Brief Title
A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma
Official Title
A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma
Brief Summary
Uveal melanoma is the most common primary intra-ocular malignancy in adults with an incidence
of 0.6 - 0.7 per 100,000 per year.
Prognosis of metastatic uveal melanoma is poor. In retrospective analyses a median survival
time after detection of metastases of 5 months (Flaherty et al, 1998) and 7 months (Kath et
al, 1993) was reported. For patients receiving no treatment reported median survival was 2.0
months compared with 5.2 months for those receiving treatment for metastases (Gragoudas et
al, 1991).
Up to now there is no established treatment of metastatic uveal melanoma. Some therapeutic
approaches with locoregional treatment or systemic chemotherapy have been undertaken:
In case of metastatic disease which is confined to the liver in about 85% of patients with
uveal melanoma surgical resection led to a median survival of 14 months (Mariani et al, 2009)
or 19 months and a 5-year survival rate of 22% in a selected patient population (Adam et al,
2006).
As locoregional treatment option treatment with fotemustine via direct intra-arterial hepatic
infusion was investigated and led to a median survival of 15 months (Peters et al, 2006).
This was not a randomized trial, but a report on 101 consecutive treated patients. Additional
debulking surgery was performed whenever feasible.
A randomized phase III trial comparing intra-arterial hepatic fotemustine administration with
intravenous systemic fotemustine and overall survival as primary endpoint is still ongoing
(EORTC 18021).
Thus, no systemic chemotherapy is approved for metastatic uveal melanoma. Although no
specific genes have been linked to the pathogenesis of uveal melanoma, 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.
Thus, sorafenib as inhibitor of b-Raf and Raf-1 (c-Raf or c-Raf-1), pro-angiogenic vascular
endothelial growth factor receptor (VEGFR), and platelet-derived growth factor receptor
(PDGFR) may potentially lead to a benefit for patients with metastatic uveal melanoma in
terms of disease control and prolongation of survival.
Detailed Description
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.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Progression Free Survival
Secondary Outcome
Number of patients with adverse events
Condition
Uveal Melanoma
Intervention
Placebo
Study Arms / Comparison Groups
Sorafenib blinded Phase
Description: 400 mg Sorafenib bid until PD
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
200
Start Date
June 2011
Completion Date
June 2017
Primary Completion Date
June 2016
Eligibility Criteria
Inclusion criteria:
1. Signed and dated written informed consent before the start of specific protocol
procedures
2. Metastatic uveal melanoma with histological or cytological confirmation of liver
metastasis
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
antiepileptics)
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
splinters
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
participation
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Max E. Scheulen, Prof., ,
Location Countries
Germany
Location Countries
Germany
Administrative Informations
NCT ID
NCT01377025
Organization ID
STREAM
Secondary IDs
2010-022687-12
Responsible Party
Sponsor-Investigator
Study Sponsor
Prof. Dr. med. Max. E. Scheulen
Collaborators
ClinAssess GmbH
Study Sponsor
Max E. Scheulen, Prof., Principal Investigator, Universiätsklinikum Essen
Verification Date
December 2014