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Ovarian CarcinomaEarly Phase 1NCT03382574

Pilot Study of Denosumab in BRCA1/2 Mutation Carriers Scheduled for Risk-Reducing Salpingo-Oophorectomy

A Early Phase 1 study testing Denosumab and Salpingo-Oophorectomy in people with Ovarian Carcinoma, run by National Cancer Institute (NCI) at 6 sites in 2 countries.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial summary

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. Read more about this study

Who is it for?
Ages 18 years and older, women only
Conditions the study is for
Ovarian Carcinoma
What is being tested?
Denosumab and Salpingo-Oophorectomy
Type of treatment
Surgery or procedure
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2 participants
Where
6 sitesin 2 countries
Study dates
14 Mar 2019to 22 Oct 2021
Phase
Early Phase 1
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • Women only
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Participants must be premenopausal (defined as < 3 months since last menstrual period OR serum follicle-stimulating hormone [FSH] < 20 mIU/mL)
  • Documented germline pathogenic or likely pathogenic variant in the BRCA1 or BRCA2 genes
  • Participants must be scheduled for or in the process of scheduling a risk-reducing salpingo-oophorectomy with or without hysterectomy - either bilateral or unilateral (if prior unilateral oophorectomy or salpingectomy for benign condition)
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Leukocytes >= 3,000/microliter
  • Absolute neutrophil count >= 1,500/microliter
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  • Platelets >= 100,000/microliter
  • Total bilirubin =< 2 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])) =< 1.5 x institutional ULN
  • Creatinine clearance >= 30 mL/min
  • Serum calcium or albumin adjusted >= 8.0 mg/dL and =< 11.5 mg/dL
  • Participant must have a negative urine or serum pregnancy test 14 days prior to randomization or drug administration; the effects of denosumab on the developing human fetus at the recommended therapeutic dose may cause fetal harm when administered to pregnant women; women of childbearing potential must agree to use adequate contraception from time of drug administration to time of surgery; should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her study physician immediately
  • Women currently on hormonal contraception (i.e., oral contraceptives, Mirena intrauterine device [IUD]) are eligible to participate if they have been on a stable dose for at least 3 months; women who have undergone bilateral tubal ligation are also eligible to participate in this study; there will be stratification for hormonal contraceptive use within 3 months prior to registration
  • Participants must be willing to take supplemental oral calcium 1000 mg (two 500 mg tablets) and vitamin D3 1000 IU daily for six months (which will be supplied by the research study) after receiving denosumab treatment or no treatment
  • Ability to understand and the willingness to sign a written informed consent document in English or Spanish or Hebrew
  • Participants must have a dental examination =< 6 months of study registration
  • Willing to not undergo any other elective surgery procedure with general anesthesia or conscious sedation during the treatment period; the treatment period is completed after the last injection of denosumab is administered

Who cannot join

  • History of ovarian cancer; history of breast cancer or any other malignancy is permitted if last chemotherapy treatment was greater than 6 months prior to registration and participant is not using endocrine therapy
  • Previous treatment with denosumab (including Prolia for osteoporosis or Xgeva for bone metastases) or use of bisphosphonate within 3 months of registration to the study
  • Participants receiving any other investigational agents
  • History of allergic reactions or hypersensitivity attributed to denosumab or any components of denosumab or compounds of similar chemical or biologic composition to denosumab, such as other RANKL inhibitors
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant and breastfeeding women are excluded from this study because denosumab is an agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events (AEs) in nursing infants secondary to treatment of the mother with denosumab, breastfeeding should be discontinued if the mother is treated with denosumab; there is no minimum amount of time since pregnancy/breastfeeding required before enrolling into the study; however, the date of delivery, pregnancy termination, or weaning from breastfeeding will be documented on case report forms; female subjects of child bearing potential and not willing to use, in combination with her partner, highly effective contraception during treatment will be excluded
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  • Use of endocrine therapy (selective estrogen receptor modulator, aromatase inhibitor, gonadotrophin releasing hormone [GnRH] agonist) within 6 months of registration to the study
  • Prior history or current evidence of osteonecrosis or osteomyelitis of the jaw, evidence of untreated local gum or oral infection, or non-healed dental or oral surgery
  • Active dental or jaw conditions which require oral surgery/dental procedures, including tooth extraction within 6 months of registration to the study; dental fillings are permitted within 6 months of study registration
  • Other risk factors for the development of osteonecrosis of the jaw (ONJ) including poor oral hygiene, use of a dental appliance, immunosuppressive therapy, treatment with angiogenesis inhibitors, systemic corticosteroids, diabetes, or gingival infections
  • Known sensitivity to any of the products to be administered during the study (e.g., calcium or vitamin D)
  • Known serious infections, including a history of active hepatitis B, hepatitis C, or human immunodeficiency virus (HIV); screening for these infections is not required for study enrollment
  • Hypocalcemia (serum calcium or albumin adjusted calcium < 8.0 mg/dL) or renal dysfunction (creatinine clearance < 30 mL/min)
  • Women with known osteoporosis or history of osteoporotic (fragility) fracture of the spine

Trial locations and contacts

6 sites in 2 countries.

6 sites in 2 countries

United States4 sites

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • M D Anderson Cancer Center

    Houston, Texas, 77030

  • NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

    New York, New York, 10032

  • NYP/Weill Cornell Medical Center

    New York, New York, 10065

Other trials in United States

Israel2 sites

  • Tel Aviv Sourasky Medical Center

    Tel Aviv, 64239

  • Chaim Sheba Medical Center

    Tel HaShomer, 52621

Other trials in Israel

About this study

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.

Read the detailed description

PRIMARY OBJECTIVE:

  1. 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:

  1. 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.

Being tested
Denosumab, Salpingo-Oophorectomy
Medical subject headings
Ovarian Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • DenosumabBiological

    Also called AMG 162, AMG-162, Denosumab Biosimilar MW032, Denosumab Biosimilar QL1206

    Given SC

  • Salpingo-OophorectomyProcedure or surgery

    Undergo risk-reducing salpingo-oophorectomy

Study groups in NCT03382574
Study groupRoleWhat they receive
Arm I (denosumab, risk-reducing salpingo-oophorectomy)ExperimentalBeginning 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.
Receives: Biological: Denosumab; Procedure: Salpingo-Oophorectomy
Arm II (risk-reducing salpingo-oophorectomy)Active comparatorPatients receive no treatment for 2-8 weeks and then undergo risk-reducing salpingo-oophorectomy.
Receives: Procedure: Salpingo-Oophorectomy

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 12 months

Secondary outcomes (6)

  1. 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.

    Measured: Up to 12 months

  2. 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.

    Measured: Up to 12 months

  3. 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.

    Measured: Up to 12 months

  4. 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.

    Measured: Up to time of surgery

  5. 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.

    Measured: Baseline up to 12 months after start of intervention

  6. 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.

    Measured: Up to 12 months after start of treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted26 Dec 2017
  2. Study start14 Mar 2019
  3. Primary completion22 Oct 2021
  4. Study completion22 Oct 2021

Why it stopped: it was decided that due to lack of accrual on the trial, and low potential for accruing over the near future, the trial will be shut down.

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Early Phase 1
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
2 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03382574
Sponsor's protocol ID
NCI-2017-02314
Other IDs
NCI-2017-02314, AAAR6281, N01-CN-2012-00034, AAAR6281, MDA2017-09-03, N01CN00034, P30CA016672, 2018-0478
Status last verified
May 2022
First submitted
22 Dec 2017
Last updated
14 Jun 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
Yes: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

Questions about this trial

What is this clinical trial studying?

A Early Phase 1 study testing Denosumab and Salpingo-Oophorectomy in people with Ovarian Carcinoma, run by National Cancer Institute (NCI) at 6 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 17 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 14 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 6 sites in United States, Israel. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Early Phase 1 (sometimes called Phase 0) studies give a very small amount of a treatment to a few people, mainly to see how the body handles it.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 14 Jun 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Ki67 Proliferation Index Fallopian Tube Fimbrial Epithelial Cells (time frame: Up to 12 months). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03382574.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Jun 2022.

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