Breast Neoplasm
Conditions
Brief 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.
Interventions
DRUGdoxorubicin, cyclophosphamide, paclitaxel, trastuzumab
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)
DRUGPLD, cyclophosphamide, trastuzumab, paclitaxel
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)
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 | 8 cycles of chemotherapy and subsequently one year of planned trastuzumab treatment | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | During the 8 courses 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. |
| Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | 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. |
| Number of Participants Who Survived Without Relapse | Approximately 2 years | Relapse-free survival would have been determined by Kaplan-Meier method. This was not calculated, since the 2 year follow-up was curtailed. |
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen 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) | 120 |
| Doxorubicin Based Regimen doxorubicin 60 mg/m\^2 intravenous (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) | 59 |
| Total | 179 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 3 |
| Overall Study | Discontinued for study-related reasons | 0 | 1 |
| Overall Study | Physician Decision | 2 | 0 |
| Overall Study | Protocol Violation | 4 | 5 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Doxorubicin Based Regimen | Total |
|---|---|---|---|
| Age, Continuous | 50.2 years STANDARD_DEVIATION 10.97 | 52.5 years STANDARD_DEVIATION 9.32 | 50.9 years STANDARD_DEVIATION 10.49 |
| Sex: Female, Male Female | 120 Participants | 59 Participants | 179 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 115 / 120 | 58 / 59 |
| serious Total, serious adverse events | 20 / 120 | 7 / 59 |
Outcome results
Primary
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.
Time frame: 8 cycles of chemotherapy and subsequently one year of planned trastuzumab treatment
Population: ITT, defined as all participants who were randomized and received at least 1 dose of any study medication.~Each participant could not contribute more than 1 event.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | 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 | 5 Participants |
| Doxorubicin Based Regimen | 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 | 11 Participants |
Secondary
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.
Time frame: During 1 year of trastuzumab therapy
Population: ITT, defined as all participants who were randomized and received at least 1 dose of any study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Level 1 Cardiotoxicity | 1 Participants |
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Level 2 Cardiotoxicity | 4 Participants |
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Inability to Administer Trastuzumab | 4 Participants |
| Doxorubicin Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Inability to Administer Trastuzumab | 8 Participants |
| Doxorubicin Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Level 1 Cardiotoxicity | 0 Participants |
| Doxorubicin Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During 1 Year of Trastuzumab Therapy | Level 2 Cardiotoxicity | 10 Participants |
Secondary
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.
Time frame: During the 8 courses of chemotherapy
Population: ITT, defined as all participants who were randomized and received at least 1 dose of any study medication.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Level 1 Cardiotoxicity | 1 Participants |
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Level 2 Cardiotoxicity | 1 Participants |
| Pegylated Liposomal Doxorubicin (PLD) Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Inability to Administer Trastuzumab | 0 Participants |
| Doxorubicin Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Level 1 Cardiotoxicity | 0 Participants |
| Doxorubicin Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Level 2 Cardiotoxicity | 3 Participants |
| Doxorubicin Based Regimen | Number of Participants Who Experienced Cardiac Events (Level 1 or 2) or Inability to Administer Trastuzumab During the 8 Cycles of Chemotherapy | Inability to Administer Trastuzumab | 0 Participants |
Secondary
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.
Time frame: Approximately 2 years