysis Software (nanoString Technologies, Washington \[WA\]) will be used. Geometric mean is used for calculation of normalization factors. Student's t test is used to calculate differential expression.
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Tel Aviv Sourasky Medical Center
Tel Aviv, Israel
Chaim Sheba Medical Center
Tel Litwinsky, Israel
Time frame: Up to 12 months
Serum Biomarkers Including Progesterone, Estradiol, and Denosumab Drug Levels
Values of serum biomarkers measurements such as tissue Ki67 proliferation index, serum progesterone, etc., which are continuous variables, will be summarized by descriptive statistics including mean, standard deviation, median and range.
Time frame: Up to time of surgery
Change in Serial Serum C-terminal Telopeptide Levels
2-sample t-test may be applied to evaluate any change in serum biomarkers from baseline to after intervention. To investigate the overall changes in serum biomarkers, a linear mixed model that accommodates intra-participant correlation due to repeated measurements will be utilized adjusting for any potential covariates.
Time frame: Baseline up to 12 months after start of intervention
Toxicity Profile and Frequency of Adverse Effects in Premenopausal BRCA1/2 Mutation Carriers
Categorical variables, such as adverse events, will be summarized by frequency and proportion.
Time frame: Up to 12 months after start of treatment