Phase II Trial to Compare the Safety of Two Chemotherapy Plus Trastuzumab Regimens as Adjuvant Therapy for HER2-positive Breast Cancer (Study P05048)

Study Overview
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Brief Summary
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The purpose of this study is to compare the incidence of cardiac dysfunction in subjects with human epidermal growth factor receptor 2 (HER2) positive breast cancer treated with either doxorubicin or pegylated liposomal doxorubicin (PLD), both in combination with trastuzumab.

Official Title
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Randomized Phase II Multinational Trial to Evaluate the Safety of Two Chemotherapy Plus Trastuzumab Regimens as Adjuvant Therapy in Patients With HER2-positive Breast Cancer: Caelyx + Cyclophosphamide + Trastuzumab (C+C+H) or Doxorubicin + Cyclophosphamide (A+C), Each Followed by Paclitaxel + Trastuzumab (T+H) BACH

Conditions
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Breast Neoplasm

Intervention / Treatment
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* Drug: doxorubicin, cyclophosphamide, paclitaxel, trastuzumab
* Drug: PLD, cyclophosphamide, trastuzumab, paclitaxel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with operable, node-positive or high-risk node-negative (see #3 below) HER2-positive breast carcinoma are eligible for the study, provided they satisfy the following criteria. Subjects must demonstrate willingness to and be able to participate in the study and to adhere to dose and visit schedules Subjects must be of female gender and >= 18 years of age Subjects must have been diagnosed with operable, histologically confirmed adenocarcinoma of the breast with no clinical or radiological evidence of metastatic disease but with otherwise high or intermediate risk tumor characteristics: node-positive: T1-3, N1-2, M0 (level of T [tumor involvement], N [lymph node involvement], & M [matastases]) OR node-negative AND at least one of the following features: Tumor >2 cm or Tumor >1 cm and Negative estrogen receptor/progesterone receptor (ER/PR) or Malignancy Grade 2-3 or Presence of peritumoral vascular invasion or Age <35 years HER2-positive by fluorescence in situ hybridization (FISH)(with gene amplification) or 3+ using immunohistochemistry Subjects must have had complete resection (R0) of the primary tumor and axillary lymph nodes (or must have negative sentinel node[s]) Baseline left ventricular ejection fraction (LVEF) by multiple gated acquisition (MUGA) scan or echocardiogram (ECHO) >=55% Easter Cooperative Oncology Group (ECOG)-performance status of 0-1 Adequate postoperative bone marrow function with neutrophils >=1.5 x 10^9/l, platelets >=100 x 10^9/l and hemoglobin >= lower limit of normal (LLN) Adequate renal function: calculated creatinine clearance >=50 ml/min Adequate postoperative liver function with a total bilirubin < upper limit of normal (ULN), alkaline phosphatase <2.5 times the ULN and aspartate aminotransferase (AST) <1.5 times the ULN Subjects must be free of any clinically relevant disease that would, in the principal investigator's and/or sponsor's opinion, interfere with the conduct of the study or study evaluations Subjects of childbearing potential (including women who are less than one year postmenopausal and will be sexually active during the study) must agree to use a medically accepted method of contraception, while receiving protocol-specified medication and for 30 days (or as per local requirements) after stopping the medication or be surgically sterilized prior to screening Subjects must be able to provide written informed consent Exclusion Criteria: Subject who meets any of the following exclusion criteria will be disqualified from participation in the study: Clinical or radiological evidence of metastatic disease Prior radiotherapy, chemotherapy or biotherapy for the currently diagnosed breast cancer prior to randomization Clinically significant pericardial effusion Serious cardiac illness including, but not confined to history of documented congestive heart failure history of any form of cardiomyopathy or active treatment for any form of cardiomyopathy history of angina pectoris or documented transmural myocardial infarction, or active angina pectoris requiring medication serious ventricular arrhythmias requiring medication or implantable cardioverter-defibrillator (ICD) therapy, uncontrolled supraventricular arrhythmias clinically significant valvular disease poorly controlled arterial hypertension (systolic blood pressure (BP) >180 mmHg, diastolic BP >100 mmHg) Sensory/motor neuropathy > grade 2 as defined by National Cancer Institure - Common Toxicity Criteria (NCI-CTC) Pregnancy, or intending to become pregnant during the study Nursing (breastfeeding) or intending to be nursing during the study Any of the following clinical conditions: Chronic obstructive pulmonary disease, requiring chronic treatment Clinically significant active infections A history of a psychological illness of condition, preventing the subject to understand the requirements of the study Unstable regulation of diabetes mellitus A situation or condition that, in the opinion of the investigator, may interfere with optimal participation in the study Is on staff, affiliated with, or a family member of the staff personnel directly involved with this study Usage of any investigational product within 30 days prior to enrollment Participation in any other interventional clinical study involving drug, device or biological. This would not prohibit the patient from participating in a quality of life (QOL), questionnaire, blood collection, or observational study. Allergy to or sensitivity to the study drug or its excipients

Ages Eligible for Study
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Minimum Age: 18 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Doxorubicin Based Regimen<br> | Drug: doxorubicin, cyclophosphamide, paclitaxel, trastuzumab<br>* doxorubicin 60 mg/m^2 IV push + cyclophosphamide 600 mg/m^2 IV over 30-90 minutes given every 21 days for 4 courses (12 weeks) followed by Paclitaxel 80 mg/m^2 IV over 60 minutes with trastuzumab 2 mg/kg IV over 30 minutes (first administration 4 mg/kg IV over 90 minutes) given weekly for 12 weeks (4 courses)<br>|
| Experimental: Pegylated Liposomal Doxorubicin (PLD) Based Regimen<br> | Drug: PLD, cyclophosphamide, trastuzumab, paclitaxel<br>* PLD 35 mg/m^2 IV over 60 minutes + cyclophosphamide 600 mg/m^2 IV over 30-90 minutes given every 21 days + trastuzumab 2 mg/kg IV over 30 minutes (first dose 4 mg/kg IV over 90 minutes) given once weekly for 4 courses (12 weeks) followed by Paclitaxel 80 mg/m^2 IV over 60 minutes with trastuzumab 2 mg/kg IV over 30 minutes given weekly for 12 weeks (4 courses)<br>* Other names: pegylated liposomal doxorubicin (SCH 200746);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Cardiac Events (Level 1 or 2), or Inability to Administer Trastuzumab Either During the 8 Cycles of Chemotherapy or According to Package Insert for a Total Duration of 1 Year | Cardiac events defined as: Level 1: Cardiac death due to heart failure (HF), myocardial infarction or arrhythmia, or probable cardiac death defined as sudden, unexpected death within 24 hours of a definite or probable cardiac event, or severe symptomatic HF, concomitant with a left ventricular ejection fraction (LVEF) drop of >10 percentage points from baseline and to ≤50% LVEF Level 2: Asymptomatic systolic dysfunction or mildly symptomatic HF concomitant with an LVEF drop of >10 percentage points from baseline and to <50% LVEF; the LVEF drop was to have been confirmed within 3-4 weeks. | 8 cycles of chemotherapy and subsequently one year of planned trastuzumab treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Cardiac events defined as: Level 1: Cardiac death due to heart failure (HF), myocardial infarction or arrhythmia, or probable cardiac death defined as sudden, unexpected death within 24 hours of a definite or probable cardiac event, or severe symptomatic HF, concomitant with a left ventricular ejection fraction (LVEF) drop of >10 percentage points from baseline and to ≤50% LVEF Level 2: Asymptomatic systolic dysfunction or mildly symptomatic HF concomitant with an LVEF drop of >10 percentage points from baseline and to <50% LVEF; the LVEF drop was to have been confirmed within 3-4 weeks. | During the 8 courses of chemotherapy | 
| Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Cardiac events defined as: Level 1: Cardiac death due to heart failure (HF), myocardial infarction or arrhythmia, or probable cardiac death defined as sudden, unexpected death within 24 hours of a definite or probable cardiac event, or severe symptomatic HF, concomitant with a left ventricular ejection fraction (LVEF) drop of >10 percentage points from baseline and to ≤50% LVEF Level 2: Asymptomatic systolic dysfunction or mildly symptomatic HF concomitant with an LVEF drop of >10 percentage points from baseline and to <50% LVEF; the LVEF drop was to have been confirmed within 3-4 weeks. | During 1 year of trastuzumab therapy | 
| Number of Participants Who Survived Without Relapse | Relapse-free survival would have been determined by Kaplan-Meier method. This was not calculated, since the 2 year follow-up was curtailed. | Approximately 2 years |