| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic clear cell renal cell carcinoma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 7 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10038415 |
|
| 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 efficacy of the combination of bevacizumab and interferon alfa-2a as compared with interferon alfa-2a and placebo in patients with metastatic RCC, based on overall survival.
PK substudy: To evaluate the potential effect of bevacizumab on the pharmacokinetics of interferon alpha-2a under treatment conditions. |
|
| E.2.2 | Secondary objectives of the trial |
•To determine the progression free survival, time to disease progression, time to treatment failure and objective response rates of bevacizumab and interferon alfa-2a as compared with interferon alfa-2a and placebo.
•To characterize the safety profile of the combination of bevacizumab and interferon alfa-2a as compared with interferon alfa-2a and placebo.
•To explore the potential existence of anti-bevacizumab antibodies.
PK substudy: To assess the pharmacokinetics of bevacizumab under treatment conditions. |
|
| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent (approved by the Institutional Review Board [IRB]/Independent Ethics Committee [IEC]) obtained prior to any study specific screening procedures.
2. Patient must be willing and able to comply with the protocol.
3. Age 18 or over.
4. Patient was nephrectomised for primary renal cell carcinoma (clear cell type). Partial nephrectomy is allowed only if the resection margins were clearly negative.
5. Patient with renal cell carcinoma (RCC) for whom a majority component (> 50%) of conventional clear cell type is mandatory. (Patient with true papillary, sarcomatoid features without any clear cell component, chromophobe, oncocytoma, collecting duct tumours, Bellini tumours and transitional cell carcinoma are not allowed). If metastatic disease is diagnosed more than two years from the date of the initial diagnosis (of RCC), histological or cytological confirmation of renal cell carcinoma (clear cell type) origin of the metastatic lesion(s) is mandatory.
6. Females with a negative serum pregnancy test (to be confirmed by urine test if serum test was performed more than 7 days prior to the treatment start) unless childbearing potential can be otherwise excluded (postmenopausal, hysterectomy or oophorectomy) and not lactating.
7. Fertile women (<2 years after last menstruation) and men of childbearing potential must use effective means of contraception (oral contraceptives, intrauterine contraceptive device, barrier method of contraception in conjunction with spermicidal jelly or surgical sterilisation).
8. Measurable or non-measurable disease (as per RECIST criteria).
9. Karnofsky Performance status equal to or greater than 70%.
10. Life expectancy greater than 4 months.
11. Absence of proteinuria at baseline as defined by < 0.5 g of protein/24 hr on mandatory 24-hour urine collection.
12.The required laboratory values at baseline are as follows:
Haematology:
Absolute neutrophil count (ANC) ≥ 1.5 x 10(9)/L, Platelet count ≥ 100 x 10(9)/L, Haemoglobin ≥ 9 g/dL (may be obtained or exceeded by the use of erythropoietin, excluding transfusion for anaemia), International Normalized Ratio (INR) ≤ 1.5, aPTT ≤ 1.5 x ULN
Biochemistry:
Total bilirubin ≤ 1.5 x upper limit of normal (ULN), AST, ALT ≤ 2.5 x ULN in patients without liver metastases, ≤ 5 x ULN in patients with liver metastases, Serum Creatinine ≤ 2.0 mg/dL or ≤ 177 micromol/L
PK substudy:
- Patients having received, prior to the PK visit, three infusions of bevacizumab (or placebo) dosed at 10mg/kg at two weekly intervals.
- Patients having received interferon alpha-2a treatment at a dose regimen stable over the two weeks prior to treatment cycle ≥4.
|
|
| E.4 | Principal exclusion criteria |
1. Prior systemic treatment for metastatic RCC disease (including neo-adjuvant therapy).
2. 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.
3. Serious non-healing wound, ulcer or bone fracture.
4. Evidence of current central nervous system (CNS) metastases or spinal cord compression. Patient must undergo an MRI or CT scan of the brain (with contrast, if possible) within 28 days prior to randomisation.
5. Seizure(s) not controlled with standard medical therapy.
6. Other malignancies within 5 years prior to randomisation (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix).
7. Evidence of bleeding diathesis or coagulopathy.
8. Ongoing or recent (within 10 days prior to study treatment start) need for full therapeutic dose of oral or parenteral anticoagulants or chronic daily treatment with aspirin (> 325 mg/day).
9. Uncontrolled hypertension (greater than or equal to 160 mm Hg systolic and/or greater than or equal to 90 mm Hg diastolic) while receiving chronic medication.
10. Clinically significant (i.e. active) cardiovascular disease, for example cerebrovascular accidents (≤ 6 months before randomisation), myocardial infarction (≤ 6 months before randomisation), unstable angina, New York Heart Association (NYHA) grade II or greater congestive heart failure, or serious cardiac arrhythmia requiring medication.
11. Recent (within the 30 days prior to randomisation) treatment with another investigational drug or participation in another investigational study.
12. Chronic treatment with corticosteroids (dose of ≥10 mg/day methylprednisolone equivalent), excluding inhaled steroids.
13. 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. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Analysis of overall survival will be performed after approximately 445 deaths have been observed. |
|
| 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 | Yes |
| 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 | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Potential existence of anti-bevacizumab antibodies, |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| 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 | Yes |
| 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.8.5 | 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 | 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
|
| This is an event driven trial. Final analysis will occur after 445 deaths have occurred. This is expected to occur approx. 18 months after the last patient was randomized. As for the last patient randomised it is expected that this patient will not stay longer than 36 months in the study (based on the median survival time of approx. 30 months for a patient from the patient group with favourable risk according to Motzer et al). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| 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 | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
Print
