Carboplatin+Nab-paclitaxel, Plus Trastuzumab (HER2+) or Bevacizumab (HER2-) in the Neoadjuvant Setting

RATIONALE: Drugs used in chemotherapy, such as carboplatin and paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Monoclonal antibodies, such as bevacizumab and trastuzumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Giving more than one drug (combination chemotherapy) and monoclonal antibody therapy together before surgery may make the tumor smaller and reduce the amount of normal tissue that needs to be removed.

PURPOSE: This phase II is studying the side effects and how well giving carboplatin and paclitaxel albumin-stabilized nanoparticle formulation together with bevacizumab or trastuzumab before surgery works in treating women with stage II or stage III breast cancer.

PRIMARY OBJECTIVES:

I. To estimate 2 year progression-free survival in patients with breast cancer more than 1 cm and/or lymph node positive breast cancer treated with weekly Carboplatin/Nab-Paclitaxel (with trastuzumab in patients with HER2+ disease, and with bevacizumab in HER2-).

II. To measure clinical response rates in patients treated in the neoadjuvant setting.

III. To measure the microscopic pathological response rate of this regimen in patients treated in the neoadjuvant setting.

IV. To measure the toxicity and delivered dose intensity of this regimen. V. To assess the association between microscopic pathologic complete response and clinical complete response at the primary tumor site in these patients.

VI. To measure the outcome of patients treated with doxorubicin and cyclophosphamide with patients not treated with doxorubicin and cyclophosphamide.

SECONDARY OBJECTIVES:

I. Develop quantitative analysis methods to obtain pre-treatment tumor characteristic morphological, enhancement kinetic, and Choline metabolic parameters in breast cancer. Select an optimal set of features using the logistic regression analysis and the Artificial Neural Network (ANN) to predict pathologic complete remission (pCR) in HER-2 positive and negative arm.

II. Investigate whether the early response patterns, analyzed using the percent tumor size changes, or changes in other lesion characteristic parameters, can be used to predict pathologic complete remission (pCR) in HER-2 positive and negative arm.

III. Investigate whether combining the pre-treatment tumor characteristic parameters, and the early response pattern during the treatment course, can achieve a higher "area under the receiver operating characteristic (ROC) curve" (AUC) in prediction of pCR than those based on pre-treatment MRI characteristics or tumor response patterns alone.

OUTLINE: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and carboplatin IV over 60 minutes once weekly for 12 weeks. Patients with HER2-positive disease receive trastuzumab IV over 30-90 minutes once weekly for 12 weeks and patients with HER2-negative disease receive bevacizumab IV over 30-90 minutes once every two weeks for 5 doses. Treatment continues in the absence of disease progression or unacceptable toxicity. Beginning 21-40 days later, patients undergo surgery.

After completion of study treatment, patients are followed for 5 years.

• Drug: Carboplatin
  Given IV
  Other Names:

  • Carboplatin Hexal
  • Carboplatino
  • CBDCA
• Drug: paclitaxel albumin-stabilized nanoparticle formulation
  Given IV
  Other Names:

  • Albumin-Stabilized Nanoparticle Paclitaxel
  • nab paclitaxel
  • nab-paclitaxel
  • nanoparticle albumin-bound paclitaxel
  • Nanoparticle Paclitaxel
• Drug: bevacizumab
  Given IV
  Other Names:

  • anti-VEGF humanized monoclonal antibody
  • anti-VEGF monoclonal antibody
  • anti-VEGF rhuMAb
  • recombinant humanized anti-VEGF monoclonal antibody
  • rhuMAb VEGF
• Drug: trastuzumab
  Given IV
  Other Names:

  • anti-c-erB-2
  • MOAB HER2
  • monoclonal antibody c-erb-2
  • monoclonal antibody HER2
  • rhuMAb HER2
• Procedure: magnetic resonance imaging
  Optional correlative studies
  Other Names:

  • MRI
  • NMR imaging
  • NMRI
  • nuclear magnetic resonance imaging
• Procedure: therapeutic conventional surgery
  Post-chemotherapy surgery for patients with a response or stable disease must take place no sooner than 21 days after last dose of Herceptin; and 40 days after last dose of bevacizumab to allow for normalization of blood counts

• Experimental: Arm I (HER-2 positive)
  Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes, carboplatin IV over 60 minutes, and trastuzumab IV over 90 minutes , then weekly over 30-60 minutes. Treatment repeats every week for 12 weeks in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery.
  Interventions:

  • Drug: Carboplatin
  • Drug: paclitaxel albumin-stabilized nanoparticle formulation
  • Drug: trastuzumab
  • Procedure: magnetic resonance imaging
  • Procedure: therapeutic conventional surgery
• Experimental: Arm II (HER-2 negative)
  Patients receive paclitaxel albumin-stabilized nanoparticle formulation and carboplatin as in Arm I. Patients also receive bevacizumab IV over 90 or 60 or 30 minutes once every two weeks for 5 doses in the absence of disease progression or unacceptable toxicity. In both arms, beginning 21-40 days later, patients undergo surgery.
  Interventions:

  • Drug: Carboplatin
  • Drug: paclitaxel albumin-stabilized nanoparticle formulation
  • Drug: bevacizumab
  • Procedure: magnetic resonance imaging
  • Procedure: therapeutic conventional surgery

Inclusion criteria

• Are between 21 and 90 years old,
• Have large Stage I, II or III breast cancer which is not immediately treatable with surgery,or with clinically documented enlarged lymph nodes
• Other than having cancer, are in general good health (determined by history, physical and laboratory assessment),

Exclusion criteria

• Are pregnant,
• Have early stage breast cancer that could potentially be treated with surgery alone,
• Have congestive heart failure,
• Are unwilling to give informed consent.

Exclusion criteria for receiving bevacizumab treatment

• Have renal impairment
• Have hepatic dysfunction

Exclusion criteria for participating in MRI monitoring sub-study

• Implanted prosthetic heart valves, pacemaker, neuro-stimulation devices, surgical clips (hemostatic clips) or other metallic implants.
• Engaged in occupations or activities which may cause accidental lodging of ferromagnetic materials, or have imbedded metal fragments from military activities.
• Received orthodontic work involving ferromagnetic materials.
• Claustrophobia (a fear of enclosed spaces).
• Previously had an allergic response to MRI contrast agents (gadolinium).
• Known history of severe renal insufficiency, asthma, allergic conditions, sickle cell anemia, chronic hemolytic anemia, and gastrointestinal disorders.

• National Institutes of Health (NIH)
• National Cancer Institute (NCI)