Pertuzumab, Trastuzumab, and Paclitaxel Albumin-Stabilized Nanoparticle Formulation in Treating Patients With HER2-Positive Advanced Breast Cancer

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