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. |
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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. |
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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. |
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E.2.2 | Secondary objectives of the trial |
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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 lapatinibtreated 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. |
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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.
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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. |
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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 |
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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 |
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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 | 5 |
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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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 |