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Trial record 7 of 38 for:    GDC-0973 | Recruiting, Not yet recruiting, Available Studies

Vemurafenib Plus Cobimetinib in Metastatic Melanoma (REPOSIT)

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ClinicalTrials.gov Identifier: NCT02414750
Recruitment Status : Recruiting
First Posted : April 13, 2015
Last Update Posted : May 2, 2018
Sponsor:
Collaborators:
Hoffmann-La Roche
VU University Medical Center
The Netherlands Cancer Institute
Information provided by (Responsible Party):
A.J.M. van den Eertwegh, Netherlands Working Group on Immunotherapy of Oncology

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Melanoma Drug: Vemurafenib plus cobimetinib Device: Positron Emission Tomography Procedure: Tissue sampling Procedure: Blood sampling Phase 2

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 90 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
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
Study Start Date : December 2014
Estimated Primary Completion Date : December 2018
Estimated Study Completion Date : December 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Melanoma

Arm Intervention/treatment
Experimental: Treatment with BRAF/MEK inhibitor

Treatment 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.

Drug: Vemurafenib plus cobimetinib
Molecular targeted therapy for BRAF mutated advanced melanoma patients
Other Name: Zelboraf plus GDC-0973

Device: Positron Emission Tomography
Patient will need to undergo FDG and FLT PET scanning before and during treatment, and at time of progression

Procedure: Tissue sampling
Before and during treatment and at time of progression patients will undergo tissue sampling of a melanoma lesion
Other Name: Biopsy

Procedure: Blood sampling
Before and during treatment and at time of progression patients will undergo blood sampling




Primary Outcome Measures :
  1. 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. ]
  2. Standardized Uptake Value (SUV) of 18F-FDG and 18F-FLT as measured by PET. [ Time Frame: Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months. ]
  3. RECIST 1.1 tumor size measurement on diagnostic CT. [ Time Frame: Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months. ]
  4. Cut-off values of metabolic tracer uptake of 18F-FDG/FLT on PET as a measure of response. [ Time Frame: Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months. ]

Secondary Outcome Measures :
  1. 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. ]
  2. 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. ]
  3. 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. ]
  4. 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 ]
  5. 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 ]
  6. 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 ]
  7. 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 ]
  8. Overall Survival (OS) [ Time Frame: 3 years ]
  9. ECOG Performance status [ Time Frame: Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months. ]


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02414750


Contacts
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Contact: Bernies Van der Hiel, MD +31205126129 b.vd.hiel@nki.nl

Locations
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Netherlands
The Netherlands Cancer Institute Recruiting
Amsterdam, Netherlands, 1066CX
Contact: Bernies Van der Hiel, MD    +31205126129    b.vd.hiel@nki.nl   
Principal Investigator: John B.A.G. Haanen, Prof.         
VU medical center Recruiting
Amsterdam, Netherlands
Contact: Fons J.M. Van den Eertwegh, MD PhD    +31204444336    vandeneertwegh@vumc.nl   
Principal Investigator: Fons J.M. Van den Eertwegh, MD PhD         
Medisch Spectrum Twente Not yet recruiting
Enschede, Netherlands
Contact: D. Piersma, MD PhD       d.piersma@mst.nl   
Principal Investigator: D. Piersma, MD PhD         
University Medical Center Groningen Recruiting
Groningen, Netherlands
Contact: G. A.P. Hospers, Prof.       g.a.p.hospers@umcg.nl   
Principal Investigator: G. A.P. Hospers, Prof.         
Leiden University Medical Center Recruiting
Leiden, Netherlands
Contact: H. W. Kapiteijn, MD PhD       h.w.kapiteijn@lumc.nl   
Principal Investigator: H. W. Kapiteijn, MD PhD         
Maastricht University Medical Center Recruiting
Maastricht, Netherlands
Contact: M. J.B. Aarts, MD       mjb.essers.aarts@mumc.nl   
Principal Investigator: M. J.B. Aarts, MD         
University Medical Center St Radboud Recruiting
Nijmegen, Netherlands
Contact: R. H.T. Koornstra, MD       r.koornstra@onco.umcn.nl   
Principal Investigator: R. H.T. Koornstra, MD         
Erasmus Medical Center Recruiting
Rotterdam, Netherlands
Contact: W. H.J. Kruit, MD PhD       w.kruit@erasmusmc.nl   
Principal Investigator: W. H.J. Kruit, MD PhD         
University Medical Center Utrecht Recruiting
Utrecht, Netherlands
Contact: F. Y.F.L. de Vos, MD PhD       f.devos@umcutrecht.nl   
Principal Investigator: F. Y.F.L. de Vos, MD PhD         
Isala Klinieken Recruiting
Zwolle, Netherlands
Contact: J. W.B. de Groot, MD PhD       j.w.b.de.groot@isala.nl   
Principal Investigator: J. W.B. de Groot, MD PhD         
Sponsors and Collaborators
Netherlands Working Group on Immunotherapy of Oncology
Hoffmann-La Roche
VU University Medical Center
The Netherlands Cancer Institute
Investigators
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Principal Investigator: Fons JM Van den Eertwegh, MD PhD VU University Medical Center

Additional Information:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
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Responsible Party: A.J.M. van den Eertwegh, Medical Oncologist, Netherlands Working Group on Immunotherapy of Oncology
ClinicalTrials.gov Identifier: NCT02414750     History of Changes
Other Study ID Numbers: M14REP
First Posted: April 13, 2015    Key Record Dates
Last Update Posted: May 2, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by A.J.M. van den Eertwegh, Netherlands Working Group on Immunotherapy of Oncology:
Vemurafenib/cobimetinib (GDC-0973)
Melanoma
Positron Emission Tomography
Tumor Characteristics
Response monitoring
Resistance prediction
molecular targeted therapy
Additional relevant MeSH terms:
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Melanoma
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Nerve Tissue
Nevi and Melanomas
Vemurafenib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action