Phase III Trial Comparing Capecitabine in Combination With Sorafenib or Placebo in the Treatment of Locally Advanced or Metastatic HER2-Negative Breast Cancer
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Sorafenib (Nexavar, BAY43-9006); Placebo; Capecitabine
Intervention description: Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Sorafenib was administered orally at a dose of 600 mg (200 mg in the morning, 400 mg in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and sorafenib dose to a total daily dose of 800 mg for that subject.; Capecitabine was administered orally at a dose of 1,000 mg/m^2 twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle. Placebo matching to sorafenib was administered orally, 3 tablets (1 tablet in the morning, 2 tablets in the evening) daily, continuously (that is, Days 1 to 21, inclusive). A treatment cycle consisted of 21 days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily and placebo dose to a total daily dose of 4 tablets (2 tablets twice daily) for that subject.; Capecitabine was administered orally at a dose of 1,000 milligram per square meter (mg/m^2) twice daily (12 hours apart) on Days 1 through 14 of each 21-day cycle.days. If tolerability criteria were met for a subject, capecitabine dose was escalated to 1,250 mg/m^2 twice daily,
Intervention MeSH terms: Capecitabine; Sorafenib
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 537.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Breast Cancer; HER2-neu

Summary:

      The objective of this phase-III trial is to compare the efficacy and safety of sorafenib in
      combination with capecitabine versus capecitabine in combination with placebo in the
      treatment of subjects with locally advanced or metastatic HER2-negative breast cancer who are
      resistant to or have failed prior taxane and an anthracycline or for whom further
      anthracycline therapy is not indicated. After signing consent there can be up to 28 days
      before starting the treatment during which time a number of tests will be carried out which
      will include tumor evaluations and medical history. The following tests and evaluations will
      have to be done within 7 days of the start of treatment,on Day 1 of every cycle and at the
      end of study: Electrocardiogram, blood tests, patient quality of life questionnaires and a
      complete physical exam and vital signs. Treatment will be given in 21 day cycles with
      sorafenib/placebo to be taken every day for 21 days and capecitabine to be taken for the
      first 14 days. Patients will come in weekly for the first 6 weeks and then on Day1 for every
      cycle after the first 2 cycles. During the weekly visits the subjects will be check for any
      side effects and blood draws will happen for the study on Day 1 of each cycle. Subjects will
      be followed for overall survival.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Age is >=18 years

          -  Subject has histologically or cytologically confirmed HER2-negative adenocarcinoma of
             the breast. HER2 status should be determined by an accredited laboratory

          -  Subject has locally advanced or metastatic disease; locally advanced disease must not
             be amenable to resection with curative intent. Must have measurable or non-measurable
             disease (according to RECIST [Response Evaluation Criteria for Solid Tumors] 1.1)

          -  All computer tomography (CT; with contrast) and magnetic resonance imaging (MRI) used
             to document disease must have been done <= 4 weeks before randomization. Bone scans
             (if clinically indicated) must have been done <= 12 weeks prior to randomization

          -  Subject must have received up to two prior chemotherapy regimens
             (adjuvant/neo-adjuvant treatments are considered one regimen), and no more than one
             prior regimen for advanced and/or metastatic disease. Chemotherapy regimens include
             both targeted and biologic therapy

          -  Prior regimens must have included an anthracycline (eg, doxorubicin, epirubicin) and a
             taxane (eg, paclitaxel, docetaxel), either in combination or in separate regimens, in
             either the neo-adjuvant/adjuvant or the metastatic setting or both, as either
             monotherapy or as part of a combination with another agent. Sequential regimens will
             count as a single regimen; multiple neo-adjuvant / adjuvant regimens will count as a
             single regimen

          -  Subjects are either resistant to or have failed prior taxane and anthracycline OR
             Resistant to or have failed prior taxane AND for whom further anthracycline therapy is
             not indicated (for example, intolerance or cumulative doses of doxorubicin or
             doxorubicin equivalents [for example, epirubicin)

          -  Subjects who relapse beyond 12 months after the last taxane or anthracycline dose
             given in the adjuvant, neo-adjuvant, or metastatic setting are eligible. Further
             therapy with the agent(s) for a subsequent regimen must have been considered and ruled
             out, for example due to prior toxicity or intolerance, or based on the local standard
             of practice

          -  Prior experimental chemotherapy treatment is allowed, provided it is given in
             combination with at least one drug approved for the treatment of breast cancer
             (excluding drugs that target VEGF [Vascular Endothelial Growth Factor] or VEGFR
             [Vascular Endothelial Growth Factor Receptor], eg, bevacizumab, brivanib, sunitinib,
             vatalinib).

          -  Prior hormonal therapy for locally advanced or metastatic breast cancer is allowed.
             Subjects who are refractory to hormonal therapy are allowed.

          -  Prior neo-adjuvant or adjuvant chemotherapy is allowed.

          -  Subject must have discontinued prior chemotherapy (including both targeted and
             biologic therapies), prior therapeutic radiation therapy, or prior hormonal therapy
             for locally advanced or metastatic disease >= 4 weeks (28 days) before randomization.
             Start of study treatment is allowed within less than 28 days of the prior therapy
             provided that 5 half-lives of the prior treatment drug(s) have elapsed

          -  ECOG (Eastern Cooperative Oncology Group) performance status 0 or 1

          -  Adequate bone marrow, liver and renal function within 7 days prior to randomization

          -  All acute toxic effects of any prior treatment have resolved to NCI-CTCAE (National
             Cancer Institute-Common Terminology Criteria for Adverse Events) v4.0 Grade 1 or less

          -  Women of childbearing potential must have a negative serum pregnancy test performed
             within 7 days prior to randomization

          -  Subjects (men and women) of childbearing potential must agree to use adequate
             contraception beginning at the signing of the ICF (Informed Consent Form) until at
             least 30 days after the last dose of study drug.

          -  Subject must be able to swallow and retain oral medication

        Exclusion Criteria:

          -  HER2 positive breast cancer

          -  Unknown hormone receptor status (estrogen and progesterone receptor).

          -  Subjects with bilateral breast cancer or a history of two distinct breast cancers.

          -  Subjects with inflammatory breast carcinoma.

          -  Subjects who have received no prior taxane and anthracycline for the treatment of
             breast cancer (either in adjuvant, neo-adjuvant or metastatic setting).

          -  Prior use of sorafenib or capecitabine

          -  Subjects considered by the treating investigator to be appropriate candidates for
             hormonal therapy as current treatment for locally advanced/metastatic breast cancer

          -  Subjects with locally advanced disease who are considered by the treating investigator
             to be appropriate candidates for radiation therapy as current treatment for locally
             advanced breast cancer

          -  Subjects with active brain metastases or leptomeningeal disease.

          -  Subjects with seizure disorder requiring medication.

          -  Radiation to any lesions <= 4 weeks prior to randomization. Palliative radiation to
             bone metastasis for pain control is permitted with provisions

          -  Major surgery, open biopsy, or significant traumatic injury <= 4 weeks

          -  Evidence or history of bleeding diathesis or coagulopathy. Uncontrolled hypertension,
             active or clinically significant cardiac disease. Subject with thrombotic, embolic,
             venus or arterial events

          -  Subjects with any hemorrhage/bleeding event of NCI-CTCAE v4.0 Grade 3 or higher within
             4 weeks before randomization

          -  Subjects with an infection of NCI-CTCAE v4.0 > Grade 2

          -  Subjects with a history of human immunodeficiency virus infection or current chronic
             or active hepatitis B or C infection.

          -  Subjects who have used strong CYP3A4 inducers (eg, phenytoin, carbamazepine,
             phenobarbital, St. John's Wort [Hypericum perforatum], dexamethasone at a dose of
             greater than 16 mg daily, or rifampin [rifampicin], and/or rifabutin) within 28 days
             before randomization.

          -  Subjects with any previously untreated or concurrent cancer that is distinct in
             primary site or histology from breast cancer

          -  Subjects with a history DHPD (Dihydropyrimidine dehydrogenase) reaction to
             fluropyrimidine or history of known or suspected allergy or hypersensitivity to any of
             the study drugs

          -  Presence of a non-healing wound, non-healing ulcer, or bone fracture

          -  Women pregnant or breast feeding

          -  Any condition which, in the investigator's opinion, makes the subject unsuitable for
             trial participation