Dasatinib In Combination With Weekly Paclitaxel For Patients With Metastatic Breast Carcinoma CA 180 194

Inclusion Criteria

• Female or male patients with diagnosis of invasive adenocarcinoma of the breast confirmed at MSKCC.
• For the phase I portion, patients with any ER/PR/HER2 disease status, no longer eligible for hormonal therapy or HER2-targeted therapy, will be eligible.
• For the phase II portion, there needs to be documentation of negative HER2 (IHC 0-1+ or FISH/CISH negative) status. Patients with any ER/PR disease status are eligible.
• A paraffin-embedded tissue block or unstained slides from prior surgery must be available.
• Evidence of recurrent or progressive locally advanced or metastatic breast cancer.

Presence of:

• For the phase I portion: at least one evaluable or measurable metastatic lesion ,
• For the phase II portion: at least one measurable metastatic lesion according to the RECIST criteria which has not been irradiated (i.e. newly arising lesions in previously irradiated areas are accepted). Ascites, pleural effusion, and bone metastases are not considered measurable. Minimum indicator lesion size: > or = to 10 mm measured by spiral CT or > or = to 20 mm measured by conventional techniques.

Prior therapies:

For the phase I portion: Any number of prior endocrine or biologic therapies is permitted . In addition, patients may be untreated in the metastatic setting or have received any number of prior cytotoxic regimens.

For the phase II portion: 0-2 prior therapies for metastatic disease are allowed.

Prior taxane therapy, either in the adjuvant or in the metastatic setting, either deliver weekly, q 2 weeks or q 3 weeks, will be permitted. Prior therapy with bevacizumab will be allowed. All previous chemotherapy, radiotherapy and intravenous biphosphonates must have been discontinued at least 3 weeks prior to study entry, 3 weeks also for trastuzumab and bevacizumab. All acute toxic effects (excluding alopecia) of any prior therapy must have resolved to NCI CTC (Version 3) Grade ≤1.

• Endocrine therapy with an aromatase inhibitor, SERM (ie, tamoxifen) or fulvestrant is permitted, however it must be discontinued before enrolling in the study.
• ECOG performance status of 0 or 1.
• Age > or = to 18 years old. Adequate Organ Function
• Total bilirubin ≤ 1.5 times the institutional Upper Limit of Normal (ULN)
• Hepatic enzymes (AST, ALT ) ≤ 2.5 times the institutional ULN
• Serum Na, K+, Mg2+, Phosphate and Ca2+≥ Lower Limit of Normal (LLN)
• Serum Creatinine ≤ 1.5 time the institutional ULN
• Neutrophil count, Platelets, both Grade 0-1
• PT (INR) and PTT Grade 0-1, except for patients on Coumadin or low molecular weight heparin
• Ability to take oral medication (dasatinib must be swallowed whole)

Concomitant Medications:

• Patient agrees to discontinue St. Johns Wort while receiving dasatinib therapy
• Patient agrees that IV biphosphonates will be withheld for the first 8 weeks of dasatinib therapy due to risk of hypocalcemia. Concomitant Medications, any of the following should be considered for exclusion:

Patient agrees to discontinue QT-prolonging agents strongly associated with Torsades de Pointes including: (patients must discontinue drug ≥ 7 days prior to starting dasatinib) such as:

• quinidine, procainamide, disopyramide
• amiodarone, sotalol, ibutilide, dofetilide
• erythromycin, clarithromycin
• chlorpromazine, haloperidol, mesoridazine, thioridazine, pimozide
• cisapride, bepridil, droperidol, methadone, arsenic, chloroquine, domperidone, halofantrine, levomethadyl, pentamidine, sparfloxacin, lidoflazine.
• The concomitant use of H2 blockers or proton pump inhibitors with dasatinib is not recommended. The use of antacids should be considered in place of H2 blockers or proton pump inhibitors in patients receiving dasatinib therapy. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of dasatinib.
• Patient may not be receiving any potent CYP3A4 inhibitors. These are prohibited (patients must discontinue drug ≥7 days p