Trial Information

Summary: Paclitaxel with or without Sorafenib in Treating Patients with Locally Recurrent or Metastatic Breast Cancer

The primary objective of this study is to compare progression free survival of patients with locally recurrent or metastatic breast cancer treated with sorafenib and paclitaxel versus placebo and paclitaxel as first line therapy.

Rationale:
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. 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. Giving paclitaxel together with sorafenib may kill more tumor cells.

Patients will be randomized to 1 of 2 treatment arms:

• ARM1- Patients receive paclitaxel IV over 1 hour once weekly for 3 weeks. Patients also receive oral sorafenib twice daily.
• ARM2-Patients receive paclitaxel as in ARM 1 and oral placebo twice daily.

In both arms, treatment repeats every 28 days until disease progression or unacceptable toxicity.

Study inclusion criteria:

• Histologically or cytologically confirmed adenocarcinoma of the breast.
• Measurable or evaluable locally recurrent or metastatic disease. (Locally recurrent disease must not be amenable to resection with curative intent.) All scans used to document measurable or evaluable disease must be done within 4 weeks prior to randomization.
• Age =18 years
• Patients must not have had adjuvant or neoadjuvant taxane therapy within 12 months of randomization.
• Patients must have discontinued other adjuvant chemotherapy at least 3 weeks prior to randomization.
• Prior hormonal therapy for locally recurrent or metastatic disease is allowed, but this must have been discontinued at least 3 weeks prior to randomization.
• Prior radiation therapy is allowed but must be completed at least 3 weeks prior to randomization. Previously radiated area(s) must not be the only site of disease.
• ECOG Performance Status of 0 or 1
• Adequate bone marrow, liver, and renal function as assessed by the following:
  • Hemoglobin = 9.0 g/dl
  • Absolute neutrophil count (ANC) = 1,500/mm3
  • Platelet count = 100,000/mm3
  • Total bilirubin = 1.5 times the upper limit of normal
  • ALT and AST = 2.5 x upper limit of normal (=5 x upper limit of normal for patients with liver involvement)
  • INR = 1.5 and aPTT within normal limits. Patients receiving anti-coagulation treatment with an agent such as warfarin or heparin may be allowed to participate. For patients on warfarin, the INR should be measured prior to initiation of sorafenib/placebo and monitored at least weekly, or as defined by the local standard of care, until INR is stable.
  • Creatinine = 1.5 times the upper limit of normal
• Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to randomization and must agree to use adequate contraception (barrier method of birth control) prior to randomization and for the duration of study participation.
• Patients must be able and willing to sign a written informed consent. A signed informed consent must be appropriately obtained prior to any study specific procedures.
• Patients must be able to swallow and retain oral medication.

Exclusion criteria :

• Patients with breast cancer over-expressing HER-2 (gene amplification by FISH or 3+ over-expression by immunohistochemistry). Patients with unknown HER-2 status are not eligible.
• Patients with active brain metastases. Patients with neurological symptoms must undergo a contrast computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain to exclude active brain metastasis. Patients with treated brain metastases are eligible provided they have no evidence of brain disease and are off definitive therapy (including steroids) within 3 months prior to randomization.
• Prior chemotherapy for locally recurrent or metastatic breast cancer
• Major surgery, open biopsy, or significant traumatic injury within 4 weeks of randomization
• Evidence or history of bleeding diathesis or coagulopathy
• Serious, non-healing wound, ulcer, or bone fracture
• Substance abuse, or medical, psychological, or social condition that may interfere with the patient’s participation in the study or evaluation of the study results
• Pre-existing peripheral neuropathy = Grade 2
• Use of cytochrome P450 enzyme-inducing anti-epileptic drugs (such as phenytoin, carbamazepine, or phenobarbital)
• Clinically significant cardiac disease including congestive heart failure > class II NYHA (see Appendix V), unstable angina (angina symptoms at rest) or new-onset angina (began within the last 3 months), myocardial infarction within the past 6 months prior to randomization
• Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy and or uncontrolled hypertension (systolic blood pressure >150 mmHg or diastolic pressure >90 mmHg) despite optimal medical management
• Thrombolic, embolic, venous, or arterial events such as a cerebrovascular accident including transient ischemic attacks within the past 6 months. No pulmonary hemorrhage/bleeding event > NCI-CTCAE Grade 2 within 4 weeks of randomization. No other hemorrhage/bleeding event = CTCAE Grade 3 within 4 weeks of randomization
• Active clinically serious infection > NCI-CTCAE Grade 2
• Known human immunodeficiency virus infection or chronic hepatitis B or C
• Previous or concurrent cancer that is distinct in primary site or histology from breast cancer EXCEPT cervical cancer in situ, treated basal cell carcinoma, superficial bladder tumors [Ta and Tis], or any cancer curatively treated >5 years prior to randomization
• Known or suspected allergy to sorafenib or hypersensitivity to paclitaxel or drugs using the vehicle Cremophor
• Use of St. John’s Wort or rifampin (rifampicin) within 3 weeks of randomization
• Prior treatment with bevacizumab or any other drugs (licensed or investigational) that target VEGF or VEGF-R
• Concurrent anti-cancer therapy (chemotherapy, radiation therapy, surgery, immunotherapy, biologic therapy or tumor embolization) other than paclitaxel and sorafenib/placebo
• Women that are pregnant or breast feeding
• Use of any investigational drug within 30 days or 5 half-lives, whichever is longer, preceding randomization taxane therapy within 12 months of randomization.

If you would like to learn more about participating in this study, please send an e-mail message using the form below.