HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

• Status: Unknown status
• Trial end date: 2019-10-01
• Target enrollment: 0
• Participant gender: All

Summary

This is a mono-center open-label proof-of-concept pharmacologic study to explore the efficacy and safety of vorinostat in advanced BRAF mutated melanoma, which became resistant for BRAF-inhibitors or the combination of BRAF- and MEK-inhibitors.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: The Netherlands Cancer Institute
• Treatments: Histone Deacetylase Inhibitors; Vorinostat

Criteria

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;