E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
|
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The objective of this study is to evaluate the efficacy, safety, tolerability and pharmacokinetics of intrapatient dose escalation in previously untreated subjects with mRCC. The initial dose of sorafenib will be 400mg bid administered orally, on a continuous basis. Intrapatient dose escalation will occur as defined in the table below, providing no grade 3 or 4 toxicities (except for alopecia, nausea and vomiting) are observed.
The primary objective is to assess the response rates (by independent assessment) observed in subjects treated with a continuous, daily dose of 400 mg bid sorafenib dose escalated up to 800mg bid. |
|
E.2.2 | Secondary objectives of the trial |
The secondary objectives are to assess the following: • Safety and tolerability • Pharmacokinetics • Progression free survival (PFS) • Time to progression (TTP)
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age > 18 years. • Histological or cytological documentation of metastatic and/or unresectable clear cell RCC is required • Subjects with at least one uni-dimensional measurable lesion. Lesions must be measured by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumours (RECIST). • ECOG Performance Status of 0 or 1 • MSKCC good or intermediate category • Life expectancy of at least 12 weeks. • 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/dl • Absolute neutrophil count (ANC) >1,500/mm3 • Platelet count 100,000/l • Total bilirubin < 1.5 times the upper limit of normal • ALT and AST < 2.5 x upper limit of normal (< 5 x upper limit of normal for subjects with liver involvement of their cancer) • Alkaline phosphatase < 2.5 x ULN PT-INR/PTT < 1.5 x upper limit of normal. Subjects who are being therapeutically anticoagulated with an agent such as coumadin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in these parameters exists. For subjects 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 (exluding subjects being anticaogulated for deep vein thrombosis and/or pulmonary embolus occurring within 12 months of the start of treatment). • Serum creatinine < 1.5 x upper limit of normal • Signed informed consent must be obtained prior to any study specific procedures. • Subjects must have received no prior systemic anticancer therapy for the treatment of their renal cell carcinoma • Prior nephrectomy • Prior palliative radiotherapy to metastatic lesion(s) is permitted
|
|
E.4 | Principal exclusion criteria |
• History of cardiac disease; • congestive heart failure >NYHA class 2 • active CAD (MI more than 6 mo prior to study entry is allowed) • cardiac arrhythmias requiring anti-arrhythmic therapy( beta blockers or digoxin are permitted) • uncontrolled hypertension (defined as blood pressure >160mmHg systolic and/or > 90mmHg diastolic on medication) • History of HIV infection or chronic hepatitis B or C • Active clinically serious infections (> grade 2 NCI-CTCAE version 3.0) • Symptomatic metastatic brain or meningeal tumors unless the subject is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study entry. Also the subject must not be undergoing acute steroid therapy or taper therapy (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies) • Subjects with seizure disorder requiring medication (such as steroids or anti-epileptics) • History of organ allograft • Subjects with evidence or history of bleeding diathesis • Deep vein thrombosis and/or pulmonary embolus within 12 months of the start of treatment. • Delayed healing of wounds, ulcers or bone fractures • Subjects with pre-existing thyroid abnormality whose thyroid function cannot be maintained within the normal range by medication • Subjects undergoing renal dialysis • 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 > 3 years prior to study entry. • Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study • Pregnant or breast-feeding subjects. Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to 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 and three months after the completion of trial. The investigator is requested to advise the subject how to achieve an adequate contraception.
• Subjects unable to swallow oral medications. This applies to subjects with severe obstruction of upper GI that require gavage. Excluded therapies and medications, previous and concomitant: • Any prior systemic anticancer therapy including cytotoxic therapy, targeted agents, experimental therapy (adjuvant or neo-adjuvant therapy including IFN-IL2-5FU is permitted). • Prior adjuvant sorafenib is excluded. • Radiotherapy during study or within 3 weeks of start of study drug • Major surgery within 4 weeks of start of study • Autologous bone marrow transplant or stem cell rescue within 4 months of study • Use of biologic response modifiers, such as G-CSF, within 3 week of study entry. [G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction.] Subjects taking chronic erythropoietin are permitted provided no dose adjustment is undertaken within 2 months prior to the study or during the study. • Investigational drug therapy outside of this trial during or within 4 weeks of study entry • Substance abuse, medical, psychological or social conditions that may interfere with the subject’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.
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Primary end point is to assess the response rates observed for patients treated with continuous daily dose of sorafenib escalated from 400mg to 600mg to a maximum of 800mg bid. |
|
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 | 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
| 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.8.5.1 | Number of sites anticipated in the EEA | 20 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
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
| |
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 |