| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic 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 compare the efficacy of T-DM1 vs. capecitabine plus lapatinib in patients with HER2-positive locally advanced or metastatic breast cancer as measured by PFS based on an independent review of tumor assessments To compare the safety of T-DM1 with the safety of capecitabine plus lapatinib |
|
| E.2.2 | Secondary objectives of the trial |
| To compare 1-year and overall survival (OS) between the two treatment arms To compare PFS between the two treatment arms based on investigator review of tumor assessments To compare the overall objective response rate between the two treatment arms based on both investigator and independent review of tumor assessments To estimate the duration of objective response within each treatment arm based on both investigator and independent review of tumor assessments To compare the clinical benefit rate (the proportion of patients with complete response, partial response, or stable disease at 6 months after randomization) between the two treatment arms based on both investigator and independent review of tumor assessments To compare time to treatment failure (TTF) between the two treatment arms et al. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. HER2 status must be prospectively, centrally tested and be HER2-positive (i.e., IHC 3+ and/or gene-amplified by FISH) based on central laboratory assay results for this study to be eligible for enrollment. 2. Histologically or cytologically confirmed invasive breast cancer (incurable locally advanced or metastatic disease) 3. Prior treatment for breast cancer must include both: A taxane, alone or in combination with another agent, and Trastuzumab in the adjuvant, locally advanced, or metastatic setting 4. Documented progression of incurable locally advanced or metastatic breast cancer, defined by the investigator Progression must occur during or after treatment for advanced or metastatic disease or within 6 months of completing adjuvant therapy. 5. Measurable and/or nonmeasurable disease b. General Criteria 6. Age 18 years 7. Cardiac ejection fraction 50% by either ECHO or MUGA 8. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 9. Adequate organ function, evidenced by the following laboratory results within 2 weeks prior to randomization: Absolute neutrophil count >1500 cells/mm3 Platelet count >100,000 cells/mm3 Hemoglobin >9.0 g/dL Patients are allowed to be transfused red blood cells to this level. Albumin > 2.5 g/dL Total bilirubin 1.5 upper limit of normal (ULN) SGOT (AST), SGPT (ALT), and alkaline phosphatase <2.5�ULN with the following exception: Patients with bone metastases: alkaline phosphatase <5�ULN Creatinine clearance >50 mL/min based on Cockroft-Gault glomerular filtration rate (GFR) estimation: (140 &#8722;Age) � (weight in kg) �(0.85 if female)/72 � serum creatinine International normalized ratio (INR) and activated partial thromboplastin time (aPTT)<1.5�ULN (unless on therapeutic coagulation) For women of childbearing potential, agreement to use an effective form of contraception (patient and/or partner, e.g., surgical sterilization, two reliable barrier methods, birth control pills, or contraceptive hormone implants) and to continue its use for the duration of the study according to local health authority guidelines. 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 |
| 1. History of treatment with T-DM1 2. Prior treatment with lapatinib or capecitabine. 3. Peripheral neuropathy of Grade >3 per National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE), Version 3.0 4. History of other malignancy within the last 5 years, except for appropriately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, synchronous or previously diagnosed HER2-positive breast cancer, or cancers with a similar outcome as those mentioned above. 5. History of receiving any chemotherapy or investigational treatment within 21 days prior to randomization and recovery of treatment-related toxicity consistent with other eligibility criteria 6. History of radiation therapy within 14 days of randomization. If the patient has a history of recent radiation therapy, the patient must have recovered from any resulting acute toxicity (to Grade 1) prior to randomization. 7. Brain metastases that are untreated, symptomatic, or require therapy to control symptoms; or any radiation, surgery, or other therapy, including steroids, to control symptoms from brain metastases within 2 months of randomization b. Cardiopulmonary Function 8. History of symptomatic CHF or ventricular arrhythmia requiring treatment 9. History of myocardial infarction or unstable angina within 6 months of randomization 10. Severe dyspnea at rest due to complications of advanced malignancy or current requirement for continuous oxygen therapy c. General Criteria 11. Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease) 12. Pregnancy or lactation 13. Current known active infection with HIV, hepatitis B virus, or hepatitis C virus 14. Presence of conditions that could affect gastrointestinal absorption: malabsorption syndrome, resection of the small bowel or stomach, and ulcerative colitis 15. History of intolerance (such as Grade 3&#8722;4 infusion reaction) to trastuzumab 16. Known hypersensitivity to 5-fluorouracil or known dihydropyrimidine dehydrogenase deficiency 17. Current treatment with sorivudine or its chemically related analogs, such as rivudine 18. Assessed by the investigator to be unable or unwilling to comply with the requirements of the protocol (i.e., unable to swallow pills) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| PFS, defined as the time from randomization to the first occurrence of progression or death on study (within 30 days of the last dose of study treatment) from any cause, as determined by independent review of tumor assessments using modified RECIST Incidence, nature, and severity of adverse events |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | 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 | 11 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 70 |
| 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 | 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
|
| Lo studio verra` considerato concluso quando saranno state riportati approssimativamente 417 decessi. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
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