| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| HER2/neu positive metastatic breast cancer |
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| 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 |
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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 progression-free survival (as assessed by independent central disease assessment review) of taxane based chemotherapy plus lapatinib for 24 weeks followed by single agent lapatinib therapy to taxane based chemotherapy plus trastuzumab for 24 weeks followed by single agent trastuzumab therapy, in women with HER2/neu positive breast cancer (by local or central laboratory testing) which is metastatic, and with no prior chemotherapy and/or HER2/neu targeted therapy in the metastatic setting. |
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| E.2.2 | Secondary objectives of the trial |
| To evaluate and compare the two treatment arms with respect to: Overall survival Time to CNS metastases at the time of first progression Incidence rates of CNS metastases at the time of progression Overall objective response rate (complete or partial response), time to response, and duration of response - only patients with at least one measurable lesion at baseline Clinical benefit response rate, as determined by the total number of patients who achieve a complete or partial response (patients with at least one measurable lesion at baseline) plus those patients who have stable disease for at least 24 weeks (all patients - with or without measurable disease at baseline) Adverse event profile Quality of life as measured by the EORTC QLQ-C30 instrument and a Trial Specific Checklist Clinical outcomes using biomarker changes in biological samples Health economics, including both healthcare utilization and health utilities (Canadian and Australian centres only). |
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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:Amend.1 Data:2008/06/05 Titolo:Vedere titolo protocollo Obiettivi:Vedere sinossi e protocollo
ALTRI SOTTOSTUDI: Biomarcatori molecolari (opzionali), metastasi primarie per cui vengono firmati diversi consensi informati oltre a quello dello studio principale
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| E.3 | Principal inclusion criteria |
| 1.Histologically confirmed adenocarcinoma of the breast. 2.Metastatic breast cancer (stage IV) at primary diagnosis or at relapse after curative intent therapy. 3.Local or central laboratory confirmed HER2/neu overexpressing and/or amplified disease in the invasive component of the primary or metastatic lesion as defined by: 3+ over expression by IHC (> 30% of invasive tumour cells); 2+ or 3+ (in 30% or less neoplastic cells) overexpression by IHC AND fluorescence or chromogenic in situ hybridization (FISH/CISH) test demonstrating HER2/neu gene amplification;HER2/neu gene amplification by FISH/CISH (> 6 HER2/neu gene copies per nucleus, or a FISH/CISH ratio (HER2 gene copies to chromosome 17 signals) of > 2.2) 4.Formalin fixed, paraffin embedded tumour specimen from the invasive component of the primary or metastatic lesion must be available for central HER2/neu testing to occur either prior to or afterrandomization. The specimens will be used for central laboratory testing of the mandatory tumour phenotype markers ER, PgR, EGFR, CK5/6 and Ki67, once study accrual is completed. 5.Patients must have evidence of metastatic disease, but measurable disease is not mandatory. To be considered evaluable for the overall response rate (complete and partial response), patients must have at least one measurable lesion as follows:X-ray, physical exam > 20 mm, Conventional CT scan, MRI > 20 mm, Spiral CT scan > 10 mm 6.Prior treatment with chemotherapeutic agents including taxanes in the neoadjuvant or adjuvant setting is permitted provided that at least 12 months has elapsed since the last dose of therapy and all treatment related adverse events are < grade 1 at the time of randomization. 7.Prior treatment with HER2/neu targeted therapy in the neoadjuvant or adjuvant setting is permitted provided that at least 12 months has elapsed since last dose of HER2/neu targeted therapy and all treatment related adverse events are < grade 1 at the time of randomization. 8.Prior treatment with endocrine therapy in the neoadjuvant or adjuvant or metastatic setting is permitted provided that therapy has been discontinued and all treatment related adverse events are < grade 1 at the time of randomization. 9.Prior treatments with radiation therapy in the adjuvant and/or metastatic setting are permitted provided that at least 2 weeks have elapsed since the last fraction of radiation therapy and all treatment related adverse events are < grade 1 at the time of randomization. 10. Prior radiation to a solitary metastatic lesion is permitted provided that progression post radiation has been documented. 11.Patients > 18 years of age. 12.life expectancy > 6 months. 13.ECOG performance status 0, 1 or 2 14.Adequate organ and marrow function measured within 14 days prior to randomization as defined below: Hemoglobin > 100 g/L (10 g/dL, 6.206 mmol/L), absolute granulocyte count (AGC) > 1.5 x 109/L (1,500 cells/mm3), Platelet count > 75 x109/L (75,000/mm3), Serum creatinine < 2.0 x institutional upper limit of normal, Total bilirubin < 1.5 x institutional upper limit of normal, ALT(SGPT) +/- AST(SGOT) < 2.5 x institutional upper limit of normal for patients who will be treated with docetaxel therapy ALT (SGPT) +/- AST (SGOT) < 5 x institutional upper limit of normal for patients who will be treated with paclitaxel therapy 15.Left ventricular ejection fraction > 50% as demonstrated by MUGA scan/echocardiogram within 4 weeks prior to randomization. 16.Imaging investigations must be done within 4 weeks prior to randomization, including: chest x-ray or CT chest, CT abdomen, bone scan / PET (if this is the institution's standard procedure for assessing bone metastases), with plain radiographs to confirm disease, as necessary, other scans as necessary to document all sites of disease 17.CT/MRI of the brain within 4 weeks prior to randomization 18.WOBC must have a negative serum or urine pregnancy test within 7 days prior to r |
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| E.4 | Principal exclusion criteria |
| 1 Patients with a history of other malignancies, except: adequately treated DCIS, adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumours (non-breast) curatively treated with no evidence of disease for > 5 years. 2 Patients who have received prior chemotherapy, immunotherapy, biologic therapy or HER2/neu targeted therapy for recurrent or metastatic breast cancer. 3 Patients receiving ongoing anticancer treatment or other investigational anti-cancer agents for breast cancer or patients who have used an investigational drug within 30 days or 5 half-lives (if known), whichever is longer, preceding the date of randomization. 4 Patients with CNS metastases (including leptomeningeal involvement). 5 Patients with serious cardiac illness or condition including, but not limited to: history of documented congestive heart failure (CHF) or systolic dysfunction (LVEF<50%) high risk uncontrolled arrhythmias (ventricular tachycardia, high-grade AV-block, supraventricular arrhythmias which are not adequately rate-controlled) unstable angina pectoris requiring anti-anginal medication clinically significant valvular heart disease evidence of transmural infarction on ECG inadequately controlled hypertension (systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg). New York Heart Association (NYHA) Class III or IV functional status (see Appendix X) 6 Pregnant or lactating women. 7 Patients with serious illness or medical condition which would not permit the patient to be managed according to the protocol including, but not limited to: History of significant neurologic or psychiatric disorder which would impair the ability to obtain consent or limit compliance with study requirements. Active uncontrolled infection. Serious or non-healing wound, ulcer, or bone fracture. 8 Patients with peripheral neuropathy grade 2 or greater. 9 Patients with GI tract disease resulting in an inability to take oral medication such as but not limited to malabsorption syndrome, a requirement for IV alimentation, prior surgical procedures affecting absorption (for example resection of stomach or small bowel) or uncontrolled inflammatory GI disease (e.g. Crohn’s, ulcerative colitis). 10 Patients receiving CYP3A4 inhibitors or inducers are not eligible unless it has been > 7 and > 14 days, respectively since the last dose of medication before the start of protocol treatment. For amiodarone in particular, dosing is prohibited for at least 6 months prior to the start of protocol treatment. 11 Patients with history of allergic or hypersensitivity reactions to any study drug or their excipients or with a history of allergic reactions attributed to compounds with similar chemical composition to any of the study drugs. Previous allergic reactions to taxanes that were adequately treated and that, according to the treating physician, would not prohibit further treatment with taxanes, are allowed. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-Free Survival |
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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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| biomarcatori molecolari, qualita' della vita |
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| 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 | 12 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 120 |
| 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
| |
| 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 | |
| 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 |
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