E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced or recurrent cervical carcinoma |
carcinoma della cervice avanzato o recidivo |
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E.1.1.1 | Medical condition in easily understood language |
Advanced or recurrent cervical carcinoma |
carcinoma della cervice avanzato o recidivo |
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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 | 21.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10008229 |
E.1.2 | Term | Cervical 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 |
- To evaluate the progression free survival |
sopravvivenza libera da progressione |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the toxicity and safety profile - To evaluate the response rate and overall survival - To explore the effect on patient reported health status as measured by QOL-cx24 and EORTCQLQ-C30 questionnaires |
1. Valutare la sicurezza e la tossicità della combinazione. 2. Valutare il tasso di risposta secondo i criteri Recist 1.1 e la sopravvivenza globale. 3. Valutare l'effetto del trattamento sulla qualità di vita misurata con i questionari EORTC-QOL-Cx24 e QLQ-C30.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Women age > 18 2. Histologically or cytologically confirmed advanced (FIGO stage IVB), or recurrent/persistent squamous cell carcinoma, adenosquamous carcinoma, or adenocarcinoma of the cervix will be eligible. 3. No prior chemotherapy for recurrent cervical cancer. •Prior concomitant cisplatinum chemotherapy during radiotherapy is allowed (except if recurrence is within 6 months after the end of the platinum containing chemotherapy). •Cases primarily treated with neoadjuvant chemotherapy before radical local surgery are eligible at the time of first recurrence. (except if recurrence is within 6 months after the end of the platinum containing chemotherapy). •Cases primarily treated with neoadjuvant chemotherapy before radical local surgery followed by adjuvant radiochemotherapy are eligible at the time of first recurrence (except if recurrence is within 6 months after the end of the platinum containing chemotherapy). •Cases primarily treated with neoadjuvant chemotherapy before radical local surgery followed by adjuvant radiotherapy are eligible at the time of first recurrence (except if recurrence is within 6 months after the end of the platinum containing chemotherapy). 4. Life expectancy at least (3 months) 5. ECOG performance status score of 0 or 1 6. At least one measurable lesion according to RECIST 1.1 criteria. 7. Signed and dated written informed consent prior to admission to the study in accordance with ICH-GCP guidelines and to the local legislation
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1. Età maggiore di 18 anni. 2. Carcinoma della cervice uterina avanzato (stadio FIGO IVB) o recidivato, squamoso, adenocarcinoma, o adenosquamoso. 3. Nessuna precedente chemioterapia per recidiva di malattia. Una precedente chemio concomitante alla radioterapia è consentita se la recidiva si verifica oltre sei mesi dall'ultima somministrazione. Le pazienti trattate con chemioterapia neoadiuvante sono eleggibile se la recidiva si verifica oltre i sei mesi dall'ultima somministrazione. Le pazienti trattate con chemioterapia neoadiuvante prima della chirurgia seguita da radio-chemioterapia concomitante sono eleggibili se la recidiva si verifica oltre i sei mesi dall'ultima somministrazione di chemioterapia. Le pazienti trattate con chemioterapia neoadiuvante prima della chirurgia e successivamente trattate con radioterapia adiuvante sono eleggibili se la recidiva si verifica oltre i sei mesi dall'ultima somministrazione di chemioterapia. 4. Aspettativa di vita superiore a 3 mesi. 5. PS secondo ECOG 0 o 1. 6. Almeno una lesione misurabile secondo i criteri Recist 1.1. 7. Consenso informato firmato e datato prima dell'inclusione nello studio.
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E.4 | Principal exclusion criteria |
8. Prior chemotherapy except platin-based concomitant chemotherapy during radiotherapy 9. Prior treatment with nintedanib or any otherVEGFRinhibitor 10. Known hypersensitivity to the trial drugs or to their excipients (includingpeanut or soya). 11. Brain or leptomeningeal metastases 12. Centrally located tumors with radiographic evidence(CT or MRI)of local invasion of major blood vessels 13. Tumor infiltrating themucosa of the bowel or bladder, or known fistulas between the tumor and the gastrointestinal or urinary tract. 14. Radiographic evidence of cavitary or necrotic tumours 15. Treatment with other investigational drugs or treatment in another clinical trial within the past 4 weeks before start of therapy or concomitantly with the trial 16. Therapeutic anticoagulation with drugs requiring INR monitoring (except low-dose heparin and/or heparin flush as needed for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy(except for low-dose therapy with acetylsalicylic acid < 325 mg per day) 17. Major injuries within the past 4 weeks prior to start of study treatment with incomplete wound healing and/or planned surgery during the on-treatment study period 18. Historyof clinically significant haemorrhagic or thromboembolic event in the past6months 19. Known inheritated predisposition to bleeding or thrombosis 20. Significant cardiovascular diseases(i.e.uncontrolled hypertension, unstable angina, history of infarction within the past12months prior to start of study treatment, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardialeffusion) 21. History of a cerebral vascular accident, transient ischemic attack or subarachnoid haemorrhage within the past6months. 22. Abnormal renal, liver or bone marrow function defined as: • ProteinuriaCTCAE grade2or greater • Creatinine >1.5ULNorGFR<45ml/min • Hepatic function: total bilirubin outside of normal limits; ALTorAST> 1.5ULN in pts without liver metastasis. For Pts with liver metastases: total bilirubin outside of normal limits, ALTorAST>2.5ULN • Coagulation parameters: International normalised ratio(INR)>2, prothrombin time(PT) and partial thromboplastin time(PTT)>50% of deviation of institutionalULN • Absolute neutrophil count(ANC)<1500/µl, platelets <100000/µl, Haemoglobin <9.0 g/dl 23. Other malignancies within the past 3 years or other malignancy with recurrence the past3years or with high risk of recurrence in the first year. In exception to this rule, the following malignancies may be included: non-melanomatous skin cancer (if adequately treated) , any premalignant (e.g. in situ) carcinoma, or basocellular carcinoma. 24. Active serious infections in particular if requiring systemic antibiotic or antimicrobial therapy 25. Active or chronic hepatitis C and/or B infection or known HIV infection (based on medical file, only for Italy a mandatory screening test for HIV should be performed for all patients who did not have this test within the last 3 months before the study treatment start). 26. Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug 27. Serious illness or concomitant non-oncological disease such as neurologic, psychiatric, infectious disease or active ulcers(gastrointestinal tract, skin)or laboratory abnormality that may increase the risk associated with study participation or study drug administration and in the judgment of the investigator would make the patient inappropriate for entry into the study 28. Patients who are sexually active and unwilling to use a medically acceptable method of contraception(e.g.such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females,)during the trial and for at least three months after end of active therapy 29. Pregnancy or breast feeding, female patients must have a negative pregnancy test (ß-HCG test in urine or serum)prior to commencing study treatment
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1 Precedente chemioterapia per malattia recidivata. 2. Precedente terapia con Nintedanib o altri inibitori di VEGFR. 3. Ipersensibilità ai farmaci o i loro ingredienti (soia, arachidi). 4. Metastasi cerebrali o meningee. 5. Recidive centrali con evidenza TC o RMN di infiltrazione dei grossi vasi. 6. Neoplasia infiltrante la mucosa della vescica o dell'intestino o con fistole entero-urinarie o entero-enteriche. 7. Trattamento con altri farmaci sperimentali nelle 4 settimane precedenti la randomizzazione. 8. Evidenza radiografica dei tumori cavitari o necrotici. 9. Trattamento anticoagulante terapeutico con farmaci che richiedono monitoraggio dell’INR (ad eccezione eparina a basse dosi e/o soluzione eparinata per il mantenimento di un catetere endovenosa permanente) o anti-aggregante (ad eccezione di terapia a basse dosi con acido acetilsalicilico < 325 mg al giorno).
10. Ferite nelle 4 settimane precedenti all'inizio del trattamento, non completamente guarite. 11. Storia di eventi emorragici o tromboembolici clinicamente significativi nei precedenti sei mesi. 12. Difetti ereditari della coagulazione o dell'emostasi. 13. Malattie cardiovascolari significative (ad es. ipertensione non controllata, angina instabile, infarto del miocardio negli ultimi 12 mesi prima dell’inizio del trattamento in studio, scompenso cardiaco > NYHA II, aritmia cardiaca grave, versamento pericardiaco).
14. Accidenti vascolari cerebrali, TIA, o emorragie sub-aracnoidee negli ultimi sei mesi. 15. Alterazioni significative della funzione renale, epatica o midollare. 16. Altri tumori maligni negli ultimi 3 anni. 17. Malattie infettive significative che richiedono terapia antimicrobica. 18. Epatite B o C attiva o cronica, documentata infezione HIV (in Italia è obbligatorio un test di screening per l’HIV per tutte le pazienti che non hanno fatto il test negli ultimi 3 mesi prima dell’inizio del trattamento in studio). 19. Disordini gastrointestinali che possono interferire con l'assunzione orale del farmaco. 20. Malattie gravi o concomitanti quali neurologiche, psichiatriche, infettive o ulcere attive (gastrointestinale o cutanea) o esami di laboratorio che, nel giudizio dello sperimentatore, possano aumentare il rischio alla partecipazione allo studio.
21. Donne in età fertile che sono sessualmente attive e non disposte a utilizzare un metodo di contraccezione accettabile (ad es. impianti iniettabili, contraccettivi orali, dispositivi intrauterini, partner vasectomizzato, astinenza sessuale) durante lo studio e per almeno 3 mesi dopo la fine della terapia dello studio.
22 Gravidanza o allattamento. Se applicabile, le pazienti devono avere un test di gravidanza negativo (test ß HCG di urina o siero) prima di iniziare il trattamento in studio.
23. Fattori quali psicologici, familiari, sociologici, o geografici che possano interferire con la compliance della paziente al protocollo e al follow-up.
24. Abuso attivo di alcool o droghe.
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary objective of this trial is to determine whether BIBF in combination with standard chemotherapy significantly prolongs progression-free survival in comparison with placebo combined with standard chemotherapy.
The primary analyses will take an intent-to-treat approach of all randomised patients that will be treated with the study drug (BIBF/Placebo).
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The analysis is event driven and will be performed once 87 events have occured
Estimated: 1.5 years after last patient in |
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E.5.2 | Secondary end point(s) |
To evaluate toxicity and safety profile
To evaluate the response rate and overall survival
To explore the effect on patient reported health status as measured by QOL-Cx 24/QOQ-C30 questionnaires |
To evaluate toxicity and safety profile
To evaluate the response rate and overall survival
To explore the effect on patient reported health status as measured by QOL-Cx 24/QOQ-C30 questionnaires |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
The analysis is driven by survival information
Estimated: at latest 5 years after last patient in |
The analysis is driven by survival information
Estimated: at latest 5 years after last patient in |
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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 | 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) | 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 | 12 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 | Information not present in EudraCT |
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 clinical trial will be considered completed as soon as the last patient has died or was lost to follow-up or at the time of the final analysis at the latest.
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LVLS |
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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 | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
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 |