['neoplasms']
['sorafenib']

        Inclusion Criteria:

          1. Histological or cytological documentation of incurable locally advanced or metastatic
             solid malignancy for which no standard therapy exists.

          2. Patients eligible for the expansion cohort must be willing to undergo tumor and skin
             biopsies, while tumor and skin biopsies are optional for patients enrolled in the
             escalation cohort. Primary tumor or metastatic site must be accessible for biopsy.
             Bone metastases are excluded as a biopsy site.

          3. Evaluable disease by RECIST version 1.1. criteria (see appendix III; at least 1 target
             or non-target lesion for the dose escalation cohorts; at least 1 target lesion the for
             dose expansion cohorts).

          4. Patients must have documented radiographic or clinical progressive disease.

          5. Age ≥ 18 years.

          6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 1 (appendix IV).

          7. Normal 12-lead ECG (clinically insignificant abnormalities permitted), and left
             ventricular ejection fraction (LVEF) > 50% evaluated by multigated acquisition scan
             (MUGA) or echocardiogram.

          8. Normal or regulated thyroid function - supplementation or blocking drugs permitted.

          9. Urine analysis: no clinically significant abnormalities.

         10. Albumin higher than 25 g/L.

         11. Adequate bone marrow, liver and renal function as assessed by the following laboratory
             requirements to be conducted within 14 days prior to screening:

               -  Hemoglobin ≥ 5,6 mmol/L

               -  Absolute neutrophil count (ANC) ≥ 1,5 x 10*9/l

               -  Platelet count ≥ 100 x 10*9/l

               -  Total bilirubin ≤ 1.5 times the upper limit of normal (ULN). Patients with known
                  Gilbert's disease who have serum bilirubin ≤ 3x ULN may be enrolled.

               -  ALT and AST ≤ 2.5 x ULN (in case of liver metastases: ≤ 5 times ULN).

               -  Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min (based on MDRD).

               -  PT-INR/PTT < 1.5 x ULN, unless coumarin derivatives are used.

               -  Activated partial thromboplastin time < 1.25 x ULN (therapeutic anticoagulation
                  therapy is allowed, if this treatment can be interrupted for a biopsy as judged
                  by the treating physician).

        Exclusion Criteria:

          1. Evidence of a significant uncontrolled concomitant disease, such as cardiovascular
             disease (including stroke, New York Heart Association Class III or IV cardiac disease
             or myocardial infarction within 6 months prior to screening, unstable arrhythmia,
             clinically significant valvular heart disease and unstable angina); nervous system,
             pulmonary (including obstructive pulmonary disease and history of symptomatic
             bronchospasm), renal, hepatic, endocrine, or gastrointestinal disorders; or a serious
             non-healing wound or fracture.

          2. Prior radiotherapy in the abdominal or thoracic area or in > 3 vertebrae in the spine
             (if long interval since previous radiotherapy or radiotherapy in ≤ 3 vertebrae,
             eligibility will be decided on an individual basis by the primary investigator).

          3. Poorly controlled hypertension despite adequate blood pressure medication. Blood
             pressure must be ≤ 160/95 mmHg at the time of screening on a stable antihypertensive
             regimen. Blood pressure must be stable on at least 2 separate measurements.

          4. Seizure disorders requiring anticonvulsant therapy.

          5. Major surgery, other than diagnostic surgery, within 4 weeks prior to day 1, without
             complete recovery.

          6. Known active bacterial, viral, fungal, mycobacterial, or other infection (including
             HIV and atypical mycobacterial disease, but excluding fungal infection of the nail
             beds).

          7. Known hypersensitivity to sorafenib or to its excipients.

          8. Presence of any significant central nervous system or psychiatric disorder(s) that
             would interfere with the patient's compliance.

          9. Drug or alcohol abuse.

         10. Any evidence of a disease or condition that might affect compliance with the protocol
             or interpretation of the study results or render the patient at high risk from
             treatment complications.

         11. Unwillingness or inability to comply with study and follow-up procedures.

         12. Chemotherapy, radiotherapy, or biologic therapy within the previous 4 weeks;
             Nitrosoureas or mitomycin C within the previous 6 weeks; Investigational agents within
             the previous 4 weeks.

         13. Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis.

         14. Untreated or active central nervous system (CNS) metastases (progressing or requiring
             anticonvulsants or corticosteroids for symptomatic control).

         15. Patients with a history of treated CNS metastases are eligible, provided that all of
             the following criteria are met:

               -  Presence of evaluable or measurable disease outside the CNS

               -  Radiographic demonstration of stabilization upon completion of CNS-directed
                  therapy and no evidence of interim progression between completion of CNS-directed
                  therapy and the screening radiographic study

               -  Completion of radiotherapy ≥ 8 weeks prior to the screening radiographic study

               -  Discontinuation of corticosteroids and anticonvulsants ≥ 4 weeks prior to the
                  screening radiographic study

         16. Pregnant or breast-feeding subjects. 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 agree to use adequate barrier birth control
             measures (e.g., cervical cap, condom, or diaphragm) during the course of the trial.
             Oral birth control methods alone will not be considered adequate on this study,
             because of the potential pharmacokinetic interaction between study drug and oral
             contraceptives. Concomitant use of oral and barrier contraceptives is advised.
             Contraception is necessary for at least 6 months after receiving the study protein
             kinase inhibitor.

         17. Concomitant medication with drugs having proarrhythmic potential (such as sotalol,
             haloperidol, flecainide) is not permitted during the study.
      