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

Estimated by the Kaplan-Meier method.

Estimated by the Kaplan-Meier method.
The corresponding median survival time (with 90% confidence limits) will be determined.

Response rate (complete response [CR] + partial response [PR]) based on the RECIST version 1.1

PFS (MBC patients)

Estimated with 95% confidence intervals.

Estimated by the Kaplan-Meier method.
The corresponding median survival time (with 90% confidence limits) will be determined.

9 weeks

Time from initiation of treatment until objective disease progression, assessed up to 5 years

45

50

<p>Inclusion Criteria:</p><ul><li>Patients must be diagnosed with metastatic cytologically or histologically confirmed adenocarcinoma of the breast with HER2 over-expression; patients must have measurable and&#x2F;or evaluable lesions</li><li>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</li><li>Tumor positive or negative for expression of hormone receptors (&lt; 1% or &gt; 1%) and overexpressing HER2 by immunohistochemistry (IHC), or, in case of IHC of 2, positive by fluorescence in situ hybridization (FISH) &gt;= 2 or by alternative gene testing</li><li>Prior adjuvant chemotherapy and trastuzumab more than or equal to 6 months prior to enrollment are allowed</li><li>No prior chemotherapy or trastuzumab for treatment of metastatic breast cancer</li><li>Left ventricular ejection fraction (LVEF) &gt;= 50% (determined by echocardiogram or multigated acquisition scan) within 42 days of treatment</li><li>Eastern Cooperative Oncology Group performance status of 0 or 1</li><li>Prior radiotherapy is allowed provided that there is documentation of progression (either locally or systemically)</li><li>Patients may have had prior chemotherapy in the adjuvant setting</li><li>Toxic effects from prior therapy must have resolved to grade 1 or less except for peripheral neuropathy and alopecia</li><li>Hemoglobin &gt;= 90 g&#x2F;dl - Leukocytes &gt;= 3.0 x 10^9&#x2F;L</li><li>Absolute neutrophil count (ANC) &gt;= 1.5 x 10^9&#x2F;L</li><li>Platelets &gt;= 100 x 10^9&#x2F;L</li><li>Total bilirubin =&lt; 1.3 mg&#x2F;dl (institutional upper limit of normal)</li><li>Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])&#x2F;alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2 x institutional upper limit of normal (=&lt; 5 times the upper limit of normal [ULN] for patients with liver metastases)</li><li>Creatinine within normal institutional limits or creatinine clearance &gt; 50 mL&#x2F;min&#x2F;1.73
m^2 for patients with creatinine levels above institutional normal (using Cockcroft-Gault formula)</li><li>All radiology studies must be performed =&lt; 4 weeks prior to the start of therapy</li><li>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</li><li>Currently, no active second malignancy other than non-melanoma skin cancer; Note: patients are not considered to have a &quot;current active&quot; malignancy if they have completed anti-cancer therapy and are considered by their physicians to have a less than 30% chance of relapse</li><li>All patients must have the ability to understand and the willingness to sign an informed consent</li><li>Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of child-bearing potential</li><li>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 6 months prior to enrollment into this study; patients with a prior diagnosis of malignancy treated &gt;= 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</li></ul><p>Exclusion Criteria:</p><ul><li>Known active hepatitis B or C (due to the potential for disease treatment-related pharmacological and liver function-specific interactions)</li><li>Known active human immunodeficiency virus (HIV) (due to the complexity and potential pharmacological interactions between the standard neoadjuvant therapeutic agents, and highly active antiretroviral therapy [HAART])</li><li>Prior breast cancer or other invasive malignancy treated within 5 years</li><li>Pregnancy</li><li>Neuropathy &gt; grade 1</li><li>Any other intercurrent medical&#x2F;psychological problem deemed exclusionary by the treating physician or investigators&#x2F;principal investigator (PI)</li><li>Recurrence &lt; 6 months since completion of adjuvant treatment</li><li>Prior chemotherapy or trastuzumab treatment for metastatic disease</li><li>Cumulative dose of doxorubicin or equivalent of &gt; 360 mg&#x2F;m^2 during prior adjuvant therapy</li><li>LVEF &lt; 50% during previous trastuzumab therapy</li><li>Central nervous system metastases</li><li>Another malignancy excluding basal cell skin cancer</li><li>Hemoglobin &lt; 9 g&#x2F;dL</li><li>ANC &lt; 1500&#x2F;mcL</li><li>Platelet &lt; 100,000&#x2F;mcL</li><li>Creatinine clearance =&lt; 50 mL&#x2F;min as measured by either the Cockcroft-Gault method or 24-hour creatinine clearance)</li><li>AST (SGOT)&#x2F;ALT (SGPT) &gt; 2 x institutional upper limit of normal</li><li>Uncontrolled hypertension or unstable angina, congestive heart failure (New York Heart Association classification), or myocardial infarction within 6 months of enrollment</li><li>Pregnant women</li></ul>

<p>Inclusion Criteria:</p><ul><li>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</li><li>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</li><li>Tumor positive or negative for expression of hormone receptors (&lt; 1% or &gt; 1%) and overexpressing HER2 by immunohistochemistry (IHC) (3+), or, HER2-amplified by fluorescence in situ hybridization (FISH) or by alternative gene testing</li><li>For patients with LABC, no prior therapy is allowed</li><li>For patients with MBC, prior adjuvant chemotherapy and trastuzumab more than or equal to 12 months prior to enrollment are allowed</li><li>No prior chemotherapy or trastuzumab for treatment of metastatic breast cancer</li><li>Left ventricular ejection fraction (LVEF) &gt;= 50% (determined by echocardiogram or multigated acquisition scan) within 42 days of treatment</li><li>Eastern Cooperative Oncology Group performance status of 0 or 1</li><li>Hemoglobin &gt;= 9 g&#x2F;dl</li><li>Leukocytes &gt;= 3.0 x 10^9&#x2F;L</li><li>Absolute neutrophil count &gt;= 1.5 x 10^9&#x2F;L</li><li>Platelets &gt;= 100 x 10^9&#x2F;L</li><li>Total bilirubin =&lt; 1.3 mg&#x2F;dl (institutional upper limit of normal)</li><li>Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])&#x2F;alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =&lt; 2 x institutional upper limit of normal</li><li>Creatinine within normal institutional limits or creatinine clearance &gt; 50 mL&#x2F;min&#x2F;1.73
m^2 for patients with creatinine levels above institutional normal (using Cockcroft-Gault formula)</li><li>All radiology studies must be performed =&lt; 4 weeks prior to the start of therapy</li><li>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</li><li>Currently, no active second malignancy other than non-melanoma skin cancer; note: patients are not considered to have a &quot;current active&quot; malignancy if they have completed anti-cancer therapy and are considered by their physicians to have a less than 30% chance of relapse</li><li>All patients must have the ability to understand and the willingness to sign an informed consent</li><li>Negative serum or urine beta-human chorionic gonadotropin (hCG) pregnancy test at screening for patients of child-bearing potential</li><li>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 &gt;= 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</li></ul><p>Exclusion Criteria:</p><ul><li>Known active hepatitis B or C</li><li>Known active human immunodeficiency virus (HIV)</li><li>Prior breast cancer or other invasive malignancy treated within 5 years</li><li>Pregnancy</li><li>Neuropathy &gt; grade 1</li><li>Any other intercurrent medical&#x2F;psychological problem deemed exclusionary by the treating physician or investigators&#x2F;principal investigator (PI)</li><li>Cumulative dose of doxorubicin or equivalent of &gt; 360 mg&#x2F;m^2 during prior adjuvant therapy</li><li>LVEF &lt; 50% during previous trastuzumab therapy</li><li>Central nervous system metastases</li><li>Another malignancy excluding basal cell skin cancer</li><li>Pregnant women</li><li>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</li></ul>

2014-01

2014-05

2014-01-21

2014-05-21

2014-01-23

2014-05-23

This phase II trial studies how well giving pertuzumab, trastuzumab, and paclitaxel albumin-stabilized nanoparticle formulation together works in treating patients with human epidermal growth factor receptor (HER)2-positive metastatic 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

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.

<p>PRIMARY OBJECTIVES:</p><p>I. To determine the preliminary efficacy of administration of pertuzumab in combination with trastuzumab with nab-paclitaxel (paclitaxel albumin-stabilized nanoparticle formulation) in subjects with stage IV HER-2 overexpressing breast cancer as measured by progression free survival (PFS).</p><p>SECONDARY OBJECTIVES:</p><p>I. To evaluate the safety of pertuzumab when added to trastuzumab and abraxane (paclitaxel albumin-stabilized nanoparticle formulation) in stage IV HER-2 overexpressing breast cancer assessed by the frequency and severity of adverse events (AEs), abnormal findings on physical examination, laboratory tests, and vital signs.</p><p>II.
To evaluate the objective response rate and duration of response.</p><p>III.
To evaluate the objective tumor response (Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1 criteria) where possible.</p><p>IV.
To assess the overall survival.</p><p>V. To perform exploratory protein and glycomic biomarker profiling.</p><p>VI.
To perform exploratory micro ribonucleic acid (RNA) and exosome profiling.</p><p>OUTLINE:</p><p>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.
Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.</p><p>After completion of study treatment, patients are followed up every 3 months for 4 years and then every 6 months for 1 year.</p>

<p>PRIMARY OBJECTIVES:</p><p>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).</p><p>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).</p><p>SECONDARY OBJECTIVES:</p><p>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.</p><p>II.
To evaluate the objective response rate (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) and duration of response in MBC.</p><p>III.
To evaluate the efficacy of the regimen by assessing tumor response including assessment of residual cancer burden (RCB) scores in LABC.</p><p>IV.
To assess the progression free survival (MBC), relapse-free survival (LABC) and overall survival in all patients.</p><p>V. To perform exploratory circulatory gene, micro-ribonucleic acid (RNA), and exosome profiling as well as protein and glycomic profiling.</p><p>VI.
To assess the feasibility of molecular profiling in both primary and metastatic tumor samples.</p><p>VII.
To assess numerical and qualitative aspects of circulating tumor cells and circulating tumor-derived deoxyribonucleic acid (DNA).</p><p>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).</p><p>After completion of study treatment, patients are followed up every 3 months for 4 years and then every 6 months for 1 year.</p>