A Phase III Trial of Pertuzumab Retreatment in Previously Pertuzumab Treated Her2-Positive Advanced Breast Cancer
- Conditions
- HER2-positive Locally Advanced or Metastatic Breast Cancer
- Interventions
- Registration Number
- NCT02514681
- Lead Sponsor
- Japan Breast Cancer Research Group
- Brief Summary
The purpose of this study is to evaluate the efficacy and safety of pertuzumab, trastuzumab and chemotherapy as a pertuzumab retreatment compared to trastuzumab and chemotherapy in locally advanced or metastatic breast cancer patients for previously treated with pertuzumab
- Detailed Description
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.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- Female
- Target Recruitment
- 370
- 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.
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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).
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Persistent Grade >3 non-hematologic toxicity according to NCI-CTCAE v4.0-JCOG resulting from previous therapy at the time of enrollment.
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Symptomatic or uncontrolled central nervous system metastases.
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Multiple malignancies without history of breast cancer(within 10 years if invasive breast cancer and within 5 years if malignancies except invasive breast cancer)
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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.
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Current uncontrolled hypertension (systolic > 150 mmHg and/or diastolic > 100 mmHg) or unstable angina.
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History of CHF of any New York Heart Association criteria, or serious cardiac arrhythmia requiring treatment (exception, atrial fibrillation, paroxysmal supraventricular tachycardia).
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History of myocardial infarction within 6 months of enrollment.
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Dyspnea at rest due to complications of advanced malignancy.
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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
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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.
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Uncontrolled malignancy-associated hypercalcemia syndrome under bisphosphonates or denosumab treatment.
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Radiation related grade >2 adverse event within 14 days before enrollment.
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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.
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Pregnant woman or positive pregnancy test.
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Nursing woman
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History of receiving any investigational treatment within 28 days before enrollment.
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Current known and active infection with human immunodeficiency virus, hepatitis B virus or hepatitis C virus.
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Receipt of intravenous antibiotics for infection within 14 days before enrollment.
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Current chronic daily treatment (continuous for > 3 months) with corticosteroids (dose equivalent to or greater than 10 mg/day methylprednisolone), excluding inhaled steroids.
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Known hypersensitivity to pertuzumab or trastuzumab without infusion reaction related to these drugs
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Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Trastuzumab+ pertuzumab + chemotherapy Paclitaxel Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Nab-paclitaxel Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Paclitaxel Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Trastuzumab Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Docetaxel Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Nab-paclitaxel Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Eribulin Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Vinorelbine Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Capecitabine Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Docetaxel Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Pertuzumab Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Eribulin Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Vinorelbine Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Trastuzumab Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab + chemotherapy Gemcitabine Trastuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel ,Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine Trastuzumab+ pertuzumab + chemotherapy Capecitabine Trastuzumab+ pertuzumab + chemotherapy Chemotherapy regimen is chosen from the following; Docetaxel, Paclitaxel, nab-paclitaxel, Vinorelbine, Eribulin, Capecitabine or Gemcitabine
- Primary Outcome Measures
Name Time Method Progression-free survival (assessed by investigators) 4 years
- Secondary Outcome Measures
Name Time Method Response rate 4 years PFS in patients treated with trastuzumab emtansine (T-DM1) as the latest regimen 4 years Progression-free survival (assessed by independent review) 4 years Patient-reported-outcome 4 years Difference in terms of patient-reported outcome (PRO) between standard group and Pertuzumab treated group FACT-G, FACT-B and EQ-5D are used as assessment tools for PRO.
Safety assessed by Incidence/Grade of Serious Adverse Events (SAEs), Pertuzumab-specific adverse events, laboratory abnormalities Percentage and number of subjects who discontinued for adverse event. 4 years Safety for HER2-positive locally advanced or metastatic breast cancer subjects who were previously treated with Pertuzumab
Biomarkers 4 years To find Prognostic and predictive biomarker markers for patients receiving anti-HER2 treatment. Changes in immunologic markers on peripheral blood mononuclear cells determined by flow cytometry after anti-HER2 treatment Changes in tumor-derived gene mutations (e.g. PIK3CA, APOBEC3, CDH1...etc.) in ctDNA after anti-HER2 therapy Changes in proteins (e.g. HER2, HER3...etc.) and micro RNAs expression in extracellular vesicle after anti-HER2 therapy Changes in glycans and proteins expression in the plasma after anti-HER2 therapy.
Duration of response, Overall survival 4 years
Trial Locations
- Locations (3)
Japan Breast Cancer Research Group
🇯🇵Chuo-ku, Nihonbashi, Koami-cho, Tokyo, Japan
Kumamoto University Hospital
🇯🇵Kumamoto City, Kumamoto, Japan
Aichi Cancer Center
🇯🇵Chikusa-ku, Aichi, Japan