E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with metastatic colorectal cancer refractory to standards therapies |
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E.1.1.1 | Medical condition in easily understood language |
refractory colorectal cancer |
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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 | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10052362 |
E.1.2 | Term | Metastatic colorectal cancer |
E.1.2 | System Organ Class | 100000004864 |
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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 objective of this Phase III study is to evaluate the efficacy and safety of nintedanib in patients with mCRC after failure of previous treatment with standard chemotherapy and biological agents. |
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E.2.2 | Secondary objectives of the trial |
Secondary objectives are Objective tumour response, disease control, quality of life and safety. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Age ≤ 18 years
- Signed informed consent
- Histologically or cytologically confirmed colorectal adenocarcinoma
- Metastatic or locally advanced disease not amenable to curative surgery and/or radiotherapy
- Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1
- At least one measurable lesion according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1
- Progression on standard therapies or withdrawn from standard treatment due to unacceptable toxicity. Previous standard treatment must include all of the following:
- - fluoropyrimidine
- - oxaliplatin: Patients treated with oxalipatin in adjuvant setting should have progressed within 6 months of completion of adjuvant therapy or they must have been treated with oxaliplatin for metastatic disease
- - irinotecan
- - bevacizumab or aflibercept
- - cetuximab or panitumumab for patients with K-Ras wt or Ras wt tumours
- - previous treatment with regorafenib is allowed
- - Life expectancy of at least 12 weeks
- - Hepatic function: aspartate aminotransferase (AST)/ Alanine Amino Tranferase (ALT) ≤ 1.5 X Upper Limit of Normal (ULN) and bilirubin ≤ ULN for patients without liver metastases. AST/ALT ≤ 2.5 X ULN and bilirubin ≤ ULN for patients with liver metastases. Patients with Gilbert syndrome and bilirubin < 2 X ULN and normal AST/ALT are eligible
- Coagulation parameters: International normalised ratio (INR) < 2 and prothrombin Time (PTT) ≤ 2xULN
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E.4 | Principal exclusion criteria |
- Previous treatment with nintedanib
- toxicity attributed to previous anticancer therapy that did not resolve to Common Terminology Criteria for Adverse Events (CTCAE) grade ≤ 1
- History of other malignancies in the last 5 years, in particular those that could interfere with interpretation of results.
- Serious concomitant disease or medical condition affecting compliance with trial requirements or which are considered relevant for the evaluation of the efficacy or safety of the trial drug,
- Significant cardiovascular diseases
- History of severe haemorrhagic or thromboembolic event in the past 12 months
- Bleeding or thrombotic disorders requiring anticoagulant therapy such as warfarin, or similar agents requiring therapeutic INR monitoring
- Gastrointestinal disorders or abnormalities that would interfere with absorption of study drug
- Patient with brain metastases that are symptomatic and/or require therapy.
- Patients of childbearing potential who are sexually active and unwilling to use a highly effective method of contraception
- Pregnancy or breast-feeding. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Co-primary endpoints: progression-free survival (PFS) by central review assessment and overall survival (OS)
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1: Objective tumour response
2: Disease control
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: 22 months
2: 22 months
3: 22 months
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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 | Yes |
E.6.11 | Pharmacogenomic | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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 | 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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 66 |
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 |
Czech Republic |
Denmark |
France |
Germany |
Hong Kong |
Israel |
Italy |
Japan |
Korea, Republic of |
Luxembourg |
Mexico |
Netherlands |
Poland |
Portugal |
Russian Federation |
Singapore |
Spain |
Sweden |
Taiwan |
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 trial will occur when the last patient completes his/her REP period and the required number of OS events has occurred |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 2 |