HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma
|ClinicalTrials.gov Identifier: NCT02836548|
Recruitment Status : Unknown
Verified October 2018 by The Netherlands Cancer Institute.
Recruitment status was: Recruiting
First Posted : July 19, 2016
Last Update Posted : October 17, 2018
|Condition or disease||Intervention/treatment||Phase|
|Melanoma Skin Neoplasms||Drug: Vorinostat||Phase 1 Phase 2|
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.
|Study Type :||Interventional (Clinical Trial)|
|Estimated Enrollment :||22 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma|
|Study Start Date :||June 2016|
|Estimated Primary Completion Date :||June 2019|
|Estimated Study Completion Date :||October 2019|
Vorinostat 360 mg once daily
vorinostat 360 milligram once daily
Other Name: HDAC inhibitor
- 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. ]Overall response rate measured by RECIST v 1.1.
- Tolerability (incidence and severity of adverse events per CTCAE v4.03) [ Time Frame: Up to 28 days after last drug intake ]Incidence and severity of adverse events per CTCAE v4.03
- progression free survival (PFS) per RECIST v1.1 [ 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 ]PFS measured by RECIST v 1.1.
- Overall survival (ORR) per RECIST v1.1 [ 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 ]ORR measured by RECIST v 1.1.
- Plasma concentrations of vorinostat [ Time Frame: On day 1 and 15 in cycle 1(each cycle is 28 days). ]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.
- Determinants and mode of response -Target proteins [ Time Frame: At baseline, cycle 1(each cycle is 28 days) day 1, day 15 and at treatment discontinuation (expected 6-9 months after start) ]Change in expression and/or phosphorylation status target proteins (e.g. pMEK, pERK, acetylated Histone 3) before, during and after treatment
- Pharmacogenetics profiling to assess predictors of response and resistance- inducing mutations [ Time Frame: before treatment, every 6 weeks up to 24 months and at treatment discontinuation (expected 6-9 months after start) ]Pharmacogenetic profiling to assess predictors of response and resistance-inducing mutations.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02836548
|Contact: S Wilgenhof, MD, PhDfirstname.lastname@example.org|
|Contact: SCFA Huijberts, MDemail@example.com|
|Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital||Recruiting|
|Amsterdam, Netherlands, 1066 CX|
|Contact: N Steeghs, MD, PhD|
|Principal Investigator:||S Wilgenhof, MD, PhD||AVL-NKI|