Treatment of patients with metastatic melanoma (AJCC stage IV or III unresectable) with the PDE-inhibitor Tadalafil:A Pilot Trial for Proof of Principle”

Recruitment & Eligibility

Status: Pending

Sex: All

Target Recruitment: 12

Inclusion Criteria

a) Histologically proven metastatic melanoma
b) Clinical stage IV or III unresectable (AJCC 2010)
c) = 18 to 75 years of age
d) Presence of cutaneous or accessible lymph node metastases (tumor biopsies)
e) Measurable disease (at least one lesion that can be accurately measured in two perpendicular diameters, with at least one diameter = 5 mm and the other dimension = 5 mm assessed by ultrasound)
f) ECOG performance status of 0-2
g) At least one prior treatment for metastatic disease, including established treatments like Ipilimumab.
h) No medical contraindication to biopsy of target lesion.
i) Willingness and ability to understand the informed consent and the quality of life questionnaires and to give signed written informed consent.
j) Women of childbearing potential must agree to use effective contraception during the study.

Exclusion Criteria

a) Any evidence of brain metastases
b) Patients with severe cardiac disease (e.g. NYHA Functional Class II, III or IV, myocardial infarction within 6 months, ventricular tachyarrhythmia requiring ongoing treatment, unstable angina pectoris, sinusbradycardia).
c) Concurrent medication with nitrates, alpha-Blockers e.g. Doxazosin or other interacting medications (CYP3A4 inhibitors e.g. Ketoconazole, Erythromycin, Clarithromycin, Intraconazol and grape fruit juice, CYP3A4 inductors e.g. Rifampicin, Phenobarbital, Phenytoin and Carbamazepin)
d) Uncontrolled blood pressure (<90/50mm Hg or uncontrolled hypertone)
e) laboratory data (to be obtained within 4 weeks of initiation):
Platelets < 75,000/mm³
Calculated Creatinine Clearance (CRCL) < 60 ml/min
ALAT or ASAT > 2 x ULN
Total serum bilirubin > 1.5 mg/dl
f) Patients who have a history of depression requiring hospitalization
g) Patients with seizure disorders requiring anticonvulsant therapy
h) Concurrent systemic glucocorticoids or any other systemic immunosuppressive therapy
i) History of ischemic neuropathy of the optical nerve (NAION)
j) Brain insult within the last 6 months
k) Anatomic penis deformation or history of priapismus or predisposing illness like sickle cell anemia or hyperglobulinaemia
l) Patients with a history of a curatively treated malignancy must be disease-free and have a survival prognosis that exceeds five years.
m) Concurrent treatment with other anti-cancer therapy or parallel participation in another therapeutic trial
n) Known hypersensitivity reaction to Tadalafil or other ingredients of Cialis®.
o) Unwilling or unable to comply with the requirements of the protocol
p) Pregnant or lactating women
q) Unwillingness or inability to employ an effective barrier method of birth control throughout the study and for up to 3 months after end of treatment

Study & Design

Study Type: interventional

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Immune response as assessed by number of CD8+ cells in fresh tumor tissue by Flow cytometric analysis (FACS) at 4 weeks after beginn of treatment

Secondary Outcome Measures

Name	Time	Method
- Other immune response parameters as number of CD4+ and CD8+ cells in tumor tissue by immunehistochemistry and proliferation of CD8+ lymphocytes in peripheral blood mononuclear cells by flow cytometry (FACS) 4 weeks after begin of treatment<br>- Response rate (CR + PR) and Disease control rate (CR + PR +SD) according to immune related response criteria (irRC) and RECIST 8 weeks after beginn of treatment<br>- Tolerability <br>- Optimal dosing schedule for Tadalafil<br>- Treatment-related side effects <br>- Progression-free survival after 8 weeks of treatment<br>- Quality of life (questionnaires: EORTC-QLQ-C30, SF-12) every 4 weeks<br>