Dabrafenib and Trametinib in People With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease

Phase 2

Completed

Conditions: BRAF V600E Mutation

Interventions: Drug: Dabrafenib Mesylate
Drug: Trametinib Dimethyl Sulfoxide

Registration Number: NCT02281760

Lead Sponsor: National Human Genome Research Institute (NHGRI)

Brief 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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 9

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Combination therapy with dabrafenib and trametinib in patients with ECD	Trametinib Dimethyl Sulfoxide	Patients with Erdheim Chester Disease (ECD) and BRAFV600E mutation received combination therapy with dabrafenib, a BRAFV600E inhibitor 150mg orally every twelve hours, and trametinib, an inhibitor of MEK, downstream of BRAF, 2mg orally daily.
Combination therapy with dabrafenib and trametinib in patients with ECD	Dabrafenib Mesylate	Patients with Erdheim Chester Disease (ECD) and BRAFV600E mutation received combination therapy with dabrafenib, a BRAFV600E inhibitor 150mg orally every twelve hours, and trametinib, an inhibitor of MEK, downstream of BRAF, 2mg orally daily.

Primary Outcome Measures

Name	Time	Method
Clinical Response Rate to Dabrafenib/Trametinib Combination Therapy in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease.	24 months	Clinical response rate to dabrafenib and trametinib combination therapy in patients as measured by the percentage of patients who met RECIST 1.1 criteria for a partial response.
Number of Participants With Adverse Events to Dabrafenib and/or Trametinib	24 months	Safety of dabrafenib and trametinib as combination therapy, or either drug as single-agent therapy among participants, as measured by the adverse event characteristics of participants. See the adverse event table for list of specific adverse events experienced.
Number of Participants With Partial Response to Dabrafenib and Trametinib	24 months	Efficacy of dabrafenib and trametinib as combination therapy in patients with BRAFV600E positive Erdheim Chester Disease based on RECIST 1.1 criteria of a partial response greater than or equal to 30% decrease in at least one target lesion size.

Secondary Outcome Measures

Name	Time	Method
Time Response to Dabrafenib/Trametinib Combination Therapy in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease.	12 months	Time to response to combination therapy defined as the minimum length of time elapsed during the active treatment phase to reach at least a partial response, as defined by RECIST 1.1 criteria.
Progression-free Survival in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease	24 months	Progression free survival rate using RECIST 1.1 criteria among participants during the entire study period of 24 months. Progression is defined as a 20% increase in the diameter of target lesions, or a significant increase in a non-target lesion, or the appearance of new lesions.
Overall Survival in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease	24 months	Overall survival rate among participants defined as the number of patients alive at the end of the 24-month study period.
Disease Resistance to Dabrafenib/Trametinib Combination Therapy in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease	12 months	Disease resistance to the combination therapy during the active treatment phase of the study. Resistance is defined as evidence of disease progression per RECIST 1.1 in a participant previously exhibiting stable disease or at least a partial response according to RECIST 1.1 criteria. Also, disease progression is defined as the requirement of dosage escalation in order to maintain current efficacy.