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

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

This study will evaluate the preliminary safety, pharmacokinetics, and anti-tumor activity of pasireotide s.c. in patients with metastatic melanoma or metastatic Merkel cell carcinoma. The study consists of three phases: screening, intra-patient dose-escalation, and follow-up phases.

In the screening phase patient will be informed of all aspects of the study and sign informed consent forms and then be screened for study eligibility.

During the intra-patient dose escalation phase, 18 patients will be treated with pasireotide s.c. 300 μg t.i.d. for 2 weeks. If there are no unacceptable AEs, defined as drug-related clinically meaningful, uncontrolled grade 3 or any grade 4 toxicities, patients will be dose escalated to 600 μg t.i.d. for 2 more weeks, then 900 μg t.i.d. for 2 weeks and then 1200 μg for 2 weeks provided that there are no unacceptable AEs. Each patient will be in the dose escalation phase for a maximum of 8 weeks.

At end of the intra-patient dose escalation phase, patients will be allowed to switch to 80 mg pasireotide LAR i.m. q 28 d (or a lower dose in case of toxicity) for an additional 6 months or until disease progression, or unacceptable AEs, or patient withdraws consent. In addition, all patients will keep their pasireotide s.c. t.i.d. treatment (same dose as that at the end of the 8-week dose escalation phase) during the first 2 weeks of the LAR follow-up phase, except on the day receiving the first LAR dose because of an anticipated initial burst of drug release.

Inclusion criteria:

1. Patients must have histologically or cytologically confirmed unresectable (stage III) and/or metastatic (stage IV) melanoma or unresectable and/or metastatic Merkel cell carcinoma.
2. Melanoma patients should have no mutation in BRAF and NRAS genes
3. Patients should have lesions that can be biopsied, in addition measurable and non-measurable metastatic lesions and at 1 lesion suitable for 18FDG-PET scan or CT/MRI.
4. ECOG Performance Status of 0 or 1
5. Presence of measurable or non-measurable disease according to RECIST 1.0
6. Adequate organ function: adequate bone marrow function (WBC ≥ 2.5 x 109/L, ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, hemoglobin ≥ 9 g/dL); serum creatinine ≤ 1.5 mg/dL or estimated glomerular filtration rate (eGFR) > 40 ml/min/m2; serum lipase ≤ 1.5 ULN

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

15. Patients with known history of hypothyroidism are eligible if they are on adequate and stable replacement thyroid hormone therapy for at least 3 months prior to baseline

16. Patients with QT-related exclusion criteria

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)

Other protocol-defined inclusion/exclusion criteria may apply.