Sorafenib and Radioembolization With Sir-Spheres® for the Treatment of Metastatic Ocular Melanoma

Primary objective:

To evaluate the safety and tolerability of sorafenib in combination with SIR-Spheres® radioembolization in uveal melanoma patients metastatic to the liver.

Secondary objectives:

• Translational research on biomarkers (blood and liver biopsies) as well as on radiological exam by using microbubble contrast enhanced ultrasound. Angiogenic markers such as VEGF, IGF-2, TFG Angiopoietin-2 and IL-8 will be monitored. Correlations will be investigated between the angiogenic markers (blood & tumor tissue), angiogenic radiological exam and the response to the treatment.
• To evaluate the response, clinical benefit, PFS and survival of the patients.

Inclusion criteria

• Metastatic uveal melanoma with proven histology (stage IV)
• Presence of liver metastases
• Concomitant non life-threatening metastases outside the liver are allowed
• Palliative radiotherapy will be allowed outside the liver
• Previous chemotherapy or immunotherapy at least 4 weeks before study treatment is allowed
• Age ≥ 18 years
• ECOG Performance Status of 0 or 1
• Life expectancy of at least 12 weeks
• Subjects with at least one uni-dimensional (by RECIST) measurable lesion. Lesions must be measured by CT-scan or MRI
• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to study treatment

• Hemoglobin ≥ 9.0 g/dl
• Absolute neutrophil count (ANC) ≥ 1,500/mm3
• Platelet count ≥ 100,000/ul
• Total bilirubin ≤ 1.5 times the upper limit of normal (ULN)
• ALT and AST ≤ 5 x ULN
• Alkaline phosphatase < 4 x ULN
• PT-INR/PTT < 1.5 x ULN
• Serum creatinine ≤ 1.5 x ULN
• Signed and dated informed consent before the start of specific protocol procedures

Exclusion criteria

• History of cardiac disease: congestive heart failure >NYHA class 2; active coronary artery disease (myocardial infarction more than 6 months prior to study entry is allowed); cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted) or uncontrolled hypertension.
• History of HIV infection or chronic hepatitis B or C.
• Active clinically serious infections (> grade 2 NCI-CTC version 4.0).
• Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks before treatment start and is clinically stable with respect to the tumor at the time of study treatment).
• Patients with seizure disorder requiring medication (such as steroids or anti-epileptics).
• History of organ allograft.
• Patients with evidence or history of bleeding diasthesis.
• Patients 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 tumor (Ta, Tis and T1) or any cancer curatively treated > 3 years prior to study treatment.
• Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test 72h before all investigations related to the protocol. Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and two weeks after the completion of trial (and men for at least 3 months after last administration of study medication).
• Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study.
• Patients unable to swallow oral medications.
• Pre-treatment with any antiangiogenic agents (Bevacizumab, Sunitinib, or other TKI inhibitors affecting the vessels)
• Radiotherapy on the liver
• Major surgery within 4 weeks of start of treatment
• Autologous bone marrow transplant or stem cell rescue within 4 months of study treatment.
• Use of biologic response modifiers, such as G-CSF, within 3 weeks of study treatment.
• Investigational drug therapy outside of this trial during or within 4 weeks of study treatment
• Prior exposure to the study drug
• Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results