RATIONALE: Sorafenib may stop the growth of tumor cells by blocking some of the enzymes
needed for cell growth and by blocking blood flow to the tumor. Drugs used in chemotherapy,
such as paclitaxel, work in different ways to stop the growth of tumor cells, either by
killing the cells or by stopping them from dividing. Giving sorafenib together with
paclitaxel may kill more tumor cells.
PURPOSE: This phase II trial is studying the side effects of giving sorafenib together with
paclitaxel and to how well it works in treating patients with metastatic breast cancer.
- To evaluate the efficacy of sorafenib tosylate and paclitaxel by measuring tumor
response, as defined by RECIST criteria, in patients with metastatic, HER2-negative
- To evaluate time to disease progression in patients treated with this regimen.
- To evaluate six-month progression-free survival of patients treated with this regimen.
- To evaluate time to treatment failure in patients treated with this regimen.
- To evaluate clinical benefit rate (tumor response and stable disease) at 24 weeks in
patients treated with this regimen.
- To evaluate duration of response in patients treated with this regimen.
- To evaluate the tolerability of this regimen in these patients.
- To examine the relationship of gene expression and tissue/serum protein markers, where
available, related to response to therapy focusing on growth factor receptor pathways.
OUTLINE: This is a multicenter study.
Patients receive oral sorafenib tosylate twice daily on days 1-28 and paclitaxel IV over 1
hour on days 1, 8, and 15. Treatment repeats every 28 days in the absence of disease
progression or unacceptable toxicity.
After completion of study treatment, patients are followed at 4 weeks.
- Histologically* confirmed breast cancer
- Stage IV (metastatic) disease
- Radiographic evidence of metastases NOTE: *Histological confirmation of the
actual metastasis is not required.
- Measurable disease by RECIST criteria defined as ≥ 1 unidimensionally measurable
lesion ≥ 20 mm by conventional techniques (i.e., physical examination, CT scan, MRI,
or x-ray) or ≥ 10 mm by spiral CT scan
- No prior radiotherapy unless growth has been documented following radiotherapy
- Primary tumor or metastatic tumor HER2-negative, defined as the following:
- Immunohistochemistry of 0 or 1+ OR the equivalent, if an automated quantitative
assay is used
- HER2 fluorescent in situ hybridization (FISH) assay negative as defined by a
HER2:chromosome 17 centromeric probe ratio < 1.8 (or < 2.2 if
immunohistochemistry is less than 3+ or equivalent) OR equivalent values for
negative FISH assays that do not normalize to chromosome 17
- Hormone-receptor positive (estrogen receptor-[ER] or progesterone receptor
[PgR]-positive) disease or hormone receptor-negative (ER- or PgR-negative) disease
- Tumor block from initial breast cancer primary or a biopsy of a metastatic site must
be available for correlative studies
- Brain metastases allowed provided the patient is stable after completion of treatment
(i.e., surgery and/or radiotherapy), asymptomatic, and off steroids with 2
consecutive stable brain scans at least 4 weeks after radiotherapy
- Bone-only or other nonmeasurable-only disease
- Newly diagnosed brain metastases
- ECOG performance status 0-1
- Life expectancy > 6 months
- Menopausal status not specified
- WBC ≥ 3,000/mcL
- Absolute neutrophil count ≥ 1,500/mcL
- Platelets ≥ 100,000/mcL
- Total bilirubin < 1.5 times upper limit of normal (ULN)
- AST and ALT transaminases ≤ 2.5 times ULN (< 5 times ULN if liver involvement)
- Creatinine < 1.5 times ULN OR creatinine clearance > 60 mL/min
- INR < 1.5 OR PT/PTT normal
- Not pregnant or nursing
- Negative pregnancy test
- Fertile patients must use effective contraception prior to and during (women and men)
and for at least 3 months after (men) study therapy
- Able to swallow and absorb oral medications
- Active or uncontrolled medical illness (e.g., active infection > CTCAE grade 2),
including any of the following:
- HIV or chronic hepatitis B or C
- Uncontrolled diabetes
- NYHA class II-IV uncompensated congestive heart failure
- Unstable angina (anginal symptoms at rest)
- New onset angina (i.e., began within the past 3 months)
- Coronary artery disease
- Myocardial infarction within the past 6 months
- Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy
- Evidence of bleeding diathesis or coagulopathy
- Pulmonary hemorrhage/bleeding event > CTCAE grade 2 within 4 weeks of first dose of
- Any other hemorrhage/bleeding event > CTCAE grade 3 within 4 weeks of first study
- Thrombotic or embolic events (i.e., cerebrovascular accident), including transient
ischemic attacks within the past 6 months
- Hypertension that cannot be controlled with medication to ≤ 150/90 mm Hg
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to sorafenib tosylate
- Prior invasive cancer other than breast cancer except nonmelanoma skin cancer
- Chronic nonhealing wound or ulcer
PRIOR CONCURRENT THERAPY:
- No more than 1 prior chemotherapy regimen for metastatic breast cancer (MBC)
- At least 3 weeks since prior hormonal therapy for MBC or adjuvant or neoadjuvant
- More than 1 year since adjuvant paclitaxel
- At least 4 weeks since major thoracic, abdominal, or pelvic surgery and recovered
- At least 3 weeks since prior and no concurrent investigational drugs
- Concurrent bisphosphonates allowed
- Concurrent anticoagulation agents (i.e., warfarin or heparin) allowed
- No anticipated need for or concurrent radiotherapy
- No concurrent Hypericum perforatum (St. John wort) or rifampin (rifampicin)
- No other concurrent anti-neoplastic drugs