PRIMARY OBJECTIVES:
I. To assess the effect of denosumab in Her2/neu negative ER+ and/or PR+ metastatic breast
cancer patients who are in partial response (PR) or stable disease (SD) after starting
systemic therapy with bone metastases and >= 5 circulating tumor cells (CTCs) by measuring
the fraction of patients with reduction in CTCs after 3 cycles of denosumab.
SECONDARY OBJECTIVES:
I. To assess the effect of denosumab on CTCs enumeration considered as a continuous variable
(percent change from baseline) in this population.
II. To evaluate median progression-free survival (m-PFS).
TERTIARY OBJECTIVES:
I. CTC enumeration after enrichment. II. To assess the effect on CTC profiling and
characterization of stem cell phenotype (CTC-EMT).
III. To evaluate the type of progressive disease (new site versus [vs.] progression of
lesions in previous sites).
IV. To analyze the expression of RANKL.
OUTLINE:
Patients receive denosumab subcutaneously (SC) on day 1. Treatment repeats every 28 days for
up to 3 courses in the absence of disease progression, unexpected toxicity, or patient
withdrawal or death.
After completion of study treatment, patients are followed up every 12 weeks for up to 2
years.
Inclusion Criteria:
- Patients must have histologically or cytologically confirmed ER and/or PR positive,
HER-2/neu negative metastatic breast cancer; they can be enrolled in any line of
therapy without investigational agents and should have stable disease or a partial
response (which can be determined clinically) on current systemic treatment; patients
must also have pathologic OR radiographic evidence of bone metastases and >= 5 CTCs;
(Note: the pathology report that is used by the physician to determine diagnosis, will
be used to determine patient eligibility; ER and PR status should be available at the
time of registration)
- Patients may have either measurable or non-measurable within 30 of days of
registration; (lesions treated with radiation therapy must not be used as a target
lesion); (Note: per Response Evaluation Criteria in Solid Tumors [RECIST] criteria
version [v.] 1.1, measurable disease is defined as at least one lesion that can be
accurately measured in at least one dimension; non-measurable disease is defined as
all other lesions, including small lesions [longest diameter < 10 mm or pathological
lymph nodes with P10 to < 15 mm short axis] as well as truly non-measurable lesions;
lesions considered truly nonmeasurable include: leptomeningeal disease, ascites,
pleural or pericardial effusion, and inflammatory breast disease, lymphangitic
involvement of skin or lung, abdominal masses/abdominal organomegaly identified by
physical exam that is not measurable by reproducible imaging techniques)
- Patients may be enrolled in any line of standard treatment (without investigational
agents); the start date of current treatment should be at least two 2 weeks or more
prior to registration; (Note: patients will continue to receive the planned active
treatment with chemotherapy or endocrine therapy [standard of care] and initiate
denosumab at the recommended dose for this protocol)
- Eastern Cooperative Oncology Group (ECOG) performance status 0-2
- Leukocytes >= 3,000/mcL (without growth factor)
- Platelets >= 100,000/mcL (with or without transfusion)
- Hemoglobin >= 8 (with or without transfusion)
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (serum
glutamic-oxaloacetic transaminase [SGOT] and serum glutamate pyruvate transaminase
[SGPT]) =< 2.5 times institutional upper limit of normal (for patients with liver
metastasis up to =< 5 times of upper limit of normal [ULN] is allowed)
- Bilirubin =< 1.5 ULN (for patients with liver metastasis up to =< 5 times of ULN is
allowed)
- Serum creatinine =< 1.5 ULN
- Creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above
institutional normal (creatinine clearance should be calculated per institutional
standard)
- Patients must have a serum calcium of >= 2.0 mmol/L (8.0 mg/dL) or albumin-adjusted
serum calcium =< 2.9 mmol/L (11.5 mg/dL) within 30 days of registration; (Note: if
patients are undergoing treatment for hypocalcemia and the serum calcium value at
screening is > 8.0 mg/dl, then the patient will be eligible for this study)
- Females of child-bearing potential (FOCBP) and males with his or her partner must
agree to use two acceptable methods of effective contraception, at study entry, for
the duration of study participation, and for 5 months following completion of therapy;
subjects who are surgically sterile (e.g., history of bilateral tubal ligation,
hysterectomy) or whose sexual partner is sterile (e.g., history of vasectomy) are not
required to use additional contraceptive measures; should a female patient become
pregnant or suspect she is pregnant while participating in this study, she should
inform her treating physician immediately; likewise, if a male patient impregnates his
female partner, he should inform the treating physician immediately; NOTE: a FOCBP is
any woman (regardless of sexual orientation, having undergone a tubal ligation, or
remaining celibate by choice) who meets the following criteria:
- Has not undergone a hysterectomy or bilateral oophorectomy
- Has had menses at any time in the preceding 12 consecutive months (and therefore
has not been naturally postmenopausal for > 12 months)
- FOCBP must have a negative serum OR urine pregnancy test =< 7 days prior to
registration
- Ability to understand and willingness to sign a written informed consent and Health
Insurance Portability and Accountability Act (HIPAA) consent document prior to
registration
- Willingness and ability of subject to comply to study requirements
Exclusion Criteria:
- Patients may not be receiving any other investigational agents; a 2 week washout
period for investigational agents is required before registration
- Patients with clinically symptomatic brain metastases or who required treatment for
brain metastases within 4 weeks of registration (stable sequelae acceptable if
treatment has been completed; these lesions cannot be used as target lesions)
- Patients who have a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to denosumab are not eligible (i.e. same class of
drugs) (Note: prior bisphosphonates are allowed; patients could have received
bisphosphonates or be bisphosphonate-naive; patients who were previously on
bisphosphonates can be enrolled in the study, as long as they have a wash-out period
of 2 weeks prior to registration)
- Patients who are on corticosteroids or immunosuppressant's are not eligible; a 2 week
wash-out period for is required before registration
- Patients who have a known additional malignancy that is progressing or requires active
treatment are not eligible; patients who have had a prior diagnosis of cancer and if
it has been < 3 years since their last treatment are also not eligible; NOTE:
exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the
skin that has undergone potentially curative therapy or in situ cervical cancer
- Patients who have an uncontrolled intercurrent illness including, but not limited to
any of the following, are not eligible:
- Hypertension (defined as 160/90 mmHg for 3 consecutive readings 2-5 mins apart)
that is not controlled on medication
- Symptomatic congestive heart failure
- Unstable angina pectoris
- Psychiatric illness/social situations that would limit compliance with study
requirements
- Any other illness or condition that the treating investigator feels would
interfere with study compliance or would compromise the patient's safety or study
endpoints
- Subject is pregnant or breast feeding, or planning to become pregnant within 5 months
after the end of treatment
- Known human immunodeficiency virus (HIV)-positive patients who are on combination
antiretroviral therapy; (this is because of the potential for pharmacokinetic
interactions with denosumab)
- No known prior history or current evidence of osteonecrosis/osteomyelitis of the jaw
- No known prior history or current evidence of untreated local gum or oral infection
- No known/planned active dental or jaw condition which requires oral surgery, including
tooth extraction
- No known non-healed dental/oral surgery, including tooth extraction
- Patients have planned invasive dental procedures during the course of the study
