E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Recurrent clear cell carcinoma of the ovary or endometrium |
Carcinome à cellules claires de l’ovaire ou de l’endomètre en rechute |
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E.1.1.1 | Medical condition in easily understood language |
ovarian or endometrial clear cell cancer that has come back or started to grow again |
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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 | PT |
E.1.2 | Classification code | 10009252 |
E.1.2 | Term | Clear cell endometrial carcinoma |
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 | 19.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10066697 |
E.1.2 | Term | Ovarian cancer recurrent |
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 this research is to estimate progression-free survival (PFS) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib, and to compare this with PFS in women treated with chemotherapy. |
Evaluer la survie sans progression chez des femmes en rechute d’un carcinome de l’ovaire et de l’endomètre à cellules claires, traitées par Vargatef ® (nintedanib) et la comparer à la survie sans progression chez des femmes traitées par chimiothérapie. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this research are to estimate or assess the following and compare them between women receiving chemotherapy and women receiving Nintedanib:
-Estimate overall survival, response rate, disease control rate. -Assess toxicity, quality of life,Q-TWIST (quality-adjusted time without symptoms of disease or toxicity of treatment)in women with clear cell carcinoma of the ovary, -Q-TWIST in women with clear cell carcinoma of the endometrium -Estimate progression-free survival, overall survival, response rate, disease control rate and to record treatment received post-progression. |
Les objectifs secondaires de cette étude cherchent à évaluer entre les femmes recevant une chimiothérapie et celles recevant du Nintedanib les éléments suivants : - La survie sans progression, le taux de réponse global, le taux de contrôle de la maladie, le traitement reçu après récidive, la survie globale. - La toxicité, la qualité de vie, le temps de qualité ajusté sans symptômes de la maladie ou de toxicité au traitement (Q-TWIST)
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Progressive or recurrent ovarian clear cell carcinoma, or progressive or recurrent endometrial clear cell carcinoma. The primary diagnosis must be histologically confirmed and central pathological review of the presenting tumour or biopsy of relapsed disease must find at least 50% clear cell carcinoma with no serous differentiation. Progressive disease as defined by RECIST 1.1. 2.Failure after ≥1 prior platinum containing regimen which may have been given in the adjuvant setting. For patients with ovarian clear cell carcinoma, progression must have occurred within 6 months of their last platinum dose. 3.ECOG Performance status of ≤2. 4.Life expectancy of >3 months. 5.Adequate hepatic, bone marrow coagulation and renal function a.Hepatic function: total bilirubin within normal limits; ALT and AST < 2.5 x ULN b.Coagulation parameters: INR <2 x ULN and prothrombin time and activated partial thromboplastin time < 1.5 x ULN in the absence of therapeutic anticoagulation c.absolute neutrophil count (ANC) ≥ 1.5 x 109/L d.platelets ≥ 100 x 109L e.haemoglobin ≥ 9.0 g/dL f.proteinuria < grade 2 CTCAE (version 4) g.Glomerular Filtration Rate ≥40ml/min. (calculated using Cockroft & Gault equation or measured by EDTA clearance) 6.Female and > 18 years of age. 7.Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and local legislation. 8.Willingness and ability to comply with scheduled visits, treatment plans and laboratory tests and other study procedures.
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1. Carcinome de l’ovaire ou de l’endomètre à cellules claires en progression ou en rechute. Le diagnostic initial doit être confirmé histologiquement par une revue centralisée du bloc de tumeur ou de la biopsie de la maladie en rechute. La confirmation du diagnostic implique la présence d’au moins 50 % de cellules claires sans différentiation séreuse. Maladie progressive selon la définition des critères RECIST 1.1) 2. Echec après 1 ou plusieurs cures à base de sels de platine administrées dans le cadre d’un traitement adjuvant. Pour les patientes avec un carcinome de l’ovaire à cellules claires, la progression doit être survenue dans les 6 mois suivant la dernière dose de sels de platine. 3. Indice de performance ECOG 2. 4. Espérance de vie ≥ 3 mois. 5. Fonctions rénale, hépatique et coagulation suffisantes : a. Fonction hépatique : bilirubine totale dans les limites de la normale ; ALAT et ASAT < 2.5 LSN. b. Paramètres de coagulation : INR < 2 x LSN et temps de prothrombine et temps de thromboplastine partielle activée (aPTT) < 1.5 x LSN en l’absence de traitement anticoagulant. c. Polynucléaires neutrophiles ≥ 1.5 x 109/L. d. Plaquettes ≥ 100 x 109/L. e. Hémoglobine ≥ 9.0 g/dL. f. Protéinurie < grade 2 (CTCAE version 4). g. Taux de filtration glomérulaire ≥ 40 ml/min (calculé selon la formule de Wright ou Cockroft & Gault ou mesuré par la clairance EDTA). 6. Age ≥ 18 ans. 7. Consentement signé et daté avant l’admission dans l’étude. 8. Souhait et la capacité de se conformer aux visites programmées, au plan de traitement, aux tests de laboratoire et aux procédures de l’essai.
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E.4 | Principal exclusion criteria |
1.Prior treatment with Nintedanib or other angiogenesis inhibitor/VEGF targeted therapy, except for prior treatment with bevacizumab which is permitted.. 2.Treatment within the last 4 weeks with any investigational drug, radiotherapy, immunotherapy, chemotherapy, hormonal therapy or biological therapy. Palliative radiotherapy may be permitted for symptomatic control of pain from bone metastases in extremities, provided that the radiotherapy does not affect target lesions, and the reason for the radiotherapy does not reflect progressive disease. 3.Previous treatment with the chemotherapy regimen selected as the control arm by the investigator. (Prior therapy with paclitaxel given on a three weekly regimen is permitted for patients receiving weekly paclitaxel). 4.Other malignancy diagnosed within 5 years of enrolment except for: a.non-melanomatous skin cancer (if adequately treated) b.cervical carcinoma in situ (if adequately treated) c.carcinoma in situ of the breast (if adequately treated) d.For patients with ovarian clear cell cancer, prior or synchronous endometrial cancer (if adequately treated), provided all of the following criteria are met: •disease stage FIGO Stage 1a (tumour invades less than one half of myometrium) •Grade 1 or 2 5.Patients with any other severe concurrent disease, which may increase the risk associated with study participation or study drug administration and, in the judgement of the investigator, would make the patient inappropriate for entry into this study, including significant neurologic, psychiatric, infectious, hepatic, renal, or gastrointestinal diseases or laboratory abnormality. 6.Symptoms or signs of gastrointestinal obstruction requiring parenteral nutrition or hydration or any other gastro-intestinal disorders or abnormalities, including difficulty swallowing, that would interfere with drug absorption. 7.Serious infections in particular if requiring systemic antibiotic (antimicrobial, antifungal) or antiviral therapy, including known hepatitis B and/or C infection and HIV-infection. 8.Symptomatic CNS metastasis or leptomeningealcarcinomatosis. 9.Known, uncontrolled hypersensitivity to the investigational drugs or their excipients. 10. Hypersensitivity to Nintedanib, peanut or soya, or to any of the excipients of Nintedanib. 11.Significant cardiovascular diseases, including uncontrolled hypertension, clinically relevant cardiac arrhythmia, unstable angina or myocardial infarction within 6 months prior to enrolment, congestive heart failure > NYHA III, severe peripheral vascular disease, clinically significant pericardial effusion. 12.History of major thromboembolic event, such as pulmonary embolism or proximal deep vein thrombosis,unless on stable therapeutic anticoagulation 13.Known inherited predisposition to bleeding or thrombosis. 14.History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past 6 months. 15.History of clinically significant haemorrhage in the past 6 months. 16.Major injuries or surgery within the past 28 days prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period. 17.Pregnancy or breastfeeding. Patients with preserved reproductive capacity must have a negative pregnancy test (β-HCG test in urine or serum) prior to commencing study treatment. 18.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. 19.Radiographic evidence of cavitating or necrotic tumours with invasion of adjacent major blood vessels. 20.Any psychological, familial, sociological or geographical consideration potentially hampering compliance with the study protocol and follow up schedule; those considerations should be discussed with the patient before registration in the trial.
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1. Traitement antérieur par nintedanib ou autre thérapie ciblée comportant un inhibiteur de l’angiogenèse/VEGF, à l’exception du bevacizumab qui est autorisé. 2. Traitement dans les 28 jours avant randomisation avec un traitement expérimental, une radiothérapie, une immunothérapie, une chimiothérapie, une hormonothérapie ou une thérapie ciblée. La radiothérapie palliative est permise dans le cas où elle permet de contrôler la douleur de métastases osseuses au niveau des extrémités, à condition que la radiothérapie n’affecte pas les lésions cibles et que cette radiothérapie n’est pas imputée à une progression de la maladie. 3. Traitement antérieur par la chimiothérapie qui sera choisi dans le bras contrôle par l'investigateur (un traitement antérieur par paclitaxel donné trois fois par semaine est autorisé pour les patientes recevant du paclitaxel hebdomadaire. Un traitement antérieur par paclitaxel en hebdomadaire est autorisé dans le cadre de la prise en charge de première ligne et si la dernière dose de paclitaxel a eu lieu il y a plus de 6 mois. Le placitaxel hebdomadaire n’est pas autorisé en traitement antérieur dans le cadre de la rechute). 4. Autre pathologie maligne dans les 5 dernières années, à l’exception de : a. un cancer cutané non-mélanomateux (si traité de manière adéquate) b. un carcinome in situ du col utérin (si traité de manière adéquate) c. un carcinome du sein in situ (si traité de manière adéquate) d. un cancer de l'endomètre (si traité de manière adéquate) antérieur ou synchrone pour les patientes atteintes de cancer à cellules claires de l'ovaire , à condition que les tous critères suivants soient respectés : • Stade FIGO Ia (tumeur envahissant moins de la moitié du myomètre) • Grade 1 ou 2 5. Patientes atteintes d'une autre maladie concomitante sévère, qui peut augmenter le risque associé à la participation à l'étude ou au médicament de l’étude administré et, de l'avis de l'investigateur, qui peut rendre la patiente inappropriée à l'inclusion dans cette étude, y compris les maladies significatives neurologiques, psychiatriques, infectieuses, hépatiques, rénales ou gastro-intestinales ou toute anomalie biologique. 6. Symptômes ou signes d'obstruction gastro-intestinale nécessitant une nutrition parentérale ou une hydratation ou tout autre trouble ou anomalie gastro-intestinal, y compris la difficulté à avaler, pouvant interférer avec l'absorption du médicament. 7. Infections graves, en particulier si elles nécessitent la prise d’un antibiotique en intraveineux (antimicrobien, antifongique) ou une thérapie antivirale, y compris les infections connues telles que l'hépatite B et / ou C et le VIH. 8. Métastases symptomatiques du SNC ou une carcinose leptoméningée. 9. Hypersensibilité non contrôlée aux médicaments expérimentaux ou à leurs excipients. 10. Hypersensibilité au nintedanib, à l’arachide ou au soja, ou à tout autre excipient du nintedanib.. 11. Maladies cardio-vasculaires cliniquement significative, y compris une hypertension non contrôlée, une arythmie cardiaque cliniquement significative, une angine de poitrine non stabilisée ou un infarctus du myocarde dans les 6 mois précédant la randomisation, une insuffisance cardiaque congestive > NYHA III, une maladie vasculaire périphérique sévère ou un épanchement péricardique cliniquement significatif. 12. Antécédent d’événement thromboembolique majeur, tel qu’une embolie pulmonaire ou une thrombose veineuse profonde proximale, excepté en cas de stabilisation par un traitement anticoagulant. 13. Prédisposition héréditaire connue aux hémorragies ou aux thromboses. 14. Antécédents d'accident vasculaire cérébral, d’accident ischémique transitoire ou d’hémorragie sous-arachnoïdienne dans les 6 derniers mois. 15. Antécédents d'hémorragie cliniquement significative dans les 6 derniers mois. 16. Blessures graves ou chirurgie dans les 28 jours précédant le début du traitement de l’étude avec guérison incomplète de la plaie et / ou chirurgie programmée au cours de la période sous traitement de l’étude. 17. Grossesse ou allaitement. Les patientes avec des capacités de reproduction conservées doivent avoir un test de grossesse négatif (test β - HCG dans les urines ou sérum) avant de commencer le traitement de l'étude. 18. Pour les patientes en âge de procréer, l’absence de volonté d'utiliser une méthode de contraception médicalement acceptable pendant la durée de l'essai et les 3 mois suivants. 19. Preuve radiographique de tumeurs nécrotiques ou encavées avec invasion des vaisseaux sanguins majeurs adjacents. 20. Toute considération psychologique, familiale, sociologique ou géographique qui peut potentiellement entraver la compliance au protocole de l'étude et le suivi, ces considérations devant être discutées avec la patiente avant l’inclusion dans l’essai.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary outcome measure is to estimate the progression free survival (PFS)as defined by RECIST 1.1 criteria, in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to PFS in women treated with chemotherapy. PFS is defined as the duration of time from date of randomisation to date of progression or death, which ever occurs earlier. CA125 progression alone will not be considered as progressive disease.
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease evaluation will be performed based on tumour imaging. All patients will undergo baseline evaluation tumour assessment with a CT scan or MRI of abdomen and pelvis plus a thoracic CT or CXR imaging within 28 days prior to starting study treatment. The same modality should be used for the duration of the study. From date of randomisation until wk 48 or until progressive disease occurs, patients will undergo imaging every 8 weeks. Patients who have not progressed by wk 48 will have a further scan at wk 72. In patients who do not progress by wk 72, subsequent imaging will be performed only as clinically indicated. Patients that come off treatment for reasons other than progression continue to have imaging scans at the specified time points. |
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E.5.2 | Secondary end point(s) |
To estimate overall survival (OS) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to OS in women treated with chemotherapy.
To estimate response rate (RR) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to RR in women treated with chemotherapy.
To estimate disease control rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and compare this to DCRS in women treated with chemotherapy.
To assess toxicity in women with relapsed clear cell carcinoma of the ovary and endometrium treated with Nintedanib and compare this to women treated with chemotherapy.
To assess quality of life in women with relapsed clear cell carcinoma of the ovary and endometrium treated with Nintedanib and compare this to women treated with chemotherapy.
To assess Q-TWiST (Quality-Adjusted Time Without Symptoms of Disease or Toxicity of Treatment) in women with relapsed clear cell carcinoma of the ovary treated with Nintedanib and and compare this with those treated with chemotherapy.
To assess Q-TWiST in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate progression free survival (PFS) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate overall survival (OS) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate response rate (RR) in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To estimate disease control rate (DCR = Complete Response, Partial Response and Stable Disease) at 12 weeks in women with relapsed clear cell carcinoma of the endometrium treated with Nintedanib and those treated with chemotherapy.
To record treatment received post progression.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
-Toxicity: day 1 of each cycle of treatment (NCI CTC AE version 4.0). -Q-TWiST: This is assessed by combining toxicity and progression data.Progression is assessed using the imaging data (see 23-1). -RR and DCR: Assessed from imaging data (see 23-1). -Quality of life (QoL): QoL questionnaires will be completed at screening, and day 1 of cycle 2, 4 and 6. For patients on chemotherapy QoL assessments will be performed at the end of treatment visit and every 8 weeks subsequently and for patients on Nintedanib, day 1 of every cycle from cycle 7 onwards. QoL assessments will continue 2 monthly post progression as long as the PI considers it appropriate and the patient continues to consent -Patients will be followed up for survival after progression (every 2 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 | No |
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 | Yes |
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 | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | Yes |
E.8.2.2 | Placebo | No |
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 | 16 |
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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For the purpose of the Clinical Trial Authorisation the trial is deemed to have ended 30 days after the last patient remaining on treatment receives the last dose of Nintedanib.
For the purposes of the main REC approval, the study end date is deemed to be the date of last data capture. |
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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 | 5 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | 1 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 1 |