E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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MedDRA Classification |
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 evaluate and compare the anti-tumour activity, in terms of progression-free survival, of trastuzumab plus lapatinib versus lapatinib monotherapy in subjects with ErbB2 amplified metastatic breast cancer. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate and compare the two treatment groups with respect to the following: overall survival, tumor response rate (complete (CR) or partial (PR)), clinical benefit (CR, PR, and stable disease for at least 6 months), time to response, duration of response. - To determine the qualitative and quantitative toxicities associated with oral lapatinib administered daily in combination with trastuzumab versus lapatinib monotherapy. - To collect and store serum specimens for comparing baseline and on-treatment serum concentrations of ErbB1 and ErbB2 extracellular domains, for potential proteomic analysis, to identify changes in the protein profile and correlate to treatment response. - To further characterize the patient population by determination of intra-tumoral expression of ErbB1, ErbB2, and downstream biomarkers. - To evaluate quality of life status within the study population and compare between treatment groups. |
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E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
E.3 | Principal inclusion criteria |
1. Able to give signed informed consent. 2. Female ≥ 18 years. Women of childbearing potential must have a negative serum pregnancy test at screening and must use an approved contraceptive method, if appropriate (for example, intrauterine device [IUD], birth control pills, or barrier device) beginning 2 weeks before the first dose of investigational product and for 28 days after the final dose of investigational product. 3. Metastatic breast cancer, histologically/cytologically confirmed. If the disease is restricted to a solitary lesion, its neoplastic nature must be confirmed by cytology or histology. 4. Stage IV breast cancer that has progressed in either the adjuvant or metastatic setting. Prior therapies must include, but are not limited to: - Taxane-containing regimen for at least 4 cycles, or 2 cycles provided disease progression occurred while on taxane. - Anthracycline-containing regimen for at least 4 cycles, or 2 cycles provided disease progression occurred while on anthracycline. 5. Subjects must have documented progression following at least ONE trastuzumab plus cytotoxic chemotherapy or anti-hormonal regimen in the metastatic setting. 6. Subjects must have archived tumour tissue available for testing. 7. Documented amplification of the ErbB2 gene by fluorescence in situ hybridization (FISH) or documented overexpression of the ErbB2 protein by IHC in primary or metastatic tumor tissue. The IHC or FISH amplification may be documented by a local or central laboratory for randomization into the study. Subjects may be randomized on the basis of ErbB2 positivity by IHC 3+ overexpression or FISH amplification. 8. Lesion eligibility is as follows: • at least one measurable lesion(s) according to Response Evaluation Criteria in Solid Tumors [RECIST], or • bone-only disease. Note: Tumor lesions which are situated in a previously irradiated field, and have well-defined margins which are located in soft tissue will be defined as measurable disease. 9. Subjects with stable CNS metastases defined as asymptomatic and off systemic steroids and anticonvulsants for at least 1 month. Treatment with prophylactic anticonvulsants is permitted, unless listed within the Prohibited Medications 10. Radiotherapy if received within 2 weeks prior to initiation of IMP to a limited area (e.g., palliative treatment for painful disease) other than the sole site of measurable disease is allowed; however, subject must have completed treatment and recovered from all treatment-related toxicities prior to administration of the first dose of IMP. 11. Except for prior trastuzumab treatment, at least 3 weeks since prior chemotherapy, immunotherapy, biologic therapy, hormonal therapy for cancer, or surgery (except for minor surgical procedures) before beginning investigational product. Subjects must have recovered or stabilized sufficiently from treatment-related toxicities prior to administration of the first dose of investigational product. 12. Bisphosphonate therapy for bone metastases is allowed; however, treatment must be initiated prior to the first dose of IMP. Prophylactic use of bisphosphonates in is permitted only for the treatment of osteoporosis. 13. ECOG Performance Status of 0 to 2. 14. Able to swallow and retain oral medication. 15. Cardiac ejection fraction within institutional range of normal as measured by echocardiogram. MUGA scans will be accepted in cases where an echocardiogram cannot be performed or is inconclusive. 16. Subject must have adequate organ function as defined in the protocol 17. Subjects may continue anti-estrogen therapy only if treatment was initiated at least 1 month prior to the first dose of investigational product (IP). After randomization, no anti-hormonal therapy may be initiated. |
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E.4 | Principal exclusion criteria |
1. Pregnant or lactating females. 2. Prior therapy with an ErbB1 and/or ErbB2 inhibitor other than trastuzumab. 3. Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel. Subjects with ulcerative colitis are also excluded. 4. History of other malignancy. However, subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible. 5. Concurrent disease or condition that would make the subject inappropriate for study participation or any serious medical disorder that would interfere with the subject's safety. 6. Unresolved or unstable, serious toxicity from prior administration of another investigational drug and/or of prior cancer treatment. 7. Active or uncontrolled infection. 8. Dementia, altered mental status, or any psychiatric condition that would prohibit the understanding or rendering of informed consent. 9. Known history of uncontrolled or symptomatic angina, arrhythmias, or congestive heart failure. 10. Known history or clinical evidence of leptomeningeal carcinomatosis. 11. Concurrent cancer therapy (chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy). 12. Concurrent treatment with an investigational agent or participation in another clinical trial. 13. Used an investigational drug within 3 weeks or 5 half-lives, whichever is longer, preceding the first dose of investigational product. 14. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trastuzumab or lapatinib or their excipients. 15. Current active hepatic or biliary disease |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Yes |
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) | 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 | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
Cross over is only from lapatinib monotherapy to the combination arm |
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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.8.5 | The trial involves multiple Member States | Yes |
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 | Information not present in EudraCT |
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 | 1 |
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 | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |