| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| unresectable and/or metastatic renal cell carcinoma |
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| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To compare progression-free survival (PFS) of randomised metastatic RCC patients receiving sorafenib 400 mg bid versus standard therapy (interferon alpha-2a) as a first-line therapy. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the disease control rate during the randomised phase (proportion of patients with stable disease or confirmed complete or partial response)
To assess changes in patient´s reported outcomes of disease-related symptom response / symptom benefit and patient satisfaction with treatment
To evaluate the overall best response rate (proportion of patients with confirmed complete and partial responses as per the RECIST criteria and overall duration of response during the randomised phase.
To determine PFS, DCR and response rate of patients escalated to 600 mg bid
To determine PFS, DCR and response rate of patients during sorafenib therapy after patients have crossed over from standard therapy with IFN because of progression
To document overall survival
To evaluate steady state trough plasma sorafenib concentrations over time at 400 mg bid and to evaluate the change in steady state trough plasma sorafenib concentrations in patients escalated from 400 mg bid to 600 mg bid.
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| E.2.3 | Trial contains a sub-study | Information not present in EudraCT |
| E.3 | Principal inclusion criteria |
Patients who give written informed consent prior to any study specific screening procedures with the understanding that the patient has the right to withdraw from the study at any time, without prejudice.
Male or female patients > 18 years of age
Patients who have a life expectancy of at least 12 weeks
Patients, who suffer from unresectable and/or metastatic, measurable predominantly clear cell RCC histologically or cytologically documented.
Patients must have undergone prior (at the time of primary diagnosis) complete surgical excision of primary RCC tumor.
Patients must have had no prior systemic therapy for advanced RCC. Prior systemic therapy is defined as any treatment with a chemotherapy agent (or regimen), an immunotherapy agent (or regimen) or an investigational treatment agent (or regimen) against the renal cell carcinoma. Megestrol acetate or medroxyprogesterone will constitute as a prior systemic therapy.
Patients who have at least one uni-dimensional measurable lesion by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST) (Appendix 11.4).
Patients who have an Eastern Co-operative Oncology Group (ECOG) performance status of 0 or 1 (Appendix 11.1).
Adequate bone marrow, liver , and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to screening,
Hemoglobin >9.0 g/l
Absolute neutrophil count ( ANC)>1,500/mm3
Platelets> or = 100,000/µl
Total bilirubin < 1.5 x the upper limit of normal.
ALT and AST < 2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement of their cancer).
Amylase and lipase < 1.5 x the upper limit of normal.
Serum creatinine < 2.0 x the upper limit of normal.
PT or INR and PTT < 1.5 x upper limit of normal (patients who receive anti-coagulation treatment with an agent such as warfarin or heparin will be allowed to participate. For patients on warfarin, close monitoring of at least weekly evaluations will be performed until INR is stable based on a measurement at pre dose, as defined by the local standard of care).
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| E.4 | Principal exclusion criteria |
Previous or concurrent cancer that is distinct in primary site or histology from the cancer being evaluated in this study EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors ( Ta, Tis &T1) or any cancer curatively treated > 5 years prior to study entry.
Complete renal shut-down requiring hemo- or peritoneal dialysis
History of cardiac disease : congestive heart failure>NYHA class 2 ( Appendix 11.5): active cardiovascular disease( MI more than 6 months prior to study entry is allowed); cardiac arrhythmia requiring anti-arrythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension
Active clinically serious bacterial or fungal infections (> grade 2 NCI-CTCAE, Version 3)
Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C
Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to this brain tumour site at the time of study entry. Also the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies (head CT or MRI at screening always required)
Patients with seizure disorder requiring medication (such as steroid anti-epileptics)
History of organ allograft
Substance abuse, medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results
Known or suspected allergy to the investigational agent or any agent given in association with this trial
Any condition that is unstable or which could jeopardise the safety of the patient and his/her compliance in the study
Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial.
Concurrent anti-cancer chemotherapy, immunotherapy (including monoclonal antibodies) or hormonal therapy, except for bisphosphonates, during or within 30 days prior to start of study drug
Concomitant treatment with Megestrol acetate or Medroxyprogesterone
Investigational drug therapy during or within 30 days prior to randomisation
Prior use of inhibitors of the Ras / Raf-, MEK-, AKT kinase- and mTOR-signaling pathway or of Farnesyl transferase inhibitors
Prior use of investigational or licensed angiogenesis inhibitors (targeting VEGF/VEGFR, PDGF/PDGFR and other key molecules in angiogenesis) for example Bevacizumab
Biological response modifiers, such as G-CSF or GM-CSF, within 3 weeks prior to study entry or during study. (G-CSF and other hematopoietic growth factors may only be used in the management of acute toxicity such as febrile neutropenia when medically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction.) [Patients taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study]
Significant surgery within four weeks prior to start of study drug
Autologous bone marrow transplant or stem cell rescue within 4 months of study
Concomitant Rifampicin and St John’s Wort (Warfarin may be used only with very close monitoring.
Radiotherapy during study or within 3 weeks of start of study drug. [Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section]
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary objective is to compare the progression-free survival (PFS) between patients treated with BAY 43-9006 versus patients treated with standard therapy (IFN). PFS will be measured from the date of randomisation until the date of progression radiological or clinical, whichever is earlier or death (if death occurs before progression). Patients without tumor progression or death at the time of analysis will be censored at their last date of evaluation. |
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| 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) | 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 | 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 | Yes |
| 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
| Information not present in EudraCT |
| 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
| |
| 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 | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
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