| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly diagnosed or recurrent (after surgery) stage IV (TNM/AJCC v.7) HER-2 positive (IHC 3+ or or HER-2 gene amplification by in situ hybridization) invasive breast cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
| Her-2 positive metastatic breast cancer |
|
| 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 | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 the eficacy (as measured by progression free survival at 6 months)of pertuzumab combined with trastuzumab (PH) or PH plus metronomic chemotherapy (PHM) in an elderly metastatic breast cancer population and to select attractive treatments for further development in phase III. |
|
| E.2.2 | Secondary objectives of the trial |
Evaluate the impact of Pertuzumab + Herceptin and Pertuzumab + Herceptin + Metronomic chemotherapy on patient's functional status, frailty and Quality of Life as assessed by the EORTC Minimal Data Set (plus Activities of Daily Living questionnaire), Short Physical Performance Battery and the QLQ-30/ELD-15 questionnaire.
Evaluate the efficacy of TDM-1 after progression on pertuzumab ad trastuzumab
Evaluate the evolution of potential ageing biomarkers and their predictive potential for toxicity, decline in functionality and fraility status and outcome. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
-Female patients with histologically proven HER-2 positive (IHC 3+ or or HER-2 gene amplification by in situ hybridization [FISH, SIS-Patients must have measurable (RECIST v. 1.1) or evaluable disease (please refer to chapter 7)
-Performance status (PS) 0-3 (WHO)
-Age ≥ 70 years of age, or ≥ 60 years old with required number of dependencies as described below :
•65 – 69 in combination with functional restriction defined as limitation in at least 2 of 8 iADL or 1 of 6 ADL or Charlson comorbidity score > 2
•60 – 64 in combination with functional restrictions defined as limitation in at least 3 of 8 iADL 2 of 6 ADL or Charlson comorbidity score > 3
-Life expectancy of more than 12 weeks
-Previous adjuvant chemotherapy/anti HER-2 therapy after surgery is allowed, given that the time interval from end of previous treatment to initiation of treatment for metastatic disease is ≥6 months.
-Up to one line of anti-HER therapy (trastuzumab or lapatinib) is allowed in combination with hormone therapy for hormone sensitive metastatic breast cancer.
-Adequate organ function, evidenced by the following laboratory results within 3 weeks prior to randomization: (patients with a buffer range from the normal values of +/- 5% for hematology and +/- 10% for biochemistry [with the EXCEPTION of Glomerular Filtration Rate] are acceptable)
-Absolute neutrophil count > 1500 cells/mm3
-Platelet count > 100,000 cells/mm3
-Hemoglobin > 8.5 g/dL
-Total bilirubin ≤ 1.5 upper limit of normal (ULN)
-SGOT (AST), SGPT (ALT), and alkaline phosphatase ≤ 2.5× ULN (for alkaline phosphatase limit applies in the absence of bone metastases)
-Glomerular Filtration Rate (GFR) ≥ 30 ml/min according to MDRD formula or Cockcroft and Gault Formula (see Appendix D)
-Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before registration in the trial
-Before patient randomization, written informed consent must be given according to ICH/GCP, and national/local regulations.
mula or Cockcroft and Gault Formula (see Appendix D)H or CISH]) invasive breast cancer, based on the results of local laboratories of the participating centers. All histologies are eligible.
-Newly diagnosed or recurrent (after surgery) stage IV disease (TNM/AJCC v.7).
Evaluate the evolution of potential ageing biomarkers and their predictive potential for toxicity, decline in functionality and fraility status and outcome. |
|
| E.4 | Principal exclusion criteria |
-Current symptomatic brain metastases.
-Prior chemotherapy for metastatic disease.
-Prior treatment with pertuzumab.
-History of exposure to the following cumulative doses of anthracyclines:
•Doxorubicin or liposomal doxorubicin > 360 mg/m2
•Epirubicin > 720 mg/m2
•Mitoxantrone > 120 mg/m2
•Idarubicin > 90 mg/m2
•If another anthracycline or more than 1 anthracycline has been used, then the cumulative dose must not exceed the equivalent of 360 mg/m2 of doxorubicin.
-History of palliative radiotherapy within 14 days of /prior to randomization.
-History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell or spinocellular carcinoma of the skin.
-Current uncontrolled hypertension (persistent systolic > 180 mmHg and/or diastolic > 100 mmHg) (with or without medication).
-LVEF below 50%.
-History of significant cardiac disease defined as:
•Symptomatic CHF (NYHA classes II-IV, see Appendix C)
•High-risk uncontrolled arrhythmias, i.e. atrial tachycardia with a heart rate > 100/min at rest, significant ventricular arrhythmia (ventricular tachycardia) or higher-grade AV-block (second degree AV-block Type 2 [Mobitz 2] or third degree AV-block)
•History of myocardial infarction within 6 months prior to randomization
•Clinically significant valvular heart disease
•angina pectoris requiring anti-angina treatment
-Peripheral neuropathy of Grade ≥3 per NCI CTCAE version 4.0.
current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures, known infection with HIV, active hepatitis B and/or hepatitis C virus)
-Major surgical procedure or significant traumatic injury within 28 days prior to randomization or anticipation of the need for major surgery during the course of study treatment.
-History of receiving any investigational treatment within 28 days of randomization.
-History of intolerance (including Grade 3-4 infusion reaction) to trastuzumab.
-Unwillingness or inability to comply with the requirements of the protocol as assessed by the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression free survival rate at 6 months |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression free survival will be measured at 6 months. |
|
| E.5.2 | Secondary end point(s) |
1. Overall survival (OS)
2. Breast cancer specific survival (BCSS)
3. Toxicity (with specific attention to cardiac toxicity)
4. Tumor response rate as measured by RECIST v1.1
5. For those patients receiving T-DM1 after progression: toxicity, tumor response, progression free survival after starting T-DM1
6. Evolution of Health Related Quality of Life as assessed by EORTC QLQ-C30 and ELD 15 questionnaires
7. Evolution of geriatric assessment during treatment. This will be based on the EORTC minimum dataset (G8, Instrumental Activities of Daily Living and social situation), the Activities of Daily Living and frailty assessment by Short Physical Performance Battery. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. OS will be measured from the date of randomization until the date of death.
2. BCSS will be measured from the date of randomization until the date of death due to breast cancer.
3. At each treatment cycle on day 1 before treatment administration and at the end of protocol treatment.
4. Tumour response rate will be classified as the best response from the start of study treatment until the end of treatment. It will be assessed every 9 weeks until disease progression.
5. Same timepoints as for other protocol treatments.
6. QoL questionnaires will be completed at 9 weeks, 27 weeks and 1 year after treatment initiation.
7. G8, IADL and ADL scores, and social situation will be evaluated at baseline, 9 weeks, 27 weeks and 1 year after treatment initiation. |
|
| 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 | Yes |
| E.6.13.1 | Other scope of the trial description |
Health Related Quality of Life (HRQoL) - aims to assess the general evolution of HRQoL in these patients and map the differences between the two arms using the EORTC Quality of Life Questionnaire (QLQ-C30).
Evolution of geriatric assessment during treatment - based on the EORTC minimum dataset (G8, Instrumental Activities of Daily Living and social situation), the Activities of Daily Living and frailty assessment by Short Physical Performance Battery.
|
|
| 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 | 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 | 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 31 |
| 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
|
End of study occurs when all of the following criteria have been satisfied:
1. 27 months after the last patient entered the study
2. The trial is mature for the analysis of the primary endpoint as defined in the protocol, as well as for the analysis of T-DM1 safety.
3. The database has been fully cleaned and frozen for both of these analyses |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| 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 | 3 |
| 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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