E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
newly diagnosed primary HER2 positive early or locally advanced 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 | 17.1 |
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.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 17.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10072740 |
E.1.2 | Term | Locally advanced 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 |
The primary objective of this study is to demonstrate comparable clinical efficacy of SB3 to Herceptin®, in terms of Pathologic complete response rate of the primary breast tumour in women with HER2 positive Early breast cancer or Locally advanced breast cancer in neoadjuvant setting. |
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E.2.2 | Secondary objectives of the trial |
* To evaluate the efficacy of SB3 compared to Herceptin® by
- total pathological complete response (tpCR) rate
- overall clinical response rate
- event-free survival
- overall survival
* To evaluate the safety and tolerability of SB3 compared to Herceptin®
*To evaluate the pharmacokinetics of SB3 compared to Herceptin®
* To evaluate the immunogenicity of SB3 compared to Herceptin® |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Female aged 18-65 years
2. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
3. Non-metastatic, unilateral newly diagnosed primary breast cancer of clinical stage II to III including inflammatory breast cancer with:
a. tumour size ≥ 2 cm
b. histologically confirmed primary invasive adenocarcinoma of the
breast
c. HER2-positivity confirmed by a central laboratory or an accredited local laboratory and defined as immunohistochemistry (IHC) 3+ or fluorescence in situ hybridisation (FISH) +:
4. Known hormone receptor (oestrogen receptor and progesterone receptor) status
5. Baseline LVEF ≥ 55% measured by echocardiography or mmultiple gated acquisition (MUGA) scan
6. Subjects must be able to provide informed consent, which must be obtained prior to any study related procedures |
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E.4 | Principal exclusion criteria |
1. Metastatic (stage IV) or bilateral or multifocal/multicentric breast cancer
2. History of any prior invasive breast carcinoma, except for subjects with a past history of ductal carcinoma in situ (DCIS) and/or lobular carcinoma in situ (LCIS) treated with surgery only.
3. Past or current history of malignant neoplasms within 5 years prior to Randomisation, except for curatively treated carcinoma in situ of uterine cervix, basal cell carcinoma of the skin or squamous cell carcinoma of the skin (malignant neoplasm occurring more than 5 years prior to Randomisation are permitted if curatively treated with surgery only)
4. Previous history of radiation therapy (RT), immunotherapy, chemotherapy or biotherapy (including prior HER2 directed therapy)
5. Major surgery within 4 weeks prior to Randomisation and minor surgery within 2 weeks prior to Randomisation (major surgery is defined as surgery which requires general anaesthesia)
6. Serious cardiac illness that would preclude the use of trastuzumab such as:
a. history of documented CHF (NYHA class II or greater heart disease)
b. LVEF < 55% by echocardiography or MUGA scan
c. angina pectoris requiring anti-anginal medication
d. evidence of transmural infarction on Electrocardiogram (ECG)
e. uncontrolled hypertension (systolic > 180 mmHg and/or diastolic > 100 mmHg)
f. clinically significant valvular heart disease
g. high risk uncontrolled arrhythmias
7. Serious pulmonary illness enough to cause dyspnoea at rest or requiring supplementary oxygen therapy
8. Known history of HBV, HCV or HIV infection
9. Other concurrent serious illnesses that may interfere with planned treatment including severe cardiovascular, pulmonary, metabolic or infectious conditions
10. Known hypersensitivity to the IPs, non-IPs or any ingredients or excipients of the IPs or non-IPs
11. Known hypersensitivity to murine proteins
12. Known history of dihydropyrimidine dehydrogenase (DPD) deficiency
13. Pre-existing peripheral sensory or motor neuropathy ≥ grade 2, defined by NCI-CTCAE v4.0
14. Any of the following abnormal laboratory tests
a. serum total bilirubin > 1.5 × upper limit of normal (ULN); in cases of known Gilberts syndrome, level of total bilirubin within 3 × ULN is permitted
b. aspartate transaminase (AST) and/or alanine transaminase (ALT) > 1.5 × ULN
c. alkaline phosphatase (ALP) > 2.5 × ULN
d. serum creatinine > 1.5 × ULN
e. haemoglobin (Hb) < 9 g/dL
f. absolute neutrophil count (ANC) < 1500/mm3 (< 1.5 × 109/L)
g. platelets count < 100000/mm3 (< 100 × 109/L)
15. Pregnant or lactating women. A pregnancy test result is required for all women of childbearing potential including women who had menopause onset within 2 years prior to Randomisation. Women of childbearing potential must agree to use non-hormonal contraceptive methods (see section 7.4.2.) during the study and 6 months after the last dose IP
16. Concurrent hormonal therapy including birth control pills, ovarian hormone replacement for menopause, selective oestrogen receptor modulator (SERM) either for osteoporosis or breast cancer prevention
17. Subjects unwilling to follow the study requirements |
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E.5 End points |
E.5.1 | Primary end point(s) |
The Pathologic complete response rate of the primary breast tumour |
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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) |
• Total pathologic complete response, defined as the absence of invasive residual in both breast and lymph nodes
• Overall clinical response rate during neoadjuvant therapy (tumour size will be measured by ultrasound or caliper)
• Event-free survival (EFS), defined as the time from the date of randomisation to the date where an event occurs. An event is disease recurrence or progression (local, regional, distant or contralateral) or death due to any cause
• Overall survival (OS), defined as the time from the date of randomisation to the date of death, regardless of the cause of death. Subjects who were alive at the time of analysis will be censored at the date of the last follow up assessment |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Measured at various intervals in the study from beginning to end as per Protocol. |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
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 | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 52 |
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 |
Bulgaria |
Czech Republic |
India |
Korea, Republic of |
Mexico |
Philippines |
Poland |
Romania |
Russian Federation |
Ukraine |
United Kingdom |
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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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
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 | 2 |
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 |