| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| MedDRA Classification |
| 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 |
| Definition of the safety profile and maximum tolerated dose (MTD) of sorafenib administered in combination with temozolomide |
|
| E.2.2 | Secondary objectives of the trial |
1.Evaluation of the tumor response rate in patients treated with this combination using the RECIST criteria.
2. Evaluation of the overall survival in patients treated with this combination.
3. Evaluation of the progression-free survival in patients treated with this combination.
4. Evaluation of the effect of this combination on tumor vascularization by DCE-US (Dynamic contrast enhanced ultrasonography).
5. Evaluation of the PK profile of temozolomide in the presence of sorafenib and comparison with the known PK profile of temozolomide.
6. Evaluation of the number and functions of lymphocytes with this combination.
7. Evaluation of the correlation between the tumor response rate and the BRAF mutations in the tumor.
8. Evaluation of the correlation between the response rate and the activity of the 06-methylguanine-DNA-methyltransferase (MGMT) in the tumor. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1) Unresectable metastatic stage III or IV melanoma
2) Previously or non-previously treated for metastatic disease
3) Men and women ≥18 years, WHO performance status of 0 or 1 and life expectancy > 3 months
4) Patients who have at least one uni-dimensional measurable lesion by CT-scan or MRI according to Response Evaluation Criteria in Solid Tumors (RECIST), evaluated within 28 days prior to inclusion.
5) Adequate bone marrow function as assessed by the following laboratory requirements to be conducted within 7 days prior to inclusion: hemoglobin >9.0 g/dl, absolute neutrophil count (ANC)>1,500/mm3, platelets> or = 100,000/mm3.
6) Adequate liver function as assessed by the following laboratory requirements to be conducted within 7 days prior to inclusion: ALT and AST < 2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement of their cancer). Total bilirubin < 1.5 x the upper limit of normal. Amylase and lipase < 1.5 x the upper limit of normal.
7) Adequate renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to inclusion: Serum creatinine < 1.5 x the upper limit of normal.
8) Adequate coagulation function as assessed by the following laboratory requirements to be conducted within 7 days prior to inclusion: 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).
9) Vital functions : respiratory, cardiac and neurologic in the normal ranges.
10) 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 |
|
| E.4 | Principal exclusion criteria |
1) Known evolutive CNS tumors including metastatic brain disease.
2) Known or suspected allergy to the investigational agent or dacarbazine or any agent to be administered in the trial.
3) Anti-cancer chemotherapy, immunotherapy (including monoclonal antibodies), hormonal therapy, or investigational drug within 30 days prior to start of study drug. 4) Prior use of temozolomide or sorafenib.
5) Radiotherapy within 3 weeks of start of study drug.
6) Use of biologic response modifiers, such as G-CSF, within 3 weeks of study entry.
7) History of cardiac disease: congestive heart failure > class II New York Heart Association (NYHA); active coronary artery disease (CAD), history of myocardial infarction less than 6 months prior to study entry; cardiac arrhythmias requiring anti-arrhythmic therapy other than beta blockers or digoxin, uncontrolled hypertension.
8) Active clinically serious infection (> grade 2 NCI-CTCAE version 3.0).
9) Known history of human immunodeficiency virus (HIV) infection or chronic hepatitis B or C.
10) Patients with seizure disorder requiring medication (such as anti-epileptics).
11) History of organ allograft.
12) History of lactase deficiency, galactokinase-deficiency galactosemia, glucose or galactose malabsorption syndrome.
13) 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) and any cancer curatively treated > 3 years prior to study entry.
14) Participation in another clinical trial and administration of any investigational drug within 30 days prior to study screening.
15) Pregnant women or breast feeding, women of child-bearing potential.
16) People deprived of freedom or under supervision (including trusteeship).
17) Any condition that is unstable or which could jeopardize the safety of the patient and his/her compliance in the study; substance abuse, medical, psychological, social or geographic conditions that may interfere with the patient’s participation in the study or evaluation of the study results.
18) Patients unable to swallow oral medications |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Safety profile of the association: temozolomide + sorafenib at escalating dose levels. Definition of DLT:The DLT will be defined of appearance of at least one of the following study drugs combination-related event:- Grade 4 neutropenia (absolute neutrophil count less than 500/mm3) for 7 days- febrile neutropenia (< 1.0 x 109/l with fever ³ 38.5°C) lasting > 3 days- Platelet count < 25,000/mm3- Grade 3 or 4 non-hematologic toxicity (excluding grade 3 nausea and vomiting and transient fever) as defined by NCI Common Terminology Criteria version 3.0. |
|
| 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 | Yes |
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Immunomonitoring, echography |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| first combination therapy of sorafenib-temozolomid in melanoma with this temozolomide dose regimen |
|
| 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 | No |
| E.8.1.2 | Open | No |
| 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
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| 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 | No |
| 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 | 6 |
| E.8.9.1 | In the Member State concerned days | |
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