| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| EARLY AND LOCALLY ADVANCED HER2-POSITIVE BREAST CANCER |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| 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 the study is to assess the safety and tolerability of trastuzumab solution injected subcutaneously (vial or single-use injection device [SID]) in patients with HER2-positive early breast cancer (eBC) or locally advanced breast cancer (LABC) |
|
| E.2.2 | Secondary objectives of the trial |
-Exposure to study medication
-Duration of treatment, follow-up, and safety observation
-Efficacy:
-DFS, OS -In the Neo-adjuvant setting activity of two sequential drug regimens, Anthracycline-containing regimen followed by concomitant administration of Taxane and Trastuzumab SC, assessed as the incidence of pathological Complete Response in breast and nodes (pCR; ypT0-is ypN0)
-Patient Satisfaction using SID -HCP satisfaction
Explorative Secondary Objective: - assessment of PI3K mutation in tumor tissues and in circulating free DNA (cfDNA) in blood, performed:
-to evaluate the agreement between the PI3K mutation assessment in tumor tissue (gold standard) and in circulating free DNA (experimental)
-to correlate the baseline mutation status (in tumor tissue and cfDNA) with clinical outcome (pathological response to treatment in the neoadjuvant arm)
-to correlate the pharmacodynamic change of the cfDNA before and after treatment with clinical outcome |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Female and male patients aged ≥ 18 years
2. Signed informed consent before any specific study procedure
3. Able and willing to comply with protocol
4. Eastern Cooperative Oncology Group (ECOG) performance status 0–1
5. Pre and post-menopausal status
6. HER2-positive disease immunohistochemistry (IHC) 3+ or in situ hybridization (ISH) positive, as determined in a local laboratory that is experienced/certified in HER2-expression testing using an accurate and validated assay
7. Estrogen and progesterone receptor status (ER and PgR) assessed as negative or positive
8. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast. Stage of disease: T1-4, N0-3, M0. For T1a-b concomitant axillary involvment is required).
9. Left ventricular ejection fraction (LVEF) of ≥ 55% measured by echocardiography (ECHO) or multiple gated acquisition (MUGA) scan prior to first dose of trastuzumab SC
10. Availability of formalin–fixed paraffin-embedded (FFPE) tissue block or partial block from diagnostic core biopsy (only neoadjuvant patients) and from surgical specimens (both adjuvant and neoadjuvant patients), with representative invasive part of the tumor for additional biomarker analysis
11. Intact skin at site of SC injection on the thigh |
|
| E.4 | Principal exclusion criteria |
Exclusion Criteria
1. History of other malignancy which could affect compliance with the protocol or interpretation of results Patients with curatively treated carcinoma in situ of the cervix or basal cell carcinoma, and patients with other curatively treated malignancies, other than breast cancer, who have been disease-free for at least 5 years, are eligible
2. Severe dyspnea at rest or requiring supplementary oxygen therapy
3. Concurrent serious diseases that may interfere with planned treatment, including severe pulmonary conditions/illness
4. Serious cardiac illness or medical conditions that would preclude the use of trastuzumab, specifically: history of documented congestive heart failure (CHF), high-risk uncontrolled arrhythmias, angina pectoris requiring medication, clinically significant valvular disease, evidence of transmural infarction on electrocardiogram (ECG), diagnosed poorly controlled hypertension
5. Known infection with human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or hepatitis C virus (HCV)
6. Pregnant or lactating women. Positive serum pregnancy test in women of childbearing potential, premenopausal or less than 12 months of amenorrhea post-menopause, within 7 days prior to the first dose of study drug
7. Women of childbearing potential, premenopausal or less than 12 months of amenorrhea post-menopause (unless surgically sterile), and male patients with partners of childbearing potential who are unable or unwilling to use adequate contraceptive measures during study treatment. In this study, menopause is defined as a minimum of 12 consecutive months of amenorrhea during which time no other biological or physiological cause had been identified as a potential cause of this state. Examples of adequate contraceptive measures are intrauterine device, barrier method (condoms, diaphragm) also in conjunction with spermicidal jelly, or total abstinence. Oral, injectable, or implant hormonal contraceptives are not acceptable
8. Concurrent enrolment in another clinical trial using an investigational anti-cancer treatment, including hormonal therapy, bisphosphonate therapy and immunotherapy, within 28 days prior to the first dose of study treatment
9. Known hypersensitivity to trastuzumab, murine proteins, to any of the excipients of Herceptin® including hyaluronidase, or the adhesive of the SC device (for cohort B), or a history of severe allergic or immunological reactions, e.g. difficulty to control asthma
10. No compliance or adherence with the requirements of the protocol
11. Inadequate bone marrow function (as indicated by any of the following):
a) Absolute neutrophil count (ANC) < 1,500 / mm3 (< 1.5 × 109/L)
b) Platelets < 100,000 / mm3 (< 100 × 109/L)
c) Hemoglobin < 10 g/dL
12. Impaired hepatic function (as indicated by any of the following):
a) Serum total bilirubin > 1.5 × upper limit of normal (ULN)
b) Alanine amino transferase (ALT) and/or aspartate amino transferase (AST) > 2.5 × ULN
c) Alkaline phosphatase (ALP) > 2.5 × ULN
13. Inadequate renal function, as indicated by serum creatinine > 1.5 × ULN
14. Hormonal treatment concomitant with chemotherapy (allowed in adjuvant phase with adjuvant Trastuzumab SC.)
15. Pre-existing motor or sensory neuropathy of Grade >1 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Adverse event (AE) collection will be the primary endpoint for this study. Summaries to be produced will include:
Incidence and severity by NCI CTCAE version 4.0 of AEs and serious adverse events (SAEs)
AEs leading to premature discontinuation of study treatment
Cardiac safety
Cardiac AEs
CHF (according to NCI CTCAE version 4.0 and New York Heart Association [NYHA] Classification)
LVEF over time. In the event of an asymptomatic decline in LVEF, an algorithm (Appendix 2 in the protocol) will be used to determine whether to continue trastuzumab SC treatment |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of safety endpoints will be performed after all patients have completed the study (treatment phase and follow-up of security, (4 weeks after the last dose of study treatment.) The final analysis will be conducted when the last patient has been followed for at least 24 months after his last study treatment, or sooner if one of the following situations will be documented for all patients: withdrawal of consent, loss to follow-up or death.
In addition, there will be an interim analysis on an annual basis for the evaluation of the safety and presentation of data of Safety and Effectiveness. The first interim analysis will be conducted one year after the first visit and the last one when the last patient has completed the follow-up period . |
|
| E.5.2 | Secondary end point(s) |
The secondary objectives include:
-Secondary safety assessments will include the following:
Exposure to study medication
Duration of treatment, follow-up, and safety observation
ECOG
Concomitant medications
Pag. 15 of 119
Trastuzumab—Roche S.p.A.
Protocol ML28879, Version 1.0 dated 08-07-2013
Laboratory data, vital signs and physical examination
Premature withdrawals and major protocol violations
- Efficacy outcome measures will be evalueted by:
DFS, OS
Diagnosis of breast cancer relapse will be made based on routine clinical, radiological and laboratory criteria. In case of uncertainly, disease progression should be confirmed by histological or cytological examination of a suspicious lesion, if possible.
In the Neo-adjuvant setting, the activity of two sequential drug regimens, Anthracycline-containing regimen followed by concomitant administration of Taxane and Trastuzumab SC, will be assessed as the incidence of pathological Complete Response in breast and nodes (pCR) (ypT0-is ypN0). Residual in situ disease (ypTis) is considered as pCR.
- Patient Satisfaction will be assessed by Patient Satisfaction Questionnaire only in Cohort B (use of Trastuzumab SC SID).
In Cohort B, a questionnaire will be completed by patients able to use SID, who completed a minimum of 14 administrations of trastuzumanb SC using SID ( at least 10 self- administered).
Health Care Professional (HCP) satisfaction will be assessed by a Health Care Professional Questionnaire (HCPQ). A questionnaire will be completed by both the Investigator and a study nurse at each site when at least 4 patients from their site have received at least 5 cycles of adjuvant study treatment. (For that recruit <4 patients, the investigator and a study nurse will each complete an HCPQ when the last patient at their site has received at least 5 cycles of study treatment). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| A preliminary analysis of secondary endpoints (Safety, DF and OS), the final analysis of pCR, analysis of patient satisfaction and health care professionals will be conducted when all patients will have received 18 cycles of Herceptin SC and have completed safety follow-up assessments (4 weeks after the last dose of study treatment). The final safety analysis, OS and DFS will be conducted when the last patient has been followed for at least 24 months after his last study treatment, or sooner if one of the following situations will be documented for all patients: withdrawal of consent , loss to follow-up or death. |
|
| 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 | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| 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 |
|
| 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 | 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 | Information not present in EudraCT |
| 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 | 60 |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 0 |
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