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, suchas vemurafenib or dabrafenib; or a combination of BRAF - and MEK inhibitors, such astrametinib and dabrafenib;

3. Previous documented response (partial or complete) for at least 4 weeks to treatmentwith BRAFi and/or BRAFi+MEKi;

4. Start with vorinostat treatment within a maximum period of 1 week afterdiscontinuation of BRAFi and/or BRAFi+MEKi. The BRAFi and/or BRAFi+MEKi can be continued after progression to provide sufficienttime 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 andantitumor 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 ≤ 2.5x 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 creatinineclearance ≥ 50 ml/min (by Cockcroft-Gault formula, or MDRD).

12. Negative pregnancy test (urine/serum) within 72 hours before receiving the firstdose of study medication for female patients with childbearing potential;

13. Able and willing to undergo fresh histological tumor sampling prior to start, upontreatment and upon progression of vorinostat.

Exclusion Criteria:

1. Any treatment with investigational drugs, except BRAFi and MEKi, within 28 daysprior to receiving the first dose of investigational treatment; or 21 days forstandard 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 thecondition and/or who are asymptomatic in the absence of corticosteroid therapy areallowed to enroll. Patients are not permitted to receive enzyme inducinganti-epileptic drugs or corticosteroids;

5. Clinical progression of melanoma in the first week of discontinuation of BRAFi orBRAFi/MEKi;

6. Woman who are pregnant or breast feeding;

7. Unreliable contraceptive methods. Both men and women enrolled in this trial mustagree to use a reliable contraceptive method from screening until 30 days after thelast dose of study medication (adequate contraceptive methods are: oral or injectedor implanted hormonal methods of contraception, condom, sterilization, other barriercontraceptive measures preferably in combination with condoms, true abstinence);

8. Radiotherapy within the last 4 weeks prior to receiving the first dose ofinvestigational treatment; except 1x8 Gray for pain palliation;

9. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2type patients;

10. Patients with a known history of hepatitis B or C;

11. Recent myocardial infarction (< 6 months before receiving the first dose of studymedication) or unstable angina;