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

Phase 2
18 Years
Open (Enrolling)
Uveal Melanoma

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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

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.

Inclusion Criteria

Inclusion criteria:

1. Signed and dated written informed consent before the start of specific protocol

2. Metastatic uveal melanoma with histological or cytological confirmation of liver

3. By means of whole body MRI documented disease according to RECIST version 1.1 with at
least one unidimensional measurable lesion ≥ 10 mm

4. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

5. Male or female patients ≥ 18 years of age

6. Estimated life-expectancy more than 5 months

7. Hematologic function, as follows:

- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

- Platelet count ≥ 100 x 109/L

- Hemoglobin ≥ 9 g/dL

8. Renal function, as follows

-Creatinine ≤ 1.5 x upper limit of normal (ULN)

9. Hepatic function, as follows

- Aspartate aminotransferase (AST) ≤ 2.5 x ULN

- Alanine aminotransferase (ALT) ≤ 2.5 x ULN

- Total bilirubin ≤ 3 mg/dl

- Alkaline phosphatase ≤ 4.0 x ULN

10. PT-INR/PT < 1.5 x ULN

11. Females of childbearing potential (FCBP) must have a negative pregnancy test within
7 days of the first application of study treatment and must agree to use effective
contraceptive birth control measures

12. Males must agree to use barrier birth control measures (condoms) during the course of
the trial.

Exclusion criteria:

1. Previous or concurrent tumor other than uveal melanoma with the exception of cervical
cancer in situ, adequately treated basal cell carcinoma, superficial bladder tumors
(Ta, Tis, and T1) or any curatively treated tumors > 3 years prior to enrollment

2. History of cardiac disease: congestive heart failure ≥ NYHA class 2; active coronary
artery disease ([CAD], myocardial infarction more than 6 months prior to study entry
is allowed), cardiac arrhythmias requiring antiarrhythmic therapy (only beta blockers
or digoxin are permitted)

3. QT/QTc-interval prolongation (QTc> 450 msec) on ECG, known Long QT syndrome or known
Long QT syndrome in relatives

4. Known HIV infection

5. Known chronic infection with hepatitis B or C

6. Hypokalemia, hypocalcemia, hypomagnesemia or patients under actual treatment against
hypokalemia, hypocalcemia, hypomagnesemia

7. Active infection requiring systemic antibiotic/antiviral/antifungal treatment or any
uncontrolled infection > Grade 2 NCI-CTCAE

8. Symptomatic brain or meningeal tumors (unless patient is > 6 months from definitive
therapy, had a negative imaging study within 4 weeks of study entry and is clinically
stable with respect to the tumor at the time of study enrollment)

9. Patients with seizure disorder requiring medication (such as steroids or

10. History of organ allograft

11. Patients with evidence or history of bleeding diathesis

12. Thrombotic or embolic events within the last 6 months

13. Serious non-healing wound, ulcer or fracture

14. Uncontrolled arterial hypertension with systolic blood pressure >150 mm Hg and/ or
diastolic blood pressure > 90 mg Hg despite optimal treatment, determined twice
within one week

15. Pregnant or breast-feeding patients

16. Marked claustrophobia

17. Cardiac pacemaker, cochlea implants or other implanted metal devices, residual metal

18. Known allergy to the used study drug sorafenib or to any of its excipients

19. Known hypersensitivity to gadolinium based contrast agents

20. Subject unwilling or unable to comply with study requirements

21. Substance abuse, medical, psychological or social conditions that may interfere with
the patient's participation in the study or evaluation of the study results

22. Participation in any clinical study or treatment with an experimental drug or
experimental therapy within 28 days prior to study enrollment or during study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Progression Free Survival

Outcome Time Frame:

Every 8 weeks for 1 year

Safety Issue:


Principal Investigator

Max E. Scheulen, Prof.

Investigator Role:

Principal Investigator

Investigator Affiliation:

Universiätsklinikum Essen


Germany: Federal Institute for Drugs and Medical Devices

Study ID:




Start Date:

June 2011

Completion Date:

June 2017

Related Keywords:

  • Uveal Melanoma
  • Melanoma
  • Uveal Neoplasms