E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Cáncer colorrectal metastático con progresión de la enfermedad durante un tratamiento estándar en primera línea (bevacizumab y quimioterapia basada en fluoropirimidinas / oxaliplatino, o bevacizumab y quimioterapia basada en fluoropirimidinas / irinotecan). (Los pacientes no deben ser candidatos a resección metastática primaria). Metastasic colorectal cancer |
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MedDRA Classification |
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 assess Overall survival (OS) |
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E.2.2 | Secondary objectives of the trial |
- To assess OS from time of starting first line therapy - To assess PFS (after first progression) overall and on treatment population - To evaluate the Response rate (RECIST) - To evaluate the Safety profile in both arms |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Patients with histological confirmed diagnosis of metastatic CRC and disease progression (according to RECIST assessed by investigator, documented by CT or MRI), previously treated with first-line Therapy (Bevacizumab and Fluoropyrimidin / Oxaliplatin based or Bevacizumab and Fluoropyrimidin/ Irinotecan based CTx) and are no candidates for primary metastectomy. - Disease Progression ? 2 months after last bevacizumab administration - Evaluation of tumour disease according to RECIST by investigator, 4 weeks or less prior to randomization - No major surgery within 4 weeks prior to randomization. Wound healing has to be completed - Age ?18 years - Life expectancy > 3 month - ECOG ? 2 - Neutrophils ? 1.500/µl - Platelets ? 100.000µl - Hemoglobin > 9 g/dl - Creatinine clearance > 30 ml/min (Dosage modification for Capecitabine if creatinine clearance < 30-50 ml/min), serum creatinine < 1,25 x upper normal limit, - Serum bilirubin < 1,25x upper normal limit, AST / ALT < 2.5 x UNL - In case of liver metastasis, serum bilirubin < 1,5 x upper normal limit, AST/ALT < 5 x UNL - Signed written informed consent - Fertile women and men of childbearing potential (<2 years after last menstruation in women) must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgically sterile) |
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E.4 | Principal exclusion criteria |
?Diagnosis of progression of disease more than 2 m after last Bevacizumab (BV) administration ? First Line patients who had a PFS in first-line of < 3 m ? Patient receiving less than 3 consecutive months of BV in first line therapy ? Treatment with any other investigational agent or other biological agent (e.g. cetuximab) ? Participation in another clinical trial within 30 d prior to entering this study ? Concomitant use with St John?s Wort (for capecitabine based CTx) ? Inadequately controlled hypertension (defined as systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg ? Prior history of hypertensive crisis or hypertensive encephalopathy ? NYHA Class II or greater CHF ? History of myocardial infarction or unstable angina within 6 m prior to Day 1 ? Known CNS disease, expect for treated brain metastasis (treated brain metastases are defined as having no evidence of progression or haemorrhage after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging during the screening period. Anticonvulsants are allowed. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 m of start of study therapy will be excluded. ? Significant vascular disease (e.g. aortic aneurysm requiring surgical intervention, pulmonary embolism or recent peripheral arterial thrombosis) within 6 m prior start of study treatment. ? History of haemoptysis (? ½ tsp of bright red blood per episode) within 1 m prior start of study treatment ? Evidence of bleeding diathesis or significant coagulopathy (in absence of therapeutic anticoagulation) ? Major surgical procedure, open biopsy, or significant traumatic injury within 28 d prior to start of study therapy, or anticipation of need for major surgical procedure during the course of the study ? Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 d prior start of study therapy ? History of abdominal fistula or gastrointestinal perforation within 6 m prior start of study therapy. ? Serious, non healing wound, active ulcer, or untreated bone fracture ? History or evidence upon physical/neurological examination of CNS disease (unrelated to cancer) (unless adequately treated with standard medical therapy) e.g. uncontrolled seizures ? Past or current history (within the last 2 years prior to treatment start) of other malignancies except metastatic colorectal cancer (patients with curatively treated basal and squamous cell carcinoma of the skin or in situ carcinoma of the cervix are eligible) ? Known hypersensitivity to any of the study drugs ? Acute intra abdominal inflammatory process ? Evidence of any other disease, metabolic dysfunction, physical examination finding or laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or puts the patient at high risk for treatment-related complications ? Patients with contraindication for cross over chemotherapy (e.g. patients treated with irinotecan based first line therapy and serious polyneuropathy > grade 1, not feasible for oxaliplatin based cross over second line therapy, or patients treated with oxaliplatin based first line therapy and hereditary fructose intolerance not feasible for Irinotecan based cross over second line therapy) ? Previous radiotherapy: Patients must have recovered from any radiotherapy toxicity prior to enrolment ? Contraindication for CTX regimen as indicated in relevant SmPC ? Life expectancy less than 3 m ? Inability or unwillingness to comply with the protocol ? Inadequate haematological function: ANC < 1.5 x 1.000.000.000/L; platelets < 100 x 1.000.000.000/L, Haemoglobin (Hb) < 9 g/dL (may be transfused prior to enrolment) ? INR >1.5 within 7 d prior to starting study treatment. aPTT > 1.5 x ULN within 7 d prior to starting study treatment. EXEMPTION: patients on full anticoagulation due to VTE must have an in-range INR [usually between 2-3]. Any anticoagulation therapy must be at stable dosing prior to enrolment. ? Liver function: Serum bilirubin > 1.5 x ULN; alkaline phosphatase and transaminases > 5 x ULN (liver metastases) ? Serum Creatinine > 1.5 x ULN ? Urine dipstick for proteinuria ?2+. If urine dipstick is ? 2+, 24-h urine must demonstrate ? to 1 g of protein in 24 h for patient to be eligible ? Pregnancy or lactation. ? Positive serum pregnancy test within 7 d of starting study treatment in pre-menopausal women and women < 2 years after the onset of menopause. ? Fertile women (< 2 years after last menstruation) and men of childbearing potential unwilling or unable to use effective means of contraception. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- To assess Overall survival (OS). |
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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 | 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 | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | 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 | 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 | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
CTx-Cross-over dep. on 1st line:Fluoropyrimidine/Irinotecan or fluoropyrimidine/Oxaliplatin based CT |
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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 | 40 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 228 |
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 | Information not present in EudraCT |
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 |
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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 end of the trial is defined as the date of the last visit of the last patient to complete the follow up phase of the study or the last observation of the last subject undergoing the follow up phase of the study which was required for statistical analyses (613 overall survival events), which ever is the later date. |
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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 | 6 |
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 | 6 |
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 |