| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Adjuvant treatment for patients who have undergone surgery for Colon cancer, AJCC/UICC high-risk Stage II & stage III |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 8.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009957 |
| E.1.2 | Term | Colon carcinoma |
|
| 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 |
Primary objective of the study were:
• To demonstrate that the combination of bevacizumab and FOLFOX-4 is superior to FOLFOX-4 alone in terms of disease-free survival in chemotherapy-naïve patients who underwent surgery with curative intent for colon carcinoma.
• To demonstrate that the combination of bevacizumab and XELOX is superior to FOLFOX-4 alone in terms of disease-free survival in chemotherapy-naïve patients who underwent surgery with curative intent for colon carcinoma.
In case both primary objectives are achieved, one secondary objective was to further investigate if the combination of bevacizumab and XELOX is at least as efficacious as the combination of bevacizumab and FOLFOX-4 in terms of disease-free survival and overall survival.
The primary efficacy analysis (cut off date: 30th June 2010) showed that the study did not meet the co-primary objectives of prolonging disease-free survival in stage III colon carcinoma patients. |
|
| E.2.2 | Secondary objectives of the trial |
• To further follow-up patients in terms of overall survival.
• To evaluate and compare the safety profiles of the treatment groups.
• To evaluate the immunogenicity of bevacizumab measured as induction of HAHA (completed with the primary efficacy analysis). |
|
| 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 |
| Arrhythmia Substudy - separate sub-study will be conducted in a limited number of centers to study the arrythmogenic potential of FOLFOX, XELOX with and without Avastin. The substudy and written Informed Consent will be submitted for approval separately. |
|
| E.3 | Principal inclusion criteria |
1. Signed written informed consent obtained prior to any study specific screening procedures.
2. Patient must be willing and able to comply with the protocol.
3. Age ≥ 18.
4. Histologically confirmed colon carcinoma, AJCC/UICC Stage II or Stage III defined as a tumour location ≥15 cm from the anal verge by endoscopy or above the peritoneal reflection at surgery. The patient must not be a candidate for (neo) adjuvant radiotherapy.
Note! Stage II patients have to be considered as high-risk patients fulfilling one of the following criteria:
– T4 tumours,
– Patients presenting with bowel obstruction or perforation,
– Histological signs of vascular invasion (i.e. blood and lymphatic vessels) or perineural invasion,
– Patients aged less than 50 years,
– Patients with sub-optimal surgery (less than 12 nodes analyzed).
5. Curative surgery not less than 4 and not more than 8 weeks prior to randomization.
6. ECOG performance status 0 or 1.
7. Life expectancy of ≥ 5 years.
|
|
| E.4 | Principal exclusion criteria |
1. Macroscopic or microscopic evidence of remaining tumour. Patients should never
have had any evidence of metastatic disease (including presence of tumour cells in the ascites). The isolated finding of cytokeratin positive cells in bone marrow is not considered evidence of metastatic disease for purposes of this study.
2. Carcinoembryonic antigen > 1.5 x ULN after surgery (during screening period).
3. For patients with colostomy, unwilling to delay revision until at least 28 days after treatment completion.
4. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to study treatment start, not fully healed wounds, or anticipation of the need for major surgical procedure during the course of the study. CVAD for chemotherapy administration must be inserted at least 2 days prior to treatment start.
5. Previous anti-angiogenic treatment for any malignancy; cytotoxic chemotherapy, radiotherapy or immunotherapy for colon cancer.
6. Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
7. Females with a positive or no pregnancy test (within 7 days before treatment start) unless childbearing potential can be otherwise excluded (postmenopausal i.e. amenorrheic for at least 2 years, hysterectomy or oophorectomy).
8. Lactating women.
9. Fertile women (<2 years after last menstruation) and men of childbearing potential not willing to use effective means of contraception.
10. History or evidence upon physical examination of CNS disease (e.g., primary brain tumour, seizure not controlled with standard medical therapy, any brain metastases).
11. History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake.
12. Clinically significant (i.e. active) cardiovascular disease. This includes, but is not limited to the following examples: 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 arrhythmia requiring medication, clinically significant ECG findings (e.g. QTc ≥ 440 mcecs [male] 460 msecs [female] or ≥ 2° AV Block, etc.] (abbr.)
13. Lack of physical integrity of the upper gastro-intestinal tract, malabsorption syndrome, or inability to take oral medication.
14. Interstitial pneumonia or extensive symptomatic fibrosis of the lungs.
15. Known peripheral neuropathy ≥ CTCAE v 3.0 Grade 1. Absence of deep tendon reflexes (DTRs) as the sole neurological abnormality does not render the patient ineligible.
16. Organ allografts requiring immunosuppressive therapy.
17. Serious, non-healing wound, ulcer, or bone fracture.
18. Evidence of bleeding diathesis or coagulopathy.
19. 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.
20. Chronic, daily treatment with high-dose aspirin (>325mg/day) or clopidogrel (>75mg/day)
21. Chronic treatment with corticosteroids (dose of ≥ 10 mg/day methylprednisolone equivalent) (excluding inhaled steroids).
22. Serious intercurrent infections (uncontrolled or requiring treatment).
23. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
24. Current or recent (within the 28 days prior to randomization) treatment with another investigational drug or participation in another investigational study.
25. 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 components of the study drugs.
26. History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications.
27. Presence of proteinuria at baseline as defined by:
- Patients with > 1g of protein/24 hr by a 24-hour urine collection.
28. Any laboratory values at baseline are as follows:
Haematology:
- Absolute neutrophil count (ANC) < 1.5 x 109/L
- Platelet count < 100 x 10[9]/L
- Haemoglobin < 9 g/dL (may be transfused to maintain or exceed this level)
- International Normalized Ratio (INR) > 1.5
- APTT ≥ 1.5 x Upper Limit of Normal (ULN)
Biochemistry:
- Total bilirubin > 1.5 x ULN
- AST, ALT > 2.5 x ULN
- Alkaline phosphatase > 2.5 x ULN
- Serum Creatinine > 1.5 x ULN or creatinine clearance ≤ 50 mL/min |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Disease free survival determined when approximately 836 events have occurred. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Potential existence of anti-bevacizumab antibodies & precautionary biomaker sampling. |
|
| 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.8.2.3.1 | Comparator description |
| 5-Fluorourcil and leucovirin used in combination therapy |
|
| 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.8.6 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 |
|
| 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
|
| The end of the BO17920 study is defined as the last patient last visit at the end of the follow up period (see Protocol sections 3.1 and 5.2.4). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 8 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 8 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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