E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Locally advanced, inflammatory or early stage 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 | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006194 |
E.1.2 | Term | Breast cancer NOS stage I |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10065430 |
E.1.2 | Term | HER-2 positive breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006196 |
E.1.2 | Term | Breast cancer NOS stage III |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10006195 |
E.1.2 | Term | Breast cancer NOS stage II |
E.1.2 | System Organ Class | 100000004864 |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10021974 |
E.1.2 | Term | Inflammatory breast cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 compare between SC trastuzumab and IV trastuzumab in the neoadjuvant setting
• the serum trough concentrations (Ctrough) observed pre-surgery
• the efficacy (pathological complete response, pCR)
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E.2.2 | Secondary objectives of the trial |
To compare between SC trastuzumab and IV trastuzumab
• the observed Ctrough concentrations post-surgery
• the predicted Ctrough concentrations pre-surgery and post-surgery
• the pharmacokinetic profile
To evaluate in the SC trastuzumab and IV trastuzumab arm
• total pathological complete response (tpCR)
• overall response rate (ORR)
• time to response (TTR)
• event-free survival (EFS)
• overall survival (OS)
• safety and tolerability
• immunogenicity
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients must have signed and dated an informed consent form
2. Female
3. Age ≥ 18 years
4. Non-metastatic primary invasive adenocarcinoma of the breast which is clinical stage I (T1, N0, M0) to IIIC (any T, N3, M0) including inflammatory and multicentric/multifocal breast cancer
a. with tumor size ≥ 1 cm by ultrasound or ≥ 2 cm by palpation
b. histologically confirmed
c. centrally confirmed HER2 positive (IHC3+ or ISH+)
5. At least one measurable lesion in breast or lymph nodes (>= 1cm by ultrasound or >=2cm by palpation), except for inflammatory carcinoma (T4d)
6. Performance status ECOG of 0-1
7. Baseline LVEF ≥ 55% measured by echocardiography or MUGA scan prior to first dose of trastuzumab
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E.4 | Principal exclusion criteria |
1. History of any prior (ipsi- and/or contralateral) invasive breast carcinoma
2. Past or current history of malignant neoplasms, except for curatively treated:
a. Basal and squamous cell carcinoma of the skin
b. in situ carcinoma of the cervix
3. Metastatic disease
4. Any prior therapy with anthracyclines
5. Prior use of anti-HER2 therapy for any reason or other prior biologic or immunotherapy
6. Concurrent anti-cancer treatment in another investigational trial, including immunotherapy
7. Patients with severe dyspnoea at rest or requiring supplementary oxygen therapy, patients with other concurrent serious diseases that may interfere with planned treatment including severe pulmonary conditions/illness
8. Serious cardiac illness or medical conditions that would preclude the use of trastuzumab, specifically: history of documented CHF, high-risk uncontrolled arrhythmias, angina pectoris requiring medication , clinically significant valvular disease, evidence of transmural infarction on ECG, poorly controlled hypertension
9. Medical conditions that would preclude the use of 5-fluorouracil, epirubicin, cyclophosphamide or docetaxel, including: cystitis, urinary obstruction, active infections or severe mucositis
10. History of severe allergic and immunological reactions, e.g. difficult to control asthma
11. Known hypersensitivity to any of the study drugs or any of the excipients, known hypersensitivity to murine proteins
12. Known dihydropyrimidine dehydrogenase (DPD) deficiency
13. Any of the following abnormal laboratory tests at baseline:
a. Biochemistry:
i. serum total bilirubin > 1.25 x upper limit of normal (ULN)
ii. alanine amino transferase (SGPT, ALT) or aspartate amino transferase (SGOT, AST) > 2.5 x ULN
iii. alkaline phosphatase (ALP) > 2.5 x ULN
iv. serum creatinine > 1.5 x ULN;
b. Hematology:
i. absolute neutrophil count (ANC) < 1.5 x 10e9/L
ii. platelets < 100 x 10e9/L
iii. haemoglobin < 10 g/dl
14. Pregnant or lactating women
15. Women of childbearing potential or less than one year after menopause (unless surgically sterile) who are unable or unwilling to use adequate contraceptive measures during study treatment
16. Patients unwilling or unable to comply with protocol procedures
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E.5 End points |
E.5.1 | Primary end point(s) |
1) The primary efficacy variable is pathological Complete Response (pCR). This is defined as the absence of invasive neoplastic cells of the primary tumor in the breast after surgery.
2) The primary variable for the pharmacokinetic analysis will be the observed trough concentration Ctrough of trastuzumab at cycle 7 (ie. the measured pre-dose concentration value at cycle 8). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) pathologic complete response: after surgery between cycles 8 and 9
2) PK analysis: at cycle 7 (ie. the measured pre-dose concentration value at cycle 8). |
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E.5.2 | Secondary end point(s) |
1) Trastuzumab serum concentrations, comparing sc versus iv administration after surgery and PK profile
2) Total pathologic complete response
3) Overall response rate
4) Time to response
5) Event free survival
6) Overall survival
7) Safety and tolerability
8) Immunogenicity
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) throughout cycles 9 to 13 and cycle 18
2) after surgery between cycles 8 and 9
3) at cycle 3, 5, 7 and 8
4) at baseline, cycle 3, 5, 7 and surgery
5) at cycle 3, 5, 7 and 8 before surgery and event driven afterwards
6) event-driven
7) throughout the study
8) at cycle 2, 5, 13, 18 and follow up visit at 3, 6, 12, 18, 24, 30, 36, 42, 48, 54 and 60 months months after last dose of study drug
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
non-inferiority study; PK comparability study for Ctrough |
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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 | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
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 | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 41 |
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 |
Brazil |
Canada |
Colombia |
Czech Republic |
Estonia |
France |
Germany |
Guatemala |
Hong Kong |
Hungary |
Italy |
Korea, Republic of |
Mexico |
Panama |
Peru |
Poland |
Russian Federation |
Slovakia |
South Africa |
Spain |
Sweden |
Taiwan |
Thailand |
Turkey |
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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 will be when the last patient has completed at least 60 months of follow-up after end of treatment. |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |