Personalized Treatment Selection for Metastatic Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Dasatinib; AZD6244
Intervention description: 100 mg tablet by mouth daily; 75 mg by mouth twice daily.
Intervention MeSH terms: Dasatinib
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 97.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Dasatinib; Metastatic Breast Cancer; Sprycel; BMS-354825; Genetic testing; AZD6244; Selumetinib

Summary:

      The goal of this clinical research study is to learn if researchers can use genetic tests to
      predict who may benefit from treatment with SprycelTM (dasatinib) or selumetinib (AZD6244).
    

Eligibility criteria:

        Inclusion Criteria:

          1. (Turnstile One - Applies only to inclusion criteria 1 - 4): Histologically confirmed
             breast cancer and evidence of metastatic disease that can be biopsied with acceptable
             risk. Patients must agree to mandatory fine needle aspiration of the cancer for
             response marker determination. Patient must have a positive gene expression profile.
             Positive gene expression signature obtained separately on trial LAB11-0337 will also
             be acceptable for eligibility.

          2. Patients must have measurable or evaluable disease as defined by the Response
             Evaluation Criteria in Solid Tumors (RECIST) criteria.

          3. Subject, age > 18 years (the safety and efficacy of dasatinib and the appropriate dose
             has not been established for children).

          4. Signed written informed consent including a HIPAA form according to institutional
             guidelines.

          5. (Turnstile Two Applies Only to Inclusion Criteria 5 -17) - Therapy with Dasatinib -
             Patient must have a positive gene expression profile. Positive gene expression
             obtained separately on trial LAB11-0337 will also be acceptable for eligibility.

          6. Performance status Zubrod scale 0-2 (Appendix B) within 8 days of starting therapy.

          7. Full physical examination and history including documentation of weight, height, and
             vital signs within 8 days of starting therapy.

          8. Patients may have received any number of previous therapies for metastatic breast
             cancer. Patients must have received, had a contraindication to, or declined treatment
             with an anthracycline and taxane (and Herceptin if HER-2 positive) in either the
             adjuvant or metastatic setting.

          9. Adequate organ function assessed within 14 days of study therapy, defined as: (a)Total
             bilirubin </= 2.0 times the institutional Upper Limit of Normal (ULN); (b) Hepatic
             enzymes (AST, ALT ) </= 2.5 times the institutional ULN; (c) Serum Na, K+, Mg2+,
             Phosphate and Ca2+ >/= lower limit of normal (LLN); (d) Serum Creatinine < 1.5 time
             the institutional ULN; and (e) Hemoglobin, Neutrophil count, Platelets, PT, PTT all
             Grade 0-1.

         10. A baseline EKG within 14 days of starting therapy, with a QTc interval not > 460 msec
             in women, or > 450 in men.

         11. Ability to take oral medication (dasatinib must be swallowed whole).

         12. Patient must agree to discontinue St. Johns Wort while receiving dasatinib therapy if
             previously taken.

         13. Patient must agree that IV bisphosphonate therapy will be withheld for the first 8
             weeks of dasatinib therapy due to risk of hypocalcemia. (After the need for Ca2+
             supplementation has been assessed and levels documented to be >LLN, subjects on prior
             bisphosphonate may be restarted with caution at the investigator's discretion).

         14. Females of childbearing potential must have a negative serum pregnancy test within 7
             days of starting therapy.

         15. Persons of reproductive potential must agree to use and utilize a barrier method of
             contraception throughout treatment and for at least 4 weeks after study drug is
             stopped.

         16. Concurrent medications must be assessed, and patient must agree to discontinue all
             restricted medications within 7 days of starting therapy.

         17. Stable brain metastasis for at least 3 months

        Exclusion Criteria:

          1. (Only turnstile II applies to Exclusion Criteria): Known allergy to study drug.

          2. Concurrent medical condition which may increase the risk of toxicity, including: (a)
             pleural or pericardial effusion of any grade; (b) uncontrolled angina, congestive
             heart failure or MI within (6 months); (c) history of congenital long QT syndrome or
             prolonged QTc interval on pre-entry electrocardiogram > 460 msec in women and >450
             msec. in men; (d) any history of clinically significant ventricular arrhythmias (such
             as ventricular tachycardia, ventricular fibrillation, or Torsades de pointes);
             continued in excl # 3

          3. Continued from exclusion # 2: (e) subjects with hypokalemia or hypomagnesemia if it
             cannot be corrected prior to dasatinib administration; (f) history of significant
             bleeding disorder unrelated to cancer, including diagnosed congenital bleeding
             disorders (e.g., von Willebrand's disease) or acquired bleeding disorder within one
             year (e.g., acquired anti-factor VIII antibodies); (g) ongoing or recent (3 months)
             significant gastrointestinal bleeding

          4. Concomitant medications with any of the following drugs should be considered for
             exclusion unless discontinued 7 days prior to starting dasatinib: (a) Category I drugs
             that prolong QT interval and are generally accepted to have a risk of causing Torsades
             de Pointes including: quinidine, procainamide, disopyramide, amiodarone, sotalol,
             ibutilide, dofetilide, erythromycin, clarithromycin, chlorpromazine, haloperidol,
             mesoridazine, thioridazine, pimozide, cisapride, bepridil, droperidol, methadone,
             arsenic, chloroquine, and domperidone. Cont. in exclusion # 5

          5. Continued from exclusion criterion # 4: halofantrine, levomethadyl, pentamidine,
             sparfloxacin, lidoflazine.

          6. CYP3A4 inhibitors. Dasatinib is primarily metabolized by the CYP3A4 enzyme. Therefore,
             potent inhibitors of CYP3A4 may increase dasatinib plasma concentrations: (i)
             ketoconazole, itraconazole, erythromycin, clarithromycin,ritonavir, atazanavir,
             indinavir, nefazodone, nelfinavir, saquinavir; (ii) telithromycin; and (iii) subjects
             should be advised not to consume substantial quantities of grapefruit juice.

          7. Medications which durably inhibit platelet function or inhibit anticoagulation.
             Medications which directly and durably inhibit platelet function or coagulation
             include: (i) aspirin or aspirin-containing combinations, clopidogrel, dipyridamole,
             tirofiban, dipyridamole, epoprostenol, eptifibatide, cilostazol, abciximab,
             ticlopidine, cilostazol; and (ii) warfarin, heparin/low molecular weight heparin
             [e.g., danaparoid, dalteparin, tinzaparin, enoxaparin]. Exceptions: low-dose warfarin
             for prophylaxis to prevent catheter thrombosis, and heparin for flushes of IV lines is
             allowed.

          8. Women who are unwilling or unable to use a barrier method of contraception to avoid
             pregnancy for the entire study period and for at least 4 weeks after cessation of
             study drug, or have a positive pregnancy test at baseline, or are pregnant or
             breast-feeding. Prior to study enrollment, women of childbearing potential must be
             advised of the importance of avoiding pregnancy during trial participation and the
             potential risk factors for an unintentional pregnancy.

          9. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
             treatment of either a psychiatric or physical (e.g., infectious) illness.

         10. Exclusion from Selumetinib therapy include Uncontrolled hypertension (BP >/=150/95
             mmHg), Heart failure (NYHA >/= Class II), prior or current cardiomyopathy (LVEF </=
             50%), Atrial fibrillation (heart rate >100 bpm), Unstable ischaemic heart disease (MI
             within 6 months prior, or angina requiring use of nitrates more than once weekly).