Clinical Trials /

HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

NCT02836548

Description:

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.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma
  • Official Title: HDAC Inhibitor Vorinostat in Resistant BRAF V600 Mutated Advanced Melanoma

Clinical Trial IDs

  • ORG STUDY ID: N16VOM
  • NCT ID: NCT02836548

Conditions

  • Melanoma
  • Skin Neoplasms

Interventions

DrugSynonymsArms
VorinostatHDAC inhibitorvorinostat

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
vorinostatExperimentalVorinostat 360 mg once daily
  • Vorinostat

Eligibility 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;
      
Maximum Eligible Age:N/A
Minimum Eligible Age:N/A
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

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.
Safety Issue:
Description:Overall response rate measured by RECIST v 1.1.

Secondary Outcome Measures

Measure:Tolerability (incidence and severity of adverse events per CTCAE v4.03)
Time Frame:Up to 28 days after last drug intake
Safety Issue:
Description:Incidence and severity of adverse events per CTCAE v4.03
Measure: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
Safety Issue:
Description:PFS measured by RECIST v 1.1.
Measure: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
Safety Issue:
Description:ORR measured by RECIST v 1.1.
Measure:Plasma concentrations of vorinostat
Time Frame:On day 1 and 15 in cycle 1(each cycle is 28 days).
Safety Issue:
Description: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.
Measure: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)
Safety Issue:
Description:Change in expression and/or phosphorylation status target proteins (e.g. pMEK, pERK, acetylated Histone 3) before, during and after treatment
Measure: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)
Safety Issue:
Description:Pharmacogenetic profiling to assess predictors of response and resistance-inducing mutations.

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:The Netherlands Cancer Institute

Trial Keywords

  • advanced melanoma
  • BRAF V600 mutation
  • vorinostat
  • HDAC inhibitor

Last Updated

July 18, 2016