Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer
Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer
This phase II trial studies how well pertuzumab, trastuzumab, and paclitaxel
 albumin-stabilized nanoparticle formulation work in treating patients with human epidermal
 growth factor receptor (HER) 2-positive stage II-IV breast cancer. Monoclonal antibodies,
 such as pertuzumab 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. Drugs used in chemotherapy, such as paclitaxel
 albumin-stabilized nanoparticle formulation, work in different ways to kill tumor cells or
 stop them from growing. Giving pertuzumab and trastuzumab together with paclitaxel
 albumin-stabilized nanoparticle formulation may be a better way to block tumor growth.
PRIMARY OBJECTIVES:

 I. To determine efficacy of administration of pertuzumab in combination with trastuzumab with
 nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) in subjects with
 stage IV human epidermal growth factor receptor (HER)-2 overexpressing metastatic breast
 cancer (MBC) as measured by progression free survival (PFS).

 II. To determine the efficacy as neoadjuvant treatment of the regimen in HER2+ locally
 advanced breast cancer (LABC) as defined by pathologic complete response (pCR).

 SECONDARY OBJECTIVES:

 I. To evaluate the safety of pertuzumab when added to trastuzumab and nab-paclitaxel in HER-2
 overexpressing MBC and LABC cancer as assessed by the frequency and severity of adverse
 events (AEs), abnormal findings on physical examination, laboratory tests, and vital signs.

 II. To evaluate the objective response rate (Response Evaluation Criteria in Solid Tumors
 [RECIST] 1.1) and duration of response in MBC.

 III. To evaluate the efficacy of the regimen by assessing tumor response including assessment
 of residual cancer burden (RCB) scores in LABC.

 IV. To assess the progression free survival (MBC), relapse-free survival (LABC) and overall
 survival in all patients.

 V. To perform exploratory circulatory gene, micro-ribonucleic acid (RNA), and exosome
 profiling as well as protein and glycomic profiling.

 VI. To assess the feasibility of molecular profiling in both primary and metastatic tumor
 samples.

 VII. To assess numerical and qualitative aspects of circulating tumor cells and circulating
 tumor-derived deoxyribonucleic acid (DNA).

 OUTLINE: Patients receive pertuzumab intravenously (IV) over 30-60 minutes on day 1,
 trastuzumab IV over 30-90 minutes and paclitaxel albumin-stabilized nanoparticle formulation
 IV over 30 minutes on days 1, 8, and 15. Treatment repeats every 21 days in the absence of
 disease progression or unacceptable toxicity (patients with MBC) or for 6 courses in the
 absence of disease progression or unacceptable toxicity (patients with LABC).

 After completion of study treatment, patients are followed up every 3 months for 4 years and
 then every 6 months for 1 year.
Inclusion Criteria:

 -  Patients must be diagnosed with metastatic cytologically or histologically confirmed
 adenocarcinoma of the breast with HER2 over-expression or with newly diagnosed locally
 advanced (including inflammatory) breast cancer (LABC) with stage II-III disease;
 patients with metastatic (stage IV) disease (MBC) must have measurable lesions

 -  Women of child-bearing potential and men must agree to use adequate contraception
 (hormonal or barrier method of birth control or abstinence) prior to study entry and
 for six months following duration of study participation; should a woman become
 pregnant or suspect that she is pregnant while participating on the trial, she should
 inform her treating physician immediately

 -  Tumor positive or negative for expression of hormone receptors (< 1% or > 1%) and
 overexpressing HER2 by immunohistochemistry (IHC) (3+), or, HER2-amplified by
 fluorescence in situ hybridization (FISH) or by alternative gene testing

 -  For patients with LABC, no prior therapy is allowed

 -  For patients with MBC, prior adjuvant chemotherapy and trastuzumab more than or equal
 to 12 months prior to enrollment are allowed

 -  No prior chemotherapy or trastuzumab for treatment of metastatic breast cancer

 -  Left ventricular ejection fraction (LVEF) >= 50% (determined by echocardiogram or
 multigated acquisition scan) within 42 days of treatment

 -  Eastern Cooperative Oncology Group performance status of 0 or 1

 -  Hemoglobin >= 9 g/dl

 -  Leukocytes >= 3.0 x 10^9/L

 -  Absolute neutrophil count >= 1.5 x 10^9/L

 -  Platelets >= 100 x 10^9/L

 -  Total bilirubin =< 1.3 mg/dl (institutional upper limit of normal)

 -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
 [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
 =< 2 x institutional upper limit of normal

 -  Creatinine within normal institutional limits or creatinine clearance > 50 mL/min/1.73
 m^2 for patients with creatinine levels above institutional normal (using
 Cockcroft-Gault formula)

 -  All radiology studies (study requiring staging) must be performed within 35 days prior
 to the start of therapy

 -  No serious medical conditions such as myocardial infarction within 6 months prior to
 entry, congestive heart failure, unstable ventricular arrhythmia, uncontrolled
 hypertension, uncontrolled diabetes mellitus, uncontrolled psychotic disorders,
 serious infections, active peptic ulcer disease, psychiatric illness, or any other
 medical conditions that might be aggravated by treatment or limit compliance

 -  Currently, no active second malignancy other than non-melanoma skin cancer; note:
 patients are not considered to have a "current active" malignancy if they have
 completed anti-cancer therapy and are considered by their physicians to have a less
 than 30% chance of relapse

 -  All patients must have the ability to understand and the willingness to sign an
 informed consent

 -  Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at
 screening for patients of child-bearing potential

 -  No prior therapies (except for anti-estrogen therapy) are allowed for the treatment of
 the newly diagnosed metastatic breast cancer; patients are allowed to have had prior
 chemotherapy for breast cancer in the adjuvant setting for at least 12 months prior to
 enrollment into this study; patients with a prior diagnosis of malignancy treated >= 5
 years ago are eligible, provided that they have not received prior nab-paclitaxel as
 part of their prior treatment regimen, and that they meet all eligibility criteria

 Exclusion Criteria:

 -  Known active hepatitis B or C

 -  Known active human immunodeficiency virus (HIV)

 -  Prior breast cancer or other invasive malignancy treated within 5 years

 -  Pregnancy

 -  Neuropathy > grade 1

 -  Any other intercurrent medical/psychological problem deemed exclusionary by the
 treating physician or investigators/principal investigator (PI)

 -  Cumulative dose of doxorubicin or equivalent of > 360 mg/m^2 during prior adjuvant
 therapy

 -  LVEF < 50% during previous trastuzumab therapy

 -  Central nervous system metastases

 -  Another malignancy excluding basal cell skin cancer

 -  Pregnant women

 -  Subjects will be excluded who, in the opinion of the investigator, may not be able to
 comply with the safety monitoring requirements of the study