Therapy for Locally Advanced Breast Cancer Using Doxil, Paclitaxel, and Cyclophosphamide With Avastin
Condition: Invasive Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: Doxil, Paclitaxel, Cyclophosphamide, Avastin
Intervention description: Regimen A: Doxil 25 mg/M2 iv and Avastin 10 mg/kg iv every 2 weeks x 3, then paclitaxel 175 mg/M2 i.v. and Avastin 10 mg/kg iv every 2 weeks x 3, then cyclophosphamide 600 mg/M2 i.v. and Avastin 10 mg/kg iv every 2 weeks x 3 . Patients who experience <pCR to primary chemotherapy will receive an additional year of Avastin 15 mg/kg iv every 3 weeks, beginning 6-8 weeks after operation.
Regimen B: Doxil 30 mg/M2 iv and Avastin 10 mg/kg iv every 2 weeks x 3, then paclitaxel 175 mg/M2 i.v. and Avastin 10 mg/kg iv every 2 weeks x 3, then cyclophosphamide 600 mg/M2 i.v. and Avastin 10 mg/kg iv every 2 weeks x 3. Patients who experience <pCR to primary chemotherapy will receive an additional year of Avastin15 mg/kg iv every 3 weeks, beginning 6-8 weeks after operation.
Intervention MeSH terms: Paclitaxel; Cyclophosphamide; Bevacizumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 32.0
Sex: Female
Minimum age: 19 Years
Healthy volunteers: No
Keywords: Breast cancer

Summary:

      This study will evaluate the rate of pathological complete response (pCR) to the sequential
      therapy of Doxil, paclitaxel, and cyclophosphamide with concurrent Avastin for patients with
      locally advanced invasive (T2,T3, Nany, M0) breast carcinoma. Also, the study will evaluate
      the clinical and subclinical cardiotoxic effect(s) of this regimen, assess how feasible and
      safe the study is. Survival without any progression of disease will also be calculated.

      A regimen of chemotherapy will be given to replicate the high rate of pCR seen with
      conventional chemotherapy in patients with locally advanced breast cancer. Doxil will
      substitute the normally given doxorubicin. It is expected that the low effect or minimal
      effect of Doxil on cardiac function will minimize any additional risk of cardiotoxicity from
      Avastin. It is expected that clinical and subclinical rates of cardiotoxicity will be very
      low at the total doses to be given in this clinical trial.
    

Eligibility criteria:

        Inclusion Criteria:

          -  Histologically confirmed, measurable, invasive breast carcinoma T >2cm, Nany, M0.

          -  Patients with node-negative, ER or PR-positive tumors ≤4 cm in size whose tumors are
             low risk (defined as a score of 0-17) on an Oncotype DX profile are not eligible.

          -  19 years of age or greater

          -  Known ER, PR and HER-2 status (FISH assay to be done on specimens with 2+ or 3+
             immunohistochemical staining for HER-2): patients with gene amplification on FISH
             study will be considered to be HER-2 positive. Patients for this study must be FISH
             negative if immunohistochemical stain is 2+ or 3+ positive; patients with negative, 0
             or 1+ immunohistochemical stain for HER-2 are eligible.

          -  Known axillary nodal status: aspiration cytology or biopsy

          -  Documented menopausal status premenopausal (having menstrual periods or FSH <35) or
             postmenopausal (≥12 months since last menstrual period with intact uterus and at least
             one ovary or FSH ≥35 or previous bilateral oophorectomy

          -  Non-pregnant if premenopausal (negative serum or urine pregnancy test within 7 days of
             starting chemotherapy) and not breast feeding

          -  Patients with reproductive potential must use an adequate contraceptive method (e.g.,
             abstinence, intrauterine device, barrier device with spermicide or surgical
             sterilization) during treatment and for three months after completing treatment.

          -  Life expectancy of less than 12 weeks

          -  Current, recent (within 4 weeks of the first infusion of this study), or planned
             participation in an experimental drug study other than a Genentech-sponsored Avastin
             cancer study

          -  Pregnant or lactating women.

          -  History of cardiac disease, with New York Heart Association Grade II or greater or
             clinical evidence of congestive heart failure.

          -  Serious comorbid medical conditions which would impair the ability to receive
             chemotherapy on time

          -  Previous invasive cancer within the last 5 years

          -  Altered mental status or dementia which would interfere with understanding of informed
             consent and ability to comply with study and follow-up procedures.

          -  Hypersensitivity to Doxil, doxorubicin, cyclophosphamide, cremophore (contained in
             teniposide, cyclosporine, and vitamin K), or to any component of Avastin

          -  Inadequately controlled hypertension (defined as blood pressure of >150/100 mmHg on
             antihypertensive medication)

          -  Unstable angina pectoris

          -  History of myocardial infarction or unstable angina within 12 months prior to
             beginning therapy

          -  History of stroke or TIA at any time

          -  Clinically significant vascular (e.g., aortic aneurysm requiring surgical repair or
             recent peripheral arterial thrombosis, aortic dissection) or peripheral vascular
             disease with 6 months prior to beginning therapy

          -  History of hemoptysis (greater than or equal to 1/2 teaspoon of bright red blood per
             episode) within 1 month prior to beginning therapy

          -  Evidence of bleeding diathesis or significant coagulopathy (in the absence of
             therapeutic anticoagulation)

          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days
             prior to beginning therapy or anticipation of need for major surgical procedure during
             the course of the study

          -  Patients must have a 2-d echocardiogram indicating an ejection fraction of > 50%
             within 42 days prior to first dose of study drug. The method used at baseline must be
             used for later monitoring.

          -  No distant metastases on bone scan and on CT scans of chest and abdomen (no metastasis
             on optional PET scan is an acceptable alternative; if PET scan is done for any reason
             it must show no evidence of distant metastasis). Baseline PET scan is recommended but
             not required for all patients.

          -  No CNS metastasis

          -  Hbg ≥9 gm, platelets ≥100,000, granulocytes ≥1000, total or direct bilirubin ≤1.2,
             creatinine ≤2.0 and urine protein:creatinine ratio <1.0

          -  No prior chemotherapy or radiotherapy and ≤4 weeks of prior antiestrogen or aromatase
             inhibitor therapy

          -  No concomitant hormone replacement (i.e. estrogen or progestin) therapy

          -  PS less than or equal to one

        Exclusion Criteria:

          -  Minor surgical procedure (excluding placement of a vascular access device) such as
             fine needle aspiration or core needle biopsy within 7 days of beginning therapy

          -  Urine protein:creatinine ratio ≥1.0 at initial screening

          -  Known hypersensitivity to any component of Avastin

          -  History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess
             within 6 months of beginning therapy

          -  Serious, non-healing wound, active ulcer, or untreated bone fracture

          -  Any prior history of hypertensive crisis or hypertensive encephalopathy

          -  Known CNS metastasis, except for treated brain metastasis. Treated brain metastases
             are defined as having no evidence of progression or hemorrhage after treatment and no
             ongoing requirement for dexamethasone, as ascertained by clinical examination and
             brain imaging (MRI or CT) during the screening period. Anticonvulsants (stable dose)
             are allowed. Treatment for brain metastases may include whole brain radiotherapy
             (WBRT), radiosurgery (RS; Gamma Knife, LINAC, or equivalent) or a combination as
             deemed appropriate by the treating physician. Patients with CNS metastases treated by
             neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 will
             be excluded.