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

PRIMARY OBJECTIVES:

I. To compare the effect of denosumab 120 mg subcutaneously every 4 weeks for 3-4 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: apoptosis with cleaved caspase-3 by IHC;
receptor activator of NF-KB (RANK) and RANK ligand (RANKL) expression by IHC; estrogen
receptor (ER) and progesterone receptor (PR) expression by IHC; CD44 and p53 expression by
IHC; and 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
(posttreatment) with denosumab compared to no treatment, including: progesterone; estradiol;
and 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 3-4 doses and undergo risk-reducing salpingo-oophorectomy 14-28 days
after last dose.

ARM II: Patients receive no treatment for 6 months and then undergo risk-reducing
salpingo-oophorectomy.

After completion of study treatment, patients are followed up at 6, 9, and 12 months.

Inclusion Criteria:

- 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 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 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 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 within 6 months of enrolling in the study

- Willing to not undergo any other elective surgery procedure with general anesthesia or
conscious sedation during the treatment period

Exclusion Criteria:

- History of ovarian cancer

- Previous treatment with denosumab or use of bisphosphonate within 3 months of start of
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 start of 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 the study

- 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