Advanced resistant BRAF V600E mutant melanoma
Conditions
Interventions
Product Name: Vorinostat
Pharmaceutical Form: Capsule, hard
INN or Proposed INN: Vorinostat
CAS Number: 149647-78-9
Current Sponsor code: Vorinostat
Other descriptive name: VORINOSTAT
Concentration un
Sponsors
Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital (NKI-AVL)
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Histological proof of advanced melanoma with BRAF V600 mutation; 2. Progression of disease while on treatment with BRAFi , such as vemurafenib or dabrafenib, or the combination of BRAFi and MEKi such as vemurafenib plus cobimetinib or dabrafenib plus trametinib; 3. Previous documented response (partial or complete) to treatment with the BRAFi and/or BRAFi+MEKi confirmed with an interval of four weeks or more; 4. Start with vorinostat treatment within 1 week after discontinuation of BRAFi and/or BRAFi+MEKi. The BRAFi and/or BRAFi+MEKi can be continued untill seven days before start of the treatment with vorinostat; 5. Age ? 18 years; 6. Able and willing to give written informed consent; 7. WHO performance status of 0, 1 or 2; 8. Treatment with coumarine-derivates is allowed. However, if possible switch to low molecular weight heparins (LMWH). If switching to a LMWH is not desirable, careful monitoring is recommended with a minimal control of INR once a week; 9. Able and willing to undergo blood sampling for pharmacokinetic and pharmacodynamic analysis; 10. Life expectancy ? 3 months allowing adequate follow up of toxicity evaluation and antitumor activity; 11. Evaluable disease according to RECIST 1.1; 12. Minimal acceptable safety laboratory values a. ANC of ? 1.5 x 109 /L b. Platelet count of ? 100 x 109 /L c. 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 d. Renal function as defined by serum creatinine ? 1.5 x ULN or creatinine clearance ? 50 ml/min (by Cockcroft-Gault formula, or MDRD). 13. Negative pregnancy test (urine/serum) for female patients with childbearing potential; 14. Able and willing to undergo fresh histological tumor sampling prior to start, upon treatment and upon progression of vorinostat. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 20 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range
Exclusion criteria
Exclusion criteria: 1. Any treatment with investigational drugs 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 HDACi; 3. Leptomeningeal disease; 4. Symptomatic brain metastasis. Patients previously treated or untreated for the conditions who are asymptomatic in the absence of corticosteroid therapy are allowed to enroll. Brain metastasis must be stable with verification by imaging (e.g. brain MRI or CT completed at screening demonstrating no current evidence of progressive brain metastases). Patients are not permitted to receive enzyme inducing anti-epileptic drugs or corticosteroids; 5. Woman who are pregnant or breast feeding; 6. Unreliable contraceptive methods. Both men and women enrolled in this trial must agree to use a reliable contraceptive method throughout the study (adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms) 7. Radiotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment; except 1x8 Gy for pain palliation; 8. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients 9. Patients with a known history of hepatitis B or C; 10. Recent myocardial infarction (< 6 months) or unstable angina
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: The primairy aim of this proof of principle (POP) and pharmacological study is to demonstrate significant anti-tumor activity of vorinostat in advanced BRAF V600 melanoma progressing under treatment with BRAFi or combined BRAFi and MEKi with a response rate of at least 30%.;Secondary Objective: 1. Safety of vorinostat in this population 2. progression free survival of vorinostat therapy 3. Pharmacokinetics of vorinostat 4. Pharmacodynamics (PD) of vorinostat, especially levels of phosphorylation of selected MAPK-proteins, such as MEK and ERK and quantification of levels of acetylation of Histone3 (H3) 5. Genetic determinants of response and resistance to vorinostat;Primary end point(s): The primairy aim of this proof of principle (POP) and pharmacological study is to demonstrate significant anti-tumor activity of vorinostat in advanced BRAF V600 melanoma progressing under treatment with BRAFi or combined BRAFi and MEKi with a response rate of at least 30%.;Timepoint(s) of evaluation of this end point: at the end of trial | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondairy endpoints are: safety, pharmacokinetics, pharmacodynamics, progression free survival and geneteic determinants. ;Timepoint(s) of evaluation of this end point: at the end of the trial | — |
Countries
Netherlands
Contacts
Public ContactJ.H.M. Schellens
Netherlands Cancer Institute
Outcome results
None listed