- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01377025
A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma (STREAM)
A Randomized Discontinuation, Blinded, Placebo-Controlled Phase II Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma
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.
Study Overview
Status
Conditions
Intervention / Treatment
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 Type
Enrollment (Anticipated)
Phase
- Phase 2
Contacts and Locations
Study Locations
-
-
-
Berlin, Germany, 12203
- Universitätsmedizin Berlin, Charité Campus Benjamin Franklin
-
Erlangen, Germany, 91052
- Universitatsklinikum Erlangen
-
Essen, Germany, 45147
- Univesitätsklinikum Essen
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion criteria:
- Signed and dated written informed consent before the start of specific protocol procedures
- Metastatic uveal melanoma with histological or cytological confirmation of liver metastasis
- By means of whole body MRI documented disease according to RECIST version 1.1 with at least one unidimensional measurable lesion ≥ 10 mm
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
- Male or female patients ≥ 18 years of age
- Estimated life-expectancy more than 5 months
Hematologic function, as follows:
- Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
- Platelet count ≥ 100 x 109/L
- Hemoglobin ≥ 9 g/dL
Renal function, as follows
-Creatinine ≤ 1.5 x upper limit of normal (ULN)
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
- PT-INR/PT < 1.5 x ULN
- 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
- Males must agree to use barrier birth control measures (condoms) during the course of the trial.
Exclusion criteria:
- 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
- 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)
- QT/QTc-interval prolongation (QTc> 450 msec) on ECG, known Long QT syndrome or known Long QT syndrome in relatives
- Known HIV infection
- Known chronic infection with hepatitis B or C
- Hypokalemia, hypocalcemia, hypomagnesemia or patients under actual treatment against hypokalemia, hypocalcemia, hypomagnesemia
- Active infection requiring systemic antibiotic/antiviral/antifungal treatment or any uncontrolled infection > Grade 2 NCI-CTCAE
- 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)
- Patients with seizure disorder requiring medication (such as steroids or antiepileptics)
- History of organ allograft
- Patients with evidence or history of bleeding diathesis
- Thrombotic or embolic events within the last 6 months
- Serious non-healing wound, ulcer or fracture
- 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
- Pregnant or breast-feeding patients
- Marked claustrophobia
- Cardiac pacemaker, cochlea implants or other implanted metal devices, residual metal splinters
- Known allergy to the used study drug sorafenib or to any of its excipients
- Known hypersensitivity to gadolinium based contrast agents
- Subject unwilling or unable to comply with study requirements
- Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
- 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
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Triple
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Experimental: Sorafenib blinded Phase
400 mg Sorafenib bid until PD
|
400 mg Sorafenib bid until PD if staging after Run-In was PR or CR
400 mg Sorafenib bid until PD if staging after Run-In was SD
|
Placebo Comparator: Placebo blinded Phase
Two tbl. in the morning and two tbl. in teh evening until PD
|
two tablets in the morning and two in the evening.
|
Experimental: Sorafenib Open Phase
400 mg Sorafenib bid until PD
|
400 mg Sorafenib bid until PD if staging after Run-In was PR or CR
400 mg Sorafenib bid until PD if staging after Run-In was SD
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Progression Free Survival
Time Frame: Every 8 weeks for 1 year
|
Every 8 weeks for 1 year
|
Secondary Outcome Measures
Outcome Measure |
Time Frame |
---|---|
Number of patients with adverse events
Time Frame: Every 8 weeks for 1 year
|
Every 8 weeks for 1 year
|
Overall Survival
Time Frame: Every 8 weeks for 2 years
|
Every 8 weeks for 2 years
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Max E. Scheulen, Prof., Universiätsklinikum Essen
Study record dates
Study Major Dates
Study Start
Primary Completion (Anticipated)
Study Completion (Anticipated)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Estimate)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Neoplasms by Histologic Type
- Neoplasms
- Neoplasms by Site
- Eye Diseases
- Neuroectodermal Tumors
- Neoplasms, Germ Cell and Embryonal
- Neoplasms, Nerve Tissue
- Uveal Diseases
- Neuroendocrine Tumors
- Nevi and Melanomas
- Eye Neoplasms
- Melanoma
- Uveal Neoplasms
- Molecular Mechanisms of Pharmacological Action
- Enzyme Inhibitors
- Antineoplastic Agents
- Protein Kinase Inhibitors
- Sorafenib
Other Study ID Numbers
- STREAM
- 2010-022687-12 (EudraCT Number)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Uveal Melanoma
-
Jonsson Comprehensive Cancer CenterNational Cancer Institute (NCI)TerminatedIris Melanoma | Medium/Large Size Posterior Uveal Melanoma | Stage IIA Uveal Melanoma | Stage IIB Uveal Melanoma | Stage IIIA Uveal Melanoma | Stage IIIB Uveal Melanoma | Stage IIIC Uveal MelanomaUnited States
-
National Cancer Institute (NCI)ExelisisCompletedStage IV Uveal Melanoma AJCC v7 | Recurrent Uveal Melanoma | Stage III Uveal Melanoma AJCC v7 | Stage IIIA Uveal Melanoma AJCC v7 | Stage IIIB Uveal Melanoma AJCC v7 | Stage IIIC Uveal Melanoma AJCC v7United States, Canada
-
Vanderbilt-Ingram Cancer CenterNational Cancer Institute (NCI)TerminatedStage IV Uveal Melanoma | Stage IIIA Uveal Melanoma | Stage IIIB Uveal Melanoma | Stage IIIC Uveal MelanomaUnited States
-
National Cancer Institute (NCI)CompletedIris Melanoma | Stage IV Uveal Melanoma | Medium/Large Size Posterior Uveal Melanoma | Recurrent Uveal Melanoma | Ocular Melanoma With Extraocular Extension | Small Size Posterior Uveal MelanomaUnited States, Canada
-
Alliance for Clinical Trials in OncologyWithdrawnMetastatic Uveal Melanoma | Advanced Uveal Melanoma | Unresectable Uveal Melanoma
-
Fred Hutchinson Cancer CenterNational Cancer Institute (NCI); Incyte Corporation; University of VirginiaCompletedStage IV Skin Melanoma | Recurrent Melanoma | Stage IIIB Skin Melanoma | Stage IIIC Skin Melanoma | Mucosal Melanoma | Stage IV Uveal Melanoma | Stage IIIA Skin Melanoma | Stage IIIA Uveal Melanoma | Stage IIIB Uveal Melanoma | Stage IIIC Uveal Melanoma | Recurrent Uveal MelanomaUnited States
-
National Cancer Institute (NCI)CompletedStage IV Cutaneous Melanoma AJCC v6 and v7 | Recurrent Melanoma | Stage IIIC Cutaneous Melanoma AJCC v7 | Mucosal Melanoma | Iris Melanoma | Stage IIIA Cutaneous Melanoma AJCC v7 | Stage IIIB Cutaneous Melanoma AJCC v7 | Stage IV Uveal Melanoma AJCC v7 | Medium/Large Size Posterior Uveal Melanoma | Recurrent... and other conditionsUnited States
-
National Cancer Institute (NCI)Memorial Sloan Kettering Cancer Center; Institut Curie Paris; Moffitt Cancer...Active, not recruitingMetastatic Uveal Melanoma | Stage IV Uveal Melanoma AJCC v7United States
-
National Cancer Institute (NCI)CompletedStage IV Uveal Melanoma AJCC v7 | Recurrent Uveal MelanomaUnited States
-
National Cancer Institute (NCI)CompletedStage IV Uveal Melanoma AJCC v7 | Recurrent Uveal MelanomaUnited States, France, United Kingdom
Clinical Trials on Sorafenib
-
BayerAmgenCompleted
-
Ohio State University Comprehensive Cancer CenterBayerTerminated
-
Technical University of MunichCompleted
-
Ottawa Hospital Research InstituteBayerCompletedMetastatic Colorectal CancerCanada
-
Yiviva Inc.RecruitingAdvanced Hepatocellular CarcinomaUnited States, Taiwan, China, Hong Kong
-
National Cancer Institute (NCI)CompletedNon-Small-Cell Lung CarcinomaUnited States
-
British Columbia Cancer AgencyWithdrawnLocally Advanced Squamous Cell Carcinomas of the Head and Neck (SCCHN)Canada
-
Accelerated Community Oncology Research NetworkBayerTerminatedRenal Cell CarcinomaUnited States
-
China Medical University HospitalUnknown
-
Cancer Institute and Hospital, Chinese Academy...CompletedHepatocellular Carcinoma, Radiotherapy, SorafenibChina