HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

Inclusion Criteria: 1. Histological proof of advanced melanoma with BRAF V600 mutation; 2. Progression of disease, according to RECIST 1.1, while on treatment with BRAFi, such as vemurafenib or dabrafenib; or a combination of BRAF - and MEK inhibitors, such as trametinib and dabrafenib; 3. Previous documented response (partial or complete) for at least 4 weeks to treatment with BRAFi and/or BRAFi+MEKi; 4. Start with vorinostat treatment within a maximum period of 1 week after discontinuation of BRAFi and/or BRAFi+MEKi. The BRAFi and/or BRAFi+MEKi can be continued after progression to provide sufficient time to perform baseline assessments; 5. Age ≥ 18 years; 6. Able and willing to give written informed consent; 7. WHO performance status of 0, 1 or 2; 8. Able and willing to undergo blood sampling for PK and PD analysis; 9. Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and antitumor activity; 10. Evaluable disease according to RECIST 1.1; 11. Minimal acceptable safety laboratory values * ANC of ≥ 1.5 x 109 /L * Platelet count of ≥ 100 x 109 /L * Hemoglobin ≥ 6.0 mmol/L * Hepatic function as defined by serum bilirubin ≤ 1.5 x ULN, ALAT and ASAT ≤ 2.5 x ULN, or in case of liver metastases ALAT and ASAT ≤ 5 x ULN * Renal function as defined by serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 50 ml/min (by Cockcroft-Gault formula, or MDRD). 12. Negative pregnancy test (urine/serum) within 72 hours before receiving the first dose of study medication for female patients with childbearing potential; 13. Able and willing to undergo fresh histological tumor sampling prior to start, upon treatment and upon progression of vorinostat. Exclusion Criteria: 1. Any treatment with investigational drugs, except BRAFi and MEKi, within 28 days prior to receiving the first dose of investigational treatment; or 21 days for standard chemotherapy and immunotherapy; 2. Patients who have had previous treatment with vorinostat or other HDAC inhibitors; 3. Leptomeningeal disease; 4. Symptomatic brain metastasis. Patients previously treated or untreated for the condition and/or who are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids; 5. Clinical progression of melanoma in the first week of discontinuation of BRAFi or BRAFi/MEKi; 6. Woman who are pregnant or breast feeding; 7. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method from screening until 30 days after the last dose of study medication (adequate contraceptive methods are: oral or injected or implanted hormonal methods of contraception, condom, sterilization, other barrier contraceptive measures preferably in combination with condoms, true abstinence); 8. Radiotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment; except 1x8 Gray for pain palliation; 9. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients; 10. Patients with a known history of hepatitis B or C; 11. Recent myocardial infarction (\< 6 months before receiving the first dose of study medication) or unstable angina;