A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma

• Status: Unknown status
• Trial end date: 2017-06-01
• Target enrollment: 0
• Participant gender: All

Summary

Uveal melanoma is the most common primary intra-ocular malignancy in adults with an incidence of 0.6 - 0.7 per 100,000 per year.

Prognosis of metastatic uveal melanoma is poor. In retrospective analyses a median survival time after detection of metastases of 5 months (Flaherty et al, 1998) and 7 months (Kath et al, 1993) was reported. For patients receiving no treatment reported median survival was 2.0 months compared with 5.2 months for those receiving treatment for metastases (Gragoudas et al, 1991).

Up to now there is no established treatment of metastatic uveal melanoma. Some therapeutic approaches with locoregional treatment or systemic chemotherapy have been undertaken:

In case of metastatic disease which is confined to the liver in about 85% of patients with uveal melanoma surgical resection led to a median survival of 14 months (Mariani et al, 2009) or 19 months and a 5-year survival rate of 22% in a selected patient population (Adam et al, 2006).

As locoregional treatment option treatment with fotemustine via direct intra-arterial hepatic infusion was investigated and led to a median survival of 15 months (Peters et al, 2006). This was not a randomized trial, but a report on 101 consecutive treated patients. Additional debulking surgery was performed whenever feasible.

A randomized phase III trial comparing intra-arterial hepatic fotemustine administration with intravenous systemic fotemustine and overall survival as primary endpoint is still ongoing (EORTC 18021).

Thus, no systemic chemotherapy is approved for metastatic uveal melanoma. Although no specific genes have been linked to the pathogenesis of uveal melanoma, preclinical studies suggest potential benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine kinases.

Thus, sorafenib as inhibitor of b-Raf and Raf-1 (c-Raf or c-Raf-1), pro-angiogenic vascular endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor (PDGFR) may potentially lead to a benefit for patients with metastatic uveal melanoma in terms of disease control and prolongation of survival.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Prof. Dr. med. Max. E. Scheulen
• Collaborator: ClinAssess GmbH
• Treatments: Niacinamide; Sorafenib

Criteria

Inclusion criteria:

1. Signed and dated written informed consent before the start of specific protocol procedures

2. Metastatic uveal melanoma with histological or cytological confirmation of liver metastasis

3. By means of whole body MRI documented disease according to RECIST version 1.1 with at least one unidimensional measurable lesion ≥ 10 mm

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

5. Male or female patients ≥ 18 years of age

6. Estimated life-expectancy more than 5 months

7. Hematologic function, as follows:

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

• Platelet count ≥ 100 x 109/L

• Hemoglobin ≥ 9 g/dL

8. Renal function, as follows

-Creatinine ≤ 1.5 x upper limit of normal (ULN)

9. Hepatic function, as follows

• Aspartate aminotransferase (AST) ≤ 2.5 x ULN

• Alanine aminotransferase (ALT) ≤ 2.5 x ULN

• Total bilirubin ≤ 3 mg/dl

• Alkaline phosphatase ≤ 4.0 x ULN

10. PT-INR/PT < 1.5 x ULN

11. Females of childbearing potential (FCBP) must have a negative pregnancy test within 7 days of the first application of study treatment and must agree to use effective contraceptive birth control measures

12. Males must agree to use barrier birth control measures (condoms) during the course of the trial.

Exclusion criteria:

1. Previous or concurrent tumor other than uveal melanoma with the exception of cervical cancer in situ, adequately treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, and T1) or any curatively treated tumors > 3 years prior to enrollment

2. History of cardiac disease: congestive heart failure ≥ NYHA class 2; active coronary artery disease ([CAD], myocardial infarction more than 6 months prior to study entry is allowed), cardiac arrhythmias requiring antiarrhythmic therapy (only beta blockers or digoxin are permitted)

3. QT/QTc-interval prolongation (QTc> 450 msec) on ECG, known Long QT syndrome or known Long QT syndrome in relatives

4. Known HIV infection

5. Known chronic infection with hepatitis B or C

6. Hypokalemia, hypocalcemia, hypomagnesemia or patients under actual treatment against hypokalemia, hypocalcemia, hypomagnesemia

7. Active infection requiring systemic antibiotic/antiviral/antifungal treatment or any uncontrolled infection > Grade 2 NCI-CTCAE

8. Symptomatic brain or meningeal tumors (unless patient is > 6 months from definitive therapy, had a negative imaging study within 4 weeks of study entry and is clinically stable with respect to the tumor at the time of study enrollment)

9. Patients with seizure disorder requiring medication (such as steroids or antiepileptics)

10. History of organ allograft

11. Patients with evidence or history of bleeding diathesis

12. Thrombotic or embolic events within the last 6 months

13. Serious non-healing wound, ulcer or fracture

14. Uncontrolled arterial hypertension with systolic blood pressure >150 mm Hg and/ or diastolic blood pressure > 90 mg Hg despite optimal treatment, determined twice within one week

15. Pregnant or breast-feeding patients

16. Marked claustrophobia

17. Cardiac pacemaker, cochlea implants or other implanted metal devices, residual metal splinters

18. Known allergy to the used study drug sorafenib or to any of its excipients

19. Known hypersensitivity to gadolinium based contrast agents

20. Subject unwilling or unable to comply with study requirements

21. Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results

22. Participation in any clinical study or treatment with an experimental drug or experimental therapy within 28 days prior to study enrollment or during study participation