E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Histological confirmed endometrial cancer. (FIGO 2009) stage 3C2 or stage 4 or relapsed after adjuvant therapy for stage 1-3 disease.
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E.1.1.1 | Medical condition in easily understood language |
Patients with advanced endometrial 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 | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014741 |
E.1.2 | Term | Endometrial cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014733 |
E.1.2 | Term | Endometrial cancer |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014734 |
E.1.2 | Term | Endometrial cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10014735 |
E.1.2 | Term | Endometrial cancer NOS |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014736 |
E.1.2 | Term | Endometrial cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 21.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10014740 |
E.1.2 | Term | Endometrial cancer stage III |
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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary objective: To compare Progression free survival (PFS). Progression Free Survival (PFS) is defined as the time from randomization until disease progression or death by any cause. The progression events are defined by RECIST 1.1 criteria
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E.2.2 | Secondary objectives of the trial |
Secondary objectives: • Compare Progression free survival (PFS) in the sub-populations. • Progression-free survival after consecutive treatment (PFS2). • Compare Disease Specific Survival (DSS). Disease Specific Survival (DSS) is defined as the time from start of treatment until date of death from endometrial cancer. • TSST (Time to Second Subsequent Therapy) • TFST (Time to First Subsequent Therapy) • Overall Survival (OS). A patient’s overall survival is defined as the time from start of treatment until date of death from any cause. • Response Rate (RR). • Disease Control Rate (DCR = Complete Response, Partial Response or Stable Disease for at least 12 weeks). • Patient Related Outcomes (e.g. QoL). • Toxicity in the two treatment arms • Compliance and Exposure in the two treatment arms.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion criteria A patient will be eligible for inclusion only if all of the following criteria are fulfilled:
1. Histological confirmed endometrial cancer. (FIGO 2009)
a) Stage 3C 2 b) Stage 4 A & B c) First relapse. Relapsed patients may (or may not) have received adjuvant chemo-therapy. In case a patient has received adjuvant chemotherapy, the treatment-free interval should be >6 months.
Prior therapy 2. Patients may have undergone primary surgery. 3. Patients may have received adjuvant chemotherapy for stage 1 – 3. 4. Patients may have received vaginal brachytherapy 5. Patients may have received external beam radiotherapy. Patients who are to be enrolled for stage 3C2 diseases are allowed to receive external beam radiotherapy prior to trial entry. 6. Patients may have received hormonal treatment
Disease status 7. Patients must have measurable disease or non-measurable disease on CT scan according to RECIST 1.1 outside irradiated field. For stage 3C2 disease patients without measureable or non-measureable disease are accepted. Other inclusion criteria: 8. Patients must give informed consent 9. ECOG performance status of 0 -1 10. Patients must have an adequate organ function o Hepatic function: total bilirubin within normal limits; ALT and AST ≤ 1.5 x ULN in pts without liver metastasis. For Pts with liver metastasis: total bilirubin within normal limits, ALT or AST ≤ 2.5 ULN o Coagulation parameters: International normalised ratio ( INR) < 2, prothrombin time (PT) and partial thromboplastin time (PTT) < 50% of deviation of institutional ULN o Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; platelets ≥ 100 x 109L; haemoglobin ≥ 9.0 g/dL o Proteinuria < grade 2 o Creatinine < 1,5 ULN or GFR > 45 ml/min (calculated using Cockroft & Gault equation, Jellife equation or measured by EDTA clearance ) 11. Life expectancy of at least 12 weeks 12. Patients must be fit to receive combination chemotherapy 13. Patient’s age > 18 years 14. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment
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E.4 | Principal exclusion criteria |
Exclusion criteria A patient will not be eligible for inclusion if any of the following criteria are fulfilled:
Target Disease Exceptions: 1. Sarcomas, small cell carcinoma with neuroendocrine differentiation or non-epithelial cancers.
Prohibited Treatments and/or Therapies 2. Concurrent cancer therapy 3. Previous Chemotherapy for stage 4 disease or for relapsed disease. 4. Previous treatment with anti-angiogenic/anti VEGF therapy including nintendanib. 5. Concurrent treatment with an investigational agent or participation in another clinical trial. 6. Treatment within 28 days prior to randomisation with any investigational drug, radio-therapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy. Pallia-tive radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not involve target lesions, and the reason for the radiotherapy does not reflect progressive disease. 7. Major injuries or surgery within the past 21 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period.
Other exclusion criteria 8. Relapse within six months after adjuvant chemotherapy (treatment-free interval < 182 days). 9. Previous malignant disease, except patients with other malignant disease, for which the patient has been disease-free for at least three years. Concurrent other malignant disease except for curatively treated carcinoma in situ of the cervix or basal cell carcinoma of the skin. 10. Active infection or other serious underlying medical condition, which might prevent the patient from receiving treatment or to be followed. 11. Evidence of significant medical illness, abnormal laboratory finding or psychiatric ill-ness/social situation that would, in the Investigator’s judgement, make the patient inap-propriate for this study. 12. Known contraindications to VEGF directed therapy. 13. Known uncontrolled hypersensitivity to the investigational drugs. 14. History of major thromboembolic event defined as: • Uncontrolled pulmonary embolism (PE), defined as pulmonary embolism (PE) within 6 month prior to enrolment and/or recurrent pulmonary embolism (history of at least 2 events). • Deep venous thrombosis (DVT) • Other related conditions, though patients with stable therapeutic anticoagula-tion for more than three months prior randomization are eligible for this study. 15. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 3 months. 16. History of clinically significant haemorrhage in the past 3 months. 17. Radiotherapy to the target lesion within the past 3 months prior to baseline imaging 18.Persistant grade 3 or 4 toxicity from previous chemotherapy and/or radiotherapy, ex-cept alopecia. Patients with ongoing ≥ Grade 2 neuropathy are to be excluded. 19. Active brain metastases (e.g. stable for <4 weeks, no adequate previous treatment with radiotherapy, symptomatic, requiring treatment with anti-convulsants; dexame-thasone therapy will be allowed if administered as stable dose for at least one month be-fore randomisation). 20. Leptomeningeal disease 21. Significant cardiovascular diseases ( i.e. uncontrolled hypertension (hypertension not controlled by medical therapy), unstable angina, history of infarction within the past 12 months prior to start of study treatment, conges-tive heart failure > NYHA II, clinically relevant cardiac arrhythmia, pericardial effusion) See Appen-dix 12. 22. Pregnancy or breastfeeding. Patients with preserved reproductive capacity, unwilling to use a medically acceptable method of contraception for the duration of the trial and for 3 months afterwards. 23. Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent ma-jor blood vessels. 24. Known active or chronic hepatitis C and/or B infection and/or HIV. 25. Persistence of clinically relevant therapy related toxicity from previous chemo and/or ra-diotherapy 26. Known hypersensitivity to the trial drugs, or to their excipients. 27. Contra-indication to the use of carboplatin-paclitaxel combination 28. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug 29. Unable or unwilling to swallow tablets/capsules 30. Patients unable to be regularly followed for any reason (geographic, familiar, social, psy-chologic, housed in an institution eg. prison because of a court agreement or administrative order). 31. Subjects that are depending on the sponsor/CRO or investigational site as well as on the investigator. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Primary end-point To compare Progression Free Survival (PFS) of patients treated with chemotherapy plus nintedanib against chemotherapy plus placebo. Progression Free Survival (PFS) is defined as the time from randomization until disease progression or death by any cause.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis will be perform once 124 events are registered No interim analysis is planned |
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E.5.2 | Secondary end point(s) |
Secondary end-points • Compare Progression free survival (PFS) in the sub-populations as de-scribed under stratification factors. • Progression-free survival after consecutive treatment (PFS2). PFS2 is de-fined along the same timelines as PFS but accounts for the time from ran-domization to progression or death by any cause on any subsequent line of anticancer therapy. • Compare Disease Specific Survival (DSS). Disease Specific Survival (DSS) is defined as the time from start of treatment until date of death from en-dometrial cancer. • TSST (Time to Second Subsequent Therapy) • TFST (Time to First Subsequent Therapy) • Overall Survival (OS). A patient’s overall survival is defined as the time from start of treatment until date of death from any cause. • Response Rate (RR). • Disease Control Rate (DCR = Complete Response, Partial Response or Stable Disease for at least 12 weeks). • Patient Related Outcomes (e.g. QoL). • Toxicity in the two treatment arms • Compliance and Exposure in the two treatment arms.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
only after the primary endpoint is mature |
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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 | 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 | 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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | 40 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
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 | 4 |
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 |