E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Liver metastatis of 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 |
The primary objective of this trial is to demonstrate that adjuvant treatment with the combination of bevaxizumab and XELOX is superior to XELOX alone as adjuvant chemotherapy in terms of disease free survival. |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of this trial is to demonstrate that adjuvant treatment with the combination of bevacizumab and XELOX is superior to XELOX alone as adjuvant treatment in terms of overall survival. Safety and quality of life. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Translational Research: Version translationell forskning version 1.0, 21 augusti 2007
Main objective is to answer the following questions: 1. Can we improve diagnostics by early detection of changes in protein profiles or angiogenetic markers as a systemic reflection of disease progression? i.e. can we predict a) disease relapse and/or b) treatment resistance? 2. Can comparison between serum profiles of the two treatment arms (group A and B) predict the outcome prior to treatment? 3. Can comparison between tissue expression of angiogenetic markers for treatment group A and B predict treatment results? 4. Can any of the above stated outcomes be used for selection of best treatment for the individual patient? |
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E.3 | Principal inclusion criteria |
1. Signed written informed consent obtained prior to any study-specific procedure. 2. Age ≥ 18 years. 3. Liver metastases radically resected (R0 resection) 4. Study medication started ≥4 and ≤ 8 weeks post liver surgery. 5. Histologically confirmed liver metastasis of colorectal cancer after surgery. 6. ECOG performance status 0 or 1 (Appendix 1). 7. Adequate hematology: neutrophils ≥1.5 x 109/L, platelets ≥100 x 109/L, Hb ≥5.5 mmol/L, INR ≤ 1.5, APTT < 1.5 X UNL. 8. Adequate biochemistry: total bilirubin ≤1.5 UNL, ASAT and ALAT ≤2.5 x UNL, alkaline phosphatase ≤2.5 x UNL, serum creatinin ≤1.5 UNL. 9. Urine dipstick <2+ for protein. |
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E.4 | Principal exclusion criteria |
1 Extrahepatic metastatic disease. 2 Adjuvant chemotherapy given <6 months prior to detection of the liver metastases. 3 Chemotherapy for metastatic disease. 4 Prior non colorectal malignancies, except adequately treated basalioma of the skin or carcinoma in situ of the cervix. 5 Bleeding diathesis or coagulation disorders or the need for full-dose anticoagulation. 6 Major surgical procedure <4 weeks prior to start of study treatment. 7 Females with a positive pregnancy test (within 14 days before treatment start). 8 Lactating women. 9 Fertile women (<2 years after last menstruation) and women of childbearing potential not willing to use effective means of contraception. 10 History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake. 11 Clinically significant (i.e. active) cardiovascular disease e.g. cerebrovascular accidents (≤6 months prior to randomisation), myocardial infarction (≤1 year prior to randomisation), uncontrolled hypertension while receiving chronic medication, unstable angina, New York Heart Association (NYHA) Grade II or greater congestive heart failure, or serious cardiac arrhytmia requiring medication. 12 Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication. 13 Known peripheral neuropathy, including oxaliplatin-induced neuropathy > grade 1. Absence of deep tendon reflexes as the sole neurological abnormality does not render the patient ineligible. 14 Organ allografts requiring immunosuppressive therapy. 15 Serious, non-healing wound, ulcer, or bone fracture. 16 Current or recent (within 10 days prior to study treatment start) use of full-dose oral or parenteral anticoagulants or thrombolytic agent for therapeutic purposes. 17 Chronic, daily treatment with high-dose asprin (>325 mg/day) or nonsteroidal anti-inflammatory medications (those known to inhibit platelet function at doses used to treat chronic inflammatory diseases). Patients can be rendered eligible by changing the treatment to COX II inhibitors. 18 Chronic treatment with corticosteroids (dose of ≥10 mg/day methylprednisolone equivalent excluding inhaled steroids). 19 Serious intercurrent infections (uncontrolled or requiring treatment). 20 Current or recent (within the 28 days prior to randomisation) treatment with another investigational drug or participation in another investigational study. 21 Patients with known allergy to Chinese hamster Ovary cell proteins or other recombinant human or humanized antibodies or to any excipients of bevacizumab formulation, platinum compounds or to any other component of the study drugs. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The main endpoint of this study is Disease Free Survival, DFS. From our own series of patients it could be estimated that the 3-year DFS of patients treated without chemotherapy is 25%. In the control arm, XELOX alone could increase the 3 year DFS to 35%. It is expected that the arm with XELOX plus bevacizumab should result in an improvement of further 10%, bringing the 3 year DFS to 45%. This corresponds to a hazard rate ratio of 0.761 for the bevacizumab arm.
A total of 620 patients will be randomized to this study (310 in each arm). With a yearly accrual rate of 150 patients, this number of patients could be accrued in approximately 4 years. If patients are followed for 2 years further, a total amount of 420 events (recurrences or deaths) would be observed. This number of events will provide 80% power to detect the above stated difference in the DFS curves in both arms. The total duration of the study will be 6 years (4 years accrual and 2 further years follow up). (statistics performed by O. Dalesio, Netherlands Cancer Institute)
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Information not present in EudraCT |
E.6.2 | Prophylaxis | Information not present in EudraCT |
E.6.3 | Therapy | Information not present in EudraCT |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Information not present in EudraCT |
E.6.7 | Pharmacodynamic | Information not present in EudraCT |
E.6.8 | Bioequivalence | Information not present in EudraCT |
E.6.9 | Dose response | Information not present in EudraCT |
E.6.10 | Pharmacogenetic | Information not present in EudraCT |
E.6.11 | Pharmacogenomic | Information not present in EudraCT |
E.6.12 | Pharmacoeconomic | Information not present in EudraCT |
E.6.13 | Others | Information not present in EudraCT |
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 | 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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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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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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 6 |