A Phase III Trial of Pertuzumab Retreatment in Previously Pertuzumab Treated Her2-Positive Advanced Breast Cancer

The American Society of Clinical Oncology (ASCO) Clinical Practice Guidelines recommend the use of pertuzumab, trastuzumab and taxane as first-line treatment for patients with MBC. As a second-line treatment, trastuzumab emtansine (T-DM1) is also recommended. After a pertuzumab-containing regimen and T-DM1, other HER2-targeted therapeutic regimens, including lapatinib-containing regimens and trastuzumab plus chemotherapy, are recommended as third-line treatments and beyond. However, continual pertuzumab use for progression after a pertuzumab-containing regimen and retreatment with pertuzumab are unclear based on evidence.

The efficacy and the safety of two distinct modalities of a trastuzumab plus pertuzumab-containing regimen after pertuzumab use should be assessed in MBC: continual treatment and retreatment. However, it is clinically difficult to examine the efficacy of continual treatment with a trastuzumab plus pertuzumab-containing regimen because of several circumstances including the results of the MARIANNE study.

In addition, it is also important to evaluate the usefulness of retreatment with a pertuzumab-containing regimen. Continual pertuzumab treatment for progression after pertuzumab treatment is not same as pertuzumab retreatment. HER2-HER3-signaling suppressed by pertuzumab-containing regimens could potentially be restored by anti-HER2 therapy without pertuzumab. Pertuzumab retreatment could potentially re-suppress HER2-HER3-signaling. Therefore, Pertuzumab retreatment can be more effective than trastuzumab-containing treatment without pertuzumab.

Inclusion criteria

• Histologically or cytologically confirmed invasive breast cancer
• A confirmed HER2-positive status assessed by means of immunohistochemical analysis (with 3+ indicating positive status) and/or in situ hybridization (with an amplification ratio > 2.0 indicating positive) by each institute
• History of pertuzumab and trastuzumab-containing chemotherapy for locally advanced and metastatic breast cancer(2 or 3 regimen as previous chemotherapy regimen for locally advanced or metastatic breast cancer). The latest regimen before enrollment dose not include pertuzumab.
• Patients have measurable and/or non-measurable disease according to RECIST ver1.1.
• Female patients and aged ≥ 20 years.
• Left Ventricular Ejection Fraction (LVEF) > 50% at baseline (within 28 days before enrollment) as determined by either ECHO or MUGA
• Eastern Cooperative Oncology Group performance status of 0,1 or 2.
• Life expectancy of patients is expected at least 3 months.
• Signed and written informed consent (approved by the Institutional Review Board or Independent Ethics Committee) is obtained before any study procedure.

Exclusion criteria

• History of chemotherapy > 4 regimen for locally advance or metastatic disease except for cancer chemotherapeutic agent-free treatment regimen (eg, hormonal therapy alone, combination with hormonal therapy and trastuzumab and anti-HER2 therapy alone).
• Persistent Grade >3 non-hematologic toxicity according to NCI-CTCAE v4.0-JCOG resulting from previous therapy at the time of enrollment.
• Symptomatic or uncontrolled central nervous system metastases.
• Multiple malignancies without history of breast cancer(within 10 years if invasive breast cancer and within 5 years if malignancies except invasive breast cancer)
• History of exposure to the following cumulative doses of anthracyclines:

• doxorubicin or liposomal doxorubicin > 360 mg/m2
• epirubicin > 720 mg/m2
• mitoxantrone > 100 mg/m2
• If more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
• Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina.
• History of CHF of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia).
• History of myocardial infarction within 6 months of enrollment.
• Dyspnea at rest due to complications of advanced malignancy.
• Inadequate organ function, as determined by the following laboratory results, within 28 days before enrollment:

• Absolute neutrophil count < 1,500/mm3
• Platelet count < 100,000/mm3
• Hemoglobin < 8.0 g/dL
• Total bilirubin > 2.0 mg/dL, unless the patient has documented Gilbert's syndrome
• Aspartate aminotransferase (AST [SGOT]) or alanine aminotransferase (ALT [SGPT]) > 100IU /L with the following exception (If considered that the liver dysfunction due to liver metastases > 200 IU/L, or 100 < , ≤200 IU/L with serum albumin < 2.5 g/dL)
• Serum creatinine value > 2.0 mg/dL or 177 μmol/L
• Current severe uncontrolled systemic disease(eg. Clinically significant cardiovascular, pulmonary and metabolic disease*, disorder of wound healing, ulcer and fracture)

*If gemcitabine is planned to be selected as a combination chemotherapeutic agent,patients who has symptomatic interstitial pneumonia or pulmonary fibrosis on chest X-ray should be excluded.

• Uncontrolled malignancy-associated hypercalcemia syndrome under bisphosphonates or denosumab treatment.
• Radiation related grade >2 adverse event within 14 days before enrollment.
• Major surgical procedure or significant traumatic injury within 28 days before enrollment or anticipation of need for major surgery during the course of study treatment.
• Pregnant woman or positive pregnancy test.
• Nursing woman
• History of receiving any investigational treatment within 28 days before enrollment.
• Current known and active infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus.
• Receipt of intravenous antibiotics for infection within 14 days before enrollment.
• Current chronic daily treatment (continuous for > 3 months) with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
• Known hypersensitivity to pertuzumab or trastuzumab without infusion reaction related to these drugs
• Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.