E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with locally advanced, non metastatic, resectable primary rectal cancer stage cT3 or cT4 who are subject to combined chemotherapy of the pelvic region in the pre-operative setting. |
Pazienti con carcinoma rettale primario resecabile, localmente avanzato, non metastatico, in stadio clinico T3 o T4 che sono candidati ad un trattamento combinato chemioterapico e radioterapico a livello della regione pelvica in fase pre-operatoria. |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10038038 |
E.1.2 | Term | Rectal cancer |
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 |
To determine the pathological complete response (pCR) rate in patients treated with bevacizumab and capecitabine plus standard technique radiotherapy of the pelvic region when optimal surgery is applied even by a local pathologist assessment and by a centralized evaluation. |
Determinare il tasso di risposte complete patologiche (pRC) in pazienti trattati con bevacizumab e capecitabina piu` radioterapia standard della regione pelvica dopo intervento chirurgico sia mediante una valutazione del patologo locale che mediante una valutazione centralizzata. |
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E.2.2 | Secondary objectives of the trial |
` To assess the clinical tumor and lymph node response rate to chemo-radiotherapy. ` To evaluate toxicity and the safety profile of bevacizumab plus capecitabine in combination with pelvic radiotherapy. ` To assess the sphincter saving procedure rate after pre- operative chemo- radiotherapy. ` To evaluate local control, disease free survival and overall survival until the end of the study ` To evaluate the biological evaluation of potential biomarkers predictive of treatment efficacy (K-ras and BRAF mutational status, VEGFR-2; Ki67; thymidilate sintatase; thymidilate phopshorialse; microvessel densitiy with CD34, CD68, M30). |
` Valutare il tasso di risposte cliniche a livello tumorale e linfonodale dopo chemio-radioterapia.` Valutare il profilo di tossicita` e di safety di bevacizumab e capecitabina piu` radioterapia standard della regione pelvica.`Valutare il tasso di interventi chirurgici conservativi dopo trattamento pre-operatorio chemio-radioterapico.` Valutare il controllo locale,la sopravvivenza libera da malattia e globale fino alla fine dello studio.`Effettuare una valutazione biologica dei potenziali marcatori biologici predittivi dell`efficacia del trattamento (stato mutazionale di K-ras e BRAF; VEGFR-2; Ki67; timidilato sintetasi; timidilato fosforilasi; densita` dei microvasi mediante CD34,CD69,M30). |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Patients with histologically or cytologically confirmed diagnosis of rectal carcinoma, who are subject to surgery for rectal cancer and are considered to have benefit from pre-operative combined chemo-radiotherapy, (i.e.: stage cT3, cT4, fixative tumors, tumors primarily inoperable). 2. Age >= 18 3. ECOG Performance Status 0-1 (Appendix III) 4. Life expectancy of at least 12 weeks 5. Measurable and/or evaluable lesions according to RECIST criteria 6. Laboratory requirements: ` Neutrophils >= 1.5 x 109/L and Platelets >= 100 x 109/L ` Total bilirubin <= 1.5 time the upper-normal limits (UNL) of the Institutional normal values and ASAT (SGOT) and/or ALAT (SGPT) <= 2.5 x UNL, or <= 5 x UNL in case of liver metastases, alkaline phosphatase <= 2.5 x UNL, <= 5 x UNL in case of liver metastases. ` Creatinine clearance >50 mL/min or serum creatinine <= 1.5 x UNL) ` Urine dipstick of proteinuria <2+. Patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline, should undergo a 24-hour urine collection and must demonstrate <=1 g of protein/24 hr. 7. Written informed consent. 8. Patients must be accessible for treatment and follow up. Patients registered on this trial must be treated and followed at the participating Center. |
1. Pazienti con diagnosi confermata istologicamente o citologicamente di carcinoma rettale, candidati ad intervento chirurgico per carcinoma rettale e a trattamento pre-operatorio chemio-radioterapico (stadio clinico T3, T4, tumori fissi, tumori primari inoperabili). 2. Eta` >= 18 anni 3. Performance Status ECOG 0-1 4. Attesa di vita di almeno 12 settimane 5. Lesioni misurabili e/o valutabili secondo i criteri RECIST 6. Parametri di Laboratorio: ` Neutrofili >= 1.5 x 109/L e Piastrine >= 100 x 109/L ` Bilirubina totale <= 1.5 il limite superiore normale (LSN) del range dei valori normali del Centro e ASAT (SGOT) e/o ALAT (SGPT) <= 2.5 x LSN, o <= x LSN in caso di metastasi epatiche, fosfatasi alcalina <= 2.5 x UNL, <= 5 x LSN in caso di metastasi epatiche, <= 10 x LSN in caso di metastasi ossee. ` Clearance della Creatinina >50 mL/min o creatinina serica <= 1.5 x LSN) ` Proteinuria (dipstick) <2+. Pazienti con proteinuria >= 2+ al basale, devono sottoporsi a raccolta urine di 24 ore e devono avere <= 1 g di proteine/24 ore. 7. Consenso Informato scritto. 8. Accessibilita` geografica per il trattamento e follow up. Pazienti arruolati in questo studio devono essere trattati e seguiti nel Centro partecipante. |
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E.4 | Principal exclusion criteria |
1. Prior radiotherapy or chemotherapy for rectal cancer. 2. Untreated brain metastases or spinal cord compression or primary brain tumours. 3. History or evidence upon physical examination of CNS disease unless adequately treated (e.g., seizure not controlled with standard medical therapy or history of stroke). 4. History of inflammatory bowel disease and/or acute/subacute bowel occlusion. 5. Serious, non-healing wound, ulcer, or bone fracture. 6. Evidence of bleeding diathesis or coagulopathy. 7. Uncontrolled hypertension. 8. Clinically significant (i.e. active) cardiovascular disease for example cerebrovascular accidents (≤6 months), myocardial infarction (≤6 months), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, serious cardiac arrhythmia requiring medication. 9. Current or recent (within 10 days prior to study treatment start) ongoing treatment with anticoagulants for therapeutic purposes. 10. Chronic, daily treatment with high-dose aspirin (>325 mg/day) or other medications known to predispose to gastrointestinal ulceration. 11. Treatment with any investigational drug within 30 days prior to enrolment. 12. Patients with known allergy to Chinese hamster ovary cell proteins, or any of the components of the study medications 13. Other co-existing malignancies or malignancies diagnosed within the last 5 years with the exception of basal and squamous cell carcinoma or cervical cancer in situ 14. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, or anticipation of the need for major surgical procedure during the course of the study. 15. Lack of physical integrity of the upper gastrointestinal tract, malabsorption syndrome, or inability to take oral medication. 16. Pregnant or lactating women. Women of childbearing potential with either a positive or no pregnancy test at baseline. Postmenopausal women must have been amenorrheic for at least 12 months to be considered of non-childbearing potential. Sexually active males and females (of childbearing potential) unwilling to practice contraception during the study. |
1. Precedente radioterapia o chemioterapia per carcinoma rettale. 2. Metastasi cerebrali sintomatiche e/o instabili o metastasi leptomeningee che richiedono trattamento. 3. Storia di malattia infiammatoria intestinale e/o occlusione intestinale acuta/subacuta. 4. Ulcera o ferita non rimarginata grave. 5. Evidenza di diatesi emorragica o coagulopatia. 6. Ipertensione non controllata. 7. Malattia cardiovascolare clinicamente significativa (attiva): per esempio, accidente cerebrovascolare (≤6 mesi), infarto miocardico (≤6 mesi), angina instabile, insufficienza cardiaca congestizia di grado II o maggiore secondo la New York Heart Association (NYHA), aritmia cardiaca grave che richiede trattamento. 8. Trattamento recente (nei 10 giorni precedenti l`inizio del trattamento) o in corso con anticoagulanti somministrati a scopo terapeutico. 9. Trattamento cronico, giornaliero, con aspirina ad alte dosi (>325 mg/die) o con altri farmaci che possano predisporre all`ulcera gastroinestinale. 10. Trattamento con qualsiasi farmaco sperimentale nei 30 giorni precedenti l`arruolamento. 11. Pazienti con allergia confermata alle proteine delle cellule ovariche di criceto cinese, o a uno qualsiasi dei componenti dei farmaci dello studio. 12. Altre concomitanti patologie neoplastiche diagnosticate negli ultimi 5 anni con l`eccezione del carcinoma basocellulare e del carcinoma cervicale in situ. 13. Intervento di chirurgia maggiore, biopsia a cielo aperto, o lesione traumatica significativa nei 28 giorni precedenti l`inizio del trattamento, o previsione della necessita` di un intervento di chirurgia maggiore durante il corso dello studio. 14. Assenza di integrita` fisica del tratto gastrointestinale superiore, sindrome da malassorbimento, o inabilita` ad assumere farmaci orali. 15. Donna in gravidanza o in allattamento. Donna senza test di gravidanza o con un test di gravidanza positivo al basale. La donna in postmenopausa e` considerata non fertile se amenorroica da almeno 12 mesi. Donne e maschi sessulamente attivi (o potenzialmente fertili) che non praticano un metodo contraccettivo durante lo studio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
` Pathological tumor assessment as per local pathologist evaluation after definite surgery within 6-8 weeks after completion of chemo-radiotherapy. ` Pathological tumor assessment evaluated by a central pathologist ` Clinical tumor and lymph node assessment after chemo-radiotherapy within 6 weeks. ` Adverse events, laboratory parameters. All toxicity will be graded using the NCI common toxicity criteria version 3.0. |
` Valutazione patologica tumorale da parte del patologo locale dopo intervento chirurgico radicale entro 6-8 settimane dalla fine del trattamento che mio-radioterapico. ` Valutazione patologica centralizzata del tumore ` Valutazione clinica tumorale e linfonaodale dopo chemio-radioterapia entro 6 settimane. ` Eventi avversi, parametri di Laboratorio. Tutti gli eventi avversi saranno classificati usando i criteri di valutazione della tossicita` del NCI, versione 3.0. |
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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 | No |
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 | Yes |
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 | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 9 |
E.8.5 | The trial involves multiple Member States | No |
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 | 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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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 | 62 |
E.8.9.1 | In the Member State concerned days | 0 |