| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive metastatic 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 19.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10006187 |
| E.1.2 | Term | Breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| 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 trial is to evaluate the efficacy in terms of overall survival (OS) at 24 months of a chemotherapy-free dual HER2-inbibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) and of a chemotherapy-containing dual HER2-inhibition with trastuzumab and pertuzumab (first-line) followed by T-DM1 (second-line) in patients with HER2-positive metastatic breast cancer. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate other efficacy parameter
- To evaluate the safety and tolerability profile of the two treatment strategies
- To evaluate the Quality of Life (QoL)
- To learn how patients are treated after trial treatment |
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
| Tumor tissue and blood samples will be collected from patients who have given a separate informed consent for translational research. Projects will be defined by the translational research steering committee of the trial and have to be approved by the SAKK board and the corresponding EC. |
|
| E.3 | Principal inclusion criteria |
- Histologically confirmed breast cancer with distant metastases
Notes :
1. A biopsy from the primary tumor or a metastasis can be used for diagnosis.
2. Patients with non-measurable lesions are eligible.
3. Patients with inoperable, locally advanced breast cancer with lymph node metastases other than ipsilateral locoregional (axillary, infraclavicular, parasternal) or other distant metastases are eligible.
4. Patients with bone metastases with or without bone targeted therapy (bisphosphonates, denosumab) are eligible.
5. Patients with de-novo Stage IV disease are eligible.
- HER2-positive tumor according to central pathology testing for HER2
Note:
1. A formalin-fixed paraffin-embedded (FFPE) biopsy from the primary tumor or a metastasis has to be used for HER2 status determination. If a biopsy is available from a metastasis, the HER2 testing should be performed using the metastasis.
2. Fine needle aspiration is not acceptable for HER 2 testing.
- Women aged ≥18 years
- WHO performance status 0 to 2 (see Appendix 2)
- Left Ventricular Ejection Fraction (LVEF) ≥50% as determined by either ECHO or MUGA
- Adequate organ function, evidenced by the following laboratory results:
Neutrophils >1.5x10^9/L, platelets >100x10^9/L, hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented Gilbert’s disease), AST≤3xULN, ALT ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5xULN
- At least one dose of trial therapy in the first-line treatment phase of this trial
- Proven disease progression on first-line therapy or radiotherapy of a bone metastasis
Notes:
First new parenchymal CNS metastases only do not count as progression requiring the initiation of second line trial treatment (please see Appendix 1.4, Determination and evaluation of new lesions).
Radiotherapy of a single area only for pain control is allowed and will not count as PD.
- Adequate organ function, evidenced by the following laboratory results:
Neutrophils >1.5x10^9/L, platelets >100x10^9/L, hemoglobin ≥90g/L, total bilirubin ≤1.5xULN (unless the patients has documented Gilbert’s disease), AST ≤3xULN, ALT ≤3xULN, AP ≤2.5xULN (except in patients with bone metastases: AP ≤5xULN), creatinine ≤1.5ULN
- LVEF ≥50% as determined by either ECHO or MUGA
- QoL questionnaire has been completed.
- Negative serum pregnancy test in women of childbearing potential |
|
| E.4 | Principal exclusion criteria |
- Prior chemotherapy for inoperable locally advanced or metastatic breast cancer
Note:
Prior neoadjuvant/adjuvant chemotherapy is allowed if doses for anthracylines have not exceeded 720mg/m2 and 240mg/m2 for epirubicin and doxorubicin, respectivel.
- Reexposure to paclitaxel is permitted, if the last dose of taxane was given at least 1 year before randomisation.
- Reexposure to vinorelbine is permitted, if the last dose of vinorelbine was given at least 1 year before randomisation.
- Prior anti-HER2 treatment for metastatic or inoperable breast cancer
Note:
Prior neoadjuvant/adjuvant anti-HER2 treatment with trastuzumab and/or lapatinib is allowed.
- More than one endocrine treatment line for metastatic or inoperable breast cancer exceeding a duration of 1 month
Note:
1. Adjuvant endocrine treatment is not counted as one line.
2. Patients progressing on endocrine treatment: this specific endocrine treatment must have been stopped at least 2 weeks prior to randomization.
- Prior treatment with pertuzumab and/or T-DM1
- Known leptomeningeal or CNS metastases
Note:
A brain MRI or CT scan is mandatory in case of clinical suspicion of CNS metastases.
- Single bone metastasis treated with radiotherapy (if the bone metastasis is the only tumor lesion)
- Termination of first-line therapy with trastuzumab/pertuzumab due to unacceptable toxicity without objective evidence of disease progression
- CNS metastases that are untreated, symptomatic, or require therapy to control symptoms, as well as a history of radiation, surgery, or other therapy, including steroids, to control symptoms from CNS metastases within 2 months (60 days) before registration
- Peripheral neuropathy of CTCAE grade ≥3
- Interstitial lung disease (ILD) or pneumonitis grade ≥4
- Any other adverse event which has not recovered to CTCAE grade ≤1 (except alopecia) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.2 | Secondary end point(s) |
1) OS at 24 months (secondary analysis, see section 13.2)
2) Progression free survival (PFS) of first-line treatment ignoring first central nervous system lesion (CNS) lesion
3) PFS of second-line treatment
4) PFS of second-line treatment ignoring first CNS lesion
5) Time to failure of strategy (TFS) of first- plus second-line treatment
6) OS
7) Objective response (OR) of first-line treatment (based on investigator assessment)
8) Disease control (DC) of first-line treatment (based on investigator assessment)
9) OR of second-line treatment (based on investigator assessment)
10) DC of second-line treatment (based on investigator assessment)
11) Adverse events (AEs) according to the NCI CTCAE v4.0 of first-line treatment
12) AEs according to the NCI CTCAE v4.0 of second-line treatment
13) AEs grade ≥2 until first progression (ignoring first CNS lesion)
14) QoL
15) PFS of third-line treatment
16) Further treatment lines (third-line etc.)
17) Time to CNS metastases
18) Time from first CNS metastases to 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 | 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 | 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) | 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 | 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) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
| The 2 groups will be analyzed separately for generating a basis to consider a controlled trial |
|
| 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 | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 40 |
| 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 |
| France |
| Germany |
| Netherlands |
| Switzerland |
|
| 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 | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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