Monocentric Pilot Study Investigating the Metabolic Activity of Melanoma in Vivo During Sorafenib and Dacarbazine
A total of 12 patients with skin- or superficial lymph node metastases with a diameter of at
least 1 cm will be chosen for sorafenib therapy over 56 days per os twice daily with each
400 mg and, additionally, on day 14 and 42, intravenous dacarbazine infusion (volume
depending on the body surface area (1000 mg/m2)).
On screening day, the medical history as well as the physical examination with determining
the vital signs and the analyzing the coagulation status in the venous blood are conducted.
In women, a pregnancy test will be conducted. On screening day, as well as on day 10, 16, 35
and 60, venous blood is taken for examination of hematology (hemoglobin, hematocrit, red
blood cell (RBC) count, platelets, white blood cell (WBC) count with differential (total
neutrophils, lymphocytes, monocytes, eosinophils and basophils), biochemistry (sodium,
potassium, urea, creatinine, phosphate, glucose, alanine aminotransferase (ALT), gGT,
alkaline phosphatase, total bilirubin, albumin, total lipid status with LDL-cholesterol,
HDL-cholesterol, triglyceride), S-100, LDH, and for asservation of 40 ml EDTA and 10 ml
Serum. At every consultation (screening day, day 1, 10, 14, 16, 35, 42, 60), concomitant
medication will be recorded, and vital signs will be determined. At every consultation
except of screening day and day 1, adverse events will be reported. FDG-PET/CT is conducted
on screening day, day 10, 16 and 60; afterward, one cutaneous metastasis which was included
in previous PET/CT scan, is biopsied for investigating its gene processing profile (day 60
1. Age > 18 years.
2. Histologically or cytologically confirmed unresectable (stage III) or metastatic
(stage IV) melanoma for whom treatment with dacarbazine is considered medically
3. No prior chemotherapy.
4. ECOG Performance Status of 0 or 1.
5. Life expectancy of at least 12 weeks.
6. Subjects with at least one uni-dimensional (for RECIST) or bi-dimensional (for WHO)
measurable lesion. Lesions must be measured by CT-scan or MRI.
7. Adequate bone marrow, liver and renal function as assessed by the following
laboratory requirements to be conducted within 7 days prior to screening: Hemoglobin
>= 9.0 g/dl. Absolute neutrophil count (ANC) >=1,500/mm3. Platelet count
>=100,000/ìl. Total bilirubin <= 1.5 times the upper limit of normal. ALT and AST <=
2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver
involvement of their cancer). Alkaline phosphatase < 4 x ULN. PT-INR/PTT < 1.5 x
upper limit of normal [Patients who are being therapeutically anticoagulated with an
agent such as coumadin or heparin will be allowed to participate provided that no
prior evidence of underlying abnormality in these parameters exists]. Serum
creatinine <= 1.5 x upper limit of normal.
8. Signed and dated informed consent before the start of specific protocol procedures.
9. Baseline serum LDH level > 1.1 ULN.
10. Assessable metastases (Skin or superficial lymph nodes, minimal diameter 1 cm)
1. History of cardiac disease: congestive heart failure > NYHA class
2. active CAD (MI 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.
3. History of HIV infection or chronic hepatitis B or C.
4. Active clinically serious infections (> grade 2 NCI-CTC version 3.0).
5. Symptomatic metastatic brain or meningeal tumors (unless the patient is > 6 months
from definitive therapy, has a negative imaging study within 4 weeks of study entry
and is clinically stable with respect to the tumor at the time of study entry).
6. Patients with seizure disorder requiring medication (such as steroids or
7. History of organ allograft.
8. Patients with evidence or history of bleeding diathesis.
9. Patients undergoing renal dialysis.
10. 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 tumors [Ta, Tis & T1] or any cancer curatively
treated > 3 years prior to study entry.
11. Primary ocular melanoma
Type of Study:
Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
1) Metabolic activity (glucose-uptake) in vivo, standardised uptake value (SUV) in FDG-PET/CT. 2) Quantification of soluble S100 serum and LDH. 3) Gene expression profile of cutaneous melanoma metastasis
Outcome Time Frame:
SCREEN: S100, LDH, FDG-PET/CT, biopsy. DAY10: S100, LDH, FDG-PET/CT, biopsy. DAY16: S100, LDH, FDG-PET/CT, biopsy. DAY35: S100, LDH. DAY60: S100, LDH, FDG-PET/CT, biopsy (biopsy is optional). Sorafenib: DAY1-56. DTIC: DAY 14 and 42.
Reinhard Dummer, MD
Department of Dermatology, University Hospital Zurich, Switzerland
Sorafenib and Dacarbazine
- Melanoma Stage III or IV
- No Prior Chemotherapy