Phase II Trial to Compare the Safety of Two Chemotherapy Plus Trastuzumab Regimens as Adjuvant Therapy for HER2-positive Breast Cancer (Study P05048)
Condition: Breast Neoplasm
MeSH terms: Breast Neoplasms
Intervention: doxorubicin, cyclophosphamide, paclitaxel, trastuzumab; PLD, cyclophosphamide, trastuzumab, paclitaxel
Intervention description: 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); 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)
Intervention MeSH terms: Paclitaxel; Albumin-Bound Paclitaxel; Cyclophosphamide; Doxorubicin; Liposomal doxorubicin; Trastuzumab
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 181.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      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.
    

Eligibility criteria:

        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