Phase 2b Study of Taxol Plus Sorafenib or Placebo in Patients With Advanced Breast Cancer

OBJECTIVES:

Primary

- Compare progression-free survival of patients with locally recurrent or metastatic
breast cancer treated with sorafenib tosylate and paclitaxel versus placebo and
paclitaxel as first-line therapy.

Secondary

- Compare the objective response rate and duration of response in patients treated with
these regimens.

- Compare the time to progression in patients treated with these regimens.

- Compare the survival of patients treated with these regimens.

- Compare the safety of patients treated with these regimens.

- Compare the change from baseline in the Functional Assessment of Cancer Therapy for
Breast Cancer quality of life assessment score in patients treated with these regimens.

OUTLINE: This is a double-blind, randomized, multicenter study. Patients are stratified
according to site of metastatic disease (visceral [i.e., soft internal organs of the body,
including lungs, heart, and the organs of the digestive, excretory, and reproductive systems]
vs nonvisceral [i.e., osseous or soft tissue] sites). Patients are randomized to 1 of 2
treatment arms.

- Arm I: Patients receive paclitaxel IV over 1 hour once weekly for 3 weeks. Patients also
receive oral sorafenib tosylate twice daily on days 1-28.

- Arm II: Patients receive paclitaxel as in arm I and oral placebo twice daily on days
1-28.

In both arms, treatment repeats every 28 days in the absence of disease progression or
unacceptable toxicity.

Quality of life is assessed at baseline, and every 8 weeks for 24 weeks, and then every 12
weeks for the duration of study participation.

After completion of study therapy, patients are followed every 4 months.

DISEASE CHARACTERISTICS:

- Histologically or cytologically confirmed adenocarcinoma of the breast

- Locally recurrent or metastatic disease

- Locally recurrent disease not amenable to resection with curative intent

- Measurable or evaluable disease

- No HER-2 overexpression (defined as positive for gene amplification by FISH or 3+
overexpression by IHC)

- No unknown HER-2 status

- No active brain metastases

- Patients with neurological symptoms and known brain metastases treated with
definitive therapy must undergo contrast CT scan or brain MRI to exclude active
brain metastasis

- Previously treated brain metastases allowed provided at least 3 months since
prior definitive therapy (including steroids) AND no evidence of disease

- Hormone receptor status not specified

PATIENT CHARACTERISTICS:

- Male or female

- Menopausal status not specified

- ECOG performance status 0-1

- Not pregnant or nursing for ≥ 2 weeks after completion of study therapy

- Negative pregnancy test

- Fertile patients must use effective contraception during and for ≥ 2 weeks after
completion of study therapy

- Hemoglobin ≥ 9.0 g/dL

- ANC ≥ 1,500/mm³

- Platelet count ≥ 100,000/mm³

- Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)

- ALT and AST ≤ 2.5 times ULN (≤ 5 times ULN for patients with liver involvement)

- INR ≤ 1.5 and aPTT within normal limits

- Anticoagulation therapy (e.g., warfarin or heparin) allowed

- Stable INR required for patients on warfarin

- Creatinine ≤ 1.5 times the ULN

- Able to swallow and retain oral medication

- More than 4 weeks since prior significant traumatic injury

- No evidence or history of bleeding diathesis or coagulopathy

- No serious nonhealing wound, ulcer, or bone fracture

- No substance abuse or medical, psychological, or social condition that would interfere
with study participation or evaluation of study results

- No pre-existing peripheral neuropathy ≥ grade 2

- No clinically significant cardiac disease, including any of the following:

- New York Heart Association class II-IV congestive heart failure

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

- Myocardial infarction within the past 6 months

- No cardiac ventricular arrhythmias requiring anti-arrhythmic therapy

- No uncontrolled hypertension (i.e., systolic blood pressure [BP] > 150 mm Hg or
diastolic BP > 90 mm Hg despite optimal medical management)

- No thrombolic, embolic, venous, or arterial events such as a cerebrovascular accident,
including transient ischemic attacks within the past 6 months

- No pulmonary hemorrhage or bleeding event > grade 2 within the past 4 weeks

- No other hemorrhage or bleeding event ≥ grade 3 within the past 4 weeks

- No active clinically serious infection > grade 2

- No known HIV infection or chronic hepatitis B or C

- No other prior or concurrent cancer except carcinoma in situ of the cervix, treated
basal cell skin cancer, superficial bladder tumors (e.g., Ta and Tis), or any cancer
curatively treated for > 5 years

- No known or suspected allergy to sorafenib tosylate or hypersensitivity to paclitaxel
or drugs using the vehicle Cremophor

PRIOR CONCURRENT THERAPY:

- More than 12 months since prior adjuvant or neoadjuvant taxane therapy

- At least 3 weeks since other prior adjuvant chemotherapy

- At least 3 weeks since prior hormonal therapy for locally recurrent or metastatic
disease

- No prior chemotherapy for locally recurrent or metastatic breast cancer

- More than 4 weeks since prior major surgery or open biopsy

- At least 3 weeks since prior radiotherapy

- Previously irradiated area must not be the only site of disease

- More than 30 days or 5 half-lives, whichever is longer, since prior investigational
drug

- No prior or concurrent bevacizumab or any other licensed or investigational drugs
that target VEGF or VEGF-receptor

- More than 3 weeks since prior and no concurrent Hypericum perforatum (St. John's wort
) or rifampin (rifampicin)

- No concurrent cytochrome P450 enzyme-inducing antiepileptic drugs (e.g., phenytoin,
carbamazepine, or phenobarbital)

- No concurrent irinotecan hydrochloride or doxorubicin hydrochloride

- No other concurrent anticancer therapy (i.e., chemotherapy, radiotherapy, surgery,
immunotherapy, biologic therapy, or tumor embolization)

- No concurrent nonconventional therapies (e.g., herbal)

- No concurrent palliative radiotherapy