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MelanomaPhase 1/2NCT02836548

HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

A Phase 1/2 study testing Vorinostat in people with Melanoma and Skin Neoplasms, run by The Netherlands Cancer Institute at 1 site in Netherlands.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Any age
Conditions the study is for
Melanoma, Skin Neoplasms
What is being tested?
Vorinostat
Could I receive a placebo?
No, everyone receives an active treatment
How many people
33 participants
Where
1 siteNetherlands
Study dates
Jun 2016to Nov 2023
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Any age
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Who may be able to join

  • Histological proof of advanced melanoma with BRAF V600 mutation;
  • 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;
  • Previous documented response (partial or complete) for at least 4 weeks to treatment with BRAFi and/or BRAFi+MEKi;
  • 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;
  • Age ≥ 18 years;
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  • Able and willing to give written informed consent;
  • WHO performance status of 0, 1 or 2;
  • Able and willing to undergo blood sampling for PK and PD analysis;
  • Life expectancy ≥ 3 months allowing adequate follow up of toxicity evaluation and antitumor activity;
  • Evaluable disease according to RECIST 1.1;
  • 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).
  • Negative pregnancy test (urine/serum) within 72 hours before receiving the first dose of study medication for female patients with childbearing potential;
  • Able and willing to undergo fresh histological tumor sampling prior to start, upon treatment and upon progression of vorinostat.

Who cannot join

  • 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;
  • Patients who have had previous treatment with vorinostat or other HDAC inhibitors;
  • Leptomeningeal disease;
  • 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;
  • Clinical progression of melanoma in the first week of discontinuation of BRAFi or BRAFi/MEKi;
  • Woman who are pregnant or breast feeding;
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  • 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);
  • Radiotherapy within the last 4 weeks prior to receiving the first dose of investigational treatment; except 1x8 Gray for pain palliation;
  • Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
  • Patients with a known history of hepatitis B or C;
  • Recent myocardial infarction (< 6 months before receiving the first dose of study medication) or unstable angina;

Trial locations and contacts

1 site in 1 country.

Netherlands1 site

  • Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

    Amsterdam, 1066 CX

Other trials in Netherlands

About this study

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.

Read the detailed description

Activating mutations in the BRAF gene are present in about 50% of human melanomas. BRAF inhibitors (BRAFi) inhibit the serine-threonine protein kinase BRAF, which plays a dominant role in the MAPK pathway influencing cell growth. MEK inhibitors (MEKi) inhibit MEK1 and MEK2, two regulatory proteins downstream of BRAF.

The clinical benefit of this treatment is limited due to development of drug resistance in 6-8 months for treatment with BRAFi and 9-14 months for treatment with BRAFi in combination with MEKi.This is often associated with secondary mutations in the MAPK pathway leading to re-activation of the pathway.Withholding from treatment with BRAFi and/or MEKi leads to a reversible hyperactivation of the MAPK pathway, causing a transient growth arrest. Chronic proliferation and growth arrest occur when there is a persistent hyperactivation of the MAPK pathway. Treatment of BRAFi and/or MEKi resistant melanoma with vorinostat, a histone deacetylase inhibitor (HDACi), leads to persistent hyperactivation of the pathway and a state of growth arrest with hallmarks of oncogene induced senescence.In these studies in mice with BRAFi resistant BRAF V600 mutated melanoma switch from a BRAFi to the HDACi vorinostat resulted in complete disappearance of the tumor after two months of treatment.

HDACi cause accumulation of Reactive Oxygen Species (ROS) leading to apoptosis and upregulation of the MAPK-pathway. As seen by Wang et al hyperactivation of the MAPK-pathway is an important milestone in the anti-tumor treatment of BRAF V600 melanoma.

This is a phase I, single-center, single-arm, non-randomized, open-label, clinical pharmacological proof of principal study to determine the safety of vorinostat as anti-tumor therapy in patients with advanced resistant BRAF V600 mutated melanoma. A total of 21 evaluable patients with BRAF V600 mutated melanoma who developed resistance to BRAFi and/or BRAFi+MEKi after at least 4 weeks of PR or CR response will be enrolled in this study. Vorinostat will be given at a single daily dose of 360 mg derived from the established and registered dose for treatment of cutaneous T-cell lymphoma. Treatment will be continuous in cycles of 28 days and doses will be reduced in steps of 90 mg per dose-reduction in case of unacceptable safety concerns.

Being tested
Vorinostat
Keywords
advanced melanoma, BRAF V600 mutation, vorinostat, HDAC inhibitor
Medical subject headings
Melanoma, Skin Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • VorinostatDrug

    Also called HDAC inhibitor

    vorinostat 360 milligram once daily

Study groups in NCT02836548
Study groupRoleWhat they receive
vorinostatExperimentalVorinostat 360 mg once daily
Receives: Drug: Vorinostat

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Anti-tumor response rate in at least 30% of the treated patients.

    Overall response rate measured by RECIST v 1.1.

    Measured: CT scan every 6 weeks up to 24 months and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 24 months or have been lost to follow up, whichever occurs first.

Secondary outcomes (6)

  1. Tolerability (incidence and severity of adverse events per CTCAE v4.03)

    Incidence and severity of adverse events per CTCAE v4.03

    Measured: Up to 28 days after last drug intake

  2. progression free survival (PFS) per RECIST v1.1

    PFS measured by RECIST v 1.1.

    Measured: CT scan every 6 weeks up to 24 months and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 24 months or have been lost to follow up, whichever occurs first

  3. Overall survival (ORR) per RECIST v1.1

    ORR measured by RECIST v 1.1.

    Measured: CT scan every 6 weeks up to 24 months and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 24 months or have been lost to follow up, whichever occurs first

  4. Plasma concentrations of vorinostat

    Plasma concentrations of vorinostat will be measured at day 1 and 15 in cycle 1 to determine pharmacokinetics and interindividual differences after a single dose and after multiple doses.

    Measured: On day 1 and 15 in cycle 1(each cycle is 28 days).

  5. Determinants and mode of response -Target proteins

    Change in expression and/or phosphorylation status target proteins (e.g. pMEK, pERK, acetylated Histone 3) before, during and after treatment

    Measured: At baseline, cycle 1(each cycle is 28 days) day 1, day 15 and at treatment discontinuation (expected 6-9 months after start)

  6. Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations

    Pharmacogenetic profiling to assess predictors of response and resistance-inducing mutations.

    Measured: before treatment, every 6 weeks up to 24 months and at treatment discontinuation (expected 6-9 months after start)

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Jul 2016 (estimated)
  2. Study startJun 2016
  3. Primary completionNov 2023
  4. Study completionNov 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
33 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02836548
Sponsor's protocol ID
N16VOM
Status last verified
Oct 2018
First submitted
24 Jun 2016
Last updated
10 Jul 2025
Results posted
No
Data monitoring committee
Yes
Individual data sharing
Undecided

Publications

  • Huijberts S, Wang L, de Oliveira RL, Rosing H, Nuijen B, Beijnen J, Bernards R, Schellens J, Wilgenhof S. Vorinostat in patients with resistant BRAFV600E mutated advanced melanoma: a proof of concept study. Future Oncol. 2020 Apr;16(11):619-629. doi: 10.2217/fon-2020-0023. Epub 2020 Mar 3.

    PubMed 32125175

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Vorinostat in people with Melanoma and Skin Neoplasms, run by The Netherlands Cancer Institute at 1 site in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 19 inclusion and 11 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 10 Jul 2025. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Anti-tumor response rate in at least 30% of the treated patients. (time frame: CT scan every 6 weeks up to 24 months and monthly phone call until start of subsequent anticancer therapy or until all patients have been followed up for at least 24 months or have been lost to follow up, whichever occurs first.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02836548, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 10 Jul 2025.

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