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Metastatic MelanomaPhase 2REPOSITNCT02414750

Vemurafenib Plus Cobimetinib in Metastatic Melanoma

A Phase 2 study testing Vemurafenib plus cobimetinib, Positron Emission Tomography and Tissue sampling in people with Metastatic Melanoma, run by Netherlands Working Group on Immunotherapy of Oncology at 10 sites in Netherlands.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Metastatic Melanoma
What is being tested?
Vemurafenib plus cobimetinib, Positron Emission Tomography and Tissue sampling
Could I receive a placebo?
No, everyone receives an active treatment
How many people
78 participants
Where
10 sitesNetherlands
Study dates
Dec 2014to Nov 2020
Phase
Phase 2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
Show all 9Show fewer
  • 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.

Who cannot join

  • 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.

Trial locations and contacts

10 sites in 1 country.

10 sites in 1 country

Netherlands10 sites
  • The Netherlands Cancer Institute

    Amsterdam, 1066CX

  • VU medical center

    Amsterdam

  • Medisch Spectrum Twente

    Enschede

  • University Medical Center Groningen

    Groningen

  • Leiden University Medical Center

    Leiden

  • Maastricht University Medical Center

    Maastricht

  • University Medical Center St Radboud

    Nijmegen

  • Erasmus Medical Center

    Rotterdam

  • University Medical Center Utrecht

    Utrecht

  • Isala Klinieken

    Zwolle

Other trials in Netherlands

About this study

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

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.

Read the 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.

Being tested
Vemurafenib plus cobimetinib, Positron Emission Tomography, Tissue sampling, Blood sampling
Keywords
Vemurafenib/cobimetinib (GDC-0973), Melanoma, Positron Emission Tomography, Tumor Characteristics, Response monitoring, Resistance prediction, molecular targeted therapy
Medical subject headings
Melanoma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Vemurafenib plus cobimetinibDrug

    Also called Zelboraf plus GDC-0973

    Molecular targeted therapy for BRAF mutated advanced melanoma patients

  • Positron Emission TomographyDevice

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

  • Tissue samplingProcedure or surgery

    Also called Biopsy

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

  • Blood samplingProcedure or surgery

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

Study groups in NCT02414750
Study groupRoleWhat they receive
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.
Receives: Drug: Vemurafenib plus cobimetinib; Device: Positron Emission Tomography; Procedure: Tissue sampling; Procedure: Blood sampling

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Progression Free survival (PFS)

    Measured: 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.

    Measured: 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.

    Measured: 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.

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

Secondary outcomes (9)
  1. Diagnostic accuracy of metabolic tracer uptake on PET in responders and non-responders.

    Measured: 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.

    Measured: 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.

    Measured: 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.

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

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

    Measured: 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).

    Measured: 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

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

  8. Overall Survival (OS)

    Measured: 3 years

  9. ECOG Performance status

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

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Apr 2015 (estimated)
  2. Study startDec 2014
  3. Primary completionNov 2020
  4. Study completionNov 2020

Why it stopped: Slow accrual and changing treatment landscape

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Other
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
78 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02414750
Sponsor's protocol ID
M14REP
Acronym
REPOSIT
Status last verified
Nov 2022
First submitted
11 Feb 2015
Last updated
30 Nov 2022
Results posted
No
Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
Individual data sharing
Undecided

Publications

  • 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.

    PubMed 40434500
  • 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.

    PubMed 28915798

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vemurafenib plus cobimetinib, Positron Emission Tomography and Tissue sampling in people with Metastatic Melanoma, run by Netherlands Working Group on Immunotherapy of Oncology at 10 sites in Netherlands.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 6 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 30 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 10 sites in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study was stopped early (reason given: Slow accrual and changing treatment landscape). Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome 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.). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02414750, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 30 Nov 2022.

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