| Eligibility |
Inclusion Criteria:
1. Patients must have a pathologically confirmed diagnosis of invasive carcinoma of the
breast.
2. Patients must carry a diagnosis of metastatic breast cancer with predominant bone
involvement. For the purposes of this study, predominant bone involvement will be
defined as radiographically detected bone metastasis in the presence or absence of
other sites of metastatic breast cancer (i.e. visceral involvement). If visceral
involvement is present, patients must be asymptomatic and have no tumors in visceral
organs that measure >3cm in size.
3. Patients must agree to serial urine collections for measurement of Ntx.
4. Age >/= 18 years.
5. Patients must be able to swallow oral medications. Dasatinib must be taken whole and
cannot be crushed.
6. Patients must have evaluable disease using WHO Criteria for Assessment of Disease
Response in Bone or MDACC Modified Response Criteria for Assessment of Disease
Response in Bone.
7. Patients must not have had >1 chemotherapy regimens for metastatic disease. Patients
with metastasis diagnosed </= 6 months after completion of adjuvant chemotherapy are
considered to have had chemotherapy for metastatic breast cancer.
8. Patients with ER positive disease must have had disease progression on at least one
prior hormonal therapy for metastatic disease. Patients must also have developed
disease progression on their most recent hormonal therapy regimen and be agreeable to
continue this regimen in combination with protocol therapy. For the purposes of this
study disease progression while receiving hormonal therapy will be defined as:
Radiographic evidence of progressive disease according to RECIST criteria, Progression
of disease by physical exam in patients with skin involvement. Continued in # 9
9. Continuation from # 8: 25% increase in tumor marker as measured on two evaluations no
less than 72 hours apart.
10. Patients must have and ECOG performance status of </= 2.
11. Patients must not require concurrent radiation or chemotherapy while receiving
protocol therapy.
12. Patients must not have an active infection requiring the use of intravenous
antibiotics. The use of oral antibiotics as prophylaxis is allowed.
13. Patients must have a baseline ECG with QTc within the normal range within 28 days
prior to registration.
14. Patients must be informed of the investigational nature of the study and must sign and
give written informed consent.
15. Patients may have received previous radiation but must have completed radiation at
least 2 weeks (8 weeks for radiation to the brain) prior to registration. Patients
with irradiated tumor as the only site of evaluable disease will not be eligible for
protocol therapy unless there is documented disease progression within the previously
radiated site.
16. Patients must have recovered to grade </= 1 from all acute toxicity of previous
radiation or hormonal therapy.
17. Adequate hematologic and hepatic function: Granulocyte count >/= 1,500/mcL, Platelet
count >/= 100,000/mcL, Bilirubin </= 1.5 x ULN, AST and/or ALT </= 2 x ULN, Alkaline
phosphatase (liver component, if fractionated) </= 2 x ULN, Serum Na, K+, Mg2+,
Phosphate and Ca2+>/= Lower Limit of Normal (LLN) [subjects with low electrolyte
levels must be repleted to normal for protocol entry]
18. Patients must not receive any concurrent bisphosphonate therapy other than that
prescribed by the study.
19. Sexually active patients with reproductive potential must agree to use an effective
method of birth control during the course of the study and for no less than 4 weeks
after discontinuing study drug. Contraceptives must be used in a manner such that risk
of failure is minimized. Oral contraceptives should be avoided in women with estrogen
or progesterone receptor positive breast cancer.
20. Prior to study enrollment, women of childbearing potential (WOCBP) must be advised of
the importance of avoiding pregnancy during trial participation and the potential risk
factors for an unintentional pregnancy. In addition, men enrolled on this study should
understand the risks to any sexual partner of childbearing potential and should
practice an effective method of birth control.
21. All WOCBP MUST have a negative serum or urine pregnancy test within 72 hours prior to
the start of study drug administration. If the pregnancy test is positive, the patient
must not receive investigational product and must not be enrolled in the study.
22. Patients with disease progression while receiving previous therapy in combination with
bisphosphonates (including zoledronic acid) will be considered eligible for protocol
participation.
Exclusion Criteria:
1. Any malignancy (other than breast cancer) that required radiotherapy or systemic
treatment within the past 5 years.
2. Concurrent medical condition which may increase the risk of toxicity, including:
Pleural or pericardial effusion of any grade, clinically-significant coagulation or
platelet function disorder (e.g. known von Willebrand's disease)
3. Cardiac Symptoms, including the following: Uncontrolled angina, congestive heart
failure or MI within (6 months), diagnosed congenital long QT syndrome, any history of
clinically significant ventricular arrhythmias (such as ventricular tachycardia,
ventricular fibrillation, or Torsades de pointes), prolonged QTc interval on pre-entry
electrocardiogram (> normal range), subjects with hypokalemia or hypomagnesemia if it
cannot be corrected
4. History of significant bleeding disorder unrelated to cancer, including: diagnosed
congenital bleeding disorders (e.g., von Willebrand's disease), diagnosed acquired
bleeding disorder within one year (e.g., acquired anti-factor VIII antibodies),
ongoing or recent (</= 3 months) significant gastrointestinal bleeding
5. Concomitant Medications, consider the following prohibitions (Drugs must be
discontinued for 7 days prior to starting protocol therapy):
6. Women and men of child bearing potential: who are unwilling or unable to use an
acceptable method to avoid pregnancy for the entire study period and for at least 4
weeks after cessation of study drug, or women of childbearing potential (CBP) who have
a positive pregnancy test at baseline, or women who are pregnant or breastfeeding
7. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness
8. Untreated or uncontrolled brain metastasis
9. Patient inability to take or absorb oral medications
10. Current active dental problems including: ongoing infection of the teeth or jawbone
(maxilla or mandibula); current exposed bone in the mouth; and current or prior
diagnosis of osteonecrosis of the jaw
11. Recent (within 8 weeks) or planned dental or jaw surgery (e.g., extraction, implants)
12. Diagnosis of metabolic bone disease other than osteoporosis (e.g., Paget's disease of
bone)
13. Known hypersensitivity to zoledronic acid or aspirin
14. Corrected serum calcium < 8.0 mg/dL (2.0 mmol/L) or >/= 12.0 mg/dL (3.0 mmol/L) at
Visit 1. The formula to be used is: Corrected serum calcium (mg/dL) = Patient's serum
calcium (mg/dL) + [0.8 x Midrange Albumin (g/dL) - Patient's Albumin (g/dL)]. 4.0g/dL
to be used for the Midrange Albumin
15. Serum creatinine greater than or equal to 1.5 times the institutional upper limits of
normal or a creatinine clearance of <40 ml/min when calculated by the Cockcroft and
Gault formula (see protocol text for formula)
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