| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic renal cell carcinoma |
|
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 9.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10050513 |
| E.1.2 | Term | Metastatic renal cell 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 |
To assess the PFS and safety of bevacizumab (10 mg/kg i.v. every two weeks) in combination with a low dose of IFN (3 MIU s.c. three times per week) administered until disease progression as first-line treatment of mRCC, and compare these results to the ‘bevacizumab in combination with IFN 9 MIU s.c. three times per week arm’
in the AVOREN trial. Safety comparison is based on the assessment of adverse events of special interest such as fatigue, asthenia, malaise, influenza-like illness and pyrexia. |
|
| E.2.2 | Secondary objectives of the trial |
-To assess the efficacy of bevacizumab in combination with IFN 3MIU s.c. three times per week as measured by best ORR (as defined by RECIST criteria) and OS.
-To make an historical comparison between ORR and OS of bevacizumab in combination with IFN 3 MIU s.c. t.i.w, and the ORR and OS of bevacizumab in combination with IFN 9 MIU s.c. t.i.w, reported in the AVOREN trial (BO17705, the pivotal study for registration of bevacizumab in mRCC)
-To characterise the safety profile of bevacizumab in combination with IFN 3 MIU s.c. t.i.w, administered until disease progression in terms of, Grade 3-5 AE rate, overall AE rate and SAE rate
-To make a historical comparison between the safety profile of bevacizumab in combination with IFN obtained in this study and the safety profile of bevacizumab in combination with IFN reported in the AVOREN trial. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent (informed consent document to be approved by the institution’s Independent Ethics Committee and consent obtained prior to any study-specific procedure)
2. Age ≥18 years
3. Able to comply with the protocol
4. Subject with histologically and/or cytologically confirmed, metastatic RCC, with majority (>50%) of conventional clear-cell type is mandatory. (Subjects with predominantly papillary or sarcomatoid features, and subjects with chromophobe, oncocytoma, collecting duct tumours, Bellini tumours or transitional cell carcinoma are not allowed). Tumours of mixed histology should be categorised by the predominant cell type.
5. Prior total nephrectomy for primary renal cell carcinoma. Partial nephrectomy is allowed only if the resection margins were clearly negative.
6. At least one measurable or non-measurable lesion (as per RECIST criteria).
7. Eastern Cooperative Oncology Group (ECOG) PS 0-2 (≥70) (see Appendix 2 ECOG PS and KPS).
8. Good or intermediate prognosis disease as defined by Motzer score
9. Life expectancy ≥12 weeks
10. Adequate haematological function:
a. Absolute neutrophil count (ANC) ≥1.5 x 10 9/L AND
b. Platelet count ≥100 x 10 9/L AND
c. Haemoglobin ≥8 g/dL (may be obtained by the use of erythropoietin or transfusion for anaemia)
11. Adequate liver function:
a. Total bilirubin <1.5 x upper limit of normal (ULN) AND
b. Asparagine aminotransferase (AST), alanine aminotransferase (ALT) <2.5 x ULN in patients without liver metastases; <5 x ULN in patients with liver metastases
12. Adequate renal function:
a. Serum creatinine ≤1.5 x ULN AND
b. Urine dipstick for proteinuria <2+. Patients with ≥2+ proteinuria on dipstick urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate <1 g of protein in 24 hours
13. International normalised ratio (INR) (in absence of anticoagulation treatment) ≤1.5 within 7 days prior to enrolment. Anticoagulation is allowed if target INR is < 3 and if the patient is on a stable dose of anticoagulant (coumarin type, low molecular weight heparin (LMWH) or bivalirudin or argatroban) for > 2 weeks at time of enrolment.
14. Female patients should not be pregnant or breast-feeding. Women of child bearing potential (i.e. a woman who is biologically capable of becoming pregnant) must have a negative serum pregnancy test within 7 days prior to enrolment into the study. If a serum pregnancy test is not performed within 7 days prior to the first dose of bevacizumab, a confirmatory urine test (within 7 days prior to the first dose of bevacizumab) is required. Patients (men and women) must agree to use medically accepted contraceptive methods with their partners throughout the study and for 6 months after the last dose of bevacizumab and/or IFN (whichever is administered last). |
|
| E.4 | Principal exclusion criteria |
1. Prior systemic treatment for metastatic RCC disease (including neo-adjuvant therapy)
2. Current or previously treated central nervous system (CNS) metastases or spinal cord compression
3. Major surgery (incl. open biopsy) or radiation therapy within 28 days prior to enrolment. (Palliative radiotherapy to painful bone lesions is not allowed within 14 days prior to enrolment). Subject must have recovered from prior surgery (> 28 days) and radiation (> 28 days - 14 days if palliative radiotherapy to painful bone lesions).
4. Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 7 days prior to enrolment
5. Significant cardiovascular disease defined as congestive heart failure (NYHA Class II, III, or IV – see Appendix 3), unstable angina pectoris, or myocardial infarction within 6 months prior to enrolment.
6. Inadequately controlled hypertension (defined as a blood pressure of > 150 mmHg systolic and/or > 100 mmHg diastolic on medication), or any prior history of hypertensive crisis or hypertensive encephalopathy
7. History of stroke or transient ischaemic attack within 6 months prior to enrolment
8. Significant vascular disease (e.g., aortic aneurysm, aortic dissection), or symptomatic peripheral vascular disease
9. Evidence or history of recurrent thromboembolism (>1 episode of deep venous thrombosis/peripheral embolism) during the past 2 years, bleeding diathesis or coagulopathy
10. Chronic daily intake of aspirin >325 mg/day or clopidogrel >75 mg/day
11. History of abdominal or tracheo-oesophageal fistula, gastrointestinal perforation, or intraabdominal abscess within 6 months prior to study enrolment
12. Serious, non-healing wound, ulcer, or bone fracture
13. Immuno-compromised patients, including known seropositivity for human immunodeficiency virus (HIV)
14. Chronic treatment with corticosteroids (dose of >10 mg/day methylprednisolone equivalent) excluding inhaled steroids or substitution therapy
15. Known hypersensitivity to any component of the investigational drugs or excipients
16. Current active second malignancy other than non-melanoma skin cancers and post-treatment for localised prostate cancer. Patients are not considered to have a currently active malignancy if they are in complete remission for >3 years prior to study
17. Any other significant medical illness or medically significant abnormal laboratory finding that would, in the investigator’s judgment, make the patient inappropriate for this study, or would increase the risk associated with the patients’ participation in the study.
18. Treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrolment.
19. Prior treatment with bevacizumab for any indication
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint of this study is to assess the rate of PFS and evaluate the safety of bevacizumab in combination with IFN 3 MIU s.c. three times per week until disease progression as first-line treatment of metastatic RCC. |
|
| 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 | Yes |
| 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 | 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | Information not present in EudraCT |
| 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) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.3 |
The trial involves single site in the Member State concerned
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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
|
| 2 years after the last patient has been enrolled into the study or until all patients have died, whichever occurs first. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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