| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| ErbB2 Positive Locally Recurrent or Metastatic Breast Cancer. |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10027475 |
| E.1.2 | Term | Metastatic breast cancer |
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| 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 independently assessed progression free survival (PFS) following treatment with neratinib in combination with paclitaxel versus trastuzumab plus paclitaxel in subjects who have not received previous treatment for erbB-2-positive locally recurrent or metastatic breast cancer. |
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| E.2.2 | Secondary objectives of the trial |
| To compare independently assessed clinical activity between treatment arms by measuring: overall survival (OS), ORR, and duration of response (DOR) and clinical benefit rate (CBR; CR + PR + stable disease [SD] ≥ 24 weeks). To compare safety (AEs; serious adverse events [SAEs]) between treatment arms. To compare patient reported breast specific quality of life between treatment arms. To compare the frequency of and time to symptomatic or progressive central nervous system (CNS) lesions between treatment arms. |
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| 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 |
FARMACOGENETICA: Versione:Originale Data:2009/05/21 Titolo:N.A. Obiettivi:Dopo aver raccolto un consenso informato separato, un campione bioptico del tumore originale sara` studiato per: mutazioni PIK3CA negli hotspots (ie, exoni 9,20 mediante sequenziamento genico), amplificazione di PIK3CA (q-PCR o FISH), perdita di PTEN e membri della famiglia erbB (erbB-1, erbB-3, ed erbB-4) (IHC), amplificazione di c-Myc (q-PCR o FISH). Campioni di sangue saranno raccolti al tempo basale; Giorno 15 del ciclo 1; e Giorno 1 del ciclo 2, per la valutazione sierica di HER2/ECD.
L`obiettivo e` identificare i biomarker predittivi della risposta/resistenza a neratinib (diversi da erbB-2).
Confrontare l�utilizzo delle strutture sanitarie compreso le ospedalizzazioni e le visite mediche tra i gruppi di trattamento.
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| E.3 | Principal inclusion criteria |
| 1. Female subjects aged 18 years or older. 2. Histologically and/or cytologically confirmed diagnosis of breast cancer. 3. Locally recurrent or metastatic breast cancer that is not amenable to curative surgery and/or radiation. 4. Documentation of erbB-2 gene amplification by FISH (as defined by a ratio >2.2) or chromogenic in situ hybridization (CISH, as defined by the manufacturer�s kit instruction) or documentation of erbB-2-overexpression by IHC (defined as IHC3+, or IHC2+ with FISH or CISH confirmation) based on local laboratory or initial diagnostic results utilizing 1 of the sponsor-approved assays. If erbB-2 status is unavailable or was determined using a test other than a sponsor-approved assay and cannot be assessed using 1 of these assays prior to randomization, testing and study eligibility must be obtained from the sponsor-identified central laboratory prior to randomization. 5. All subjects must have tumor tissue (ie, most recent archived formalin fixed-embedded tissue [block or unstained slides]) available for central review of erbB-2 expression levels by FISH testing performed by the sponsor-identified central laboratory. 6. Documentation of ER/PgR status (positive or negative) based on local laboratory or initial diagnostic results must be available before study entry. If results are unavailable, tumor tissue may be sent to the sponsor-identified central vendor for assessment prior to study entry as per investigator�s discretion. 7. At least 1 measurable lesion as de fined by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. 8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2 (not declining within 2 weeks prior to signing informed consent). 9. Left ventricular ejection fraction (LVEF) within institutional range of normal as measured by multiple gated acquisition (MUGA) or echocardiogram (ECHO). 10. Screening laboratory values within the following parameters: Absolute neutrophil count (ANC) &#61619; 1.5 x 109 /L (1500/mm3) Platelet count &#61619;100 x 109/L (100,000/mm3) Hemoglobin &#61619;9.0 g/dL (90 g/L) Serum creatinine &#61603;1.5 x upper limit of normal (ULN) Total bilirubin &#61603;1.5 x ULN (<3 ULN if Gilbert�s disease) Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) &#61603;2.5 x ULN (&#61603;5 x ULN if liver metastases are present) 11. Recovery (to grade 1 or baseline) from all clinically significant acute adverse effects of prior therapies (excluding alopecia). 12. All subjects who are not surgically sterile or postmenopausal must agree and commit to the use of a reliable method of birth control starting 2 weeks prior to the administration of the first dose of investigational product until 28 days after the last dose of investigational product. A woman of childbearing potential is one who is biologically capable of becoming pregnant. This includes women who are using contraceptives or whose sexual partners are either sterile or using contraceptives. |
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| E.4 | Principal exclusion criteria |
| 1.Prior systemic anticancer therapy (including cytotoxic chemotherapy, signal transduction inhibitors [eg, lapatinib], biologic [eg, trastuzumab], or other investigational anticancer therapy) for locally recurrent or metastatic disease. Prior endocrine therapy in any setting is allowed. 2.Prior treatment with an erbB-2 inhibitor, other than trastuzumab, lapatinib, or the combination of the two, in the neoadjuvant or adjuvant setting. 3.Prior treatment with neoadjuvant or adjuvant anthracyclines with a cumulative dose of doxorubicin of >400 mg/m2, epirubicin dose >800 mg/m2, or the equivalent dose for other anthracyclines or derivatives (eg, 72 mg/m2 of mitoxantrone). 4.Subjects with recurrence or progression of disease within 12 months after completion of adjuvant or neoadjuvant systemic anticancer therapy (including cytotoxic chemotherapy, signal transduction inhibitors [eg, lapatinib], biologic [eg, trastuzumab], or other investigational anticancer therapy), other than endocrine therapy, for early breast cancer. 5.Subjects with bone or skin as the only site of measurable disease. Subjects with skin lesions measurable by computed tomography (CT) scans or magnetic resonance imaging (MRI) as only site of measurable disease are allowed. 6.Major surgery, chemotherapy, radiotherapy, any investigational agents, or other cancer therapy within 2 weeks before the administration of the first dose of investigational product. 7.Active uncontrolled or symptomatic CNS metastases, as indicated by clinical symptoms, cerebral edema, and/or progressive growth. Subjects with a history of CNS metastases or cord compression are eligible if they have been definitively treated and are off anticonvulsants and steroids for at least 4 weeks before first dose of investigational product. 8.Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart Association [NYHA] functional classification of &#8805;3), unstable angina, and myocardial infarction (within 12 months of study entry). 9.Inadequately controlled hypertension (ie, systolic blood pressure [BP] > 180 mm Hg or diastolic BP > 100 mm Hg). 10.Family history of congenital long or short QT syndrome, Brugada syndrome or QT/QTc interval > 0.45 second or known history of QT/QTc prolongation or torsade de pointe (TdP). 11.Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn�s disease, malabsorption, or grade &#8805;2 diarrhea of any etiology at baseline). 12.Preexisting grade 2 or greater motor or sensory neuropathy. 13.History of life-threatening hypersensitivity reaction to taxanes or trastuzumab. 14.Clinical contraindication to steroids preventing their use as part of paclitaxel premedication. 15.Women who are pregnant, breast-feeding, or women of childbearing potential who are not using effective contraception during participation in the study and do not agree to do so for at least 28 days after final dose of investigational product. 16.Inability or unwillingness to swallow oral medications. 17.Immunocompromised subjects, including known seropositivity for human immunodeficiency virus (HIV), or current or chronic hepatitis B and/or hepatitis C infection (as detected by positive testing for hepatitis B surface antigen [HbsAg] or antibody to hepatitis C virus [anti HCV] with confirmatory testing). (Note: testing is not mandatory to be eligible for the study. However if a subject is at risk for having undiagnosed HCV [due to history of injection drug use or due to geographic location for example], testing at screening should be considered.) 18.Any other cancer, including contralateral breast cancer, within 5 years prior to screening with the exception of adequately treated ductal carcinoma in situ, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell ... |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint is PFS, defined as time from date of randomization to date of progressive disease (PD) or death if no progression. The secondary endpoints include OS, ORR, CBR, DOR, breast cancer specific quality of life, safety, CNS criteria, and biomarkers. |
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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 | 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| 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 | 25 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 130 |
| 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 |
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| 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
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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 | 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 | 6 |
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