Dabrafenib and Trametinib in People With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease
Status:
Completed
Trial end date:
2018-08-29
Target enrollment:
Participant gender:
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.