Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer

Inclusion Criteria:

1. Age ≥ 18 years.

2. Histologically or cytologically confirmed breast cancer diagnosis with metastatic
disease. Patients without pathologic or cytologic confirmation of metastatic disease
should have unequivocal evidence of metastasis.

3. Measurable disease, as per RECIST criteria (Therasse et al. 2000). Measurable disease
cannot be previously irradiated unless progression was documented. Measurable disease
is defined as: at least one lesion that can be accurately measured in at least one
dimension [longest diameter to be recorded] as >20 mm with conventional techniques,
or as >10 mm with spiral computed tomography (CT) scan. Disease must be measurable,
i.e., bone-only disease or evaluable-only disease is not eligible.

4. Patients with brain metastasis may participate if they:

- have undergone appropriate treatment,

- are at least 1 month post-treatment,

- have no neurologic symptoms,

- are not on steroids,

- have a follow-up magnetic resonance imaging (MRI) scan that demonstrates no
residual active lesions, and

- have no new untreated lesions.

5 The following prior therapies are allowed:

- No prior chemotherapy in the metastatic setting. However, patients must have
received prior adjuvant or neo-adjuvant chemotherapy.

- Prior radiation therapy in either the metastatic or early-stage setting, as long
as <25% of the bone marrow has been treated. Radiation therapy must be completed
at least 14 days prior to study registration, and all radiation-related
toxicities must be resolved to ≤ grade 1 before the patient is eligible for
study inclusion.

- Any number of hormonal therapies in the neo-adjuvant, adjuvant, or metastatic
setting is allowed. Patients must discontinue hormonal therapy at least 1 week
prior to starting study treatment.

- Prior bevacizumab administered >4 weeks before initiation of study treatment is
allowed.

6 HER2-negative status. Documentation of HER2 results must be available at the
time of study enrollment. HER2-negative is defined as:

- Immunohistochemical (IHC) 0 or IHC 1+ OR

- Fluorescence in situ hybridization (FISH) negative (defined by FISH ratio <2.2)
OR

- Silver in-situ hybridization (SISH) negative (defined by SISH ratio <2.2).
Patients with an IHC 2+ will need to be validated as HER2-negative by FISH.

7 An Eastern Cooperative Oncology Group (ECOG) performance status of < or = to
2.

8. Normal bone marrow function as defined by:

- absolute neutrophil count (ANC) >1,500/μL;

- platelets >100,000/μL;

- hemoglobin >9 g/dL. 9 Normal hepatic function as defined by:

- total bilirubin within normal institutional limits;

- aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5 × the
institutional upper limit of normal (ULN) for patients without liver metastasis; <5.0
× ULN for patients with liver metastasis.

10. Normal renal function as defined by creatinine <1.5 × ULN.

11. Left ventricular ejection fraction (LVEF) within institutional limits of normal.

12. International normalized ratio (INR) <1.5 or a prothrombin time/partial
thromboplastin time (PT/PTT) within normal limits. Patients receiving
anti-coagulation treatment with an agent such as warfarin or heparin may be allowed
to participate. The INR should be measured prior to initiation of sorafenib, and for
patients on warfarin, INR should be monitored at least weekly following initiation of
protocol treatment, until the INR is stable and therapeutic.

13. Life expectancy of >6 months.

14. For women of childbearing potential, negative serum pregnancy test within 7 days
prior to starting treatment.

15. For women of childbearing potential and men, agreement to use a method of
contraception that is acceptable to their physician from time of first signing the
informed consent and for the study duration. Men should use adequate birth control
for at least three months after the last administration of sorafenib. If a woman
becomes pregnant or suspects she is pregnant while participating in this study, she
must agree to inform her treating physician immediately. As applicable, patients must
agree to discontinue breast-feeding until at least 3 weeks after their last dose of
study drug.

16. Recovery to < grade 1 toxicity due to prior therapy.

17. Ability to understand and willingness to sign a written informed consent
document.

Exclusion Criteria

1. More than one (>1) prior chemotherapy regimen.

2. Treatment with chemotherapy, biologic agents, or targeted agents within the previous
4 weeks.

3. Previous treatment with sorafenib or ixabepilone.

4. Women who are pregnant or breastfeeding.

5. Neuropathy (motor or sensory) greater than grade 1.

6. Uncontrolled intercurrent illness including (but not limited to) ongoing or active
infection >grade 2.

7. Known history of human immunodeficiency virus (HIV), Hepatitis B, or Hepatitis C
infection.

8. History of other non-breast cancer malignancy treated with curative intent within the
5 years preceding study enrollment with the exception of carcinoma in situ of the
cervix, non-melanoma skin cancer, or follicular thyroid cancer.

9. Concurrent hormonal therapy, chemotherapy other than ixabepilone, or radiation
treatments while on study as well as treatment with other investigational agents
while on study.

10. Cardiac disease:

- Congestive heart failure (CHF) greater than New York Heart Association (NYHA)
Class II (see Appendix B).

- Unstable angina (anginal symptoms at rest) or new onset angina (i.e., began
within the last 3 months).

- Myocardial infarction within the past 6 months.

- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy.

11. Uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure
>100 mmHg despite optimal medical management).

12. Thrombolic or embolic events such as cerebrovascular accident, including transient
ischemic attacks, within the past 6 months.

13. Pulmonary hemorrhage or bleeding event ≥ grade 2 within 4 weeks of the first dose of
study treatment, or any other hemorrhage or bleeding event ≥ grade 3 within 4 weeks
of the first dose of study treatment.

14. Serious non-healing wound, ulcer, or bone fracture.

15. Evidence or history of bleeding diathesis or coagulopathy.

16. Major surgery, open biopsy or significant traumatic injury within 4 weeks of the
first dose of study drugs or anticipation of the need for major surgical procedure.

17. Chronic use of CYP3A4 inducers and use of the following strong CYP3A4 inhibitors:
ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir,
telithromycin, ritonavir, amprenavir, indinavir, nelfinavir, delavirdine, and
voriconazole. Use of these agents should be discontinued at least 72 hours prior to
initiation of study treatment.

18. Use of St. John's Wort or rifampin (rifampicin).

19. Any condition that impairs patient's ability to swallow whole pills or
gastrointestinal (GI) tract disease that involves an inability to take oral
medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation,
prior surgical procedures affecting absorption, or uncontrolled inflammatory GI
disease (e.g., Crohn's disease or ulcerative colitis).

20. Psychiatric illness/social situations that would limit compliance with study
requirements.

21. Known or suspected allergy to sorafenib, Cremophor EL (polyoxyethylated castor oil)
or a drug formulated in Cremophor EL such as paclitaxel or any other agent given in
the course of this trial.