Vemurafenib Plus Cobimetinib in Metastatic Melanoma

NCT02414750 | Terminated Phase 2

• 1 other identifier: M14REP
• Study Type: interventional
• Target: 78
• Locations: 1 country
• Sites: 10

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.

Conditions

Metastatic Melanoma

Keywords

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

Outcome Measures

Primary Outcomes (4)

• Progression Free survival (PFS)

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

• Standardized Uptake Value (SUV) of 18F-FDG and 18F-FLT as measured by PET.

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

• RECIST 1.1 tumor size measurement on diagnostic CT.

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

• Cut-off values of metabolic tracer uptake of 18F-FDG/FLT on PET as a measure of response.

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

Secondary Outcomes (9)

• Diagnostic accuracy of metabolic tracer uptake on PET in responders and non-responders.

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

• Glycolytic Index, Metabolic Tumor Volume and % Injected Dose of 18F-FDG/FLT on PET.

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

• Immunohistochemical analysis of tumor tissue in responders and non-responders.

  Participants will be followed until they have progressive disease based on RECIST1.1, an expected median of 10 months.

• Changes of DNA in tumor tissue as measured by DNA deep sequencing analysis.

  Changes from Baseline to progression, an expected median of 10 months

• Changes of RNA in tumor tissue as measured by RNA expression analysis.

  Changes from Baseline to progression, an expected median of 10 months

Study Arms (1)

Treatment with BRAF/MEK inhibitor

EXPERIMENTAL

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; Device: Positron Emission Tomography; Procedure: Tissue sampling; Procedure: Blood sampling

Interventions

Vemurafenib plus cobimetinib DRUG

Molecular targeted therapy for BRAF mutated advanced melanoma patients

Also known as: Zelboraf plus GDC-0973

Treatment with BRAF/MEK inhibitor

Positron Emission Tomography DEVICE

Patient will need to undergo FDG and FLT PET scanning before and during treatment, and at time of progression

Treatment with BRAF/MEK inhibitor

Tissue sampling PROCEDURE

Before and during treatment and at time of progression patients will undergo tissue sampling of a melanoma lesion

Also known as: Biopsy

Treatment with BRAF/MEK inhibitor

Blood sampling PROCEDURE

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

Treatment with BRAF/MEK inhibitor

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Netherlands Working Group on Immunotherapy of Oncology: lead
• Hoffmann-La Roche: collaborator
• Amsterdam UMC, location VUmc: collaborator
• The Netherlands Cancer Institute: collaborator

Study Sites (10)

The Netherlands Cancer Institute

Amsterdam, 1066CX, Netherlands

Location

VU medical center

Amsterdam, Netherlands

Location

Medisch Spectrum Twente

Enschede, Netherlands

Location

University Medical Center Groningen

Groningen, Netherlands

Location

Leiden University Medical Center

Leiden, Netherlands

Location

Maastricht University Medical Center

Maastricht, Netherlands

Location

University Medical Center St Radboud

Nijmegen, Netherlands

Location

Erasmus Medical Center

Rotterdam, Netherlands

Location

University Medical Center Utrecht

Utrecht, Netherlands

Location

Isala Klinieken

Zwolle, Netherlands

Location

Related Publications (2)

• van der Hiel B, de Wit-van der Veen BJ, van den Eertwegh AJM, Vogel WV, Stokkel MPM, Lopez-Yurda M, Boellaard R, Kapiteijn EW, Hospers GAP, Aarts MJB, de Vos FYFL, Boers-Sonderen MJ, van der Veldt AAM, de Groot JWB, Haanen JBAG. Metabolic parameters on baseline and early [18F]FDG PET/CT as a predictive biomarker for resistance to BRAF/MEK inhibition in advanced cutaneous BRAFV600-mutated melanoma. EJNMMI Res. 2025 May 28;15(1):60. doi: 10.1186/s13550-025-01259-x.

  PMID: 40434500 DERIVED

• van der Hiel B, Haanen JBAG, Stokkel MPM, Peeper DS, Jimenez CR, Beijnen JH, van de Wiel BA, Boellaard R, van den Eertwegh AJM; REPOSIT study group. Vemurafenib plus cobimetinib in unresectable stage IIIc or stage IV melanoma: response monitoring and resistance prediction with positron emission tomography and tumor characteristics (REPOSIT): study protocol of a phase II, open-label, multicenter study. BMC Cancer. 2017 Sep 15;17(1):649. doi: 10.1186/s12885-017-3626-5.

  PMID: 28915798 DERIVED

Related Links

• Site of the Netherlands Working Group on Immunotherapy of Oncology (Wino)

MeSH Terms

Conditions

Melanoma

Interventions

Vemurafenib; cobimetinib; Positron-Emission Tomography; Biopsy; Blood Specimen Collection

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Sulfonamides; Amides; Organic Chemicals; Sulfones; Sulfur Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Tomography, Emission-Computed; Image Interpretation, Computer-Assisted; Diagnostic Imaging; Diagnostic Techniques and Procedures; Diagnosis; Image Enhancement; Photography; Radionuclide Imaging; Tomography; Diagnostic Techniques, Radioisotope; Cytodiagnosis; Cytological Techniques; Clinical Laboratory Techniques; Specimen Handling; Diagnostic Techniques, Surgical; Surgical Procedures, Operative; Investigative Techniques; Punctures

Study Officials

• Fons JM Van den Eertwegh, MD PhD

  Amsterdam UMC, location VUmc

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: OTHER
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Medical Oncologist

Study Record Dates

• First Submitted: February 11, 2015
• First Posted: April 13, 2015
• Study Start: December 1, 2014
• Primary Completion: November 1, 2020
• Study Completion: November 1, 2020
• Last Updated: November 30, 2022

Record last verified: 2022-11

Locations

NL (10)