HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

This is an interventional treatment trial for Melanoma focused on measuring advanced melanoma, BRAF V600 mutation, vorinostat, HDAC inhibitor Read More

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;