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

This study has been completed.
Bristol-Myers Squibb
Information provided by (Responsible Party):
SCRI Development Innovations, LLC Identifier:
First received: January 19, 2009
Last updated: October 6, 2014
Last verified: October 2014

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.

Condition Intervention Phase
Metastatic Breast Cancer
Drug: Sorafenib and Ixabepilone
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: Phase I/II Trial of Sorafenib Plus Ixabepilone in HER2-Negative Metastatic Breast Cancer (MBC)

Resource links provided by NLM:

Further study details as provided by SCRI Development Innovations, LLC:

Primary Outcome Measures:
  • To assess progression-free survival (PFS) of patients with HER2-negative MBC following treatment with sorafenib/ixabepilone [ Time Frame: 18 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • To evaluate 6-month progression-free survival (PFS) of patients with HER2-negative MBC following treatment with sorafenib/ixabepilone [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • To evaluate the objective response rate to the combination of sorafenib plus ixabepilone [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • To assess the overall survival (OS) following treatment with the combination of sorafenib plus ixabepilone [ Time Frame: 18 months ] [ Designated as safety issue: No ]
  • To assess the safety and tolerability of sorafenib/ixabepilone in this patient population [ Time Frame: 18 months ] [ Designated as safety issue: Yes ]

Enrollment: 83
Study Start Date: March 2009
Study Completion Date: August 2014
Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Phase I - Sorafenib and Ixabepilone
Oral targeted therapy and Systemic Chemotherapy
Drug: Sorafenib and Ixabepilone

This Phase I portion will be a dose-escalation evaluation of the first 6-24 patients to determine the maximum doses of sorafenib and ixabepilone that can be used in combination. The dosing level may be influenced by treatment-related toxicities seen throughout cycles of treatment for 3 cycles for a total of 9 weeks.

Dose Level 1: 200 mg of Sorafenib by mouth twice a day for a 3 week cycle. Ixabepilone 40mg/m2 IV on day 1 of a 21 day cycle.

Dose Level 2: 400 mg of Sorafenib by mouth twice a day for a 3 week cycle. Ixabepilone 40mg/m2 IV on day 1 of a 21 day cycle.

Dose Level -1: 200 mg of Sorafenib by mouth once a day for a 3 week cycle. Ixabepilone 40mg/m2 IV on day 1 of a 21 day cycle.

Dose Level -2: 200 mg of Sorafenib by mouth once a day for a 3 week cycle. Ixabepilone 32mg/m2 IV on day 1 of a 21 day cycle.

Other Names:
  • Nexavar (Sorafenib)
  • Ixempra (Ixabepilone)
Experimental: Phase II - Sorafenib and Ixabepilone
Oral targeted therapy and Systemic Chemotherapy
Drug: Sorafenib and Ixabepilone
Dosage for Phase II Sorafenib and Ixabepilone will proceed based on the maximum tolerated dose (MTD) determined in the Phase I portion
Other Names:
  • Nexavar (Sorafenib)
  • Ixempra (Ixabepilone)


Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No

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


  • 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


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


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


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


  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:

  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its identifier: NCT00825734

United States, Florida
Florida Cancer Specialists
Ft. Myers, Florida, United States, 33916
United States, Indiana
Providence Medical Group
Terre Haute, Indiana, United States, 47802
RHHP/ Hope Cancer Center
Terre Haute, Indiana, United States, 47802
United States, Kentucky
Baptist Hospital East
Louisville, Kentucky, United States, 40207
United States, Louisiana
Hematology Oncology Clinic, LLP
Baton Rouge, Louisiana, United States, 70806
United States, Maine
Mercy Hospital
Portland, Maine, United States, 04101
United States, Maryland
National Capital Clinical Research Consortium
Bethesda, Maryland, United States, 20817
Center for Cancer and Blood Disorders
Bethesda, Maryland, United States, 20817
United States, Missouri
St. Louis Cancer Care
Chesterfield, Missouri, United States, 63044
United States, New Hampshire
Portsmouth Regional Hospital
Portsmouth, New Hampshire, United States, 03801
United States, New Jersey
Hematology-Oncology Associates of Northern NJ
Morristown, New Jersey, United States, 07962
United States, Ohio
Oncology Hematology Care
Cincinnati, Ohio, United States, 45242
United States, South Carolina
South Carolina Oncology Associates
Columbia, South Carolina, United States, 29210
Spartanburg Regional Medical Center
Spartanburg, South Carolina, United States
United States, Tennessee
Tennessee Oncology, PLLC
Nashville, Tennessee, United States, 37023
Sponsors and Collaborators
SCRI Development Innovations, LLC
Bristol-Myers Squibb
Study Chair: Denise A. Yardley, M.D. SCRI Development Innovations, LLC
  More Information

No publications provided

Responsible Party: SCRI Development Innovations, LLC Identifier: NCT00825734     History of Changes
Other Study ID Numbers: SCRI BRE 138
Study First Received: January 19, 2009
Last Updated: October 6, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by SCRI Development Innovations, LLC:
Metastatic Breast Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Breast Diseases
Neoplasms by Site
Skin Diseases
Antimitotic Agents
Antineoplastic Agents
Enzyme Inhibitors
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Protein Kinase Inhibitors
Therapeutic Uses
Tubulin Modulators processed this record on November 25, 2014