Personalized Treatment Selection for Metastatic Breast Cancer

Exclusion Criteria

• •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).