| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| TO INVESTIGATE THE AT HOME ADMINISTRTATION OF TRASTUZUMAB SUBCUTANEOUS VIAL FOR THE TREATMENT OF PATIENTS WITH HER2-POSITIVE EARLY BREAST CANCER. |
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| E.1.1.1 | Medical condition in easily understood language |
| TO INVESTIGATE THE AT HOME ADMINISTRTATION OF THE DRUG "TRASTUZUMAB" ADMINISTRATED IN A SUBCUTANEOUS FORM TO TREAT PATIENTS HAVING A TYPE OF BREAST CANCER CALLED HER2-POSITIVE EARLY BREAST CANCER. |
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| 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 this study is to assess the overall safety and tolerability of subcutaneous (SC) trastuzumab with assisted administration using a conventional syringe and needle (vial formulation, hereafter referred to as trastuzumab SC vial) when administered at home for the treatment of patients with HER2-positive (HER2+) early breast cancer (eBC).
Secondary Objectives
To describe:
• Patient experience with trastuzumab IV administered in the hospital.
• Patient experience with trastuzumab SC vial administered in the hospital.
• Patient experience with trastuzumab SC vial administered at home.
• Patient reporting of symptoms.
• Patient reporting on the quality of care provided in the hospital and at home.
• HCP overall satisfaction and perceived time savings with trastuzumab SC vial formulation administered in the hospital.
• Disease-free survival (DFS).
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| E.2.2 | Secondary objectives of the trial |
To describe:
• Patient experience with trastuzumab IV administered in the hospital.
• Patient experience with trastuzumab SC vial administered in the hospital.
• Patient experience with trastuzumab SC vial administered at home.
• Patient reporting of symptoms.
• Patient reporting on the quality of care provided in the hospital and at home.
• HCP overall satisfaction and perceived time savings with trastuzumab SC vial formulation administered in the hospital.
• Disease-free survival (DFS).
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| 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 prior to any study specific procedure
3. Able and willing to comply with protocol
4. Eastern Cooperative Oncology Group (ECOG) performance status 0–1
5. Hormonal therapy will be allowed as per institutional guidelines
6. Left ventricular ejection fraction (LVEF) of ≥ 50% measured by echocardiography (ECHO) or multiple gated acquisition (MUGA) scan prior to first dose of trastuzumab SC, or, for those who were receiving trastuzumab when beginning the study, documented results within an acceptable limit from a cardiac assessment within 3 months prior to enrolment
7. HER2-positive disease immunohistochemistry (IHC)3+ or in situ hybridization (ISH) positive, in line with local reimbursement criteria and determined in a local laboratory that is experienced/certified in HER2-expression testing using an accurate and validated assay
8. Histologically confirmed non-metastatic primary invasive adenocarcinoma of the breast
9. No evidence of residual, locally recurrent or metastatic disease after completion of surgery and chemotherapy, or during concurrent chemotherapy (neo-adjuvant or adjuvant)
10. Use of concurrent curative radiotherapy will be permitted
11. Patients have completed the first 6 cycles of trastuzumab IV as part of the (neo)adjuvant treatment
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| E.4 | Principal 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 who have been disease-free for at least 5 years, are eligible
2. Patients with severe dyspnea at rest or requiring supplementary oxygen therapy
3. Patients with other 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, or a history of severe allergic or immunological reactions, e.g. difficult to control asthma
10. Patients assessed by the investigator to be unable or unwilling to comply 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)
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
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Safety Outcome Measures
Adverse event (AE) collection will be the primary endpoint for the study. 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
o Cardiac AEs
o CHF (according to NCI CTCAE version 4.0 and New York Heart Association [NYHA] Classification)
o 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
• Secondary safety assessments will include the following:
o Exposure to study medication
o Duration of treatment, follow-up, and safety observation
o ECOG
o Concomitant medications
o Laboratory data, vital signs and physical examination
o Premature withdrawals and major protocol violations
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary analysis of the safety endpoints will be undertaken once all patients have completed the study treatment phase and safety follow-up 4 weeks after their last dose of study treatment.
Summaries will include the incidence of AEs and SAEs, AEs leading to premature discontinuation of study treatment, and specific cardiac AEs and SAEs. For certain AEs (or groups of AEs), e.g. cardiac AEs, 95% confidence intervals (calculated using Clopper-Pearson methodology) for incidences will be provided.
Secondary safety parameters include summaries of LVEF, exposure to study medication, duration of treatment and follow-up, vital signs, weight, height, ECOG, concomitant medications, laboratory parameters, premature withdrawals, and major protocol violations.
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| E.5.2 | Secondary end point(s) |
Patient-Reported Outcome Measures
• Patient experience with the treatment provided during the in-hospital part of the study: Patients will be asked to complete a questionnaire (PSQ1, appendix 6) related to the quality of care provided during trastuzumab administration in the hospital prior to the first dose trastuzumab SC vial administered at home = prior to cycle13.
• Patient experience with the treatment provided during the at home part of the study: Patients will be asked to complete a questionnaire (PSQ2, appendix 6) related to the quality of care provided during trastuzumab SC vial administration at home prior to the fifth dose trastuzumab SC vial administered at home = prior to cycle 17.
• Patient reporting of symptoms using the MD Anderson Symptom Inventory (MDASI, appendix 4): Patients will be asked to rate the severity of 13 core items on a scale from 0 to 10. Patients will be asked to complete the MDASI 4 times: Prior to the first dose trastuzumab IV = prior to cycle 7, prior to the first dose trastuzumab SC vial = prior to cycle 10, prior to the first dose trastuzumab SC vial administered at home = prior to cycle 13 and prior to the fourth dose trastuzumab SC vial administered at home = prior to cycle 16.
HCP-Reported Outcome Measures
• HCP overall satisfaction and perceived time savings with trastuzumab SC vial in the hospital will be assessed by a Health Care Professional Questionnaire (HCPEX-1, appendix 5): The HCPEX-1 questionnaire will be completed by a HCP administering trastuzumab IV and SC vial in the hospital after at least 3 patients completed the in hospital part of the study ( 3 patients must have completed treatment period 1 and 2).
Other outcome Measures
Patients will be interviewed by a HCP to assess:
• Patient experience with trastuzumab IV and SC vial administered in the hospital.
Patients will be interviewed by a HCP to complete the PEX-P1 (appendix 7) prior to the third dose trastuzumab SC = prior to cycle 12.
• Patient experience with trastuzumab SC vial administered at home.
Patients will be interviewed by a HCP to complete the PEX-P2 (appendix 7) at the safety follow-up visit, following 4 weeks after the last trastuzumab SC vial administration at home.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The secondary analyses of patients’ experience, patient reporting of symptoms and health care professional experience and overall satisfaction will be undertaken once all patients have completed the study treatment phase and safety follow-up 4 weeks after their last dose of study treatment)
Details will be described in the statistical analysis plan that will be finalized before data base lock.
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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 | 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 | 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 | 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.8.2.4 | 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 | 13 |
| 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 | 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 |
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| 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
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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 | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
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