Dabrafenib and Trametinib in People With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease
Condition: BRAF V600E Mutation
MeSH terms: Erdheim-Chester Disease
Study type: Interventional
Phase: Phase 2

Summary: 
      Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown
      origin and pathogenesis. It has been reported mainly in adult males over the age of 40 years,
      although cases have been reported in females as well. Children are rarely affected. Mutation
      of the BRAF gene, specifically BRAFV600E, has been recently identified in 50% of Erdheim
      Chester lesions in a French cohort. This somatic mutation is believed to be the driver
      mutation in positive cases. The clinical characteristics of ECD range from asymptomatic to
      multisystemic involvement; longitudinal progression and natural history are becoming better
      understood. ECD commonly affects the bones, kidneys, retroperitoneal space, skin and brain.
      If untreated, the disease progresses rapidly, causing fatal outcomes due to severe lung
      disease, chronic renal failure, cardiomyopathy and other complications. The diagnosis of ECD
      relies upon imaging studies and specific pathologic findings in biopsies of affected organs,
      i.e., fibrosis and infiltration of tissues with foamy histiocytes, lymphocytes, and plasma
      cells. Immunohistochemistry reveals cells positive for CD68 and CD163 and negative for CD1a,
      with 20% positivity to S-100. There is no standard treatment for ECD, although chemotherapy,
      radiation, stem cell transplantation, alpha-interferon, anakinra, imatinib and sirolimus have
      been proposed. The recent discovery of the BRAFV600E mutation in several ECD patients has
      opened a new area for treatment options. Vemurafenib, an FDA approved BRAF inhibitor for the
      treatment of patients with metastatic or unresectable melanoma with the V600E mutation, binds
      to this form of mutated BRAF causing protein inactivation. The use of vemurafenib in patients
      with ECD has been reported in 3 patients who experienced remission of the disease, and is
      currently being studied in the U.S. and Europe as monotherapy. Tumor/disease resistance to
      vemurafenib has occurred in melanoma and other cancers, although it has not been reported in
      patients with ECD. In this protocol, we propose to clinically evaluate ECD patients with the
      BRAFV600E mutation and administer combination therapy with dabrafenib, a BRAFV600E inhibitor,
      and trametinib, an inhibitor of MEK, downstream of BRAF. Screening for possible
      contraindications will be made prior to the administration of the first dose. With this
      trial, we will determine the safety, tolerability, and efficacy of dabrafenib and trametinib
      in patients with ECD who harbor the BRAFV600E mutation. Dabrafenib 150mg will be given twice
      daily p.o.; trametinib 2mg will be given once daily p.o. Patients will be seen 1 week, 1
      month, 2 months, 4 months, and 6 months, 8 months, 10 months and 12 months to complete a
      one-year trial.
    

Detailed description: 
      Erdheim-Chester Diseases (ECD) is a very rare non-Langerhans cell histiocytosis of unknown
      origin and pathogenesis. It has been reported mainly in adult males over the age of 40 years,
      although cases have been reported in females as well. Children are rarely affected. Mutation
      of the BRAF gene, specifically BRAFV600E, has been recently identified in 50% of Erdheim
      Chester lesions in a French cohort. This somatic mutation is believed to be the driver
      mutation in positive cases. Other genes that are involved in this disease process include
      NRAS, MAP2K1, PIK3CA, ARAF and other genes of the RAS pathway that are currently being
      studied. The clinical characteristics of ECD range from asymptomatic to multisystem
      involvement; longitudinal progression and natural history are becoming better understood. ECD
      commonly affects the bones, kidneys, retroperitoneal space, skin and brain. If untreated, the
      disease progresses rapidly, causing fatal outcomes due to severe lung disease, chronic renal
      failure, cardiomyopathy and other complications. The diagnosis of ECD relies upon imaging
      studies and specific pathologic findings in biopsies of affected organs, i.e., fibrosis and
      infiltration of tissues with foamy histiocytes, lymphocytes, and plasma cells.
      Immunohistochemistry reveals cells positive for CD68 and CD163 and negative for CD1a, with
      20% positivity to S-100. There is no standard treatment for ECD, although chemotherapy,
      radiation, stem cell transplantation, alpha-interferon, anakinra, imatinib and sirolimus have
      been proposed. The recent discovery of the BRAFV600E mutation in several ECD patients has
      opened a new area for treatment options. Vemurafenib, an FDA approved BRAF inhibitor for the
      treatment of patients with metastatic or unresectable melanoma with the V600E mutation, binds
      to this form of mutated BRAF causing protein inactivation. The use of vemurafenib in patients
      with ECD has been reported in 3 patients who experienced remission of the disease, and is
      currently being studied in the U.S. and Europe as monotherapy. Tumor/disease resistance to
      vemurafenib has occurred in melanoma and other cancers, although it has not been reported in
      patients with ECD. In this protocol, we propose to clinically evaluate ECD patients with the
      BRAFV600E mutation and administer combination therapy with dabrafenib, a BRAFV600E inhibitor,
      and trametinib, an inhibitor of MEK, downstream of BRAF. Screening for possible
      contraindications will be made prior to the administration of the first dose. With this
      trial, we will determine the safety, tolerability, and efficacy of dabrafenib and trametinib
      in patients with ECD who harbor the BRAFV600E mutation. Dabrafenib (which initial dose was
      150mg BID, but due to high frequency pyrexia the dose was changed to 100mg BID for patients
      enrolled after amendment #6 of 12/27/2015) at a dose of 100mg will be given twice daily p.o.;
      trametinib 2mg will be given once daily p.o. Patients will be seen at 1 week, 1 month, 2
      months, 4 months, and 6 months, 8 months, 10 months and 12 months to complete one year of
      therapy and off therapy follow ups will happen at 15 months, 18 months and 24 months to
      complete a 2 year trial.
    

Intervention name(s): Dabrafenib Mesylate; Trametinib Dimethyl Sulfoxide
Intervention type(s): Drug; Drug
Intervention description(s): Description: Dabrafenib mesylate (GSK2118436B) is a potent and selective BRAF kinase inhibitor. This inhibition suppresses downstream activity of pERK, a biomarker, and has antiproliferative activity against BRAF mutant tumors.The mode of action is consistent with ATP competitive inhibition.; Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) pathways in which MEK is a critical component. Trametinib dimethyl sulfoxide inhibits activation of MEK by RAF kinases and MEK kinases.
Intervention MeSH terms: Trametinib; Dabrafenib; Dimethyl Sulfoxide
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Histiocytosis; Non Langerhans Cell Histiocytosis; BRAF Inhibitor