| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-Positive Early Breast Cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| HER2-Positive Early Breast Cancer |
|
| 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 | 23.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER2 positive breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 |
Primary efficacy objective
●To assess 3-year recurrence-free interval (3y-RFI) in patients with previously untreated HER2[+] (IHC3+) node-negative early stage breast cancer.
Primary safety objective
●To assess global health status decline rate at 1 year from start of neoadjuvant treatment. |
|
| E.2.2 | Secondary objectives of the trial |
● To assess overall efficacy by pathological complete response (pCR).
● To compare the rate of pCR by hormone receptor (HR) status.
● To evaluate residual cancer burden (RCB) and rate of breast-conserving surgery (BCS).
● To evaluate the correlation between final MRI results and BCS, pCR, and RCB at surgery.
● To analyze the rate of event-free survival, relapse-free survival, invasive disease-free survival, distant relapse-free survival, disease-free survival, overall survival, and breast cancer-specific survival (BCSS) at 3 years and 5 years.
● To assess the cardiac toxicity profile after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0.
● To assess the general toxicity profile according to CTCAE v.5.0.
● To evaluate health-related quality of life (HRQoL) as assessed by the European Organisation for Research and Treatment of Cancer (EORTC)-QLC-C30 and QLQ-BR23 questionnaires.
● To evaluate the ratio of patients who have needed chemotherapy |
|
| 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 or 1.
4. Histologically proven invasive carcinoma of the breast.
5. Tumor size must be between >5mm and <25mm in greatest dimension using breast MRI.
6. Patients must have node-negative breast cancer by clinical exam, MRI and ultrasound according to the American Joint Committee on Cancer (AJCC) 8th edition.
7. Centrally confirmed HER2[+] status with IHC score 3+.
8. Known estrogen receptor (ER) and progesterone receptor (PgR) status prior to study entry that should be performed by immunohistochemical methods according to the local institution standard protocol.
9. Patients with multifocal or multicentric breast cancer are eligible; patients with 2 lesions or less are eligible only if both lesions are sampled and meet the inclusion criteria #5, #6, and #7.
10. Normal left ventricular function and diastolic function (left ventricular ejection fraction [LVEF] ≥55%) as assessed by echocardiogram or multiple-gated acquisition scan (MUGA) documented within ≤28 days prior to first dose of study treatment.
11. Adequate bone marrow, liver, and renal function:
a. Hematological: White blood cell (WBC) count > 3.0 × 109/L, absolute neutrophil count (ANC) ≥ 1.5 × 109/L, platelet count ≥ 100.0 × 109/L, and hemoglobin ≥ 10.0 g/dL (≥ 6.2 mmol/L).
b. 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.
c. Renal: serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 50 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
d. International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
12. Patient must be accessible for treatment and follow-up.
13. Willingness and ability to provide blood samples at baseline, after two cycles of neoadjuvant therapy, before surgery and at surgery, and at each follow up visit during adjuvant treatment.
14. Willingness and ability to provide tumor tissue samples at baseline and at surgery.
15. Women of childbearing potential and men with partners of childbearing potential must be willing to use one highly effective form of nonhormonal contraception or two effective forms of nonhormonal contraception by the patient and/or partner and to continue its use for the duration of study treatment and for seven months after the last dose of study treatment.
16. Negative serum pregnancy test for premenopausal women including women who have had a tubal ligation and for women less than 12 months after the onset of menopause. |
|
| E.4 | Principal exclusion criteria |
1. Any previous treatment, including chemotherapy, anti-HER2 therapy, radiation therapy, or ET for invasive breast cancer, except for breast carcinoma in situ of the contralateral breast cancer, in the last five years.
2. HER2 disease with IHC score 0, 1+ or 2+ and in situ hybridization (ISH) positive result.
3. Evidence of metastatic disease.
Note: All patients must be willing to undergo a thorax, abdomen, and pelvis computed tomography (CT) or MRI scan assessment before enrolment to prove no evidence of metastatic disease. 4. Patients with bilateral breast cancer.
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. Uncontrolled hypertension (systolic > 150 mm Hg and/or diastolic > 100 mm Hg) despite adequate antihypertensive treatment.
8. Serious cardiac illness or medical conditions including, but not confined to, the following:
− History of NCI CTCAE v5.0 Grade ≥ 3 symptomatic congestive heart failure (CHF) or New York Heart Association (NYHA) Class ≥ II.
− High-risk uncontrolled arrhythmias (i.e., atrial tachycardia with a heart rate ≥ 100/min at rest, significant ventricular arrhythmia [ventricular tachycardia], or higher-grade atrioventricular [AV]-block, such as second-degree AV-block Type 2 [Mobitz II] or third-degree AV-block).
− Serious cardiac arrhythmia or severe conduction abnormality not controlled by adequate medication.
− Angina pectoris requiring anti-angina medication.
− Clinically significant valvular heart disease.
− Evidence of transmural infarction on electrocardiogram (ECG).
− Evidence of myocardial infarction within the last 12 months prior to study entry.
9. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe left ventricular systolic dysfunction [LVSD], left ventricular hypertrophy), coronary heart disease (symptomatic or with ischemia demonstrated by diagnostic testing), clinically significant electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia, hypocalcemia), or family history of sudden unexplained death or long QT syndrome.
10. Active uncontrolled infection at the time of enrollment.
11. Current known infection with human immunodeficiency virus (HIV), hepatitis B virus, or hepatitis C virus.
12. Patients with pulmonary disease requiring continuous oxygen therapy.
13. Grade ≥2 neuropathy as per National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI–CTCAE) version (v)5.0.
14. Previous history of bleeding diathesis.
15. Patient is currently receiving chronic treatment with corticosteroids, or another immunosuppressive agent (standard premedication for chemotherapy and local applications are allowed).
16. Major surgical procedure or significant traumatic injury within 14 days prior to study entry or anticipation of need for major surgery within the course of the study treatment.
17. Any other concurrent severe and/or uncontrolled medical condition that would contraindicate patient participation in the clinical study.
18. History of having received any investigational treatment within 28 days prior to study entry.
19. Pregnant or breast-feeding women or patients not willing to apply highly effective contraception as defined in the protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint
● 3y-RFI defined as time from start of treatment in adjuvant setting until recurrence, new invasive disease, or death from breast cancer. Recurrence will be defined in accordance with the standardized efficacy endpoints (STEEP) criteria.
Primary safety endpoint
● Global health status decline rate at 1 year from start of neoadjuvant treatment, defined as the rate of patients with a ≥10% global health status decline at 1 year from start of neoadjuvant treatment as assessed by the Global Health Status/QoL EORTC-QLC-C30 scale and its breast cancer module QLQ-BR23. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
- 3 years recurrence-free Interval .
- Global health status decline rate at 1 year from start of neoadjuvant treatment. |
|
| E.5.2 | Secondary end point(s) |
● pCR rates in the overall population.
● pCR rates according to HR-positive or HR-negative status.
● RCB score and rate of BCS.
● MRI-guided response rate by BCS, pCR, and RCB as per Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1.
● 3-year and 5-year EFS, RFI, RFS, iDFS, DRFS, DFS, OS and BCSS.
● Adverse events of cardiotoxicity after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0.
● Toxicity and safety profile at 3 and 5 years as per NCI-CTCAE v.5.0.
● Patient Reported Outcomes (PROs) HRQoL assessment as per EORTC-QLC-C30 and QLQ-BR23 questionnaires.
● Ratio of patients of cohort C who will receive adjuvant chemotherapy before T-DM1 |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- 3 years recurrence-free Interval .
- Global health status decline rate at 1 year from start of neoadjuvant treatment. |
|
| 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 |
●To assess 3-year recurrence-free interval (3y-RFI).
●To assess global health status decline rate at 1 year from start of neoadjuvant treatment.
|
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| 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 | 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 63 |
| 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 | No |
| 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
|
| The last patient last visit (LPLV) at the end of the follow-up period. |
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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 | |
| E.8.9.1 | In the Member State concerned months | 98 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial months | 98 |
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