E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable Malignant Pleural Mesothelioma |
|
E.1.1.1 | Medical condition in easily understood language |
Cancer of the pleura (the lining covering the lungs) which cannot be treated by surgery |
|
E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10059518 |
E.1.2 | Term | Pleural mesothelioma malignant |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of the randomised, parallel-controlled Phase II/III study is to evaluate the safety and efficacy in terms of progression-free survival of nintedanib + pemetrexed / cisplatin followed by nintedanib (arm A) versus placebo + pemetrexed / cisplatin followed by placebo (arm B), as first line treatment for patients with unresectable MPM. |
|
E.2.2 | Secondary objectives of the trial |
The key secondary objective is to evaluate OS in patients treated with the nintedanib regimen (arm A) versus the placebo regimen (arm B).
Further secondary objectives are to evaluate the objective tumour response rate and to evaluate the disease control rate. Further
objectives in this trial are to evaluate related measures of tumour response, to assess the percentage changes from baseline in forced vital
capacity (FVC), to obtain information on quality of life (QoL), and to examine exposure to nintedanib in patients with unresectable MPM. In
addition, biological specimens will be collected for the evaluation of molecular markers and possible correlation with treatment outcome. |
|
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 |
No individual trial protocols will be used for substudies. The following investigations are integrated in the protocol of the main study:
- Optional analysis of archived tumour tissue and serum derived biomarkers: the set of planned biomarkers is exploratory in nature and will be used as hypothesis-generating studies
- Optional pharmacogenomic analysis: Genotyping of promoter variants in the mesothelin gene, analysis of polymorphisms in the genes encoding for VEGFR1 and VEGFR3 and DNA-banking |
|
E.3 | Principal inclusion criteria |
- Histologically confirmed malignant pleural mesothelioma (MPM) (subtype: epithelioid or biphasic)
- Life expectancy of at least 3 months in the opinion of the investigator
- Eastern Cooperative Oncology Group (ECOG) score of 0 or 1
- Measurable disease according to modified Response
Evaluation Criteria In Solid Tumours (RECIST) criteria
|
|
E.4 | Principal exclusion criteria |
- Previous systemic chemotherapy for MPM
- Prior treatment with nintedanib or any other prior line of therapy
- Patients with sarcomatoid subtype MPM
- Patients with symptomatic neuropathy
- Radiotherapy (except extremities) within 3 months prior to baseline imaging
- Active brain metastases (e.g. stable for < 4 weeks)
- Radiographic evidence of cavitary or necrotic tumours or local invasion of major blood vessels by MPM
- Significant cardiovascular diseases
- Inadequate hematologic, renal, or hepatic function |
|
E.5 End points |
E.5.1 | Primary end point(s) |
1. Progression free survival measured from the time of randomisation to the time of disease progression or death of any cause, whichever occurs earlier |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
The observation period for PFS will continue until approximately 237 OS events have occurred for Phase III patients or until approximately 44 months has elapsed since the first Phase III patient was randomised
Planned timepoint: November 2018 |
|
E.5.2 | Secondary end point(s) |
- Overall survival measured from the time of randomisation to the time of death of any cause (key secondary endpoint)
- Objective response according to modified RECIST analysed by objective response rate
- Disease control according to modified RECIST analysed by disease control rate
|
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
At the time of PFS analysis (November 2018) and if patients are still ongoing or in follow-up at the time of the clinical trial report for PFS, the clinical trial database will be kept open to collect the additional data.
Final evaluation: November 2018 |
|
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 | Yes |
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 | Yes |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
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) | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 64 |
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 |
Australia |
Austria |
Belgium |
Canada |
Chile |
Czech Republic |
Denmark |
Egypt |
France |
Germany |
Israel |
Italy |
Mexico |
Netherlands |
Norway |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
|
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
|
The trial will be considered completed 18 months after the last patient was randomised. The primary analysis of PFS will be conducted and reported when approximately 237 patients have progressed or died. However, it may also be performed with fewer events within approximately 44 months total trial duration. If patients are still ongoing or in follow-up at the time of the clinical trial report for PFS, the clinical trial database will be kept open to collect the additional data. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 5 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |