| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2-positive metastatic breast cancer |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065430 |
| E.1.2 | Term | HER-2 positive breast cancer |
|
| 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 explore the efficacy of T-DM1 compared with the combination of trastuzumab and docetaxel in patients with HER2-positive MBC who have not received prior chemotherapy for metastatic disease, as measured by PFS based on investigator assessments
- To evaluate the safety of T-DM1 compared with the combination of trastuzumab and docetaxel in this population |
|
| E.2.2 | Secondary objectives of the trial |
| To explore the efficacy of T-DM1 compared with the combination of trastuzumab and docetaxel in patients with HER2-positive MBC who have not received prior chemotherapy for metastatic disease, as measured by median and 12-month PFS rate, duration of overall survival, the survival rate at 12 months, objective response rate, duration of objective response, and clinical benefit rate (the proportion of patients with CR, PR, and SD at 6 months) To characterize the PK properties of T-DM1 in this patient population To compare the time to symptom progression, as measured by the Trial Outcome Index-Physical/Functional/Breast (TOI-PFB) and patient-reported pain intensity, in the two treatment arms |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| a. Disease-Specific Criteria 1. Histologically or cytologically confirmed adenocarcinoma of the breast with locally advanced or metastatic disease, and a candidate for chemotherapy. Patients with locally advanced disease must have recurrent or progressive disease after failing initial attempts at local control. The disease must be considered to be unresectable. 2. HER2-positive (IHC 3+ or gene-amplified by FISH&#61483;) based on local laboratory assay results 3. No prior chemotherapy for MBC. (Hormonal therapy is allowed.) 4. Measurable disease per RECIST (see Appendix B)Measurable disease is defined as at least one lesion with a longest diameter of &#8805; 20 mm (&#8805; 10 mm on a spiral computed tomography [CT] scan). 5. Tumor blocks or 11 unstained slides available for confirmatory central laboratory HER2 testing b. General Criteria 6. Age &#8805; 18 years 7. LVEF &#8805; 50% at baseline (or &#8804; 4 weeks from baseline) as determined by either ECHO or MUGA 8. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1 (see Appendix G) 9. Adequate organ function, evidenced by the following laboratory results within 3 weeks prior to randomization: Absolute neutrophil count > 1500 cells/mm3, Platelet count > 100,000 cells/mm3Hemoglobin > 9.0 g/dL Total bilirubin &#8804; upper limit of normal (ULN) SGOT (AST) and/or SGPT (ALT) &#8804; 1.5 × ULN Alkaline phosphatase &#8804; 2.5 × ULN Patients with hepatic and/or bone metastases: alkaline phosphatase &#8804; 5 × ULN Creatinine < 1.5 × ULN International normalized ratio (INR) and activated partial thromboplastin time (aPTT) < 1.5 × ULN (unless on therapeutic coagulation or due to a coagulant) 10. For women of childbearing potential, agreement to use an effective form of contraception (patient and/or partner, e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants) and to continue its use for the duration of the study Specific country requirements will be followed (e.g., in the United Kingdom, women of childbearing potential and male subjects and their partners of childbearing potential must use two methods of contraception [one of which must be a barrier method] for the duration of the study). |
|
| E.4 | Principal exclusion criteria |
| a. Cancer-Related Criteria 1. History of any chemotherapy for MBC 2. An interval of < 12 months from the completion of cytotoxic chemotherapy (excluding hormonal therapy) in the neo-adjuvant or adjuvant setting until the time of metastatic diagnosis Patients who progress on or within 12 months on single-agent trastuzumab will be considered eligible (unless trastuzumab has been given &#8804; 21 days prior to randomization). 3. Trastuzumab &#8804; 21 days prior to randomization 4. Hormone therapy < 7 days prior to randomization 5. Peripheral neuropathy of Grade &#8805; 3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0 6. History of other malignancy within the last 5 years, except for carcinoma in situ of the cervix or basal cell carcinoma 7. Previous radiotherapy for the treatment of MBC is not allowed if: More than 25% of marrow-bearing bone has been irradiated. The last fraction of radiotherapy has been administered within 3 weeks prior to randomization. 8. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy to control symptoms from brain metastases within 3 months of the first study treatment CT or magnetic resonance imaging (MRI) scan of the brain is mandatory (within 4 weeks of randomization) in cases of clinical suspicion of brain metastases or in a patient with any prior history of brain metastases. 9. History of exposure to the following cumulative doses of anthracyclines: Doxorubicin or liposomal doxorubicin > 360 mg/m2 Epirubicin > 720 mg/m2 Mitoxantrone > 120mg/m2 and 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. b. Cardiopulmonary Function 10. Current unstable angina 11. History of symptomatic congestive heart failure (CHF; New York Heart Association [NYHA] classes II&#8722;IV; see Appendix H), or ventricular arrhythmia requiring treatment 12. History of myocardial infarction within 6 months of randomization 13. LVEF below 50% within 28 days of randomization 14. History of decreased LVEF or symptomatic CHF with previous adjuvant trastuzumab treatment 15. Cardiac troponin I &#8805; 0.2 ng/mL within 28 days of randomization 16. Severe dyspnea at rest because of complications of advanced malignancy or requiring current continuous oxygen therapyc. General Criteria 17. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease; wound healing disorders; ulcers; or bone fractures) 18. 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 19. Current pregnancy or lactation 20. History of receiving any investigational treatment within 28 days of randomization 21. Current known infection with HIV, active hepatitis B and/or hepatitis C virus 22. History of intolerance (including Grade 3&#8722;4 infusion reaction) or hypersensitivity to trastuzumab, murine proteins, or docetaxel 23. Known hypersensitivity to any of the study drugs, including the excipients, or any drugs formulated in polysorbate 80 24. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is PFS based on investigator assessment, defined as the time from randomization to the first occurrence of disease progression, as determined by investigator tumor assessments using RECIST, or death on study from any cause, whichever occurs earlier. Death on study is defined as death from any cause within 30 days of the last dose of study drug. |
|
| 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 | Yes |
| 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) | 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) | Yes |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 42 |
| 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 | Information not present in EudraCT |
| 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 |
|
| 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
|
| La valutazione della sopravvivenza proseguira` fino al completamento da parte dell`ultimo paziente dei 24 mesi di follow-up dall`interruzione del trattamento, rappresentando la fine studio. |
|
| 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 | 11 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 11 |
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