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

• 6-month Progression-Free Survival [ Time Frame: every 9 weeks, up to 6 months ]
  Measured from Day 1 of study drug administration to disease progression as defined by RECIST v1.1, or death on study. Progression is defined as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
• Objective Response Rate [ Time Frame: every 9 weeks until discontinuation of treatment ]
  Objective Response will be evaluated in this study using the Response Evaluation Criteria in Solid Tumors (RECIST).
• Overall Survival (OS) [ Time Frame: every 9 weeks until treatment discontinuation or death on study ]
  Measured from Day 1 of study drug administration to date of death due to any cause.
• Number of Patients With Adverse Events as a Measure of of Safety and Tolerability [ Time Frame: every 9 weeks until treatment discontinuation or unacceptable toxicity ]
  Assessments are made through analysis of reported incidence of treatment-emergent AEs and SAEs.

• To evaluate 6-month progression-free survival (PFS) of patients with HER2-negative MBC following treatment with sorafenib/ixabepilone [ Time Frame: 18 months ]
• To evaluate the objective response rate to the combination of sorafenib plus ixabepilone [ Time Frame: 18 months ]
• To assess the overall survival (OS) following treatment with the combination of sorafenib plus ixabepilone [ Time Frame: 18 months ]
• To assess the safety and tolerability of sorafenib/ixabepilone in this patient population [ Time Frame: 18 months ]

In this study, patients with metastatic HER2-negative breast cancer will receive treatment with ixabepilone and sorafenib until disease progression or unacceptable toxicity occurs. The Phase I portion of this study will determine the maximum tolerated doses (MTDs) of sorafenib and ixabepilone that may be used in combination for first- or second-line treatment of MBC. The MTDs identified in the Phase I portion of the study will be used in the Phase II portion which will evaluate the efficacy and safety of the combination of sorafenib and ixabepilone in patients who have received at least one prior chemotherapy treatment in either the adjuvant or neoadjuvant setting or following one prior MBC chemotherapy in MBC patients who had not received prior adjuvant or neoadjuvant breast cancer chemotherapy. This will be one of the initial trials investigating the use of this treatment combination for MBC.

This trial will be conducted under the leadership of the Sarah Cannon Research Institute (SCRI) Oncology Research Consortium, a community-based, multi-center, clinical trial organization.

• Drug: Sorafenib
  Dose Level 1 - Sorafenib PO BID (200mg) Dose Level -1 - Sorafenib PO BID (200mg) Dose Level 1a - Sorafenib PO BID (400mg)
  Other Name: Nexavar (Sorafenib)
• Drug: Ixabepilone
  Dose Level 1 - Ixabepilone IV every 21 days (40mg/m^2) Dose Level -1 - Ixabepilone IV every 21 days (32mg/m^2) Dose Level 1a - Ixabepilone IV every 21 days (32mg/m^2)
  Other Name: Ixempra (Ixabepilone)

• Experimental: Dose Level 1
  Sorafenib PO BID (200mg), Ixabepilone IV every 21 days (40mg/m^2)
  Interventions:

  • Drug: Sorafenib
  • Drug: Ixabepilone
• Experimental: Dose Level -1
  Sorafenib PO BID (200mg), Ixabepilone IV every 21 days (32mg/m^2)
  Interventions:

  • Drug: Sorafenib
  • Drug: Ixabepilone
• Experimental: Dose Level 1a
  Sorafenib PO BID (400mg), Ixabepilone IV every 21 days (32mg/m^2)
  Interventions:

  • Drug: Sorafenib
  • Drug: Ixabepilone

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.

Exclusion Criteria:

• Bayer
• Bristol-Myers Squibb