| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 assess the early metabolic effects of neoadjuvant treatment with trastuzumab and pertuzumab (± endocrine therapy) on the primary tumor and axillary lymph nodes and their predictive value for pathologic complete response (pCR) in the breast and axilla.
• To assess 3-year invasive disease-free survival (iDFS) in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab (± endocrine therapy) using a FDG-PET response-adapted strategy. |
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| E.2.2 | Secondary objectives of the trial |
• To assess efficacy by other pCR definitions
• To compare the rate of pCR between the treatment groups by hormone receptor (HR) status and tumor stage.
• To compare the rate of conversion to breast conserving surgery between the treatment groups.
• To compare the overall response rate (ORR) by 18F-FDG PET/CT between the treatment groups.
• To analyze optimal 18F-FDG PET/CT cut-off for pCR.
• To analyze other 18F-FDG PET quantification parameters beside SUVmax for pCR.
• To compare the ORR by MRI between the treatment groups.
• To evaluate changes in health-related quality of life assessments from baseline using the EORTC QLQ-C30 and QLQ-BR23 questionnaires
• To assess 3-year iDFS
• To assess 3-year distant disease-free survival (DDFS)
• To assess 3-year disease-free survival (DFS)
• To assess overall survival (OS)
• To assess progression-free survival (PFS) in patients with subclinic M1 at baseline 18F-FDG PET/CT |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Written informed consent prior to beginning specific protocol procedures.
2) Female or male patients ≥ 18 years of age.
3) Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
4) Histologically proven invasive breast cancer.
5) Operable breast cancer (cT1-3 and/or cN0-2 tumors).
6) Tumor size larger than or equal to 1.5 centimeter (cm) in diameter by magnetic resonance imaging (MRI) or ultrasound with a significant 18F-FDG uptake defined as maximum standardized uptake value (SUVmax) ≥1.5 x SUVmean liver + 2 SD.
Multicentric/multifocal tumors will be allowed only if:
1. Histological confirmation of at least two lesions.
2. All tumors must be HER2-positive.
3. Largest lesion must be larger than or equal to 1.5 cm in diameter by MRI or ultrasound.
7) Centrally confirmed HER2-positive disease according to the 2013 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) criteria.
8) Patient must have known estrogen receptor (ER) and progesterone receptor (PR) status locally determined prior to study entry.
Patient has adequate bone marrow, liver, and renal function:
9) Hematological: White blood cell (WBC) count > 3.0 x 109/L, absolute neutrophil count (ANC) ≥ 1.5 x 109/L, platelet count ≥ 100.0 x109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
10) Hepatic: total bilirubin ≤ institutional upper limit of normal (ULN) (except for Gilbert’s syndrome); alkaline phosphatase (ALP) ≤ 2.5 times ULN; aspartate transaminase (AST) and alanine transaminase (ALT) ≤ 1.5 times ULN.
11) Renal: serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
12) Patient must be accessible for treatment and follow-up. |
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| E.4 | Principal exclusion criteria |
1) Previous treatment with chemotherapy, anti-HER2 therapy, radiation therapy, or endocrine therapy for invasive breast cancer.
2) cT4 and/or cN3 tumors.
3) Bilateral breast cancer.
4) Evidence of metastatic disease by routine clinical assessment chest x-ray, liver ultrasound, and bone scan; or computed tomography (CT) scan of thorax and abdomen and bone scan, except patients with subclinic M1 at baseline only according to 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) that will be allowed to be included into Cohort C.
5) Known hypersensitivity reaction to any investigational or therapeutic compound or their incorporated substances.
6) History of other malignancy within the last five years prior to first dose of study drug administration, except for curatively treated basal and squamous cell carcinoma of the skin and/or in situ cervical carcinoma.
7) Left ventricular ejection fraction (LVEF) below 55% as determined by multiple-gated acquisition (MUGA) scan or echocardiography (ECHO).
8) Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.
9) Clinically significant cardiovascular disease [stroke, unstable angina pectoris, or documented myocardial infarction within six months prior to study entry; history of documented congestive heart failure (CHF) (New York Heart Association II-III-IV); symptomatic pericarditis; documented cardiomyopathy; ventricular arrytmhias with the exception of benign premature ventricular contractions; conduction abnormality requiring a pacemaker; other arrhythmias not controlled with medication].
10) Active uncontrolled infection at the time of enrollment.
11) Current known infection with HIV, hepatitis B virus, or hepatitis C virus.
12) Patients with pulmonary disease requiring continuous oxygen therapy.
13) Previous history of bleeding diathesis.
14) Patient is currently receiving anti-coagulant therapy, chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
15) Major surgical procedure or significant traumatic injury within 14 days prior to randomization or anticipation of need for major surgery within the course of the study treatment.
16) Patient has other concurrent severe and/or uncontrolled medical condition that would, in the investigator´s judgment, contraindicate her participation in the clinical study.
17) Concurrent participation in other clinical trial, except other translational studies.
18) History of receiving any investigational treatment within 28 days prior to randomization.
19) Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• The first co-primary endpoint is to evaluate the rate of pCR as defined by the absence of invasive disease in the breast and axilla (ypT0/isN0) at the time of surgery achieved with the combination of trastuzumab and pertuzumab (± endocrine therapy) as exclusive neoadjuvant treatment in PET responders patients (cohort B/PET responders) [PET/CT positive predictive value (PPV) for a pCR among patients who are PET responders].
• The second co-primary endpoint is to evaluate 3-year iDFS rate defined as time from the first date of no disease (i.e., date of surgery) to invasive recurrence, new invasive disease, or death by any cause. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria. The primary analysis will be to estimate 3-year iDFS rate in cohort B. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
-pCR at the time of surgery
-iDFS rate: 3 years from surgery |
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| E.5.2 | Secondary end point(s) |
• pCR rates in the breast and axilla (ypT0/isN0) (cohort A; cohort B; cohort B/PET non-responders).
• pCR rates in the breast (ypT0/is) (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
• RCB score (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
• pCR rates in the breast and axilla (ypT0/isN0) according to HR status and tumor stage (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
• Rate of breast conserving surgery (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
• 18F-FDG PET/CT response rate (according to the adapted EORTC criteria) (cohort A; cohort B).
• Optimal 18F-FDG PET/CT cut-off for pCR (cohort A; cohort B).
• Other 18F-FDG PET quantification parameters beside SUVmax for pCR (cohort A; cohort B).
• MRI response rate (according to the RECIST criteria version 1.1) (cohort A; cohort B; cohort B/PET responders; cohort B/PET non-responders).
• Health-related quality of life (EORTC QLQ-C30 and QLQ-BR23 questionnaires) (cohort A; cohort B; cohort C).
• 3-year iDFS (cohort A).
• 3-year DDFS (cohort A; cohort B).
• 3-year DFS (cohort A; cohort B).
• OS (cohort A; cohort B; cohort C).
• PFS (cohort C). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| 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 | No |
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
| Disease-free survival (iDFS) |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| The three arms A, B and C are compared in parallel |
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| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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
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| The end of study will be three years from surgery (for cohorts A and B and for cohort C only if surgery is performed), up to three years from randomization of the last patient (for cohort C if surgery is not performed), or the trial is terminated by the sponsor, whichever occurs first. This data point will be considered LPLV (Last Patient Last Visit). |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 2 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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