| 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 pathological complete response (pCR).
● To compare the rate of pCR by hormone receptor (HR) status and tumor stage.
● To evaluate residual cancer burden (RCB), rate of breast-conserving surgery (BCS), objective response rate and the correlation between final MRI results and BCS, pCR, and RCB at surgery.
● To analyze the rate of RFI at 5 years, event-free survival (EFS), relapse-free survival (RFS), distant relapse-free survival (DRFS), disease-free survival (DFS), invasive disease-free survival (iDFS), breast cancer-specific survival (BCSS), overall survival (OS), all at 3 and 5 years.
● To assess the cardiac toxicity profile after 1 year of adjuvant treatment according to the NCI-CTCAE v.5.0. and the general toxicity profile per 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 and 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 ≥5mm and ≤25mm using ultrasound and mammography (tumor size between ≥5mm and ≤30mm by MRI is also accepted given the precision of the technique). Note: Although tumors between ≥ 5mm and ≤ 10mm are not considered target lesions by RECIST v1.1, we will consider these lesions as targets to follow-up.
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, C3D1 before treatment infusion, pre-surgery and then after surgery: every 6 months for the first 5 years, and every year thereafter until the EoS.
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.
Note: Acceptable forms of effective contraception should include two of the following:
i. Placement of non-hormonal intrauterine device (IUD)
ii. Condom with spermicidal foam/gel/film/cream/suppository
iii. Diaphragm or cervical/vault caps with spermicidal foam/film/cream/suppository
The above contraception is not a requirement in the case the male patient, or male partner of a female patient, is surgically sterilized, the female patient is postmenopausal or the patient remains abstinent and truly abstains from sexual activity (refrains from heterosexual intercourse).
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 before treatment initiation in this study).
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 chest and pelvis computed tomography (CT)/MRI scan before enrolment to prove no evidence of metastatic disease. Bone scan will be performed at screening only if there is suspicion of bone metastases. If a bone scan cannot be performed at screening, an alternative is PET/CT using 18F-labeled sodium fluoride (18F-fluoride PET/CT).
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 highergrade 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 (pCRBREAST+LYMPH NODES -ypT0/Tis ypN0- and pCRBREAST -ypT0/Tis-) in the overall study population.
● pCR rates (pCRBREAST+LYMPH NODES -ypT0/Tis ypN0- and pCRBREAST -ypT0/Tis-) according to HR status (positive, negative), and tumor stage (T1, T2).
● RCB score in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).
● Rate of BCS in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).
● MRI-guided objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version (v.)1.1 in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).
● Correlation of MRI-guided objective response rate by RECIST v.1.1 with BCS, pCR, and RCB in the overall study population and according to HR status (positive, negative), and tumor stage (T1, T2).
● 5-year RFI in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year EFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year RFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year DRFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year DFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year iDFS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year OS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 3-year and 5-year BCSS in the overall study population and according to study arm (A, B, C), HR status (positive, negative), and tumor stage (T1, T2).
● 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 in the overall study population and in each study arm (A, B, C).
● Patient Reported Outcomes (PROs) HRQoL assessment as per EORTC-QLC-C30 and QLQ-BR23 questionnaires in the overall study population and in each study arm (A, B, C).
● 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 in all patients with previously untreated HER2[+] (IHC score 3+) node-negative early-stage breast cancer.
- 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) in all patients with previously untreated HER2[+] (IHC score 3+) node-negative early-stage breast cancer.
●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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