A Phase I, Exploratory, Intra-patient Dose Escalation Study to Investigate the Preliminary Safety, Pharmacokinetics, and Anti-tumor Activity of Pasireotide (SOM230) s.c.Followed by Pasireotide LAR in Patients With Metastaticmelanoma or Metastatic Merkel Cell Carcinoma

Exclusion Criteria

• •1. Patient with primary uveal melanoma
• •2. Patients with symptomatic CNS metastases who are neurologically unstable or requiring increasing doses of steroids to control their CNS disease
• •3. Patient who have been previously treated with somatostatin analogue or radiolabeled somatostatin analogs or patients with a known hypersensitivity to somatostatin analogs or any component of the pasireotide s.c. and i.m. formulations or their excipients
• •4. Patients for whom standard treatment is available and indicated due to rapidly progressive or aggressive disease
• •5. Patients who received more than 3 prior lines of systemic therapy for the treatment of the disease.
• •6. Patients receiving any anti-neoplastic therapy within the 4 weeks prior to baseline
• •7. Patients receiving an investigational drug within 1 month prior to baseline
• •8. Patients who have undergone major surgery/surgical therapy for any cause within 1 month prior to baseline. Patients must have recovered from the treatment and have a stable clinical condition before entering this study
• •9. Patients who have received prior radiation therapy ≤ 4 weeks, or limited field radiation ≤ 2 weeks, prior to baseline or the side effects of such therapy have not resolved to ≤ grade 1.
• •10. Patients unwilling to perform repeated biopsies
• •11. Patients with known gallbladder or bile duct disease, acute or chronic pancreatitis (patients with asymptomatic cholelithiasis and asymptomatic bile duct dilation can be included)
• •12. Patients with abnormal coagulation (PT or PTT elevated by 30% above normal limits)
• •13. Patients on continuous anticoagulation therapy. Patients who were on anticoagulant therapy must complete a washout period of at least 10 days prior to baseline and have confirmed normal coagulation parameters before study inclusion
• •14. Patients who are not biochemically euthyroid
• •17. Baseline QTcF \>450 ms
• •* History of syncope or family history of idiopathic sudden death
• •* Known history of prolong QT syndrome
• •* Sustained or clinically significant cardiac arrhythmias
• •* Patients with risk factors for torsades de pointes such as uncorrected hypokalemia, uncorrected hypomagnesemia, clinically relevant cardiac failure (NYHA class III or IV), clinically significant/symptomatic bradycardia or high-grade AV block
• •* Concomitant medications known to prolong the QT interval
• •* Known concomitant disease(s) that could prolong QT such as autonomic neuropathy (caused by diabetes mellitus or Parkinson's disease), HIV, liver cirrhosis, uncontrolled hypothyroidism or cardiac failure
• •* Patients with unstable angina, sustained ventricular tachycardia, ventricular fibrillation, high grade (NOT advanced!) heart block or history of acute myocardial infarction less than one year prior to baseline
• •18. Patients with any of the following severe and/or uncontrolled medical conditions:
• •* Uncontrolled diabetes as defined by HbA1c \> 8% despite adequate therapy
• •* Patients with the presence of active or suspected acute or chronic uncontrolled infection or with a history of immunodeficiency, including a positive HIV test result (ELISA and Western blot)
• •* Liver disease or history of liver disease such as cirrhosis, decompensated liver disease, or chronic active hepatitis B and C or chronic persistent hepatitis
• •* Life-threatening autoimmune and ischemic disorders
• •19. Patients who have a history of another primary malignancy, with the exception of locally excised non-melanoma skin cancer and carcinoma in situ of uterine cervix. Patients who had no evidence of disease from another primary cancer for 3 or more years are allowed to participate in the study
• •20. Pregnant or nursing (lactating) women
• •21. Women of child-bearing potential
• •22. Patients with baseline ALT or AST \> 3 x ULN or baseline total bilirubin \> 1.5x ULN
• •23. Patients with presence of Hepatitis B surface antigen (HbsAg) or presence of Hepatitis C antibody test (anti-HCV)
• •24. History of, or current alcohol misuse/abuse within the past 12 months prior to visit 1 (baseline)