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.

Molecular targeted therapy with BRAF inhibitor vemurafenib is 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 dacarbarzine, 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 postpone acquired resistance to BRAF
inhibition and recent studies in which both MEK inhibitors and BRAF inhibitors
are combined are very 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 (GDC-0973) in BRAFV600 mutation positive
patients with advanced stage melanoma is underway. Currently, 3 different BRAF-
and MEK-inhibitors are under investigation in phase 3 trials. 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. In addition, therapy could be adapted to new
targeted-therapies (e.g. Erk-inhibitors or PI3-kinase inhibitors) or
immunotherapies at an earlier stage.
We propose a single arm explorative phase II clinical trial in 90 subjects with
advanced stage melanoma harbouring a BRAFV600E of BRAFV600K mutation. We will
combine PET imaging and molecular diagnostics in order to monitor response to
treatment with vemurafenib plus cobimetinib (GDC-0973), examine development of
resistance and correlate changes in metabolic/proliferative activity with
extend of target inhibition in tumor tissue.

To study whether either early 18F-FDG or 18F-FLT PET is superior in detecting
response to treatment with the combination of vemurafenib plus cobimetinib
(GDC-0973) compared to standard response assessment with CT and to evaluate
whether, and which, PET-imaging is superior in predicting resistance to
vemurafenib/ cobimetinib (GDC-0973) treatment. These observations will be
correlated to several key tumor characteristics.

This study is a multi-center open-label single arm explorative phase II
clinical study.
Laboratory assessments, physical examination, dermatologic examination and
cardiac evaluation will take place to monitor safety and side effects of
vemurafenib/ cobimetinib (GDC-0973).
Patients included in this study will undergo additional imaging using 18F-FDG
PET prior to treatment, two weeks after the initiation of therapy, after seven
weeks and at progression to compare to regular CT-imaging to study whether
PET-imaging is superior in predicting early response and in predicting
resistance to vemurafenib/ cobimetinib (GDC-0973) treatment.
Blood samples will be collected for drug level monitoring of vemurafenib and
cobimetinib (GDC-0973) and to correlate its pharmacokinetics with PET imaging
and therapy response.
In twenty-five patients additional PET with 18F-FLT will be performed at
baseline, 2 weeks and at progression to investigate which radiopharmaceutical
(18F-FDG or18F-FLT) is superior in detecting early response and in predicting
resistance.
Furthermore, in biopsies taken from forty patients prior to, and during
treatment, histopathological tumor characteristics will be correlated with
functional imaging. Next-generation sequencing, IHC analysis, gene expression
analysis and phosphoproteomics will be performed in parallel to unravel new
mechanisms of resistance to this drug.

The extra PET scans, biopsies and blood samples that are made or taken in this
study will not interfere with the vemurafenib/ cobimetinib (GDC-0973) treatment
protocol. The total number of performed procedures per patient can be fairly
high, but this approach is needed to answer the clinically relevant questions
at hand. Furthermore, the extra diagnostic procedures blend with the extensive
monitoring protocol these patients already have when treated with vemurafenib,
causing the extra time-effort as minimal as possible.
Considering the severity of the disease at the time of inclusion and the short
life expectancy without the chance of cure, the radiation burden and side
effects of these diagnostic procedures are negligible.
With the results of this study we will better understand the molecular behavior
of stage IIIc and IV melanoma. We hope to identify responders from
non-responders early after the initiation of therapy and reveal resistance to
vemurafenib/ cobimetinib (GDC-0973). This way we can reduce the costs of
unnecessary expensive treatment and prevent the risk of (severe) side effects
of vemurafenib/ cobimetinib (GDC-0973). Furthermore, we believe that the
results of this study will be fundamental for further optimizing treatment on
an individual base.