| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative, node-negative early 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 | 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) |
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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 evaluate 3-year RFS in subjects with HER2-enriched, ER-negative/PR-negative, clinically node-negative breast cancers who achieve a pCR after neoadjuvant treatment with weekly paclitaxel (or docetaxel every 3 weeks) and dual HER2 blockade with pertuzumab and trastuzumab FDC SC |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate 3-year RFS in all subjects with ER-negative/PR-negative, clinically node-negative breast cancers who achieve a pCR after neoadjuvant treatment with weekly paclitaxel (or docetaxel every 3 weeks) and dual HER2 blockade with pertuzumab and trastuzumab FDC SC. |
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| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
FLEXIBLE CARE SUB-STUDY (version 1.0)
• To compare subjects’ preference for administration of pertuzumab and trastuzumab FDC SC outside the hospital versus in the hospital.
• To assess and compare the proportion of subjects deciding to receive treatment outside the hospital setting versus in the hospital after the treatment cross-over period.
• To compare QoL between subjects who choose administration in the hospital versus those who choose administration outside the hospital of pertuzumab and trastuzumab FDC SC.
• To evaluate QoL at different time points in subjects who choose administration in the hospital versus those who choose administration outside the hospital.
• To evaluate the safety and feasibility of the administration of pertuzumab and trastuzumab FDC SC outside the hospital, and to compare it with the administration of pertuzumab and trastuzumab FDC SC in the hospital.
• To evaluate subject assessed satisfaction with in the hospital versus outside the hospital administration of pertuzumab and trastuzumab FDC SC.
• To evaluate HCP’s satisfaction with SC administration of pertuzumab and trastuzumab FDC in the hospital versus outside the hospital.
• To assess cross-over rate of subjects that chose administration in the hospital versus those who chose outside the hospital during the treatment continuation period.
• To evaluate the productivity and economic impact of the administration in the hospital versus outside the hospital from the subject’s perspective
• To evaluate the productivity and economic impact of the administration in the hospital versus outside the hospital from the HCP’s perspective.
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| E.3 | Principal inclusion criteria |
1. Male or female.
2. Age ≥18 years old.
3. Eastern Cooperative Oncology Group (ECOG) performance status ≤1. (Appendix 1).
4. Subjects whose tumour measures ≥15 mm and ≤50 mm, according to clinical staging performed with imaging exams (either mammography, ultrasound or breast magnetic resonance imaging [MRI]).
5. Must have histologically confirmed diagnosis of HER2-positive and ER-negative/PR-negative breast cancer (analysis performed by the local laboratory).
a. HER2-positive defined as a score of 3+ in IHC or a positive ISH (ratio of HER2 copy number/chromosome 17 ≥2 or average HER2 copy number ≥6 signals per cell).
b. ER-negative/PR-negative defined as estrogen receptor and progesterone receptor nuclear staining <1% by IHC.
6. Subjects with multifocal or multicentric invasive disease are eligible as long as all the lesions can be characterised and are confirmed to be HER2-positive and ER and PR negative.
7. Node-negative disease (N0): no axillary lymph nodes identifiable at ultrasound, or in case of suspect axillary lymph nodes are identified, fine-needle aspiration or core biopsy must be carried out to confirm that axillary status is negative. Axillary micrometastases (i.e., if the greatest diameter of the nodal metastasis in a sentinel node is 0.2 mm or less) are not allowed.
8. Serum pregnancy test (for women of childbearing potential) negative within 7 days prior to treatment start.
9. Women of childbearing potential must agree to use 1 highly effective non-hormonal contraceptive method with a failure rate of less than 1% per year (see protocol section 5.14.1) from the signing of the ICF until at least 7 months after last dose of study drugs; or they must totally abstain from any form of sexual intercourse. Men with a partner of childbearing potential must agree to use condom in combination with a spermicidal foam, gel, film, cream, or suppository, and agreement to refrain from donating sperm, during the course of this study and for at least 7 months after the last administration of study treatment.
10. Adequate bone marrow and coagulation functions as defined below:
• Absolute neutrophil count ≥1500 /µL or 1.5x109/L
• Haemoglobin ≥9 g/dL (blood transfusions to reach these levels of haemoglobin are allowed)
• Platelets ≥100,000/µL or 100x109/L
• International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤ 1.5 ×ULN
11. Adequate liver function as defined below:
• Serum total bilirubin ≤1.5 x ULN. In case of known Gilbert’s syndrome ≤3xUNL is allowed
• AST (SGOT) and ALT (SGPT) ≤2.5 x ULN
• Alkaline phosphatase ≤2.5 x ULN
12. Adequate renal function as defined below:
• Creatinine ≤1.5 x UNL or creatinine clearance >60 mL/min/1.73 m2
13. Completion of all necessary screening procedures within 28 days prior to enrolment.
14. Adequate cardiac function, defined as a left ventricular ejection fraction ≥55% estimated by echocardiogram (ECHO) or multiple-gated acquisition scintigraphy (MUGA).
15. Availability of a pre-treatment tumour biopsy sample as specified below:
• At least one FFPE tumour block must be available for central evaluation. Whenever possible, two FFPE tumour blocks should be available (preferred).
• If a block cannot be provided, 25 unstained FFPE slides of 4 µm thickness from the pre-treatment tumour biopsy must be provided as an alternative. These slides must be freshly cut prior the shipment to the sponsor.
• In either case, the local pathologist must evaluate an H&E stained slide to ensure that the tumour surface is at least 4 mm² and that tumour cellularity is ≥10%.
Note: Tumour biopsy should be sent the central research laboratory when the patient is confirmed to be eligible for the study.
16. Signed Informed Consent form (ICF) obtained prior to any study related procedure.
17. Subject is willing and able to comply with the protocol for the duration of the study including treatment and scheduled visits and examinations.
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| E.4 | Principal exclusion criteria |
1. Pregnant and/or lactating women.
2. Bilateral invasive breast cancer.
3. Evidence of metastatic breast cancer: all subjects must have had a CT/MRI scan of the thorax/abdomen/pelvis to rule out metastatic breast cancer prior to enrolment. FDG/PET-CT can be used as an alternative to replace all the exams above. A screening bone scan must have been done if ALP and/or corrected calcium levels were above the institutional upper limits at screening (if PET/CT was used as an alternative imaging exam, a bone scan and/or CT/MRI is not required).
4. Subject with a significant medical, neuro-psychiatric, or surgical condition, currently uncontrolled by treatment, which, in the investigator’s opinion, may interfere with completion of the study.
5. Previous exposure to any anti-HER2 treatment.
6. Concomitant exposure to any investigational products as part of a clinical trial within 30 days prior to enrolment.
7. Subject with second primary malignancies diagnosed ≤ 5 years before enrolment in the study. Exceptions are: adequately treated non-melanoma skin cancer, in situ cancer of the cervix, ductal carcinoma in situ of the breast, and any other solid or haematological tumour diagnosed > 5 years before enrolment and for which no chemotherapy and no systemic treatment were necessary, with no evidence of disease recurrence.
8. Resting electrocardiogram (ECG) with QTc >470 msec detected on at 2 or more time points within a 24-hour period, or family history of long QT syndrome.
9. Serious cardiac illness or medical conditions including, but not confined to, the following:
• History of NCI CTCAE (v4) 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 2] or third-degree AV-block) – Serious cardiac arrhythmia not controlled by adequate medication, severe conduction abnormality
• Angina pectoris requiring anti-anginal medication
• Clinically significant valvular heart disease
• Evidence of transmural infarction on ECG
• Evidence of myocardial infarction within 12 months prior to randomization
• Poorly controlled hypertension (i.e., systolic 180 mm Hg or diastolic 100 mmHg)
10. History of ventricular dysrhythmias or risk factors for ventricular dysrhythmias, such as structural heart disease (e.g., severe 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.
11. Peripheral neuropathy (CTCAE version 5) grade ≥2.
12. Major surgery within 14 days prior to enrolment.
13. Subject with HIV, Hepatitis B or Hepatitis C infection documented by serology, except for those subjects with a previous exposure to Hepatitis B who developed an effective immune response (HBSAg-negative and anti-HBS-positive).
14. Previous allogeneic bone marrow transplant.
15. Known prior severe hypersensitivity to investigational product or any component in its formulations, including known severe hypersensitivity reactions to monoclonal antibodies (CTCAE grade ≥3).
16. Subjects who received live attenuated vaccines within 14 days before enrolment.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| 3-year RFS, defined as the time from enrolment until the first occurrence of one of the following events: Invasive ipsilateral breast tumour recurrence, local/regional invasive recurrence, distant recurrence, death from breast cancer, death attributable to any cause other than breast cancer, death from unknown cause; in subjects with HER2-enriched, ER-negative/PR-negative, clinically node-negative breast cancers who achieve a pCR after neoadjuvant treatment. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
| 3-year RFS in all subjects who achieve a pCR. |
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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 | Yes |
| E.6.5 | Efficacy | Yes |
| 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| dual-phase single-arm phase II |
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| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 27 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| Korea, Republic of |
| New Zealand |
| Switzerland |
| Argentina |
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| 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 is declared when all the following criteria have been met:
• The last visit of the last subject.
• 5 years after the enrolment of the last subject
• The database has been fully cleaned and locked for all analyses. |
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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 | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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