E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Unresectable Malignant Pleural Mesothelioma |
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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 |
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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 | 19.1 |
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) |
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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. |
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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) (Phase II part only), to obtain information on health-related quality of life (HRQoL) [Phase III part only], 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 |
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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 |
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 |
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E.3 | Principal inclusion criteria |
- Histologically confirmed MPM (subtype: epithelioid or biphasic for Phase II or epithelioid only for Phase III)
- Life expectancy of at least 3 months in the opinion of the investigator
- ECOG score of 0 or 1
- Measurable disease according to modified RECIST criteria
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E.4 | Principal exclusion criteria |
- Previous systemic chemotherapy for MPM
- Prior treatment with nintedanib or any other prior line of therapy
-Phase II patients with sarcomatoid subtype MPM or Phase III patients with sarcomatoid or biphasic subtype
- Radiotherapy (except extremities) within 3 months prior to baseline imaging
- Patients that may be eligible for or being considered for radical resection or elective surgery during the course of the study.
- Radical surgery within 4 weeks prior to randomisation
- Active brain metastases (e.g. stable for < 4 weeks)
- Therapeutic anticoagulation or anti-platelet therapy (except for low-dose therapy with acetylsalicylic acid < 325 mg per day)
- Major injuries within the past 4 weeks prior to randomisation with incomplete wound healing
- Other malignancies within 3 years prior to screening other than basal cell skin cancer or carcinoma in situ of the cervix |
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival measured from the time of randomisation to the time of disease progression or death of any cause, whichever occurs earlier |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For Phase II, the observation period for PFS is defined from randomisation until the earliest of disease progression, death or the cut-off of 04-Mar-2016 for the primary PFS analysis.
For Phase III, the observational period for PFS will continue until the earliest of disease progression, death or until approximately 199 PFS events have occured for Phase III patients or until approximately 23 months have elapsed since the first Phase III patient was randomised.
Planned timepoint: April 2018 |
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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 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
For Phase II, the observation period for OS is until the earliest of death or until approximately 61 Phase II patients have died, whichever occurs first.
For Phase III, the observation period for OS is from randomisation until the earliest case of death or until approximately 279 to 346 (depending on the event reassessment) OS events have occured for Phase III patients or until approximately 54 months have elapsed since the first Phase III patient was randomised. If the trial is declared positive also for OS at the time of the interim Phase III OS analysis, the observation period for OS will continue until approximately 199 PFS events have occured.
Final evaluation: November 2020 |
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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 | 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 |
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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) | 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
| 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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 74 |
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 |
Croatia |
Czech Republic |
Denmark |
Egypt |
France |
Germany |
Israel |
Italy |
Japan |
Mexico |
Netherlands |
Norway |
Poland |
Portugal |
Russian Federation |
South Africa |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
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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
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The end of the whole trial will occur when:
- The required number of OS events has occured and the last patient has completed the first follow-up vist.
- The trial is declared positive for PFS and OS at the interim OS analysis and the last patient has completed the first follow-up visit.
- The trial is declared negative at the interim OS analysis and the last patient has completed the first follow-up visit. |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 2 |
E.8.9.1 | In the Member State concerned days | 26 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 1 |
E.8.9.2 | In all countries concerned by the trial days | 0 |