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

Exclusion Criteria

• •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.
• •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.