| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Resected stage II or stage III adenocarcinoma of the colon |
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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 the trial is to compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging disease free survival (DFS). |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the trial is to compare the relative efficacy of mFOLFOX6 + bevacizumab with that of mFOLFOX6 alone in prolonging survival (S). |
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Male and female patients.
IRB approved written informed consent form must be signed.
Patients must be >_18years old.
Randomisation must occur during the 3 week interval beginning on post-operative Day 29 and ending postoperative day 50.
Distal extent of tumour must be >_12 cm from the anal verge on endoscopy, then the distal extent of tumour must be >_12cm from the anal verge as determined by surgical resection, are eligible.
Patient must have had an en bloc complete gross resection of tumour (curative resection) by open laparatomy or laparoscopically-assisted colectomy. Patients who have had a two-stage surgical procedure, to first provide decompressive colostomy and then in a later procedure to have the definitive surgical resection, are eligible.
Patients must have histologically confirmed adenocarcinoma of the colon that meets one of the criteria below:
1. Stage II carcinoma (T3,4,N0, M0). The tumour invades through the muscularis propria into the subserosa or into non-peritonealized pericolic or perirectal tissues (T3); or directly invades other organs or structures, and/or perforates visceral peritoneum (T4).
2. Stage III carcinoma (any T N1,2 M0).The tumour has invaded to any depth with involvement of regional lymph nodes.
Patients with T4 tumours that have involved an adjacent structure (e.g bladder, small intestine,ovary,etc) by direct extension from the primary tumour are eligible if all of the following conditions are met:
- all or a portion of the adjacent tumour was removed en bloc with the primary tumour;
- in the opinion of the surgeon, all grossly visible tumour was completely resected (''curative resection'')
- histologic evaluation by the pathologist confirms the margins of the resected specimen are not involved by malignant cells, and
- local radiation therapy will not be utilized
- patients with more than one synchronous primary colon tumour are eligible
- in the opinion of the investigator,patients must have a life expectancy of at least 5 years, excluding their diagnosis of cancer.
- patients must have an ECOG performance status of 0 or 1
- at the time of randomisation, the postoperative absolute granulocyte count (AGC) must be >_1500/mm3 (or <1500mm3, if in the opinion of the investigator, this represents an ethnic or racial variation of normal
- at the time of randomisation, the postoperative platelet count must be >_ 100,000/mm3
- there must be postoperative evidence of adequate hepatic function
*bilirubin must be <_ULN for the lab unless the patient has a chronic grade 1 bilirubin elevation due to Gilberts disease or similar syndrome due to slow conjugation of bilirubin
*Alkaline phosphatase must be <2.5x ULN for the lab
*AST must be <1.5x ULN for the lab
- there must be postoperative evidence of adequate renal function
* serum creatinine <_ X 1.5 ULN for the lab
* urine protein/creatinine(UPC) ratio of <1.0;patients with a UPC ratio >_1.0 must undergo a 24 hour urine collection, which must be an adequate collection and must demonstrate <1gm of protein in the 24 hour urine collection in order to participate in the study.
- patients with prior malignancies, including colorectal cancers, are eligible if they have been disease free for >_5 years and are deemed by their physician to be at low risk for rcurrence.Patients with squamous or basal cell carcinoma of the skin, melanoma in situ, carcinoma in situ of the cervix, or carcinoma in situ of the colon or rectum that have been effectively treated are eligible, even if these conditions were diagnosed within 5 years prior to randomisation
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| E.4 | Principal exclusion criteria |
- colon tumour other than adenocarcinoma, i.e sarcoma, lymphoma, carcinoid,etc
- rectal tumours, i.e a tumour located <12 cm from the anal verge on endoscopy, or by surgical exam if the patient is not a candidate for endoscopy
isolated, distant, or non-contiguous intra-abdominal metastases, even if resected
- any systemic or radiation therapy initiated for this malignancy
-any significant bleeding that is not related to the primary colon tumour within 6 months before study entry
-serious or non-healing wound, skin ulcers, or bone fracture
-gastroduodenal ulcer(s) determined by endoscopy to be active
-invasive procedures defined as follows
major surgical procedure, open biposy, or significant traumatic injury within 28 days prior to randomisation
*anticipation of need for major surgical procedures during the course of the study
*core biopsy or other minor procedure, excluding placement of a vascular access device, within 7 days prior to randomisation
- uncontrolled blood pressure defined as >150/90mmHg
- previous history of any CNS cerebrovascular ischemia
-History of peripheral arterial ischemia within 6 months
-history of visceral arterial ischemia within 6 months
-PT (INR) >1.5, unless the patient is on full-dose anti-coagulants. If so, the following criteria must be met for enrollment
*subject must have an in range INR (2-3) on a stable dose of warfarin or on a stable dose of low molecular weight heparin
*subject must not have active bleeding or a pathological condition that is associated with a high risk of bleeding
- concomitant halogenated antiviral agents
-clinically significant peripheral neuropathy at the time of randomisation (NCI CTC version 3.0) as grade 2 or greater neurosensory or neuromotor toxicity
-non malignat systemic disease that would preclude any of the study therapy drugs
*New York heart association class II or IV myocardial disease
*myocardial infarction within 6 months of study entry
*unstable angina within 6 months of study entry
*current symptomatic arrhythmia
-pregnant or lactatation at the time of proposed randomisation.Eligible patients of reproductive potential (both sexes) must agree to use adequate contraceptive methods during study therapy and for at least 3 months after the completion of bevacizumab.
-Psychiatric or addictive disorders or other conditions that, in the opinion of the investigator, would preclude the patient from meeting the study requirements
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint to be used for statistical analysis is duration of DFS. Events for DFS include first documented evidence of colon cancer recurrence, second primary cancer, or death from any cause. |
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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 | Information not present in EudraCT |
| 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) | 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 | Yes |
| E.8.1.2 | Open | Information not present in EudraCT |
| E.8.1.3 | Single blind | Information not present in EudraCT |
| E.8.1.4 | Double blind | Information not present in EudraCT |
| E.8.1.5 | Parallel group | Information not present in EudraCT |
| E.8.1.6 | Cross over | Information not present in EudraCT |
| E.8.1.7 | Other | Information not present in EudraCT |
| 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.8.2.3.1 | Comparator description |
| Fluorouracil,Oxaliplatin,Calcium Leucovorin |
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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.8.5 | The trial involves multiple Member States | Yes |
| 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 | Information not present in EudraCT |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
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