HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

NCT02836548 | Completed Phase 1 DMC

• 1 other identifier: N16VOM
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Melanoma; Skin Neoplasms

Keywords

advanced melanoma; BRAF V600 mutation; vorinostat; HDAC inhibitor

Outcome Measures

Primary Outcomes (1)

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

  Overall response rate measured by RECIST v 1.1.

  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)

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

  Up to 28 days after last drug intake

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

  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

• Overall survival (ORR) per RECIST v1.1

  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

• Plasma concentrations of vorinostat

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

• Determinants and mode of response -Target proteins

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

Study Arms (1)

vorinostat

EXPERIMENTAL

Vorinostat 360 mg once daily

Drug: Vorinostat

Interventions

Vorinostat DRUG

vorinostat 360 milligram once daily

Also known as: HDAC inhibitor

vorinostat

Eligibility Criteria

• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• 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;
• 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

You may not qualify if:

• 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;
• 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;

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead

Study Sites (1)

Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital

Amsterdam, 1066 CX, Netherlands

Location

Related Publications (1)

• 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.

  PMID: 32125175 DERIVED

MeSH Terms

Conditions

Melanoma; Skin Neoplasms

Interventions

Vorinostat; Histone Deacetylase Inhibitors

Condition Hierarchy (Ancestors)

Neuroendocrine Tumors; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Nerve Tissue; Nevi and Melanomas; Neoplasms by Site; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Anilides; Amides; Organic Chemicals; Aniline Compounds; Amines; Hydroxamic Acids; Hydroxylamines; Hydroxy Acids; Carboxylic Acids; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses

Study Officials

• S Wilgenhof, MD, PhD

  AVL-NKI

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 24, 2016
• First Posted: July 19, 2016
• Study Start: June 1, 2016
• Primary Completion: November 1, 2023
• Study Completion: November 1, 2023
• Last Updated: July 10, 2025

Record last verified: 2018-10

Locations

NL (1)