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

NCT03382574 | Terminated Early Phase 1 Results DMC FDA Drug

• 7 other identifiers: NCI-2017-02314AAAR6281N01-CN-2012-00034MDA2017-09-03N01CN00034P30CA0166722018-0478
• Study Type: interventional
• Target: 2
• Locations: 2 countries
• Sites: 6

Brief 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.

Conditions

Ovarian Carcinoma

Outcome Measures

Primary Outcomes (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.

  Up to 12 months

Secondary Outcomes (6)

• Ki67 Proliferation Index in Ovarian Surface Epithelium and Endometrium

  Up to 12 months

• Other Tissue-based Biomarkers in the Fimbrial End of the Fallopian Tube, Ovarian Surface Epithelium, and Endometrium

  Up to 12 months

• Gene Expression Profiling of RANK, Cell Proliferation, Cell Cycle Progression, and Inflammation Pathways

  Up to 12 months

• Serum Biomarkers Including Progesterone, Estradiol, and Denosumab Drug Levels

  Up to time of surgery

• Change in Serial Serum C-terminal Telopeptide Levels

  Baseline up to 12 months after start of intervention

Study Arms (2)

Arm I (denosumab, risk-reducing salpingo-oophorectomy)

EXPERIMENTAL

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.

Biological: Denosumab; Procedure: Salpingo-Oophorectomy

Arm II (risk-reducing salpingo-oophorectomy)

ACTIVE COMPARATOR

Patients receive no treatment for 2-8 weeks and then undergo risk-reducing salpingo-oophorectomy.

Procedure: Salpingo-Oophorectomy

Interventions

Denosumab BIOLOGICAL

Given SC

Also known as: AMG 162, AMG-162, Denosumab Biosimilar MW032, Denosumab Biosimilar QL1206, Denosumab Biosimilar TK-006, Prolia, TK-006, Xgeva

Arm I (denosumab, risk-reducing salpingo-oophorectomy)

Salpingo-Oophorectomy PROCEDURE

Undergo risk-reducing salpingo-oophorectomy

Arm I (denosumab, risk-reducing salpingo-oophorectomy); Arm II (risk-reducing salpingo-oophorectomy)

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• 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

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (6)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

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

New York, New York, 10032, United States

Location

NYP/Weill Cornell Medical Center

New York, New York, 10065, United States

Location

M D Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Tel Aviv Sourasky Medical Center

Tel Aviv, 64239, Israel

Location

Chaim Sheba Medical Center

Tel Litwinsky, 52621, Israel

Location

MeSH Terms

Conditions

Ovarian Neoplasms

Interventions

Denosumab; QL1206; Salpingo-oophorectomy

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Ovariectomy; Castration; Endocrine Surgical Procedures; Surgical Procedures, Operative; Urogenital Surgical Procedures; Gynecologic Surgical Procedures; Salpingectomy

Results Point of Contact

• Title: Dr. Powel Brown, Chair, Clinical Cancer Prevention
• Organization: UT MD Anderson Cancer Center

phbrown@mdanderson.org

(713) 745-3672

Study Officials

• Powel Brown

  M.D. Anderson Cancer Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 22, 2017
• First Posted: December 26, 2017
• Study Start: March 14, 2019
• Primary Completion: October 22, 2021
• Study Completion: October 22, 2021
• Last Updated: June 14, 2022
• Results First Posted: June 14, 2022

Record last verified: 2022-05

Data Sharing

• IPD Sharing: Will share

Locations

IL (2); US (4)