E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Colorectal Neoplasms |
Tumore del colon retto |
|
E.1.1.1 | Medical condition in easily understood language |
Colorectal Neoplasms |
Tumore del colon retto |
|
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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10052358 |
E.1.2 | Term | Colorectal cancer metastatic |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
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 provide mCRC patients (similar to the patients evaluated in the VELOUR phase III trial) and Investigators with access to aflibercept, prior to its marketing authorisation and/or commercial availability and to document the aflibercept overall safety in this patient population. |
Fornire ai pazienti affetti da mCRC (con caratteristiche simili ai pazienti valutati nello studio clinico di fase III VELOUR) e agli sperimentatori l’accesso ad aflibercept prima dell’ autorizzazione alla commercializzazione e/o disponibilità in commercio e documentare il profilo di sicurezza di aflibercept in questi pazienti |
|
E.2.2 | Secondary objectives of the trial |
To document the Health-Related Quality of Life (HRQL) of aflibercept in this patient population |
Documentare la qualità della vita (relativamente allo stato di salute) (HRQL) in questi pazienti,durante il trattamento con aflibercept. |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Histologically or cytologically proven adenocarcinoma of the colon or rectum Metastatic disease Eastern Cooperative Oncology Group performance status 0-1 One and only one prior chemotherapeutic regimen for metastatic disease. This prior chemotherapy must be an oxaliplatin containing regimen. Patients must have progressed during or after the oxaliplatin based chemotherapy. Patients relapsed within 6 months of completion of oxaliplatin adjuvant chemotherapy are eligible |
- Adenocarcinoma del colon o del retto, confermato istologicamente o citologicamente - Malattia metastatica - Età ≥18 anni - ECOG PS 0-1 - Uno ed un solo precedente regime chemioterapico per la malattia metastatica. Questo precedente regime chemioterapico deve contenere oxaliplatino. I pazienti devono aver avuto una progressione di malattia durante o dopo l’ultima somministrazione della chemioterapia contenente oxaliplatino. Sono eleggibili anche i pazienti che presentano recidiva entro 6 mesi dal completamento della chemioterapia adiuvante contenente oxaliplatino |
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E.4 | Principal exclusion criteria |
Prior therapy with irinotecan Inadequate bone marrow, liver and renal function: neutrophils < 1.5x109/L, platelets < 100x109/L, hemoglobin < 9.0 g/dL, total bilirubin >1.5 x upper normal limit (ULN), transaminases >3 x ULN (unless liver metastasis are present), alkaline phosphatase >3 x ULN (unless liver metastasis are present), serum creatinine > 1.5 x ULN. Less than 4 weeks from prior radiotherapy, prior chemotherapy, prior major surgery (or until the surgical wound is fully healed). Treatment with any investigational drug within the prior 30 days. Treatment with concomitant anticonvulsivant agents that are CYP3A4 inducers (phenytoin, phenobarbital, carbamazepine), unless discontinued >7 days. History of brain metastases, uncontrolled spinal cord compression, or carcinomatous meningitis or new evidence of brain or leptomeningeal disease. Prior malignancy (other than colorectal) including prior malignancy from which the patient has been disease free for < 5 years (except adequately treated basal or squamous cell skin cancer or carcinoma in situ of the cervix). Any of the following within 6 months prior to study inclusion: myocardial infarction, severe/unstable angina pectoris, coronary/peripheral artery bypass graft, severe congestive heart failure, stroke or transient ischemic attack. Any of the following within 3 months prior study inclusion: severe gastrointestinal bleeding/hemorrhage, treatment resistant peptic ulcer disease, erosive oesophagitis or gastritis, infectious or inflammatory bowel disease, diverticulitis, pulmonary embolism or other uncontrolled thromboembolic event. Occurrence of deep vein thrombosis within 4 weeks, prior to study inclusion. Known dihydropyrimidine dehydrogenase deficiency. Predisposing colonic or small bowel disorders in which the symptoms were uncontrolled. Prior history of chronic enteropathy, inflammatory enteropathy, chronic diarrhea, unresolved bowel obstruction/sub-obstruction, more than hemicolectomy, extensive small intestine resection with chronic diarrhea. Known Gilbert’s syndrome. Unresolved or unstable toxicity from any prior anti cancer therapy at the time of inclusion. History of anaphylaxis or known intolerance to atropine sulphate or loperamide or appropriate antiemetics to be administered in conjunction with FOLFIRI (irinotecan, 5-Fluorouracil, leucovorin). Severe acute or chronic medical condition, which could impair the ability of the patient to participate to the study. Urine protein-creatinine ratio (UPCR) >1 on morning spot urinalysis or proteinuria > 500 mg/24-h. Uncontrolled hypertension within 3 months prior to study inclusion. Patients on anticoagulant therapy with unstable dose of warfarin and/or having an out-of-therapeutic range INR within the 4 weeks prior to study inclusion. Evidence of clinically significant bleeding predisposition or underlying coagulopathy, non-healing wound. Pregnant or breast-feeding women. Patients with reproductive potential who do not agree to use an accepted effective method of contraception. |
-Precedente terapia con irinotecan -Inadeguata funzionalità midollare, epatica e renale: •Conta assoluta dei neutrofili (ANC) < 1.5 x 109/L •Piastrine < 100 x 109/L •Emoglobina < 9.0 g/dL •Bilirubina totale > 1.5 x ULN •Transaminasi > 3 x ULN (o > 5 x ULN in caso di presenza di metastasi epatiche) •Fosfatasi alcalina > 3 x ULN (o > 5 x ULN in caso di presenza di metastasi epatiche). -Meno di 4 settimane trascorse da un precedente trattamento radioterapico o chemioterapico, o precedente intervento di chirurgia maggiore (o fino cicatrizzazione completa della ferita chirurgica) -Trattamento con qualsiasi farmaco sperimentale nei 30 giorni precedenti -Trattamento concomitante con anticonvulsivi induttori del citocromo CYP3A4 (fenitoina, fenobarbitale, carbamazepina), se non interrotti da più di 7 giorni. -Anamnesi di metastasi cerebrali, compressione midollare non controllata, o carcinomatosi meningea o evidenza di nuova malattia cerebrale o leptomeningea. -Anamnesi di neoplasie maligne in altre sedi ad eccezione del carcinoma cutaneo basocellulare o a cellule squamose adeguatamente trattato e del carcinoma in situ della cervice; sono inoltre eleggibili pazienti con altre neoplasie maligne con intervallo libero da malattia superiore a 5 anni. -Uno qualsiasi dei seguenti eventi nei 6 mesi precedenti l’inclusione: infarto del miocardio, angina pectoris grave/instabile, bypass aortocoronarico o periferico, scompenso cardiaco congestizio grave, ictus o TIA-Uno qualsiasi dei seguenti eventi nei 3 mesi precedenti l’inclusione: gravi emorragie/sanguinamenti gastrointestinali , ulcera peptica resistente al trattamento, esofagite o gastrite erosiva, malattia intestinale di eziologia infettiva o infiammatoria, diverticolite, embolia polmonare o qualsiasi evento tromboembolico non controllato -Trombosi venosa profonda nelle 4 settimane precedenti l’inclusione. --Deficit noto di diidropirimidina deidrogenasi -Predisposizione a malattie del colon o del piccolo intestino i cui sintomi non siano controllati -Anamnesi di enteropatia cronica, enteropatia infiammatoria, diarrea cronica, ostruzione/subostruzione dell’intestino non risolta, resezione più estensiva rispetto ad emicolectomia, resezione estesa dell’intestino tenue con diarrea cronica -Pazienti affetti da sindrome di Gilbert nota. -Tossicità non risolta o instabile al momento dell'inclusione derivante da un precedente trattamento oncologico -Anamnesi di anafilassi o nota intolleranza ad atropina solfato o loperamide o antiemetici adeguati per la somministrazione in associazione a FOLFIRI (irinotecan, 5-fluoracile, leucovorina) -Altre condizioni mediche gravi, acute o croniche, che possano limitare la capacità del paziente di partecipare allo studio -Rapporto Proteine-Creatinina urinaria (UPCR) >1 sul campione di urine mattutino o proteinuria >500 mg/24ore. - Ipertensione non controllata nei 3 mesi precedenti l’inclusione nello studio.-Pazienti in terapia con anticoagulanti con dose non stabile di warfarina e/o che presentino un valore di INR al di fuori del range terapeutico (>3) nelle 4 settimane precedenti l’inclusione. -Evidenza clinica di diatesi emorragica o coagulopatia, ferite che non cicatrizzano. -Donne in gravidanza o in allattamento. -Pazienti in età fertile (di sesso maschile e femminile) che non accettino di utilizzare un metodo di contraccezione approvato. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of participants reporting adverse events - Number of participants reporting laboratory abnormalities |
Numero di partecipanti con eventi avversi e/o con valori di laboratorio anormali |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Up to 30 days after the end of treatment |
Fino a 30 giorni dopo la fine del trattamento |
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E.5.2 | Secondary end point(s) |
Health-Related Quality of Life (HRQL) assessed by using changes from baseline in scores derived from the 3 HRQL questionnaires |
- Valutazione della qualità della vita (relativamente allo stato di salute) (HRQL) sulla base dei cambiamenti, rispetto al basale, dei punteggi derivanti dai 3 questionari (HRQL) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Every 4 weeks |
ogni 4 settimane |
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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 | No |
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 | 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 | No |
E.8.1.1 | Randomised | No |
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) | Information not present in EudraCT |
E.8.2.2 | Placebo | Information not present in EudraCT |
E.8.2.3 | Other | Information not present in EudraCT |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 25 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 82 |
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 |
Chile |
Colombia |
India |
Israel |
United States |
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E.8.7 | Trial has a data monitoring committee | No |
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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In each country, patient recruitment will end when aflibercept becomes commercially available (i.e. accessible to the patient as per each country regulation). Patients already included will continue to be treated until disease progression, death, unacceptable toxicity, Investigator’s decision or patient’s refusal of further treatment. |
In ogni Paese l'inclusione dei pz. continuerà fino a commercializzazione di aflibercept. I pz già inclusi continueranno il trattamento fino a progressione di malattia, morte, tossicità inaccettabile, decisione dello Sperimentatore o rifiuto del pz. |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 0 |
E.8.9.1 | In the Member State concerned months | 24 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 0 |
E.8.9.2 | In all countries concerned by the trial months | 24 |
E.8.9.2 | In all countries concerned by the trial days | 0 |