Pilot Study of Denosumab in BRCA1/2 Mutation Carriers Scheduled for Risk-Reducing Salpingo-Oophorectomy
|The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.|
|ClinicalTrials.gov Identifier: NCT03382574|
Recruitment Status : Recruiting
First Posted : December 26, 2017
Last Update Posted : September 30, 2020
|Condition or disease||Intervention/treatment||Phase|
|Ovarian Carcinoma||Biological: Denosumab Procedure: Salpingo-Oophorectomy||Early Phase 1|
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.
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 (Clinical Trial)|
|Estimated Enrollment :||60 participants|
|Intervention Model:||Parallel Assignment|
|Masking:||None (Open Label)|
|Official Title:||Pilot Study of Denosumab in BRCA1/2 Mutation Carriers Scheduled for Risk-Reducing Salpingo-Oophorectomy|
|Actual Study Start Date :||March 14, 2019|
|Estimated Primary Completion Date :||November 20, 2021|
|Estimated Study Completion Date :||November 20, 2021|
Experimental: Arm I (denosumab, risk-reducing salpingo-oophorectomy)
Beginning within 3 days of menstrual cycle, patients receive denosumab SC every 4 weeks for 1-2 doses and undergo risk-reducing salpingo-oophorectomy 14-28 days after last dose.
Undergo risk-reducing salpingo-oophorectomy
Active Comparator: Arm II (risk-reducing salpingo-oophorectomy)
Patients receive no treatment for 2-8 weeks and then undergo risk-reducing salpingo-oophorectomy.
Undergo risk-reducing salpingo-oophorectomy
- Ki67 proliferation index fallopian tube fimbrial epithelial cells [ Time Frame: Up to 12 months ]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.
- Ki67 proliferation index in ovarian surface epithelium and endometrium [ Time Frame: Up to 12 months ]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.
- Other tissue-based biomarkers in the fimbrial end of the fallopian tube, ovarian surface epithelium, and endometrium [ Time Frame: Up to 12 months ]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.
- Gene expression profiling of RANK, cell proliferation, cell cycle progression, and inflammation pathways [ Time Frame: Up to 12 months ]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.
- Serum biomarkers including progesterone, estradiol, and denosumab drug levels [ Time Frame: Up to time of surgery ]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.
- Change in serial serum C-terminal telopeptide levels [ Time Frame: Baseline up to 12 months after start of intervention ]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.
- Toxicity profile and frequency of adverse effects in premenopausal BRCA1/2 mutation carriers [ Time Frame: Up to 12 months after start of treatment ]Categorical variables, such as adverse events, will be summarized by frequency and proportion.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03382574
|United States, Massachusetts|
|Dana-Farber Cancer Institute||Recruiting|
|Boston, Massachusetts, United States, 02215|
|Contact: Judy E. Garber 617-632-2282 email@example.com|
|Principal Investigator: Judy E. Garber|
|United States, New York|
|NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center||Recruiting|
|New York, New York, United States, 10032|
|Contact: Meghna S. Trivedi 646-317-2280 firstname.lastname@example.org|
|Principal Investigator: Meghna S. Trivedi|
|NYP/Weill Cornell Medical Center||Recruiting|
|New York, New York, United States, 10065|
|Contact: Kevin Holcomb 212-746-7553 email@example.com|
|Principal Investigator: Kevin Holcomb|
|United States, Texas|
|M D Anderson Cancer Center||Recruiting|
|Houston, Texas, United States, 77030|
|Contact: Powel H. Brown 713-792-4509 firstname.lastname@example.org|
|Principal Investigator: Powel H. Brown|
|Tel Aviv Sourasky Medical Center||Recruiting|
|Tel Aviv, Israel, 64239|
|Contact: Nadir Arber 972-3-697-3561 email@example.com|
|Principal Investigator: Nadir Arber|
|Chaim Sheba Medical Center||Recruiting|
|Tel Hashomer, Israel, 52621|
|Contact: Eitan Friedman 813-745-3549 firstname.lastname@example.org|
|Principal Investigator: Eitan Friedman|
|Principal Investigator:||Meghna S Trivedi||M.D. Anderson Cancer Center|