A Study of Sorafenib in Patients With Chemonaive Metastatic Uveal Melanoma

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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