E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
The subjects participated in the EGF105485 study, a randomized, placebo-controlled study of lapatinib in HER2-positive early-stage breast cancer. During participation in this study, subjects had blood test results that may be suggestive of liver damage. |
Los sujetos participaron en el estudio EGF105485, estudio randomizado controlado con placebo de lapatinib en pacientes con cáncer de mama HER2 positivas en fases tempranas. Durante la participación en este estudio los pacientes tuvieron resultados analíticos sugerentes de daño hepático. |
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E.1.1.1 | Medical condition in easily understood language |
subjects participated in EGF105485 study, a randomized, placebo-controlled study of lapatinib in HER2-positive early-stage breast cancer. |
Los sujetos participaron en el estudio EGF105485, estudio randomizado controlado con placebo de lapatinib en pacientes con cáncer de mama HER2 positivas en fases tempranas |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
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 |
The overall objective is to determine key events involved in sensitisation and lapatinibinduced hepatotoxicity in selected subjects. The following objectives outline key workstreams for investigation. 1) Characterisation of lapatinib-specific ex vivo stimulation and proliferation of peripheral blood mononuclear cells (PBMCs) by comparison of subjects who experienced lapatinib-induced liver injury (cases) with HLA and geographic matched, lapatinib-treated, but tolerant controls (treatment controls) and with HLA and geographic matched placebo-treated, normal liver chemistry controls (disease controls). 2) Define the phenotype (CD4/CD8 expression) and function (cytokine release, helper or cytotoxic phenotype) of lapatinib-specific T cells. Please refer to the protocol for further deatils P7. |
El objetivo principal es determinar los mecanismos fundamentales implicados en la sensibilización y la hepatotoxicidad inducida por lapatinib en algunos sujetos. Los siguientes objetivos resumen las líneas principales de investigación de este estudio. 1) Caracterización de la estimulación y proliferación ex vivo de células mononucleares de sangre periférica (CMSP) expuestas a lapatinib mediante la comparación de pacientes que presentaron lesiones hepáticas inducidas por lapatinib (casos) frente a controles tratados también con lapatinib, pero tolerantes, emparejados por HLA y región geográfica (controles de tratamiento) y frente a controles tratados con placebo, con una bioquímica hepática normal, y emparejados por región geográfica (controles de enfermedad). 2) Definición del fenotipo (expresión de CD4/CD8) y la función (fenotipo liberador de citocinas, colaborador o citotóxico) de los linfocitos T específicos de lapatinib. (Consulte el Protocolo para más detalle, pág. 15) |
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E.2.2 | Secondary objectives of the trial |
Not applicable |
No aplicable |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Note that treatment and disease controls will only be collected if their respective, matched case is able to consent and provide a blood sample.
The four groups of subjects will be selected as follows: i) lapatinib-treated subjects who had a previously reported and documented hepatic serious adverse event (cases), ii) selected lapatinib treated subjects who did not experience liver adverse events, with normal liver chemistries at baseline and throughout treatment (treatment controls) and iii) placebo treated subjects who had normal liver chemistries at baseline and throughout treatment (disease controls). Subjects for the two control groups will be matched with the casesbased on their HLA-DQA1*02:01/DRB1*07:01 allele carriage, ethnicity, study site (where possible) and country.
In addition, HLA-DRB1*07:01 and ?DQA1*02:01 alleles are inherited together in 99.8% of the study population and genetic investigation has not determined which of the two alleles is causative for hepatotoxicity. However, three EGF105485 (TEACH) subjects have been identified with a rare mismatch of inheriting only one of these highly correlated alleles: HLA-DRB1*07:01 (1 subject, lapatinib treatment) or HLADQA1* 02:01 (2 subjects, lapatinib or placebo treatment). These three subjects were characterised as controls and reside in North America. Whole blood samples will be collected to enable comparison of T cell activation following lapatinib challenge ex vivo. |
Debe tenerse en cuenta que sólo se incluirán controles de tratamiento y de enfermedad si los respectivos casos están capacitados para otorgar su consentimiento y proporcionar una muestra de sangre. Los cuatro grupos de pacientes se seleccionarán como sigue: i) pacientes tratadas con lapatinib que notificaron y documentaron anteriormente algún acontecimiento adverso hepático grave (casos); ii) pacientes seleccionadas que recibieron tratamiento con lapatinib sin presentar acontecimientos adversos hepáticos, con una bioquímica hepática normal en el momento basal y durante todo el tratamiento (controles del tratamiento); y iii) pacientes tratadas con placebo que obtuvieron resultados normales en la bioquímica hepática en el momento basal y durante todo el tratamiento (controles de la enfermedad). Se emparejará a pacientes de los dos grupos de control con los casos en función de su condición de portadoras de alelos HLA-DQA1*02:01/DRB1*07:01, su origen étnico, el centro del estudio (cuando sea posible) y el país. Además, los alelos HLA-DRB1*07:01 y HLA-DQA1*02:01 se heredan conjuntamente en el 99,8 % de la población del estudio y la investigación genética no ha determinado cuál de esos dos alelos causa la hepatotoxicidad. No obstante, se ha identificado a tres pacientes del estudio EGF105485 (TEACH) con una rara discordancia en su condición de portadoras de solo uno de esos alelos estrechamente correlacionados: HLA-DRB1*07:01 (1 paciente, tratamiento con lapatinib) o HLA-DQA1*02:01 (2 pacientes, tratamiento con lapatinib o placebo). Estas tres pacientes se han caracterizado como controles y residen en América del Norte. Se recogerán muestras de sangre completa para permitir una comparación de la activación de linfocitos T después de su exposición a lapatinib ex vivo. |
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E.4 | Principal exclusion criteria |
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E.5 End points |
E.5.1 | Primary end point(s) |
Lymphocyte proliferation by [3H]thymidine incorporation.
Cytokine release profiles of activated T cell subsets by EliSpot and specific ELISA assays of supernatant of cultured cells.
CD4/CD8 expression in T cell subsets by flow cytometry to determine whether functional activation of T cells is restricted to the CD4 or CD8 compartments. |
Proliferación de linfocitos determinada por la incorporación de [3H]timidina.
Perfiles de liberación de citocinas de subpoblaciones de linfocitos T activados mediante EliSpot y análisis ELISA específico del sobrenadante de las células cultivadas.
Expresión de CD4/CD8 en subpoblaciones de linfocitos T mediante citometría de flujo para determinar si la activación funcional de los linfocitos T se limita a los compartimentos CD4 o CD8. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Once all blood samples have been collected, they will be shipped to Quest for storage then to an expert academic research group in the UK. |
Una vez se hayan cogido las muestras de sangre serán enviadas a Quest para su almacenaje y luego a un grupo académico de expertos investigadores en Reino Unido. |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
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 | No |
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 |
Only blood samples are collected no IMP administered |
Se recogerán únicamente muestras de sangre, no se administrará ningún fármaco. |
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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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 |
no intervencionista |
Non-Interventional |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 0 |
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 24 |
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 | No |
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 |
Argentina |
Denmark |
Spain |
United States |
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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
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LVLS |
Última visita del último paciente. |
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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 | |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 9 |