Clinical Trials /

Vemurafenib Plus Cobimetinib in Metastatic Melanoma

NCT02414750

Description:

This is a single arm explorative phase II clinical trial in 90 subjects with advanced stage melanoma harbouring a BRAFV600 mutation. PET imaging and molecular diagnostics are combined in order to monitor response to treatment with vemurafenib plus cobimetinib, examine development of resistance and correlate changes in metabolic/proliferative activity with extend of target inhibition.

Related Conditions:
  • Melanoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Vemurafenib Plus Cobimetinib in Metastatic Melanoma
  • Official Title: A Phase II, Open-Label, Multicenter Study of Vemurafenib Plus Cobimetinib (GDC-0973) in Unresectable Stage IIIc or Stage IV Melanoma; Response Monitoring and Resistance Prediction With Positron Emission Tomography and Tumor Characteristics

Clinical Trial IDs

  • ORG STUDY ID: M14REP
  • NCT ID: NCT02414750

Conditions

  • Metastatic Melanoma

Interventions

DrugSynonymsArms
Vemurafenib plus cobimetinibZelboraf plus GDC-0973Treatment with BRAF/MEK inhibitor

Purpose

This is a single arm explorative phase II clinical trial in 90 subjects with advanced stage melanoma harbouring a BRAFV600 mutation. PET imaging and molecular diagnostics are combined in order to monitor response to treatment with vemurafenib plus cobimetinib, examine development of resistance and correlate changes in metabolic/proliferative activity with extend of target inhibition.

Detailed Description

      Molecular targeted therapy with BRAF inhibitor vemurafenib is now currently used as first
      line treatment for patients with unresectable stage IIIc or metastatic melanoma harboring the
      BRAFV600 mutation, which is present in about 50% of melanoma patients. Despite the
      improvement in Progression Free Survival (PFS) en Overall Survival (OS) compared to
      dacabarzine, acquired resistance that develops in virtually all patients treated with
      vemurafenib is a great concern.

      Combining a BRAF inhibitor with a MEK inhibitor that targets the MAPK pathway further
      downstream, however, may overcome acquired resistance to BRAF inhibition and recent studies
      in which both MEK inhibitors and BRAF inhibitors are combined as monotherapy seem promising.

      In a phase IB trial preliminary efficacy of vemurafenib with cobimetinib (GDC-0973), a highly
      selective inhibitor of MEK1 seems encouraging with an initial response rate of 85% and
      currently a phase III study of vemurafenib versus vemurafenib plus cobimetinib in BRAFV600
      mutation positive patients with advanced stage melanoma is underway. It is expected that in
      the near future combined BRAF and MEK inhibition will be standard of care for patients with
      BRAFV600 mutated metastatic melanoma.

      Diagnostic CT cannot assess reduction in tumor size within days after the initiation of
      therapy and anatomic size does not provide information about the development of therapy
      response or resistance at a molecular level. It has been clearly demonstrated that
      alterations in metabolism occur earlier than anatomical size reduction after the initiation
      of therapy. Molecular imaging with PET visualizes metabolic activity in tumors and is a
      sensitive method to detect alterations in cell metabolism, even shortly after the start of
      therapy. 18F-Fluorodeoxyglucose (18F-FDG) is used to visualize glucose metabolism, whereas
      18F-Fluoro-3'-deoxy-3'L-fluorothymidine (18F-FLT) is used to visualize proliferation. In
      preclinical mouse models 18F-FLT appears to predict response or resistance to therapy better
      than 18F-FDG. However, so far only 18F-FDG PET has been used to monitor response to
      vemurafenib in some BRAFV600 mutated metastatic melanoma patients, showing a rapid decline of
      18F-FDG within 2 weeks following treatment. Preclinical studies and the observation that
      melanoma is a highly proliferative malignancy in most patients suggest that 18F-FLT might be
      the radiopharmaceutical of first choice in this setting.

      By detecting these metabolic alterations, responders might be distinguished from
      non-responders at an earlier phase compared with anatomical imaging with CT. This way,
      unnecessary expensive treatment of combined BRAF/MEK-inhibitor therapy and its side effects
      can be prevented in patients who will not benefit from this therapy. Furthermore, the level
      of decline in metabolic activity in the first two weeks after the initiation of therapy might
      predict progression free survival (PFS) as preliminary results in literature suggest.

      This is a single arm explorative phase II clinical trial in 90 subjects with advanced stage
      melanoma harbouring a BRAFV600 mutation. PET imaging and molecular diagnostics are combined
      in order to monitor response to treatment with vemurafenib plus cobimetinib, examine
      development of resistance and correlate changes in metabolic/proliferative activity with
      extend of target inhibition.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment with BRAF/MEK inhibitorExperimentalTreatment with vemurafenib 2dd 960 mg 28/28 plus cobimetinib 1dd 60 mg 21/28. During treatment patient will undergo PET scanning with FLT and FDG, to compare both types of PET scanning. During the study biopsies and blood will be taken from the patients.
  • Vemurafenib plus cobimetinib

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologically confirmed melanoma, either unresectable stage IIIc or
             stage IV metastatic melanoma, as defined by AJCC 7th edition.

          -  Patients must be naïve to treatment for locally advanced unresectable or metastatic
             disease. Prior immunotherapy (including ipilimumab) is allowed.

          -  Documentation of BRAFV600E or BRAFV600K mutation-positive status in melanoma tumor
             tissue (archival or newly obtained tumor samples).

          -  Measurable disease per RECIST v1.1, which are accessible to biopsies.

          -  Biopsy lesion is within scan reach of diagnostic CT and PET-CT (thorax-
             abdomen-pelvis)

          -  ECOG performance status of 0 or 1.

          -  Male or female patient aged ≥ 18 years.

          -  Life expectancy ≥ 12 weeks.

          -  Adequate hematologic and end organ function within 14 days prior to first dose of
             study drug treatment.

        Exclusion Criteria:

          -  History of prior RAF or MEK pathway inhibitor treatment.

          -  Palliative radiotherapy, major surgery or traumatic injury within 14 days prior to the
             first dose of study treatment.

          -  Active malignancy within the past 3 years other than melanoma that could potentially
             interfere with the interpretation of efficacy measures, except for patients with
             resected BCC or SCC of the skin, melanoma in-situ, carcinoma in-situ of the cervix,
             and carcinoma in-situ of the breast.

          -  History of or evidence of retinal pathology, clinically significant cardiac
             dysfunction, patients with active CNS lesions, renal or liver dysfunction as described
             in main protocol (REPOSIT NL48639.031.14).

          -  Pregnant, lactating, or breast-feeding.

          -  Unwillingness or inability to comply with study and follow-up procedures (i.e. severe
             anxiety disorder preventing PET/CT imaging.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression Free survival (PFS)
Time Frame:Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Diagnostic accuracy of metabolic tracer uptake on PET in responders and non-responders.
Time Frame:Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.
Safety Issue:
Description:
Measure:Glycolytic Index, Metabolic Tumor Volume and % Injected Dose of 18F-FDG/FLT on PET.
Time Frame:Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.
Safety Issue:
Description:
Measure:Immunohistochemical analysis of tumor tissue in responders and non-responders.
Time Frame:Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.
Safety Issue:
Description:
Measure:Changes of DNA in tumor tissue as measured by DNA deep sequencing analysis.
Time Frame:Changes from Baseline to progression, an expected median of 10 months
Safety Issue:
Description:
Measure:Changes of RNA in tumor tissue as measured by RNA expression analysis.
Time Frame:Changes from Baseline to progression, an expected median of 10 months
Safety Issue:
Description:
Measure:Changes of phosphoproteomic profiles in tumor tissue measured by nano-liquid chromatography coupled to tandem mass spectrometry (nanoLC-MS/MS).
Time Frame:Changes from Baseline to progression, an expected median of 10 months
Safety Issue:
Description:
Measure:Changes in vemurafenib and cobimetinib drug concentrations in plasma as measured by a validated Liquid Chromotography tandem Mass Spectrometry assay
Time Frame:Changes from Baseline to progression, an expected median of 10 months
Safety Issue:
Description:
Measure:Overall Survival (OS)
Time Frame:3 years
Safety Issue:
Description:
Measure:ECOG Performance status
Time Frame:Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Netherlands Working Group on Immunotherapy of Oncology

Trial Keywords

  • Vemurafenib/cobimetinib (GDC-0973)
  • Melanoma
  • Positron Emission Tomography
  • Tumor Characteristics
  • Response monitoring
  • Resistance prediction
  • molecular targeted therapy

Last Updated

May 23, 2017