| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Node positive, or high risk node negative invasive breast cancer in patients that are HER 2 low |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10006190 |
| E.1.2 | Term | Breast cancer invasive NOS |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine whether the addition of trastuzumab to chemotherapy (TC or AC-WP) improves invasive disease-free survival (IDFS) in women with resected node-positive or high-risk node-negative breast cancer which is reported as HER2-low by all HER2 testing performed. |
|
| E.2.2 | Secondary objectives of the trial |
Disease-free survival (DFS-DCIS)
Breast cancer-free survival (BCFS)
Recurrence-free interval (RFI
Distant recurrence-free interval (DRFI)
Overall survival (OS)
Menstrual history
Toxicity
Molecular predictors of efficacy
Inflammatory correlates of outcome
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
The patient must be female.
The patient must be 18 years old
The patient must have an ECOG performance status of 0 or 1
The tumor must be unilateral invasive adenocarcinoma of the breast on histologic examination.
All of the following staging criteria (according to the 7th edition of the AJCC Cancer Staging Manual) must be met:
• By pathologic evaluation, primary tumor must be pT1-3;
• By pathologic evaluation, ipsilateral nodes must be pN0, pN1 (pN1mi, pN1a, pN1b, pN1c), pN2a, pN2b, pN3a, or pN3b If pN0, one of the following criteria must be met:
pT2 and ER negative and PgR negative; or
pT2 and ER positive (PgR status may be positive or negative) and either grade 3 histology or Oncotype DX® Recurrence Score of 25; or
pT3 regardless of hormone receptor status, histologic grade, and Oncotype DX®Recurrence Score.
HER2 status of the primary tumor must be evaluated prior to randomization; all testing performed must indicate that the tumor is HER2-low .
The patient must have undergone either a total mastectomy or breast-conserving surgery(lumpectomy)
For patients who undergo lumpectomy, the margins of the resected specimen must be histologically free of invasive tumor and DCIS as determined by the local pathologist.
For patients who undergo mastectomy, margins must be free of gross residual tumor.
The patient must have completed one of the procedures for evaluation of pathologicnodal status listed below.
• Sentinel lymphadenectomy alone:
If pathologic nodal staging based on sentinel lymphadenectomy is pN0 or pN1b;
If pathologic nodal staging based on sentinel lymphadenectomy is p1mi or
pN1a, the primary tumor must be T1 or T2 by pathologic evaluation and the nodal
involvement must be limited to 1 or 2 positive nodes.
• Sentinel lymphadenectomy followed by removal of additional non-sentinel lymph nodes if the sentinel node (SN) is positive; or
• Axillary lymphadenectomy with or without SN isolation procedure.
The interval between the last surgery for breast cancer (treatment or staging) and randomization must be no more than 84 days.
The patient must have ER analysis performed on the primary tumor prior to randomization. If ER analysis is negative, then PgR analysis must also be performed.Either the core biopsy or surgical resection specimen can be used for ER/PgR testing.)
Patients with a primary tumor that is hormone receptor-positive or receptor-negative are
eligible.
The most recent postoperative blood counts, performed within 6 weeks prior to randomization, must meet the following criteria:
• ANC must be ≥ 1200/mm3;
• Platelet count must be ≥ 100,000/mm3; and
• Hemoglobin must be ≥ 10 g/dL.
The following criteria for evidence of adequate hepatic function must be met based on the results of the most recent postoperative tests performed within 6 weeks prior to randomization:
• total bilirubin must be ≤ ULN for the lab unless the patient has a bilirubin elevation
>ULN to 1.5 x ULN due to Gilbert’s disease or similar syndrome involving slow conjugation of bilirubin; and
• alkaline phosphatase must be ≤ 2.5 x ULN for the lab; and
• AST must be ≤ 1.5 x ULN for the lab.
• Alkaline phosphatase and AST may not both be > the ULN. For example, if the alkaline phosphatase is > the ULN but ≤ 2.5 x ULN, the AST must be ≤ the ULN. If
the AST is > the ULN but ≤ 1.5 x ULN, the alkaline phosphatase must be ULN.
Note: If ALT is performed instead of AST (per institution's standard practice), the ALT
value must be ≤ 1.5 x ULN; if both were performed, the AST must be ≤ 1.5 x ULN.
Patients with alkaline phosphatase that is> ULN but ≤ 2.5 x ULN or unexplained bone
pain are eligible for inclusion in the study if a bone scan, PET-CT scan, or PET scan
performed within 90 days prior to randomization does not demonstrate metastatic disease.
The most recent postoperative serum creatinine performed within 6 weeks prior to randomization must be ≤ ULN for the lab.
LVEF assessment must be performed within 90 days prior to randomization. LVEF assessment performed by 2-D echocardiogram is preferred; however, MUGA scan may
be substituted based on institutional preferences.
• For patients who will receive the TC chemotherapy regimen, the LVEF must be
>_ 50% regardless of the cardiac imaging facility's lower limit of normal.
• For patients who will receive the AC->WP chemotherapy regimen, the LVEF
must be >_ 55% regardless of the cardiac imaging facility's lower limit of normal.
Note: Since the pre-entry LVEF serves as the baseline for comparing subsequent LVEF assessments, it is critical that this baseline study be an accurate assessment. If the
baseline LVEF is > 70%, the investigator is encouraged to have the accuracy of the initial LVEF result confirmed and repeat the test if the accuracy is uncertain
. |
|
| E.4 | Principal exclusion criteria |
Primary tumor with any of the following HER2 testing results:
• IHC staining intensity:
0 on all evaluations of specimens
3+ on evaluation of any specimen
ISH with a ratio of HER2 to CEP17 >_ 2.0 on evaluation of any specimen
ISH result indicating HER2 gene copy number>_ 4 per nucleus on evaluation of an specimen
T4 tumors including inflammatory breast cancer.
Definitive clinical or radiologic evidence of metastatic disease. (Note: Chest imaging[mandatory for all patients] and other imaging [if required] must have been performed within 90 days prior to randomization.)
Synchronous or previous contralateral invasive breast cancer.
Any previous history of ipsilateral invasive breast cancer or ipsilateral DCIS.
History of non-breast malignancies (except for in situ cancers treated only by local excision and basal cell and squamous cell carcinomas of the skin) within 5 years prior to randomization.
Previous therapy with anthracyclines, taxanes, or trastuzumab for any malignancy.
Chemotherapy or HER2-targeted therapy administered for the currently diagnosed breast cancer prior to randomization.
Whole breast RT prior to randomization or partial breast RT that cannot be completed on or before the date of randomization
(Continued endocrine therapy such as raloxifene or tamoxifen (or other SERM) or an aromatase inhibitor.
Patients are eligible if these medications are discontinued prior to randomization
Any continued use of sex hormonal therapy, e.g., birth control pills, ovarian hormone replacement therapy. Patients are eligible if these medications are discontinued prior to randomization
Cardiac disease (history of and/or active disease) that would preclude the use of the drugs included in the treatment regimens. This includes but is not confined to:
Active cardiac disease
• angina pectoris that requires the current use of anti-anginal medication;
• ventricular arrhythmias except for benign premature ventricular contractions;
• supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication;
• conduction abnormality requiring a pacemaker;
• valvular disease with documented compromise in cardiac function; and
• symptomatic pericarditis.
History of cardiac disease
• myocardial infarction documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of LV function;
• history of documented CHF; and
• documented cardiomyopathy.
Hypertension defined according to the following ineligibility criteria:
• For patients who will receive TC (regardless of the patient's age): Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP> 90 mmHg. (Patients with initial BP elevations are eligible if initiation oradjustment of BP medication lowers pressure to meet entry criteria.)
• For patients < 50 years old who will receive AC->WP: Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or diastolic BP >90 mmHg. Patients with initial BP elevations are eligible if initiation or adjustment of BP medication lowers pressure to meet entry criteria.
• For patients >_50 years old who will receive AC->WP: Uncontrolled hypertension defined as sustained systolic BP > 150 mmHg or
diastolic BP > 90 mmHg.
Controlled hypertension (systolic BP <_150 mmHg and diastolic BP
<_90 mmHg), if anti-hypertensive medication(s) are needed.
Active hepatitis B or hepatitis C with abnormal liver function tests.
Intrinsic lung disease resulting in dyspnea.
Poorly controlled diabetes mellitus.
Active infection or chronic infection requiring chronic suppressive antibiotics.
Nervous system disorder (paresthesia, peripheral motor neuropathy, or peripheral sensory
neuropathy) >_ grade 2, per the CTCAE v4.0.
Conditions that would prohibit administration of corticosteroids.
Chronic daily treatment with corticosteroids with a dose of >_ 10 mg/day
methylprednisolone equivalent (excluding inhaled steroids).
Known hypersensitivity to any of the study drugs or excipients, e.g., polysorbate 80 and Cremophor® EL.
Pregnancy or lactation at the time of study entry. (Note: Pregnancy testing must be performed within 2 weeks prior to randomization according to institutional standards
for women of childbearing potential.)
Other non-malignant systemic disease that would preclude the patient from receiving study treatment or would prevent required follow-up.
Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements.
Use of any investigational product within 30 days prior to randomization.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
IDFS: defined as time to local invasive recurrence following mastectomy, local invasive recurrence in the ipsilateral breast following lumpectomy, regional recurrence, distantrecurrence, contralateral invasive breast cancer, second non-breast primary cancer (excluding squamous or basal cell carcinoma of the skin), or death from any cause prior to recurrence or
second primary cancer. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The definitive analysis comparing chemotherapy plus
trastuzumab to Control (chemotherapy alone), using IDFS as the primary endpoint will occur when 262 events have occurred in total on the Control + chemotherapy/trastuzumab arms.
The estimated time to reach the required number of events is 5 years and 6 months from the start of accrual. |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints include disease-free survival (DFS-DCIS), breast cancer-free survival (BCFS), recurrence-free interval (RFI), distant recurrence-free interval (DRFI), and overall survival (OS). Secondary safety endpoints include the frequency and severity of adverse
events graded according to the CTCAE v4.0. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| No time points specified for Secondary enddpoints |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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