Trial Information

A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma

Rationale for treatment of uveal melanoma with sorafenib Improved understanding of the
molecular pathogenesis of cancers has led to a new generation of therapeutic agents that
interfere with a specific pathway critical in tumor development or progression. Although no
specific genes have been linked to the pathogenesis of uveal melanoma, which significantly
differs from that of cutaneous melanoma, progress has been made in identifying potential
targets involved in uveal melanoma apoptosis, proliferation, invasion, metastasis, and
angiogenesis. Accordingly, improvement of systemic therapy of metastatic uveal melanoma
could be achieved by using molecularly targeted agents that are currently in clinical use as
well as agents being tested in clinical trials. Preclinical studies suggest potential
benefit of inhibitors of Bcl-2, ubiquitin-proteasome, histone deactylase, mitogen-activated
protein kinase and phosphatidylinositol-3-kinase-AKT pathways, and receptor tyrosine
kinases. Modifiers of adhesion molecules, matrix metalloproteinase, and angiogenic factors
also have demonstrated potential benefit. (Triozzi et al, 2008).

Thus, sorafenib as oral multi-kinase inhibitor that targets the Raf/MEK/ERK signaling
pathway (CRAF, BRAF, V600E BRAF) in the cell and receptor tyrosine kinases (RTKs) such as
VEGFR-2, VEGFR-3, and PDGFR-ß involved in tumor cell proliferation and angiogenesis may
potentially lead to a benefit for patients with metastatic uveal melanoma in terms of
disease control and prolongation of survival.

In a GCP-adapted register trial approved by the ethics committee in Essen 62 patients with
metastatic uveal melanoma received treatment with sorafenib on a compassionate use basis.
Median overall survival was 10.8 months in patients receiving 200 mg bid sorafenib and 7.1
months in patients receiving 400 mg bid (Scheulen et al, 2011). These treatment results are
encouraging for further investigation of treatment with sorafenib in patients with
metastatic uveal melanoma in a randomized trial, a potential benefit of this systemic
treatment is anticipated.

Rationale for selection of a randomized discontinuation trial design The randomized
discontinuation trial (RDT) design , first proposed in 1975 (Amery et al, 1975) aims to
assess the clinical activity of a drug while minimizing the use of placebo. All patients
receive study drug for an initial run-in period, followed by random assignment of potential
responders to either the study drug or the placebo (Amery et al,1975; Kopec et al,1993). RDT
design provides more homogeneous study treatment groups by selecting patients with a
predefined response, and allows the evaluation of a drug's clinical activity with fewer
patients and increased statistical power. Thus this study design is especially useful to
distinguish anticancer activity of the drug and natural history of the underlying disease
(Kopec et al,1993; Jain L et al, 2006; Rosner et al, 2002). As pointed out by Rosner the RDT
design is a feasible phase II study design for evaluating possible activity of cytostatic
anticancer agents whereas historically anticancer drug efficacy was evaluated as being
cytotoxic (Rosner et al, 2002).

As laid down in section 3.2 sorafenib is an oral multi-kinase inhibitor that targets the
Raf/MEK/ERK signaling pathway in the cell and receptor tyrosine kinases (RTKs) such as
VEGFR-2, VEGFR-3, and PDGFR-ß involved in tumor cell proliferation and angiogenesis. The
primary clinical benefit of sorafenib is expected to be disease stabilization rather than
tumor shrinkage. As disease stabilization is substantially influenced by the natural disease
of a disease, the RDT design was chosen in several phase II trials evaluating possible
activity of sorafenib (such as Ratain et al, 2006; Eisen et al, 2006; Pacey et al, 2009)
Taking into account that uveal melanoma is a rare disease with presumably unidentified
prognostic factors the RDT design seems to be useful for objective evaluation of time to
progression and overall survival.

The RDT design will ensure that all patients receive treatment with sorafenib for a run-in
phase of 8 weeks and will receive further treatment with sorafenib if they experience
response (complete response or partial response). Patients who experience tumor progression
during this run-in phase will not remain in the study but may be offered alternative
treatment. Patients who experience tumor stabilization (stable disease) will be randomized
double-blinded to either sorafenib or placebo. Tumor response assessments will be performed
every 8 weeks, in case of progression the patient will be unblinded and offered retreatment
with sorafenib if he had been randomized to placebo. Thus, if the patient experiences
progression, the effective maximum duration of a possible placebo application is confined to
eight weeks.

Risk-benefit assessment of the treatment of patients with metastatic uveal melanoma with
sorafenib Based on the rationale for treatment of patients with metastatic uveal melanoma
with sorafenib and own clinical experience in a limited number of patients with metastatic
uveal melanoma treated with sorafenib on a compassionate use basis (section 3.3), a
potential benefit of this systemic treatment is anticipated.

Major potential side effects of the continuous oral treatment with sorafenib are
hand-foot-syndrome, diarrhoea and increase in blood pressure which can effectively be
reduced either by dose reduction or cessation of treatment with sorafenib in case of
hand-foot-syndrome or diarrhoea or antihypertonic agents in case of increase of blood
pressure.

Further on, the administration of sorafenib (oral intake) means fewer hospitalizations and
thus constitutes an improvement of quality of life.

Thus, treatment with sorafenib is a potentially effective treatment of patients with
metastatic uveal melanoma without serious side effects.

In case of short-term evaluation of inappropriate antitumor efficacy patients have the
option for alternative treatment strategies either by intra-arterial liver perfusion with
fotemustine or melphalan in case of metastatic disease confined to the liver or salvage
chemotherapy. However it should be noted that these treatments do not represent established
and authorized alternative treatment options. The only randomized phase III trial comparing
intra-arterial hepatic fotemustine administration with intravenous systemic fotemustine with
regard to overall survival as primary endpoint is still ongoing (EORTC 18021), all other
experience is based on small phase II trials or individual treatments decisions as described
in section 3.1. Any locoregional treatment such as surgery or intra-arterial hepatic
infusion with fotemustine or mephalan requires that the patient does not suffer from
disseminated metastasis of the liver or extrahepatic localisation of metastases.

Any placement of an intra-arterial catheter and to a lower extent, intravenous catheter is
associated with the risks of catheter thrombosis, dislocation, catheter stenosis/obstruction
or leakage.

The main serious side effects of melphalan and fotemustine are myelotoxicity with anemia,
leucopenia and thrombocytopenia and the risk of developing acute leucemia, gastrointestinal
toxicity with nausea, vomiting and diarrhoea, allergic reactions, alopecia, interstitial
pneumonia, liver function disorders and renal function disorders.

Considering the poor prognosis of metastatic uveal melanoma and taking into account the lack
of an established treatment to treat metastatic uveal melanoma, the risk-benefit relation of
the study is assessed as positive. The possible benefit of achieving disease control with
sorafenib outweighs the risk of possible side effects of sorafenib. Alternative treatment
options are likewise further subject to investigation, have probably more serious side
effects and certainly affect the quality of life far more as result of the
intraarterial/intravenous infusional application in contrast to oral intake of sorafenib.