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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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Phase II Prospective Open Label Study of Pertuzumab, Trastuzumab, and Nab-Paclitaxel in Patients With HER-2 Positive Advanced Breast Cancer

Conditions
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HER2-positive Breast Cancer, Recurrent Breast Cancer, Stage IIA Breast Cancer, Stage IIB Breast Cancer, Stage IIIA Breast Cancer, Stage IIIB Breast Cancer, Stage IIIC Breast Cancer, Stage IV Breast Cancer, Breast Adenocarcinoma, Inflammatory Breast Carcinoma

Intervention / Treatment
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* Biological: pertuzumab
* Biological: trastuzumab
* Drug: paclitaxel albumin-stabilized nanoparticle formulation
* Other: laboratory biomarker analysis


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (pertuzumab, trastuzumab, nab-paclitaxel)<br>Patients receive pertuzumab 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. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. | Biological: pertuzumab<br>* Given IV<br>* Other names: rhuMAb-2C4;Biological: trastuzumab<br>* Given IV<br>* Other names: MOAB HER2;Drug: paclitaxel albumin-stabilized nanoparticle formulation<br>* Given IV<br>* Other names: nanoparticle albumin-bound paclitaxel;Other: laboratory biomarker analysis<br>* Optional correlative studies<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (MBC Cohort) | Estimated using the product-limit method of Kaplan and Meier. From time of initial treatment until disease progression or death. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions. | assessed up to 5 years | 
| Five Year Disease-free Survival (LABC Cohort) | Estimated using the method of Kaplan-Meier. Disease-free survival is defined as the time from Initial treatment to recurrence of tumor or death | assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Response (MBC Cohort) | Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Up to 5 years | 
| Five Year Overall Survival | Estimated by the Kaplan-Meier method. From the initial date of treatment to date of death from any cause. | Assessed up to 5 years |