Trial of Dasatinib Plus Ixabepilone in 2nd or 3rd Line Metastatic Breast Cancer

In the Phase I portion of the study, patients will receive study treatment according to the
assigned dose level. Ixabepilone will be administered over 1 hour on Days 1, 8, and 15 of a
28-day cycle. Dasatinib will be administered continuously starting on Day 1, Cycle 1 once
daily (QD).

Three patients will be enrolled at dose level 0 and observed for dose-limiting toxicity
(DLT) for 1 course of treatment.

Dose escalation or reduction will depend on the number of patients experiencing DLT as
follows:

- If 0 of 3 patients experiences a DLT, then 3 additional patients will be enrolled at
the next higher dose level.

- If 1 of 3 patients experiences a DLT, then 3 additional patients will be enrolled at
that dose level.

- If 2 of 3 or 3 of 3 patients experience a DLT, then 3 patients will be enrolled at the
next lower dose unless 6 patients have already been treated at that dose.

- If ≥2 of 6 patients experience a DLT at that dose level, then the MTD is considered to
have been exceeded. At that point, 3 patients are treated at the next lower dose.

- If no more than 1 of the 6 patients experiences a DLT, then the dose level will be
escalated 1 level.

Maximum-tolerated dose (MTD) is defined as the dose at which ≤1 of 6 patients experience
DLT, and above which ≥2 of 6 patients experience DLT.

In the Phase II portion of the study, dasatinib and ixabepilone will be administered at the
MTD determined during Phase I. Dasatinib will be started on Day 1, Cycle 1 and will be
administered continuously once daily. Ixabepilone will be administered over 1 hour on Days
1, 8, and 15 of a 28-day cycle. Patients will be treated with both agents for up to 8
cycles, after which stable or responding patients are eligible for monotherapy with
dasatinib at the investigator's discretion in the absence of disease progression or
unacceptable toxicity.

Inclusion Criteria:

A patient must meet each of the following criteria to be considered eligible for inclusion
in this study:

1. Patient has the ability to understand and the willingness to sign a written informed
consent including form according to institutional guidelines.

2. Patient has histologically-proven breast cancer.

3. Patient has locally recurrent or metastatic disease, measurable or non- measurable by
RECIST criteria.

4. Patient has HER2-negative disease or disease that is refractory to HER2- directed
therapy.

5. Patient is female or male ≥ 18 years of age.

6. Patient has(ECOG)performance status of ≤ 2.

7. Patient must have received at least 1 but no more than 2 prior chemotherapy regimens
for locally recurrent or metastatic disease. Patients may have received neoadjuvant
and/or adjuvant chemotherapy. These prior regimens can not have included ixabepilone
or dasatinib. A line of chemotherapy will be defined as one or more agents used
continuously or discontinuously (i.e., allowing a break or chemo holiday) without the
addition of a new agent. Hormonal therapy will not be considered a line of therapy.

8. Prior chemotherapy must have been completed at least 3 weeks prior to study treatment
start (6 weeks for nitrosoureas and mitomycin), and the patient must have recovered
from all associated toxicities (except for alopecia and neuropathy grade 1 according
to CTCAE, v3.0 classification).

9. Radiation therapy, immunotherapy, biologic therapy, and hormonal/endocrine therapy
must have been completed at least 2 weeks prior to study treatment start. Any major
surgery must have been completed at least 4 weeks prior to study treatment start.

10. Patient has adequate organ, metabolic and bone marrow function as follows:

1. Total bilirubin ≤ 1.0 × institutional ULN

2. AST, ALT ≤ 2.5 × institutional ULN

3. Serum sodium, potassium, calcium, magnesium, and phosphate ≥ institutional LLN.
(Hypokalemia or hypomagnesemia must be corrected prior to dasatinib
administration.)

4. Serum creatinine < 1.5 × institutional ULN

5. Hematologic function: - ANC ≥ 1500/mm3. -Platelet count ≥ 100,000/mm3. -
Hemoglobin ≥ 10.0 g/dL

6. PT and PTT < 1.5 x institutional ULN

11. Ability to take oral medication (dasatinib must be swallowed whole).

12. Concomitant medications:

1. Patient agrees to discontinue St John's Wort at least 5 days prior to starting
dasatinib therapy and while receiving dasatinib therapy.

2. Patient agrees that IV bisphosphonates will be withheld for the first 8 weeks of
dasatinib therapy due to risk of hypocalcemia.

3. The use of CYP3A4 inducers, inhibitors, and substrates; medications that prolong
QT interval; antacids; H2 blockers and proton pump inhibitors; and medications
that inhibit platelet function and anticoagulation should be avoided during
dasatinib therapy. These are restricted therapies that are permitted with
caution when medically indicated.

13. Women of childbearing potential must have a negative serum or urine pregnancy test
prior to the start of study treatment.

14. Patients of reproductive potential must agree to use and utilize an adequate method
of contraception throughout treatment and for at least 4 weeks after study treatment
is stopped.

Exclusion Criteria:

A patient who meets any of the following criteria will be considered not eligible for
inclusion in this study:

1. Patient has had prior treatment with ixabepilone, dasatinib, or both.

2. Patient has had more than 2 prior lines of chemotherapy for locally recurrent or
metastatic breast cancer. A line of chemotherapy will be defined as one or more
agents used continuously or discontinuously (i.e., allowing a break or chemo holiday)
without the addition of a new agent. Hormonal therapy will not be considered a line
of therapy.

3. Patient has received a cumulative dose of > 360 mg/m2 of doxorubicin or > 600 mg/m2
of epirubicin.

4. Prior radiation must not have included ≥ 30% of major bone marrow containing areas
(pelvis, lumbar spine).

5. Patients with CTC grade 2 or greater neuropathy (motor or sensory) at study entry.

6. Patient has evidence CNS or brain metastases, unless CNS or brain metastases have
been treated and stable for > 3 months.

7. Patient has psychiatric illness or social situation that would limit or prohibit
compliance with study requirements.

8. Patient has an inability to take oral medication or inability to absorb oral
medication.

9. Patient has had any invasive cancer other than the one being treated in this study
within 3 years with the exception of surgically cured nonmelanoma skin cancer; in
situ carcinoma of the cervix; in situ carcinoma of the breast.

10. Patient is receiving concurrent cancer therapy (chemotherapy, radiation therapy,
immunotherapy, biologic therapy, or hormonal therapy for cancer).

11. Patient has other serious medical conditions as judged by the Principal Investigator.

12. Patient has a concurrent medical condition which may increase the risk of toxicity.

13. Patient has a pleural or pericardial effusion of any grade.

14. Patient has cardiac symptoms including any of the following:

1. Uncontrolled angina, congestive heart failure or myocardial infarction within 6
months of study entry.

2. Diagnosed congenital long QT syndrome.

3. Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de pointes).

4. Prolonged QTc on pre-entry ECG (> 450 msec).

5. Hypokalemia or hypomagnesemia if it cannot be corrected prior to dasatinib
administration.

15. Patient has a history of significant bleeding disorder unrelated to cancer,
including:

1. Diagnosed congenital bleeding disorders (e.g., von Willebrand's disease).

2. Diagnosed acquired bleeding disorder within one year (e.g., acquired anti-factor
VIII antibodies).

3. Ongoing or recent (≤ 3 months) significant GI bleeding.

16. Patient is taking any of the following concomitant medications at study entry:

a. Category I drugs that are generally accepted to have a risk of causing Torsades de
pointes including (Patients must discontinue drug 7 days prior to starting
dasatinib.):

- 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.

17. Patient has a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to ixabepilone or dasatinib. Ixabepilone is
contraindicated in patients who have a known, prior, severe (CTC grade 3 or 4)
history of hypersensitivity reaction to a drug formulated in Cremophor® EL
(polyoxyethylated castor oil).

18. Patient has received any investigational agent or therapy within 30 days prior to
study treatment start.

19. Patient is unwilling or unable to comply with study requirements.

20. Women who:

1. 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 treatment,
or

2. have a positive pregnancy test at baseline, or

3. are pregnant or breastfeeding.

21. Prisoners or subjects who are compulsorily detained (involuntarily incarcerated) for
treatment of either a psychiatric or physical (e.g., infectious) illness.