Conditions: BRAF V600E Mutation
Keywords: Histiocytosis Non Langerhans Cell Histiocytosis BRAF Inhibitor
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 9
Healthy volunteers: no

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.

Arms:
arm 1: 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.

Interventions: intervention 1: Dabrafenib Mesylate intervention 2: Trametinib Dimethyl Sulfoxide
Intervention descriptions: intervention 1: 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. intervention 2: 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.

Protocol document:
Prot_SAP_000.pdf: 
• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 1 of 77 
Project title: “A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients 
with BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease”. 
Draft/version number: 03-June-2014 / Version 1 
Draft/version number: 16-July-2014/ Version 2 
Draft/version number: 05-September-2014/Version 3 
Draft/version number: 07-November-2014/Version 4; Amendment #1-A 
Draft/version number: 26-March-2015/Version 5; Amendment #2-B 
Draft/version number: 14-December-2015/Version 6; Amendment #3-C 
Draft/version number: 26-January-2016/Version 7; Amendment #4-D 
Draft/version number: 22-August-2016/Version 8; Amendment #5-E 
Draft/version number: 17-Janaury-2017/Version 8; Update to Amendment #5-E 
Draft/version number: 03-March-2017/Version 9; Amendment # 6-F (CTEP: Amendment #11) 
Draft/version number: 16-June-2017/Version 10; Triennial Review 
Draft/version number: 11-July-2017/Version 11; Problem 6 response and amendment. 
 
NHGRI Protocol Number: 15-HG-0006  
Principal Investigator: 
William A. Gahl, M.D. PhD  
 
 
 
 
Title/Section/Branch/Institute: Clinical Director/Office of the Clinical Director/National 
Human Genome Research Institute. 
 
IND/IDE reference number: CTEP Drugs 
 
Collaborating Institutions: NCI; CTEP 
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 2 of 77 
Protocol Summary 
 
Full Title: 
“A Phase II Therapeutic Trial of the Use of Dabrafenib and 
Trametinib in Patients with BRAF V600E Mutation Positive 
Lesions in Erdheim Chester Disease”. 
 
Principal Investigator: 
William A. Gahl, MD, PhD, Medical Genetics Branch, NHGRI 
 
Sample Size: 
N= 18 
 
Accrual Ceiling: 
 
18 
 
Study Population: 
Individuals with documented Erdheim-Chester Disease 
 
Accrual Period: 
 
January 2015 – January 2019 
 
Study Design: 
 
In this phase II open-label clinical trial, we 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. We 
will determine the safety, tolerability, and efficacy of dabrafenib 
and trametinib in patients with ECD who harbor the BRAFV600E 
mutation. Patients are 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. Target lesions will be assessed using RECIS criteria.  
 
Study Duration: 
 
Start Date:  January 2015.  End Date:  January 2019. 
 
Primary Objective:  
To determine the safety, efficacy, and response rate of the 
combination of dabrafenib and trametinib in ECD. 
 
Secondary Objectives: 
Determine the time response, survival, and resistance to therapy. 
 
Exploratory Objectives: 
To monitor involvement and progression of disease and duration of 
treatment efficacy.  
 
Endpoints: 
 
The endpoint for an individual is reduction in target lesion size by 
RECIS criteria. For the trial, it is partial or complete response of at 
least 3 of the first 6 patients. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 3 of 77 
Contents 
Protocol Summary ........................................................................................................................ 2 
List of Abbreviations .................................................................................................................... 4 
1.0 
Precis ............................................................................................................................... 5 
2.0 
Objectives and specific aims................................................................................................ 6 
3.0 
Brief rationale and background ............................................................................................ 6 
4.0 
Description of study design ................................................................................................13 
5.0 
Description of procedures: .................................................................................................13 
6.0 
Description of study population ..........................................................................................52 
7.0 
Description of study statistical considerations and/or analytic plan: .........................................60 
8.0 
Description of potential benefits of study: ............................................................................64 
9.0 
Description of likelihood and seriousness of harms and how safety will be maximized: .............64 
10.0 
Description of how privacy and confidentiality of medical information/biological specimens will 
be maximized ..............................................................................................................................71 
11.0 
Assessment of risk/benefit ratio ..........................................................................................71 
12.0 
Unanticipated Problems:  Collection, monitoring, analysis and reporting of adverse events and 
protocol deviations ......................................................................................................................73 
13.0 
Description of alternatives to participation ...........................................................................73 
14.0 
Description of consent process ...........................................................................................74 
15.0 
Description of any financial compensation ...........................................................................75 
16.0 
References .......................................................................................................................75 
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 4 of 77 
 
List of Abbreviations  
 
AE 
 
Adverse Event/Adverse Experience 
CLIA  
Clinical Laboratory Improvement Amendment of 1988 
COI 
 
Conflict of Interest 
DHHS  
Department of Health and Human Services 
DSMB  
Data Safety and Monitoring Board 
GCP  
Good Clinical Practice 
ICF 
 
Informed Consent Form 
IRB 
 
Institutional Review Board 
N 
 
Number (typically refers to number of subjects/sample size) 
NHGRI 
National Human Genome Research Institute, NIH 
NIH 
 
National Institutes of Health 
OHRP  
Office for Human Research Protections 
OHSRP 
Office of Human Subjects Research Program 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetics 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
SAE 
 
Serious Adverse Event/Serious Adverse Experience 
SOP 
 
Standard Operating Procedure 
UP 
 
Unanticipated Problem 
WES  
Whole Exome Sequencing 
WGS  
Whole Genome Sequencing 
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 5 of 77 
1.0 
Precis 
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 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 (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 occur at 15 months, 18 months and 24 
months to complete a 2 year trial. 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 6 of 77 
2.0 
Objectives and specific aims 
2.1 Primary Objectives 
2.1.1 - To study the efficacy and safety of dabrafenib and trametinib as combination therapy 
in patients with BRAFV600E positive Erdheim Chester Disease. 
 
2.1.2 - To determine the clinical response rate to dabrafenib and trametinib combination 
therapy in patients with BRAFV600E positive Erdheim Chester Disease. 
2.2 Secondary Objectives 
2.2.1 - To determine time response, progression free survival and overall survival. 
2.2.2 - To assess disease resistance to this combination therapy. 
 
2.3        Exploratory Objectives: 
2.3.1 - To monitor the degree of histiocytic infiltration-fibrosis progression, stability and 
regression under combination therapy using FDG-PET scan, MRI scans, CT scans and T-
99m bone scans. 
 
2.3.2 - To monitor serum CRP, ESR, and cytokine levels as inflammatory markers prior to 
and during combination therapy. 
 
2.3.3 - To monitor renal function prior to and during combination therapy in order to assess 
for functional improvement. 
 
2.3.4 - To evaluate the level of functioning, fatigue, motor skills and ability to perform 
routine daily activities prior to and during therapy in order to assess for improvements in 
these areas as well as quality of life improvement. 
 
2.3.5 - To establish duration of treatment-endpoints in patients with BRAF V600E positive 
ECD lesions. 
3.0 
Brief rationale and background 
3.1 Study Diseases: 
The histiocytoses are a unique group of disorders with varied clinical presentations and 
outcomes. These disorders generally present in childhood; a recently increased frequency 
in adults reflects more accurate diagnosis in that age group. The histiocytoses cannot be 
categorized as entirely genetic, neoplastic, or reactive, and the pathophysiology remains 
poorly understood. For histiocytoses such as Langerhans cell histiocytosis and familial 
hemophagocytic lymphohistiocytosis, certain genetic associations have been made27. In 
addition, clonality has been proven for Langerhans cell histiocytosis, but not for other types 
of histiocytosis such as Rosai Dorfman disease, which involves the lymph nodes and 
sinuses. Because of the rarity of histiocytoses, clinical and basic research dedicated to these 
disorders has been insufficient. The histiocytoses have been divided into Langerhans cell 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 7 of 77 
or non-Langerhans cell subtypes, with dendritic, macrophage/monocytic, and malignant 
forms27. 
The clinical presentation, progression, response to therapy and outcome varies in each of 
the different histiocytoses12,18,23,27. Patients can present with no symptoms, in which case 
the disease is diagnosed incidentally based upon involvement of a single organ system, or 
they can present with multisystem disease causing organ failure. Some patients with Rosai-
Dorfman and juvenile xanthogranuloma may have a benign course or even exhibit 
regression without symptoms, while other patients progress to a complex multiorgan 
disease. Those histiocytoses classified as malignant generally prove fatal without 
treatment, and may progress even with treatment27. 
Erdheim Chester disease (ECD), first described in 193012, is a type of non-Langerhans cell 
histiocytosis that can present with no symptoms or only bone pain and fatigue, but can also 
present with multisystem involvement causing one or more of the following: cerebellar 
syndrome, panhypopituitarism, lung and cardiac disease, renal failure, bone disease and 
retroperitoneal fibrosis18,29,38. ECD is not considered a cancer, although recent findings of 
BRAF gene mutations suggest that ECD might represent a low-grade malignancy19. Its 
etiology and pathogenesis remain areas under active investigation. Animal models, cell 
lines and affected families are limited due to the rarity and sporadic nature of the cases.  In 
fact, there have never been two patients in the same family with ECD. 
ECD has been reported mainly in adult males over the age of 40 years, although females 
can be affected as well. Children are rarely affected. The pathophysiology of ECD has not 
been determined, but the disease results in part from an increased inflammatory response 
and intense immune activation. The principal players include interferon alpha, interleukin 
1/interleukin 1 receptor antagonist, interleukin 6, interleukin 12 and monocyte chemotactic 
protein 1, indicating a Th-1 oriented systemic immune disturbance3,18. A mutation in the 
BRAF gene, BRAFV600E, has been recently identified in 50% of ECD lesions in a French 
cohort, with verification in U.S. patients19. 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.  This somatic mutation may be responsible for the 
histiocytic infiltrations seen in ECD. The clinical characteristics of ECD range from 
asymptomatic to multi-systemic involvement. After diagnosis, ECD progresses rapidly, 
causing fatal outcomes due to severe lung disease, chronic renal failure, cardiomyopathy 
and other complications if left untreated. The diagnosis of ECD relies upon imaging studies 
and specific pathologic findings in biopsies of affected organs, i.e., fibrosis and infiltration 
of the affected tissues with foamy histiocytes, lymphocytes, and plasma cells. 
Immunohistochemistry reveals cells positive for CD68/CD163 and negative for CD1a; 
there is 20% positivity for S-10017,18,27.  
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 8 of 77 
The natural history of ECD is still under investigation. Past literature describes the disorder 
as a condition that mainly affects males. The average age at diagnosis is 53 years and death 
from the disease occurs approximately 3 years after diagnosis. The typical presentation 
involves lower extremity bone pain, polyuria, polydipsia, fatigue and other nonspecific 
findings. Clinical evaluations reveal renal failure and inflammation with elevated CRP. 
Imaging studies show osteosclerosis, a “hairy” appearance to the kidney, and coated aorta 
on CT scan of the abdomen. Pituitary imaging usually shows a thickened pituitary stalk 
associated with signs and symptoms of diabetes insipidus and other hormonal disturbances. 
The differential diagnosis includes Paget’s disease of the bone, lymphoma, pituitary 
adenoma, and granulomatous disorders. ECD can also be confused with adult onset storage 
disorders such as Gaucher disease and Fabry disease12. Pathology can be inconclusive; 
patients often remain undiagnosed and are treated empirically with steroids or 
chemotherapy.  
In the past decade, the natural history of ECD has become better understood, with more 
than 400 cases reported since 1930. The first sign of ECD varies widely, since patients can 
present with many manifestations or be diagnosed incidentally. Increased awareness and 
research has increased the number of reported cases and shortened the time between 
presentation and diagnoses from up to 10 years to months or weeks, depending upon the 
medical institution involved. The frequency of the main manifestations varies from patient 
to patient. In our experience at the NIH with 32 patients, bone involvement, diabetes 
insipidus, retroperitoneal fibrosis and CNS disease are among the most common 
manifestations. Age at diagnosis ranges between 19 and 68 years. The average age of 
disease onset or first signs and symptoms is in the early thirties.  
Diagnostic criteria for ECD have not been established, but the association of the 
pathological findings with elevated CRP, retroperitoneal fibrosis, pituitary stalk 
involvement and T-99m bone scan showing increased radiotracer uptake in the long bones 
are highly suggestive of ECD18. Pathology along with a positive bone scan can establish 
the diagnosis. 
There is no standard treatment for ECD. Since the exact etiology is not known, there are 
no approved drugs for this condition. Patients have been treated empirically with interferon 
alpha (3-9 million units; 135mcgr pegylated form) weekly or high dose (>18 million units; 
>180mcgr pegylated form), anakinra (100mg SC daily), imatinib (400mg daily), steroids, 
and chemotherapy such as cladribine given in 6 cycles. Less frequently used drugs include 
rapamycin, tocilizumab and infliximab. No clinical trials have been performed to assess 
the safety and efficacy of these medications; their use is anecdotal, patient therapy is  
modified on an individual basis, and the results are not promising. Patients with CNS 
disease are the group with the worst morbidity and mortality.  
ECD Treatments 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 9 of 77 
Interferon alfa: Hervier et al23. studied the efficacy of high dose (>18 million units or 
>185mcgr PEG) vs standard dose (9 million units or 135mcgr PEG) interferon alpha in 24 
patients with ECD and stability or improvement was seen in 67% of patients. The severity 
of the disease was key in patient response to interferon therapy; CNS and heart disease are 
the most difficult to treat and require high-dose interferon. Remission was partial and 
recovery was never seen. Prolonged treatment is suggested, up to several years. Treatment 
may not be tolerated by all patients due to side effects. 
 
Table 1. Results of Interferon Alpha Treatment for ECD  
Interferon 
regimen 
Stability 
Improvement 
Worsening 
No data 
Low dose : 
9M units or 
135mcgr PEG 
6/24 
1/24 
5/24 
12/24 
High dose: >18M 
units or >185mcgr 
PEG 
7/24 
11/24 
6/24 
0/24 
 
Imatinib: Janku et al28 reported the use of imatinib in 3 patients with histiocytosis. 
Response was seen within weeks of therapy, but the mechanism of action that elicited this 
response was not determined. The response might be explained by the inhibition of platelet 
derived growth factor receptor beta (PDGFB), which can be expressed in LCH and ECD 
histiocytoses and that inhibits the differentiation of CD34 positive cells to dendritic cells. 
Patients either had disease stability or progression after months of therapy. Recovery was 
not seen and prolonged treatment is recommended. 
Anakinra: Aouba et al3. promoted the use of anakinra as salvage therapy in ECD. They 
treated 3 patients with ECD localized mainly to bone and the retroperitoneal space; 
resolution of symptoms was seen in all patients as well as decrease of the retroperitoneal 
fibrosis in two patients. The anakinra dosage was 100mg subcutaneous once a week and 
treatment was prolonged. Anakinra has not been used in severe ECD affecting organs such 
as lungs, heart, cerebellum, brain and pituitary. No specific duration of treatment was 
recommended. 
Tran et al.42 treated a 10 year old girl diagnosed with ECD after presenting with elevated 
CRP and ESR as well as bone pain and failure to thrive. Imaging showed bone marrow and 
retroperitoneal involvement. The patient was initially treated with IFN 2a 3M units 3 times 
a week; this resulted in improvement after 4 months. After 10 months of treatment, the 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 10 of 77 
patient presented with fever, bone pain and increased ESR and CRP. Treatment with IFN 
was stopped and vinblastine and prednisone were given instead. This therapy showed no 
efficacy and PEG IFN 2a was started with good efficacy, but relapse was reported 12 
months later. Anakinra was then started at 2mg/kg/day and within one week, fever and 
bone pain resolved. ESR and CRP were normal after one month. After 7 months of therapy, 
the patient remained stable, but bone marrow and retroperitoneal disease was unchanged.  
Anakinra also lacks efficacy in treating CNS disease.  
Cladribine: Adam et al.1,2 reported the use of cladribine as a highly effective medication 
in patients with extensive disease including the CNS. Cladribine has very good tolerance 
as monotherapy, and is an effective drug for diseases of the juvenile xanthogranuloma 
group (ECD, diffuse juvenile xanthogranuloma and Rosai-Dorfman disease). In total, 7 
publications describe a therapeutic response to cladribine in ECD, disseminated juvenile 
xanthogranuloma and a localized form of plane xanthoma type. Some patients experienced 
a total response; there was remission in most of the cases. In one case follow up was for16 
months. 
In our experience at the NIH CC, we have seen 4 patients treated with cladribine. One had 
no response and is currently stable with imatinib. The other 3 patients had response with 
no progression of disease and recovery demonstrated by improvement of quality of life and 
energy. ECD lesions decreased in size, but there remains evidence of disease on imaging. 
Other treatments include anecdotal use of steroids, rapamycin, tocilizumab and infliximab, 
but data are lacking. Currently rapamycin, tocilizumab and infliximab are being studied in 
Italy. 
In this protocol, we propose to clinically evaluate ECD patients with BRAFV600E and 
assess the efficacy of treatment with the BRAF/MEK inhibitors dabrafenib and trametinib 
as combination therapy. Screening for possible contraindications will be performed prior 
to the administration of the first dose. 
Even though all these treatments have been used and results can be promising in a number 
of cases, the authors and treating physicians recommend that larger series and formal 
clinical trials be developed to assess the true efficacy of these or other therapies. Although 
treatment duration has not been determined, patients continue to be treated for years with 
medications such as interferon, anakinra and imatinib. 
Recently, the BRAFV600E mutation was identified in 50% of ECD patients (N=24) in 
France, and cases are being reported in the U.S. Three ECD patients treated with 
vemurafenib showed disease regression. Specifically, Haroche et al18  treated 3 ECD 
patients with BRAF V600E positive lesions with 1920mg of vemurafenib twice daily. The 
dose had to be decreased to 960mg twice daily in all patients due to cutaneous lesions. All 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 11 of 77 
patients had improvement within weeks, as demonstrated by a decrease in CRP, CT and 
FDG PET scan evidence of decrease in size of lesions, and decreased FDG uptake on PET 
Scans. This was a small series, but other patients are being seen and followed in the U.S. 
and Europe; see summary below. 
 
Table 2. Results of Vemurafenib Treatment in 3 ECD Patients20  
Patient 
Initial Treatment 
Vemurafenib* 
Patient 1 
65 year old male with ECD affecting 
bones and retroperitoneal space 
causing 
hydronephrosis. 
Thick 
pericardium and elevated CRP and 
LFTs. 
 
6/2011- 135mcgr PEG IFN for 4 
weeks than increased to 180mcgr. 
Chemistry and imaging studies were 
unchanged 
or 
worsened. 
Dose 
adjusted to 180mcgr-270mcg alt 
days. Treatment stopped on 3/2012 
due 
to 
inadequate 
response, 
depression and side effects. 
4/2012 – Vemurafenib started. CRP, 
GGT, PET scan, CT and skin lesions 
showed improvement by day 30. 
Patient 2 
59 year old female with ECD 
affecting skin, pituitary, retroorbital 
space, heart, retrosternal space and 
bones. 
3/2011 – 135 mcgr PEG IFN started 
with partial response, eye pain and 
heart 
disease 
remained. 
Dose 
increased to 180mcgr on 6/2011. 
Stopped on 3/2012 due to depression, 
fatigue, neutropenia, and inefficacy 
in retroorbital disease. 
4/2012 
– 
Vemurafenib 
started. 
Symptoms disappeared and CRP 
improved by day 30. Repeat skin 
biopsy showed no histiocytes; PET 
scan and CT improved.   
Patient 3 
31 year old female with ECD 
affecting skin, heart, retroperitoneal 
space, bones and pituitary.  
 
4/2010 – 135mcgr PEG started. On 
2/2012 
deterioration 
seen 
with 
increased pain and xanthelasma. 
3/2012 IFN dose increased to 
180mcgr with no effect.  
5/2012 – 30 days later improvement 
seen with decrease in CRP and skin 
lesions. PET scan showed decreased 
uptake and heart disease improved. 
* All patient were initially treated with 1920mg/d BID, dose was tapered to 960mg/d in all patients due to skin side effects. Follow up time was short and current 
status is unknown for us. 
In the U.S., at least 4 other patients are being studied under a therapeutic trial for BRAF 
V600-mutated cancers, but results are not yet available and the patients are being compared 
with patients having other active malignancies. To our knowledge, a total of 6 ECD patients 
have been treated with vemurafenib, and two of them withdrew from the trial due to side 
effects. 
Toxicities related to BRAF inhibitor therapy require coordinated multidisciplinary 
management. In clinical trials of vemurafenib, the most common side effects reported were 
arthralgias, rash, fatigue, nausea, and alopecia. Additionally, cutaneous squamous cell 
carcinomas (SCCs) or keratoacanthomas have been reported in approximately 20% of 
patients treated with vemurafenib. Dabrafenib has been associated with hyperkeratosis, 
cutaneous SCCs, keratoacanthomas, and pyrexia15,21,40. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 12 of 77 
Based on the melanoma and other malignancy experience, the majority of patients with a 
BRAF mutation should benefit from BRAF inhibitor therapy. However, approximately 
10% of cancer patients with a BRAFV600E mutation have tumor progression early in the 
course of therapy. Furthermore, despite seeing an initial clinical response, the vast majority 
of patients have residual tumor following maximal response and most ultimately relapse in 
less than a year. In melanoma patients, resistance to vemurafenib has developed after 6 
months of treatment in some individuals. This can also be seen with dabrafenib if used 
alone. 
Gaining further insight is critical to the development of rational strategies to effectively 
overcome this resistance.  Reactivation of MAPK , downstream of BRAF, was proposed 
as a primary mechanism of resistance, but alternative pathways also play a critical role. In 
contrast to oncogene targeted therapies that have been used with success in other 
malignancies, resistance to BRAF inhibition does not appear to be due to the accumulation 
of mutations in BRAF itself, with decreased drug binding37. Rather, a number of preclinical 
studies have shown that persistent activation of the MAPK pathway through oncogenic 
NRAS may be one mechanism of acquired resistance. This would result in sustained 
hyperactivation of MEK and ERK.  
To prevent resistance to BRAF inhibitors, the MEK inhibitor trametinib will be used in 
combination as a downstream inhibitor for superior therapy and prevention of resistance. 
The use of this therapy should inhibit histiocytic proliferation and fibrosis, decrease the 
degree of inflammation, reduce lesion size, improve the level of activity and physical 
functioning of the patients, and increase their energy level. Dabrafenib at 150mg BID with 
trametinib at 2mg once daily was the original dose regimen for this trial, but due to the 
high frequency of pyrexia the dose of dabrafenib was changed to 100mg BID for patients 
enrolled after amendment #6 of 12/27/2015; trametinib 2mg once a day remains at the same 
dosage as for the original regimen.  
The episodes of pyrexia were frequent among the currently enrolled patients, with patients 
having more than 5 episodes of pyrexia regardless of optimal steroid use and interruption 
of therapy. After the dose of dabrafenib was modified to 100mg twice daily or 75mg twice 
daily, the episodes of pyrexia decreased or did not recur; this is the reason why the initial 
dose of dabrafenib was modified. 
3.2 Rationale:   
BRAF, also referred to as proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene 
homolog B1, is a protein kinase within the RAS-RAF signaling pathway. This pathway 
regulates the expression of genes that control many cellular functions such as cell 
proliferation, cell survival, cell differentiation and apoptosis. Mutations in the BRAF gene 
result in activation of the BRAF protein. More than 30 mutations of the BRAF gene have 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 13 of 77 
been associated with human cancers, including papillary thyroid cancer, melanoma, colon 
and ovarian cancer. BRAF mutations are also associated with other genetic disorders such 
as Noonan syndrome, Leopard syndrome and cardiofasciocutaneous syndrome, but these 
are inherited disorders, not due to a somatic mutation as for ECD. Mutated BRAF may 
promote overactive signaling and cell proliferation. Hence, dabrafenib, which selectively 
binds to the BRAFV600E mutated gene producing protein inactivation, and trametinib, a 
MEK inhibitor, combine to achieve downstream inhibition of the pathway, potentially 
leading to apoptosis of the mutant cells. 
 
 
Despite many and varied attempts with known therapies, patients with ECD succumb to 
the disease within a few years of diagnosis. Several specific complications are associated 
with patient deterioration and death. Cord compression causing paralysis increases the risk 
of infection and sepsis due to the bedridden condition of patients. Renal failure causes toxic 
shock, and pulmonary fibrosis causes respiratory failure and right heart failure. For this 
reason, combination therapy with dabrafenib and trametinib should be studied in the subset 
of ECD patients that can potentially benefit based upon their molecular pathology status. 
4.0 
Description of study design  
This will be a phase II trial with no randomization. For complete description of the study 
design and statistical considerations, please see sections 5.6.1 and 9 which discuss the 
description of study statistical considerations and/or analytic plan. 
RAS-GTP
(activated RAS)
BRAF V600
MEK
ERK
Normal Cell Proliferation 
and Survival.
RAS-RAF 
Pathway: 
normal 
activation 
of 
RAS 
via 
extracellular factors. 
Dabrafenib selectively binds to 
mutated BRAF V600 decreasing 
cell proliferation and survival.  
Trametinib inhibits downstream 
MEK 
decreasing 
cell 
proliferation and survival. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 14 of 77 
5.0 
Description of procedures:  
5.1 Diagnostic tests and procedures 
Certain laboratory and imaging studies will have been performed as part of the natural 
history protocol for ECD. However, the studies described in this Section will be performed 
specifically for this treatment protocol. Baseline evaluations are to be conducted within 1 
week prior to start of protocol therapy.  Scans and x-rays must be done <4 weeks prior to 
the start of therapy.  In the event that the patient’s condition is deteriorating, laboratory 
evaluations should be repeated within 48 hours prior to initiation of the next cycle of 
therapy. See study calendar below.  
Table 4.  Study Calendar 
 
Pre- 
Study 
Wk 
1 
Wk 
4 
Wk 
8 
Wk 
16 
Wk 
24 
Wk 
32 
Wk 
40 
Wk 
48 
Off 
Therapy 
Wk 60 
Off 
Therapy 
Wk 72 
Off 
Therapy 
Wk 96 
Dabrafenib mesylate 
(GSK2118436B)  
(NSC 763760) 
 
 
 
A 
 
 
A 
A 
A 
A 
A 
A 
 
A 
 
 
C 
 
 
C 
 
 
C 
Trametinib dimethyl 
sulfoxide 
(GSK1120212B) (NSC 
763093) 
 
B 
B 
B 
B 
B 
B 
B 
B 
 
 
D 
 
 
D 
 
 
D 
Informed consent 
X 
 
 
 
 
 
 
 
 
Reviewed 
and re-
consented 
as needed. 
 
X 
 
X 
Demographics 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concurrent meds 
X 
Througout the study and modified as needed. 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and Nutrition 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance, RPM, 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 15 of 77 
Cardiology 
X 
 
X 
X 
X 
X 
X 
X 
X 
As needed 
per clinical 
assessment 
X 
X 
Dermatology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ophthalmology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Neurology 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
24h Urinea 
X 
 
X 
X 
X 
X 
X 
X 
X 
Instead of 
24 urine 
collections, 
random 
testing will 
be 
performed 
instead. 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood hematologyc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
PBMC Cytokines 
X 
 
 
X 
 
X 
 
 
X 
 
X 
X 
EKG 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Echocardiogram 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
MUGA 
As needed 
Adverse event 
evaluation 
Throughout the study 
 
RECIST 1.1 Tumor 
Size (MRI and CT)E 
 
 
X 
 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
X 
Only target 
lesions will 
be 
monitored at 
60-72-96 
wks f/u 
minimizing 
scans and 
radiation. 
 
 
 
 
X 
 
 
 
 
X 
FDG-PET 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Bone scan 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B-HCG 
Xd 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 16 of 77 
Other tests, as 
appropriate* 
X 
 
 
X 
X 
 
 
X 
 
X 
X 
X 
Other correlative 
studies (Proteomics) 
f 
Xf 
When possible 
 
A: 
Dose as assigned; administration schedule for 48 weeks (12 cycles). Therapy will stop after 12 cycles and patient will 
be followed for 48 weeks off therapy 
B: 
Dose as assigned; administration schedule for 48 weeks (12 cycles). Therapy will stop after 12 cycles and patient will 
be followed for 48 weeks off therapy 
C-D: Off therapy, if PD is seen during follow up and prior to 96 weeks off therapy, therapy will be resumed at the dose level 
of the last cycle. Patient needs to meet all eligibility criteria once more before therapy is resumed. Duration of therapy 
will be discussed with the CTEP monitor.  
E:      During the off therapy follow up period, MRI and CT scans will performed based on the target lesions followed on each 
case. All patient will have a whole body PET-CT and bone scan performed.  
 
a: 
Volume, creatinine, protein, glucose, phosphate, BRAF V600E DNA assay 
b:     Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, creatinine, glucose, LDH, 
phosphorus, potassium, total protein, SGOT [AST], SGPT [ALT], sodium, magnesium, GGT, cholesterol, triglycerides, 
HDL, LDL, uric acid 
c: 
ESR, CPR, PT, PTT 
d:     Serum pregnancy test (women of childbearing potential); must be performed within 14 days of the first dose of study 
treatment. 
e: 
Off-study evaluation.   
f:      Proteomics will be performed on biopsies of accessible tumor tissue, when available. 
g:     Dermatology evaluations will continue for 6 months after the last dose of the study agents. 
 *       For some patients, testing will be customized based upon clinical manifestations. In those cases, certain of the following  
studies will be performed at baseline and at 2, 6 and 12 months; EMG, EEG, PFTs, NO  and other clinical indicated 
tests. 
+         After problem No. 6 (June 21, 2017), BRAF V600E quantification through blood and urine was removed from the 
study. This also applies to the Spirituality tool administered through PPC. 
 
 
5.1.1 - Laboratory tests. 
At the initial NIH Clinical Center admission for this protocol, a baseline history and 
physical examination and several laboratory tests, procedures, and consultations will be 
performed on all patients. After all screenings are completed, each patient’s information 
will be recorded and disease severity will be analyzed. Patients will remain on any 
supplements and non-ECD medications that they have been receiving, except for 
prohibited drugs, e.g., those listed in Section 4.3. After the start of therapy, admissions to 
the NIH CC will occur at 1 week, one month, 2 months, 4 months, 6 months, 8 months, 10 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 17 of 77 
months and 12 months. After the completion of 12 months of therapy, patients will be 
followed at 15 months, 18 months and 24 months in order to allow for monitoring of 
disease stability and recurrence off therapy. Patients can also be seen and evaluated at 
outpatient clinics or day hospitals during follow up visits.   
Testing will be individualized based upon clinical findings, but certain studies will be 
performed on every patient. 
Laboratory tests will include one 24-hour urine collection for determination of renal tubular 
and glomerular function.  The urine will be measured for volume and assayed for 
creatinine, protein, glucose, and phosphorus; a simultaneous serum creatinine will permit 
determination of creatinine clearance. A urinalysis will be performed.  Blood will be drawn 
for CBC and differential, platelets, erythrocyte sedimentation rate, C-reactive protein, and 
an SMA-14 panel including electrolytes, calcium, magnesium, phosphorus, liver enzymes, 
gamma glutamyltranspeptidase, alkaline phosphatase, bilirubin, creatine phosphokinase 
and uric acid and glucose. Cholesterol, triglycerides, HDL, LDL prothrombin time and 
partial thromboplastin time will also be obtained. Serum pregnancy test will be performed 
on all females at every visit prior to imaging procedures. Also, serum pregnancy test must 
be performed within 14 days of the first dose of study treatment. The amount of blood 
required for these tests will be ~30 mL. In addition, PBMC cytokine analysis requires ~40 
mL of blood. These volumes are consistent with NIH guidelines, and the blood will be 
collected in two separate draws. No more than 10.5 mL/kg or 550 mL, whichever is 
smaller, will be drawn for research purposes over any 8-week period, and no more than 5 
ml/kg will be drawn in any single day. We expect that all of our study participants will 
undergo these blood tests as part of their participation.  
If possible, biopsies of accessible tissue (e.g., bone, kidney, skin) will be obtained at 
baseline and at subsequent admissions to assess for changes in tissue proteomics associated 
with therapy. 
In addition, if blood drawing limits permit, up to 30 ml of blood may be removed for 
research purposes, such as to analyze for metabolites that may be recognized in the future 
as markers of disease. These will be attempted while patients are on therapy 
5.1.2 Procedures and Imaging.   
Certain procedures and imaging will be performed as part of the ECD natural history 
protocol. For this treatment trial, however, a specific set of studies will be performed to 
follow the lesions whose sizes serve as outcome measures. The baseline measurements 
must be performed at the initial baseline admission or within 4 weeks prior to baseline. The 
studies are: 
- 
Chest /abdomen and pelvis CT with contrast, for abdominal and lung involvement. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 18 of 77 
- 
Brain/cerebellar/orbital/pituitary MRI with gadolinium (unless EGFR is <30). 
- 
Cardiac CT with contrast and cardiac MRI. These imaging studies will be performed 
through NHLBI protocols 12-H-0141 (“Prospective Evaluation of New Techniques in 
Radiation Reduction for Cardiovascular Computed Tomographic Angiography”) for 
cardiac CT and 02-H-0050 (“Technical Development of Cardiovascular Magnetic 
Resonance Imaging”) for cardiac MRI. 
- 
Echocardiogram and electrocardiogram will be performed on every visit except the 
one week follow up. 
These outcome measures will be assessed using RECIST criteria at every scheduled 
admission except the 1 week visit. 
In addition, the following studies will be performed on all patients, but will serve as 
exploratory outcome measures, since RECIST criteria are not adequate: 
Performed at baseline, 1, 2, 4, 6, 8, 10 and 12 months: 
- 
Pulmonary function tests, echocardiogram, and electrocardiogram to evaluate 
cardiopulmonary function   
 
Performed at baseline, 2, 4, 6, 8, 10 and 12 months: 
- 
Whole body technetium 99-MDP bone scan to assess bone involvement. 
- 
Whole body 18-FDG PET scan including brain to evaluate for visceral involvement. 
 
Studies performed at 15, 18 and 24 months (off therapy) follow up visits will include:  
- 
Chest, cardiac, abdomen or pelvic CT with contrast depending on the location of the 
target lesion followed on each case. 
- 
Brain, cerebellar, pituitary or orbital MRI with gadolinium depending on the location 
of the target lesion followed on each case. 
- 
Whole body technetium 99-MDP bone scan to assess bone involvement and whole 
body 18-FDG PET scan including brain to evaluate for visceral involvement. These 2 
modalities will help in determining disease recurrence according to the degree of 
uptake of the T-99MDP and FDG. 
- 
Pulmonary function tests, 6 minute walk, echocardiogram, and electrocardiogram to 
evaluate cardiopulmonary function   
 
Consultations for all patients in this treatment trial will include an ophthalmology 
examination to evaluate orbital and optic nerve involvement as well as possible side effects 
of the trial therapy. All patients will be evaluated by neurology and dermatology, to assess 
the extent of disease and to evaluate response and side effects during therapy. All patients 
will also see the Rehabilitation Medicine service for a 2-hour assessment, with evaluations 
by physical therapy, occupational therapy and, if indicated, speech and language pathology. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 19 of 77 
Rehabilitation Medicine will complete the MD Anderson Symptom Inventory Core Items 
form. For an additional assessment of function, patients will be evaluated using the multi-
dimensional fatigue inventory, 6-minute walk test, Craig hospital inventory of 
environmental factors, human activity profile, NINDS-Neuro-QOL scale, activity card 
sort, comparative pain scale, single leg stance, functional reach and grip strength using a 
dynamometer, and the group peg board test for fine motor dexterity. Quality of Life 
measures will include the Activity Card Sort and an NINDS measure.  
Clinical evaluations will also be performed during the off therapy follow up period. 
Please refer to section 4.1 Table 4: Study Calendar, for further details on these 
evaluations during the off therapy follow up period.  
5.1.3          Correlative Studies Background. 
The mechanisms by which BRAF mutations result in ECD remains unknown, but might 
involve intracellular signaling pathways (e.g., MEK) or unregulated inflammation. 
Proteomic studies of histiocytic ECD tissues, with emphasis on intracellular signaling 
proteins, can address the first possibility; accessible tissue (e.g., bone, kidney, skin) will be 
obtained at baseline when possible and also at subsequent follow-up admissions, when 
possible and while patients are on therapy. PBMC cytokine analysis, along with ESR and 
CRP measurements, can address the second possible mechanism. These studies will be 
performed at baseline and at the 2, 6, 12, 18 and 24 month return admissions or outpatient 
visits; these studies are further described in Section 5.1.6 
5.1.4       Biomarker, Correlative, and Special Studies. 
5.1.4.1      Biomarker Studies 
Biomarker: Tissue BRAF Mutation Analysis (INTEGRAL) 
Erdheim Chester disease has been associated with BRAF V600E mutation in at least 50% 
of patients affected by this condition. Current therapy is empirical and even though clinical 
stability is achieved in many cases, progression occurs and patients do not develop 
significant recovery. The association with the BRAF defect opens new doors for targeted 
treatment. The use of BRAF inhibitors has been reported in a small series (3 cases). 
Vemurafenib was the BRAF inhibitor used and patients experienced clinical improvement 
within 30 days of treatment. Continued follow up of these patients has not been reported, 
but the treating physicians emphasized the need for formal clinical trials to assess the 
efficacy of BRAF inhibitors. They also made note of the possibility of resistance to BRAF 
inhibitors as seen in other conditions such as melanoma, prompting consideration of 
combination therapy.  Molecular profiling of patients with ECD should be part of their 
diagnostic testing since targeted therapy is available for molecular findings associated with 
the BRAF gene.  Impairment of the RAS pathway through the inhibition of BRAF and 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 20 of 77 
MEK with the use of dabrafenib and trametinib should stop disease progression, reduce the 
size of ECD lesions, improve organ and system functions, decrease inflammation and 
fatigue, improve physical functions, and increase survival. 
The BRAF gene will be sequenced for all patients enrolled in NHGRI clinical protocol 11-
HG-0207, which performs clinical and basic investigations into Erdheim Chester disease. 
Subjects in whom the BRAF V600E mutation (gain of function mutation) is detected will 
be eligible for enrollment in this therapeutic trial; dabrafenib and trametinib will be used 
as BRAF pathway inhibitors. The BRAF V600E mutation will serve as an integral marker 
for inclusion criteria and treatment assignment.  
Enrollees of the NHGRI study 11-HG-0207 will have BRAF testing performed in either of 
two CLIA-certified molecular pathology laboratories. 
• Molecular pathology laboratory at NIH Clinical Center in Bethesda, MD under the 
supervision of Dr. Mark Raffeld. 
o MOLECULAR PATHOLOGY LABORATORY AT NIHCC 
CLIA: 21D0716664 
EXPIRATION: 7/16/2016 
 
• Molecular pathology laboratory at Quest Diagnostics Nichols Institute in Chantilly, VA 
under the supervision of Dr Albert Ho MD PhD. 
o QUEST DIAGNOSTICS CHANTILLY, VA. 
CLIA: 49D0221801 
EXPIRATION: 2/8/2017 
 
BRAF V600E mutation testing performed on patients locally will be repeated for 
verification in one of the above laboratories.  
Description of assays:   
• MOLECULAR PATHOLOGY AT NIH Clinical Center: 
BRAF mutation analysis is performed through DNA extracted from paraffin-embedded 
tissue and sections prepared using the Qiagen QIAamp DNA FFPE Tissue Kit. The surgical 
pathology diagnosis is required prior to testing. The percentage of atypical cells is preferred 
to be >15%, a lower recommended limit for mutation detection.  
In the first assay, the DNA is then subjected to COLD-PCR using a single primer set one 
encompassing codons 599-601 of the BRAF gene. The product is then subjected to 
pyrosequencing using a Qiagen PyroMark Q24 system. The BRAF mutation assay as 
implemented and validated in this laboratory has an analytic sensitivity of about 3% tumor 
cells (1.5% of alleles). However, given the variability of estimating the percentage of tumor 
cells in tissue, there is potential for false negative results in tissues that contain less than 
10% tumor cells. Only the V600E and V600K mutations are detected with this assay. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 21 of 77 
The second assay is a sensitive allele specific assay that only detects V600E, (T>A). This 
assay has a sensitivity reaching 0.2% tumor cells or better.  The lab has never had a false 
negative with this assay as defined by a case detected by pyrosequencing and missed by 
the allele specific PCR.   However, there is no good way to measure false negatives when 
the tumor percentage falls below detection by the other methods.   
• QUEST DIAGNOSTICS: 
Quest’s molecular oncology tests for the detection of BRAF mutations include:  
- BRAF mutation analysis by DNA-based PCR – sequencing to detect somatic mutations 
on exon 11, 12, and 15 of BRAF 
-  BRAF mutation analysis using ultra-sensitive ASO (allele specific oligonucleotide) PCR 
methodology.    
The assay is performed on FFPE blocks, or H & E with 6-8 unstained slides in 5 micron 
sections with >10-15% of tumor cells. If no mutations are present as described in the 16767 
BRAF molecular reports by mutation type and/by the words “non-detected”, the assay will 
automatically be reflexed to determine if the V600E gene is present by an ultra-sensitive 
ASO (allele specific oligonucleotide) PCR methodology. The interpretation will expand to 
include the following detail about the V600E gene: “This provides both optimal sensitivity 
for codon 600 mutations (V600E) and broader mutation detection of other activating BRAF 
mutations seen in melanoma as well as report information specific to the DNA based PCR 
sequences.”  
The sensitivity of BRAF AS-PCR is 0.1% V600E mutation bearing cells.  It does not detect 
other mutations. The sensitivity of Sanger sequencing is 15-20% tumor cells in a 
background of non-neoplastic cells.  It can detect other BRAF mutations. 
5.1.5 -Pharmacokinetics Studies  
N/A 
5.1.6 - Laboratory Correlative Studies 
Three biological studies will be performed for drug effects. First, PBMC cytokines will be 
assessed at baseline, 2 months, 6 months, 12 months after initiation of treatment and 18 
and 24 months during the off therapy follow up period. These cytokines will include both 
pro- and anti-inflammatory molecules, i.e., IL-1, IL-2, IL-1ra, IL-6, IL-8, IL-9, IL-10, IL-
13, IL-17, GM-CSF, IFN, IP-10, TNF, and they will be analyzed in the NIAMS laboratory 
of Dr. Massimo Gadina. We also plan to obtain plasma cytokine array data. 
Second, tissue proteomics will be performed by the Proteomics Core Laboratory of MD 
Anderson. The proteomics platform interrogates a broad array of proteins, but our 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 22 of 77 
investigations will specifically target components of the BRAF-MEK signaling pathway. 
These include BRAF, NRAS, KRAS (if available), MAPK, MEK, PI3K, mTOR, and ERK, 
AKT, and JAK2 if available. Tissue will not be available from every patient, but we will 
attempt to obtain biopsies of accessible tissue (e.g., bone, kidney, skin) at baseline for 
future comparisons. Post-treatment tissue will be obtained on return visits when biopsies 
are medically indicated or readily available. 
5.1.7- Special Studies 
We will obtain special stains for histological markers on histiocytic biopsy material, if 
funding permits. 
5.2  Medical information  
Medical summaries and laboratory test results will be collected and the information stored 
in a locked file cabinet and treated as confidential clinical data.  Besides this, participant’s 
information will be stored in a database under password such as Lab Matrix. Only the 
principal investigator, associated investigators and laboratory staff working with research 
samples will have access to this database.    
5.3            Diagnostic studies  
 
Diagnostic studies will be performed as stated in section 5.1. 
         5.4             Biological Specimens  
 
Biological specimens will be addressed as stated in section 5.1. 
5.5            Approved Drugs Being Used for Research  
NCI Supplied Agent(s):  Dabrafenib mesylate (GSK2118436B) (NSC 763760) and 
Trametinib dimethyl sulfoxide (GSK1120212B, MEKINIST™) (NSC 763093) have been 
approved for the treatment of unresectable and metastatic melanoma. 
 
 
5.6      
  Unapproved Drugs/Devices  
NCI Supplied Agent(s):  Dabrafenib mesylate (GSK2118436B) (NSC 763760) and 
Trametinib dimethyl sulfoxide (GSK1120212B, MEKINIST™) (NSC 763093)   
IND #:  119346 
IND Sponsor:  DCTD, NCI  


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 23 of 77 
 
5.6.1- CTEP IND Agent(s) 
5.6.1.1- Dabrafenib Mesylate (GSK2118436B)24 
The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human 
cancers.  This pathway can be constitutively activated by molecular alterations including 
BRAF activating mutations.  Approximately 90% of all identified BRAF mutations in 
human cancer consist of a T1799 transversion mutation in exon 15, which results in a V600 
E/D/K (T1799A) amino acid substitution.  This mutation appears to mimic regulatory 
phosphorylation and increases BRAF activity approximately 10-fold compared to wild 
type (wt).  RAF is a validated target in BRAF V600E-containing melanoma.  In August 2011, 
the FDA approved vemurafenib (PLX4032, Zelboraf®), an ATP-competitive selective 
RAF inhibitor for the treatment of late-stage BRAFV600E melanoma.  In the pivotal phase 
III trial of vemurafenib vs. dacabazine (Chapman et al., 2011), vemurafenib demonstrated 
significant improvement in overall survival (OS) (6-month OS of 84% vs. 64%, hazard 
ratio [HR]=0.37; P<0.001), progression-free survival (PFS) (estimated median PFS of 5.3 
months vs. 1.6 months (HR=0.26; P<0.001]), and overall response rate (ORR) (48% vs. 
5%).  However, in patients with colorectal cancer (CRC) bearing the BRAF V600E 
mutation, there was only one partial response (PR) among 20 patients treated (ORR 5%) 
and four minor responses (Kopetz et al., 2010). 
Dabrafenib mesylate (GSK2118436B, Tafinlar®; referred to as dabrafenib hereafter), a 4-
(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is an ATP-competitive, selective 
inhibitor of RAF kinase currently in clinical development.  On May 29, 2013, the U.S. 
FDA approved dabrafenib for the treatment of patients with unresectable or metastatic 
melanoma with BRAFV600E mutation as detected by an FDA-approved test (FDA, 2013).  
On January 10, 2014, the FDA granted accelerated approval to dabrafenib and MEK 
inhibitor trametinib for use in combination to treat patients with unresectable or metastatic 
melanoma with either BRAFV600E or BRAFV600K mutation as detected by an FDA-approved 
test (FDA, 2014). 
 
5.6.1.1.1- Mechanisms of Action and Preclinical Data with Dabrafenib 
Dabrafenib potently inhibits all RAF isoforms, with the strongest potency against the V600 
mutant, as compared to its activity against wt BRAF and CRAF (see below).  In a panel of 
more than 270 kinases tested outside RAF isoforms, only 10 kinases were inhibited at a 
50% inhibitory concentration (IC50) <100 nM:  LIM domain kinase 1 (LIMK1), activin 
receptor-like kinase 5 (ALK5)/ transforming growth factor (TGF)-beta receptor type-1 
(TGFβ1R), Never In Mitosis Gene A (NIMA)-related kinase 11 (NEK11), salt-inducible 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 24 of 77 
kinase 1 (SIK1), salt-inducible kinase 2 (SIK2), polycystin-2 (PKD2), protein tyrosine 
kinase 6/breast tumor kinase (BRK), pancreatic eukaryotic initiation factor-2 alpha (eIF2α) 
kinase (PEK)/eIF2α kinase (PERK), endothelium-specific receptor tyrosine kinase 2 
(TIE2) (R849W), and yeast casein kinase 1 (CK1) (IB, 2013a). 
 
Table 5. Inhibitory Activity of Dabrafenib on BRAF 
 
BRAFV600E BRAFV600K BRAFV600D wt BRAF CRAF 
IC50 
0.65 nM 
0.50 nM 
1.84 nM 
3.2 nM 
5.0 nM 
 
In a panel of >110 human tumor cell lines with confirmed BRAF mutational status, 
dabrafenib potently inhibited proliferation of a majority (73%) of BRAFV600E mutant cell 
lines with growth IC50 (gIC50) <100 nM (IB, 2013a).  In contrast, there was poor or no 
activity in other BRAF mutants or wt BRAF cell lines. 
Dabrafenib given orally (PO) for 14 days at doses ranging from 0.1-300 mg/kg 
administered once daily (QD), twice daily (BID), or three times daily (TID) inhibited tumor 
growth in mice bearing BRAFV600E A375P F11s or Colo205 tumor xenografts.  The effect 
was generally dose dependent up to 10 mg/kg/day (A375P F11s) or 30 mg/kg/day 
(Colo205), yielding 90-120% tumor reduction relative to untreated animals.  However, 
cessation of treatment was associated with regrowth of the tumors.  In A375P F11s 
melanoma xenografts, inhibition of pERK by >50% in the tumor was seen at doses of ≥3 
mg/kg.  Based on the single-dose studies, ~100 nM (52 ng/mL) dabrafenib in blood at 6 h 
post-dosing was needed for effective pharmacodynamic biomarker inhibition in the tumor.  
At repeated dosing of 30 mg/kg/day, the tumor pERK levels were reduced by >50% at 8 h 
after dosing (69% on Day 1 and 53% on Day 14).  Levels of pERK returned to baseline 24 
h post-dosing.  Similar ↓pERK effects were seen in the ES-2 ovarian xenograft model, but 
pERK inhibition was weaker in the Colo205 xenograft model.  Of note, concentrations of 
dabrafenib showing pharmacodynamic activity in xenografts did not cause a reduction in 
pERK/tERK levels in the normal intact brain.  
 
5.6.1.1.2- Clinical Pharmacokinetics (PK) and Activity of Dabrafenib 
Following single-dose oral administration of dabrafenib HPMC capsules, plasma 
concentrations peaked approximately 2.0 hours post-dose.  Oral bioavailability is near 
complete (94.5%) relative to an intravenous (IV) microdose.   
Dabrafenib is highly bound to plasma proteins (99.6%).  Its volume of distribution after IV 
dosing is 45.5 L.  Intravenous plasma clearance (12.0 L/hr) is low relative to liver blood 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 25 of 77 
flow, suggesting a low hepatic extraction ratio drug.  Median terminal half-life is 
approximately 8 hours after a single oral dose.  
Three metabolites of dabrafenib were characterized and may contribute to activity.  
GSK2285403 (hydroxy-metabolite [M7]) PK paralleled that of dabrafenib, while the 
carboxy- (GSK2298683 [M4]) and desmethyl- (GSK2167542 [M8]) metabolites exhibited 
a longer t1/2 (21-22 hours) and accumulated following repeat dosing.  M7 is the most 
abundant, accounting for 54% of the three metabolites.  Similar to dabrafenib 
concentrations, exposure for all metabolites showed a less than dose proportional increase 
with repeat dosing. 
Fecal excretion was a major route of dabrafenib elimination in humans, accounting for 
71.1% of the dose administered, and renal excretion accounted for about 23% of drug 
elimination, recovered as metabolites only. 
Administration of dabrafenib with a high-fat, high-calorie meal reduced the oral 
bioavailability of dabrafenib when compared to the fasted state with a decrease in Cmax and 
AUC of 51% and 31%, respectively, and delayed its absorption.  Therefore, the current 
recommendation is to administer dabrafenib under fasting conditions, either 1 h before or 
2 h after a meal. 
Drug-drug interactions for dabrafenib: 
Dabrafenib induces CYP3A4 and CYP2C9.  Dabrafenib decreased the systemic exposures 
of midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a 
CYP3A4/CYP1A2 substrate).  Co-administration of dabrafenib 150 mg twice daily for 15 
days and a single dose of midazolam 3 mg (a CYP3A4 substrate) decreased midazolam 
AUC by 74%. Co-administration of dabrafenib 150 mg twice daily for 15 days and a single 
dose of warfarin 15 mg decreased the AUC of S-warfarin (a CYP2C9 substrate) by 37% 
and the AUC of R-warfarin (a CYP3A4/CYP1A2 substrate) by 33%.  
In vitro studies show that dabrafenib is a substrate of CYP3A4 and CYP2C8 while 
hydroxy-dabrafenib and desmethyl-dabrafenib are CYP3A4 substrates. Co-administration 
of dabrafenib 75 mg twice daily and ketoconazole 400 mg once daily (a strong CYP3A4 
inhibitor) for 4 days increased dabrafenib AUC by 71%, hydroxy-dabrafenib AUC by 82%, 
and desmethyl-dabrafenib AUC by 68%. Co-administration of dabrafenib 75 mg twice 
daily and gemfibrozil 600 mg twice daily (a strong CYP2C8 inhibitor) for 4 days increased 
dabrafenib AUC by 47%, with no change in the AUC of dabrafenib metabolites. 
Dabrafenib is a substrate of human P-glycoprotein (P-gp) and breast cancer resistance 
protein (BCRP) in vitro.   
Pharmacodynamic effect of dabrafenib: 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 26 of 77 
Median tumor pERK inhibition was 83.9% (range:  38.0 to 93.3%) in BRAF mutant 
melanoma subjects receiving doses of 70 to 200 mg BID.  The relationship between 
exposure and % pERK inhibition was characterized using a maximum response (Emax) 
model with 100% maximum inhibition and IC50 of 134 ng/mL (95% CI:  92.7, 155) based 
on the sum of the potency-adjusted parent and active metabolite concentrations.  A dose-
related decrease in pERK was predicted with total daily doses <200 mg (100 mg BID) 
dabrafenib, with a plateau occurring beyond total daily doses of 200 mg thereafter. 
Selection of the RP2D for dabrafenib monotherapy: 
The single-agent MTD for dabrafenib was not reached.  A dose of 150 mg BID was selected 
for further single-agent development, based on the following PK/pharmacodynamics, 
safety, and activity:  a) dose increases beyond 150 mg BID yielded no increase in Cmax and 
<50% increase in AUC; b) incidence and severity of AEs was similar at 100-300 mg BID; 
c) pERK target suppression was >80%; and d) the tumor response rate (RR) was 50% at 
150 mg BID. 
Antitumor Activity of Dabrafenib Monotherapy  
Activity in patients with BRAF V600E or V600K melanoma in The FTIH monotherapy 
study (BRF112680).  The study enrolled 114 patients with BRAF V600 mutant melanoma 
in the dose escalation phase (Part 1), and 70 patients at the RP2D (150 mg BID) in Part 2.  
Within this study, a cohort of 10 patients with previously untreated asymptomatic brain 
metastasis was evaluated for intracranial response to dabrafenib (Long et al., 2011).  All 
patients had decreases in the size of the brain metastasis; three patients achieved complete 
radiographic resolution of brain lesions  as well as reduction in extracranial disease.  The 
response rates in patients treated at 150 mg BID are shown below. 
 
 
 
 
 
Table 6. FTIH Monotherapy Study (BRF112680) Response Rates in Melanoma 
 
 
 
 
  Patients 
 Subgroup 
Patient # 
ORR 
Part 1 
V600E 
77 
50% 
 V600K 
14 
20% 
Part 2, Cohort 
A 
V600E/K with brain 
mets 
10 
40% 
 V600E/K without brain 
mets 
20 
55% 
 
When dabrafenib was used at 50 mg BID (Part 2, Cohort C) in patients with BRAF V600E 
mutant melanoma, the response rate was only 17%. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 27 of 77 
Correlative studies in the phase 1 monotherapy trial: 
Preliminary genomic analysis was performed on 37 patients with melanoma, using a 
Sequenom mutation analysis for 11 genes (AKT, BRAF, CDK4, CDKN2A, GNAQ, 
GNA11, Kit, MEK1, MEK2, and NRAS), and PTEN analysis by sequencing, comparative 
genomic hybridization (CGH), and multiplex ligation-dependent probe amplification 
(MPLA) (Nathanson et al., 2011).  Nine patients (24%) had PTEN genetic alterations 
including mutation, hemi-/homozygous deletion.  PTEN deficiency was associated with 
lower responses (ORR of 11% and 54% in patients with and without PTEN alteration, 
respectively). 
Phase III trial of dabrafenib versus chemotherapy in patients with advanced BRAFV600 
mutant melanoma (BREAK3 Trial): 
Patients with previously untreated, unresectable stage III or IV BRAFV600E-mutated 
melanoma were randomized (3:1) and stratified by stage to dabrafenib (150 mg PO BID) 
or dacarbazine (DTIC) (1000 mg/m2, IV, every 3 weeks [Q3W]).  Of 250 patients 187 
received dabrafenib and 63 received DTIC.  The hazard ratio for PFS was 0.30 (95% CI:  
0.18-0.53; P<0.0001), with median PFS of 5.1 months for dabrafenib and 2.7 for DTIC.  
OS data were immature, with 30 deaths reported.  Confirmed RR was 53% for dabrafenib 
and 19% for DTIC.  Benefits in PFS and RR were observed in all subgroups evaluated. 
Activity in BRAF V600E mutant tumors other than melanoma: 
In phase 1 trial, 18 patients had cancers other than melanoma: CRC (7), papillary thyroid 
cancer (PTC) (13), NSCLC (1) and ovarian cancer (1).  Confirmed PRs were seen in one 
patient with CRC, and in 5 patients with PTC; the patient with NSCLC had an 
unconfirmed PR at 6 weeks.  Eleven patients (6 with PTC and 5 with CRC) had stable 
disease (SD) as their best response; the ovarian cancer patient had SD for approximately 
36 weeks. 
Efficacy and safety data for dabrafenib in patients with Erdheim Chester Disease are not 
available. This will be the first therapeutic trial to address this. 
5.6.1.1.3- Dabrafenib Safety Profile 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) terms is included in appendix 
2. 
As of February 20, 2012, among 184 patients treated on the FTIH phase 1 trial, 99% 
experienced at least one adverse event (AE) (any grade).  The most common (>20% of all 
subjects) AEs of any grade across all dosing cohorts in Part 1 and Part 2 were fatigue 
(42%), pyrexia (37%), headache (35%), nausea (34%), hyperkeratosis (33%), diarrhea 
(27%), arthralgia (25%), pain in extremity (25%), decreased appetite (24%), alopecia 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 28 of 77 
(23%) and rash (23%).   
Serious AEs (SAEs) were reported in 39% of patients, including SCC (12%), pyrexia (7%), 
and urinary tract infection (3%).  Sixty-four patients are reported to have had study drug 
interrupted due to the occurrence of AEs.  Pyrexia was the AE that led most frequently to 
a dose interruption.  Fifteen patients reported a dose reduction due to the occurrence of 
AEs.  There were no instances of discontinuation of study treatment due to AEs and no 
fatal AEs reported in the study among patients who received at least one dose of dabrafenib. 
AEs of special interest: 
The following events observed in dabrafenib monotherapy studies are discussed in detail 
because they may be a class effect of BRAF inhibitor compounds, have occurred at high 
frequency, and/or are potentially life-threatening. 
Dermatologic effects:  Rashes and other skin lesions, from hyperkeratosis to SCC, have 
been observed at the frequencies listed in Table 7. 
 
Table 7. Dermatologic Side Effects of Dabrafenib in FTIH Study BRF112680 
AE Term 
Any Grade 
Grade ≥3 
Hyperkeratosis 
61 (33) 
0 
Skin papilloma 
46 (25) 
1 (<1) 
Rash 
42 (23) 
1 (<1) 
Skin lesion 
26 (14) 
0 
Actinic keratosis 
21 (11) 
0 
Squamous cell carcinoma 
22 (12) 
21 (11) 
Pruritis 
22 (12) 
0 
Seborrheic keratosis 
25 (14) 
0 
Acrochordon 
19 (10) 
0 
Melanocytic nevus 
19 (10) 
0 
Rash pruritic 
11 (6) 
0 
 
Pre-malignant and malignant skin lesions:  Cutaneous SCC and keratocanthoma were 
reported in 11% and 2%, respectively, of patients treated with dabrafenib in FTIH study 
BRF112680.  SCC and proliferative skin toxicities are considered a class effect of BRAF 
inhibitors such as vemurafenib and sorafenib (Long et al., 2011).  SCC was treated with 
local excision, and treatment with dabrafenib was continued.  Most SCCs of the skin have 
been localized and generally treated with curettage, and have been without significant 
clinical sequelae.  Only one patient required a dose reduction in response to the event.  The 
median onset of the first SCC occurred on Day 67 (range:  Day 9-217). 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 29 of 77 
Other treatment-emergent malignancies:  Other treatment-emergent cutaneous 
malignancies such as basal cell carcinoma and new primary melanoma have been reported 
with BRAF inhibitors (Zelboraf, 2011). 
Pyrexia:  Across dabrafenib studies, all SAEs of pyrexia, influenza-like illness, cytokine 
release syndrome, systemic inflammatory response syndrome underwent clinical review 
for serious events of pyrexia complicated by hypotension, dehydration, circulatory 
collapse, severe rigors, or renal failure in the absence of another identifiable etiology (i.e., 
infection). 
Abnormal ejection fraction:  Left ventricular ejection fraction (LVEF) changes were not 
observed in the early safety reviews of dabrafenib.  However, these events are included in 
AEs of special interest because they are known side effects of several kinase inhibitors 
including imatinib, sunitinib, and lapatinib (Force et al., 2007). 
Cardiac valvular abnormalities:  Data from preclinical studies suggested that dabrafenib 
has the potential to cause cardiac valve abnormalities.  In a 28-day dog toxicology study, 
high doses (50 mg/kg/day; approximately 40-fold over the therapeutic dose) of dabrafenib 
in 1 dog (n=10) resulted in hypertrophy of the right atrio-ventricular valve (tricuspid valve).  
Therefore, this was monitored in clinical trials with echocardiograms. 
Uveitis:  Uveitis was reported at a frequency of 3.8% as an AE of vemurafenib in 
previously treated patients with BRAF V600 mutation-positive metastatic melanoma 
(Chapman et al., 2011; Sosman et al., 2010), and has been observed in patients receiving 
dabrafenib (incidence in study BRF112680 was 1%). 
Renal failure:  Cases of renal failure have been identified on clinical trials with a possible 
causal relationship to dabrafenib. 
 
5.6.1.2- Clinical Experience with the Combination of Dabrafenib + Trametinib25 
Data on 247 patients with metastatic melanoma and BRAFV600 mutations participating in 
the phase 1/2 study of dabrafenib and trametinib, BRF113220, have been published 
(Flaherty et al., 2012). 
PK 
Coadministration of dabrafenib 150 mg twice daily and trametinib 2 mg once daily 
resulted in no clinically relevant pharmacokinetic drug interactions.   
RP2D for the combination of trametinib and dabrafenib 
In the dose escalation portion (Part B) of study BRF113220, the MTD of the combination 
was not reached, and the RP2D was therefore 150/2 (Flaherty et al., 2012).  Pyrexia, chills, 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 30 of 77 
and nausea were the most common reasons cited for dose reductions; pyrexia, chills, and 
decreased ejection fraction were the most common reasons cited for dose interruptions.   
In the randomized, open-label, phase 2 portion (Part C) of the study, the incidence of certain 
AEs were lower with the combination as compared to single agent dabrafenib:  cutaneous 
squamous-cell carcinoma (including keratoacanthoma) (7 vs. 19%), and rash (27 vs. 36%) 
(Flaherty et al., 2012).  On the other hand, the frequencies of pyrexia appeared increased 
(39 vs. 14%).  The combination was also associated with an increased prevalence of MEK 
inhibitor-associated acneiform dermatitits (16 vs. 4%, with no grade 3 or 4 events 
reported).  There was one death from sepsis in the 150/1 combination group, and there were 
three deaths in the combination 150/2 group (two from brain hemorrhage and one from 
pulmonary embolism); none of these events were considered to be related to a study drug.  
The incidences of main AEs (all grades) observed in Part C of the trial are presented in the 
table below as patients (percent). 
 
Table 8. Adverse Events in Patients Treated with Dabrafenib Alone and in 
Combination with Trametinib 
Adverse Event 
Dabrafenib 
Monotherapy 
(n=53) 
Combination 
150/1 
(n=54) 
Combination 
150/2 
(n=55) 
Pyrexia 
14 (26) 
37 (69) 
39 (71) 
Nausea 
11 (21) 
25 (46) 
24 (44) 
Vomiting 
8 (15) 
23 (43) 
22 (40) 
Diarrhea 
15 (28) 
14 (26) 
20 (36) 
Rash 
19 (36) 
11 (20) 
15 (27) 
Hyperkeratosis 
16 (30) 
3 (6) 
5 (9) 
Cutaneous 
squamous 
cell 
carcinoma 
10 (19) 
1 (2) 
4 (7) 
Alopecia 
18 (34) 
5 (9) 
3 (5) 
Skin papilloma 
8 (15) 
4 (7) 
2 (4) 
Decreased ejection fraction 
0 
2 (4) 
5 (9) 
Cardiac failure 
0 
1 (2) 
0 
Hypertension 
2 (4) 
2 (4) 
5 (9) 
Chorioretinopathy 
0 
0 
1 (2) 
Neutropenia 
 
 
(11) 
Acneiform dermatitis 
(4) 
(11) 
(16) 
 
Activity 
Efficacy analyses were performed in the intention-to-treat population of the phase 2 portion 
(Part C) of study BRF113220, with a median follow-up of 14.1 months (Flaherty et al., 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 31 of 77 
2012).  All major efficacy endpoints were improved, including PFS, 12-month PFS, ORR, 
and duration of response.  Endpoint values as assessed by site investigators for this portion 
of the study are presented in the table below. 
Table 9. Endpoint Analysis of Patients Treated with Dabrafenib Alone and in 
Combination with Trametinib 
End Point 
Dabrafenib 
Monotherapy 
(n=54) 
Combination 
150/1 
(n=54) 
Combination 
150/2 
(n=54) 
Progression-free Survival – 
months 
Median (95% CI) 
5.8 (4.6-7.4) 
9.2 (6.4-11.0) 9.4 (8.6-16.7) 
Progression-free Survival at 
12 mo. % (95% CI) 
9 (3-20) 
26 (15-39) 
41 (27-54) 
CR or PR 
Patients (% [95% CI]) 
29 (54 [40-
67]) 
27 (50 [36-
64]) 
41 (76 [62-
86]) 
Duration of response 
Median months (95% CI) 
5.6 (4.5-7.4) 
9.5 (7.4-NA) 
10.5 (7.4-
14.9) 
 
5.6.1.3- Trametinib Dimethyl Sulfoxide (GSK1120212B, MEKINIST)25 
The RAF-MEK-ERK pathway plays a critical role in multiple cellular functions.  
Activation of the pathway can result from activating mutations of the upstream receptor 
tyrosine kinases (RTKs) and RAS, or upregulation/mutations in RAF and MEK.  Upon 
activation, RAF acts as the MAPK kinase kinase and activates MAPKK (MEK1/2), which 
in turn catalyze activation of the effectors ERK1/ERK2.  Once activated, ERK1/2 
translocate into the nucleus and phosphorylate a number of effector proteins and 
transcriptional factors that regulate cell proliferation, motility, differentiation, and survival.  
Trametinib is one of the several MEK inhibitors in clinical development.   
Experience to date indicates that MEK is a valid target.  In a phase III trial comparing 
trametinib with dacarbazine or paclitaxel in patients with BRAF V600E or V600K mutant 
metastatic melanoma, trametinib demonstrated a significantly better response rate, 
progression-free survival, and overall survival (Flaherty et al., 2012).  However, single 
agent activities are limited.  Extensive research is underway to identify patient selection 
markers and develop rational combination strategies.  Preclinical studies have provided 
strong rationale and proof of principle for combining MEK inhibitors with RTK inhibitors 
(EGFR or IGF-1R) (Gopal et al., 2010; Ebi et al., 2011), PI3K/AKT inhibitors (Engelman 
et al., 2008; Hoeflich et al., 2009), and mTOR inhibitors.  On the other hand, the optimal 
dose/schedule and patient selection criteria for combination regimens have not been 
defined.  Phase 1 results for a number of combinations have been reported, including 
AZD6244 + MK2206 (Tolcher et al., 2011) and GDC-0973 + GDC-094 (MEK+ PI3K 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 32 of 77 
inhibitor) (Bendell et al., 2011). 
 
5.6.1.3.1- Mechanisms of Action and Preclinical Data with Trametinib 
Trametinib is a dimethyl sulfoxide (DMSO) solvate compound (ratio 1:1) with potent, 
allosteric and ATP non-competitive inhibition of MEK1/2 (IC50 of 0.7 and 0.9 nM against 
MEK1 and MEK2, respectively) (Gilmartin et al., 2011).  Trametinib inhibited MEK1/2 
kinase activity and prevented RAF-dependent MEK phosphorylation (S217 for MEK1), 
producing prolonged pERK1/2 inhibition.  Trametinib showed better potency against 
unphosphorylated 
MEK1/2 
(u-MEK1/2) 
when 
compared 
with 
preactivated 
diphosphorylated MEK (pp-MEK), suggesting that u-MEK affords a higher affinity 
binding site for trametinib than does pp-MEK. 
The specificity of trametinib was confirmed against a panel of 183 kinases, including 
MEK5 (the closet kinase homolog to MEK1/2), CRAF, BRAF, ERK1, and ERK2 
(Yamaguchi et al., 2011).  Trametinib demonstrated equal potency against activated 
MEK1- and MEK2-mediated phosphorylation of ERK (sequence identity of 85% across 
the whole protein and 100% in the active site for humans).  Trametinib demonstrated 
preferential inhibition of RAF-mediated MEK1 activation (IC50 = 0.60 nM) over pMEK1 
kinase activity (IC50 = 13 nM) (Investigator’s Brochure, 2012a). 
BRAF-mutant Colo205, A375P F11s, and HT-29 human tumor xenograft mouse models 
showed the most significant mean tumor growth inhibition (TGI) (80% to 87%) at 3.0 
mg/kg trametinib, with multiple complete and partial tumor regressions.  In the Colo205 
model, tumor regression was observed even at a dose of 0.3 mg/kg (Yamaguchi et al., 
2011).  Two KRAS-mutant xenograft models, HCT-116 and A549, also showed significant 
TGI (83% and 75%) but without significant tumor regressions (Gilmartin et al., 2011).  As 
predicted by cell proliferation assays, tumor xenograft lines with wild-type (wt) RAF/RAS 
(PC3, BxPC3, and BT474) were much less sensitive, showing only modest TGI (44-46%) 
with no tumor regressions. 
Pharmacodynamic studies were performed in mice treated with trametinib for 14 days 
(Gilmartin et al., 2011).  In the A375P F11s xenograft model, the first dose of trametinib 
(3 mg/kg) significantly reduced pERK for more than 8 hours on Day 1.  pERK inhibition 
was more sustained (over 24 hours) after the Day 7 dose, probably due to an increase in 
the steady-state levels of trametinib after repeated doses.  The average Cmax in blood was 
1,410 nM on Day 7, with an estimated half-life (t1/2) of 33 hours.  In addition, 
immunohistochemistry (IHC) also confirmed inhibition of cell proliferation (reduced 
Ki67) and G1 cell cycle arrest (elevated p27Kip1/CDKN1B) following 4 days of treatment. 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 33 of 77 
5.6.1.3.2- Clinical Pharmacokinetics (PK) and Activity of Trametinib 
FTIH Phase 1 Trial of Trametinib Monotherapy (MEK111054) 
There are 3 parts in this ongoing study.  Part 1:  The dose-escalation portion involves 
administration of trametinib (repeat doses of 0.125 mg to 4.0 mg) to patients with solid 
tumors or lymphoma in one of three schedules - (1) QD for 21 days followed by 7 days 
without drug, (2) loading dose on Day 1 or Day 1-2, followed by QD with the designated 
dose, or (3) QD dosing without a drug holiday.  Part 2:  cohort expansion at the 
recommended phase 2 dose (RP2D) for pancreatic cancer, melanoma, non-small cell lung 
cancer (NSCLC), colorectal cancer (CRC), or any BRAF mutation-positive cancer.  Part 
3:  expansion to characterize the biologically active range of trametinib via analysis of 
pharmacodynamic biomarkers (biopsies or FDG-PET). 
The dose escalation part and some of the cohort expansion components have been 
completed.  The MTD of trametinib was established as 3 mg QD, but the recommended 
phase 2 dose (RP2D) was chosen at 2 mg QD based on tolerability of repeated cycles 
(Infante et al., 2010). 
PK and metabolism of trametinib: 
PK measurements were conducted under fasting conditions.  After a single dose (Day 1), 
AUC0-24 and Cmax values were dose-proportional up to 6 mg, lower than dose proportional 
following 8 mg, and greater than dose proportional following the 10 mg dose.  Median Tmax 
was 1.5 hours. 
After repeat doses (Day 15), trametinib accumulated with a mean accumulation ratio of 6.6 
at the RP2D of 2 mg QD.  Between-subject variability in exposure ranged from 27-50% 
for Cmax and 20-41% for AUC0-24 across all dosing regimens.  The effective t1/2 was 
approximately 4.5 days, and steady state was reached by approximately Day 15.  
Trametinib had a small peak:trough ratio of ~2 (Infante et al., 2010).  At 2 mg QD on Day 
15, mean AUC0-24 was 376 ng•h/mL and Cmax 23 ng/mL, and the mean trough 
concentrations ranged from 10.0 to18.9 ng/mL.  The long half-life and small peak:trough 
ratio of trametinib allowed constant target inhibition within a narrow range of exposure. 
Drug-drug interactions: 
Trametinib is metabolized predominantly via deacetylation (non-cytochrome P450 
[CYP450]-mediated) with secondary oxidation or in combination with glucuronidation 
biotransformation pathways (Investigator’s Brochure, 2012a).  The deacetylation is likely 
mediated by hydrolytic esterases, such as carboxylesterases, or amidases.  Based on in vitro 
studies, trametinib is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2D6, and 
CYP3A4.  Although trametinib was found to be an in vitro inhibitor of CYP2C8, CYP2C9, 
and 2C19; inducer of CYP3A4; and inhibitor of transporters (OATP1B1, OATP1B3, P-


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 34 of 77 
glycoprotein [P-gp], and breast cancer resistance protein [BCRP]), its low efficacious dose, 
and low clinical systemic concentration (22.2 ng/mL or 0.04 mcM at 2 mg) relative to the 
in vitro inhibition/induction potency suggests an overall low potential for drug-drug 
interactions. 
 
Pharmacodynamic effect and biomarkers: 
 
The relationship between dose and tumor biomarkers such as pERK, Ki67, and p27, 
were evaluated in patients with BRAF or NRAS mutation-positive metastatic melanoma 
(Investigator's Brochure, 2012a).  In general, increasing exposures and/or doses provided 
greater pharmacodynamic effects.  The median change observed at a dose of 2 mg QD was 
62% inhibition of pERK, 83% inhibition of Ki67, and a 175% increase in p27. 
 
Antitumor Activity in the FTIH phase 1 trial:  
 
In the FTIH phase 1 trial, 14 patients with BRAF-mutant melanoma received trametinib 
at 2 mg QD.  The overall objective response rate (ORR) was 43% (6/14), including 2 
complete responses (CRs) (Investigator's Brochure, 2012a).  In 9 patients with BRAF wt 
melanoma, 2 patients achieved a partial response (PR), and 3 stable disease (SD) (Infante 
et al., 2010).  In 26 evaluable pancreatic cancer patients, there were 2 PRs (1 PR was KRAS 
mutation-positive) and 11 SD (2 achieved ≥20% tumor reduction) (Messersmith et al., 
2011).  Among the 27 CRC patients (without selection of RAS or RAF mutations), 8 SD 
were observed. 
 
 
 
 
Antitumor Activity in Melanoma  
 
Phase 3 trial of trametinib vs. chemotherapy in advanced V600 mutant melanoma: 
In a phase 3 trial, patients with unresectable stage IIIC or IV cutaneous melanoma with a BRAF 
V600E or V600K mutation were randomized (2:1) to trametinib (2 mg, PO, QD) or 
chemotherapy (dacarbazine or paclitaxel) (Flaherty et al., 2012; MEKINIST Package Insert, 
2013).  There were 322 patients in the intention-to-treat (ITT) population, of whom 273 (85%) 
were in the primary efficacy population (patients with BRAFV600E-positive cancer who did not 
have brain metastases at baseline).  Of the patients, 214 were randomized to receive trametinib, 
and 108 were randomized to receive chemotherapy.  Investigator-assessed efficacy data are 
summarized as follows: 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 35 of 77 
Table 10. Response of Melanoma Patients to Trametinib Compared with DTIC 
Chemotherapy 
 
Trametinib 
(n=214) 
Chemotherapy (DTIC) 
(n=108) 
PFS 
Median, months (95% CI) 
 
4.8 (4.3, 4.9) 
 
1.5 (1.4, 2.7) 
HR (95% CI) 
P value (log-rank test) 
0.47 (0.34, 0.65) 
P<0.0001 
Confirmed Tumor Responses 
Objective Response Rate (95% CI) 
CR, n (%) 
PR, n (%) 
 
22% (17, 28) 
4 (2%) 
43 (20%) 
 
8% (4, 15) 
0 
9 (8%) 
Duration of response 
Median, months (95% CI) 
5.5 (4.1, 5.9) 
NR (3.5, NR) 
CI = confidence interval; CR = complete response; HR = hazard ratio; NR = not reached; PFS = 
progression-free survival; PR = partial response 
 
The 6-month OS rate was 81% in the trametinib group and 67% in the chemotherapy group.  
Mature data on OS are pending. 
Experience with Trametinib in Metastatic Melanoma Following BRAF Inhibitor Therapy 
The clinical activity of single-agent trametinib was evaluated in a single-arm, multicenter, 
international trial in 40 patients with BRAF V600E or V600K mutation-positive, unresectable, 
or metastatic melanoma who had received prior treatment with a BRAF inhibitor.  All patients 
received trametinib at a dose of 2 mg PO QD until disease progression or unacceptable toxicity.  
None of the patients achieved a confirmed PR or CR. 
 
Antitumor Activity of Trametinib in Cancer Other Than Melanoma 
In a phase 1/2 monotherapy study, acute myeloid leukemia (AML) or myelodysplastic 
syndrome (MDS) patients were given trametinib at dose levels from 1-2 mg QD.  Drug-related 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 36 of 77 
AEs in 45 patients were similar to that observed in patients with solid tumors, and 2 mg PO 
QD was selected for further investigation in this patient population.  Twelve patients (23%) 
withdrew due to an AE, including cardiac failure (2) and infection (2).  Efficacy was reported 
in 39 patients (Borthakur et al., 2010).  The best response in 13 patients with KRAS or NRAS 
mutations included 3 CRs (23%), 7 SD (54%), and 1 PD (progressive disease) (5%).  In 26 
patients with wild-type RAS or an unknown mutation, there were 2 PRs (8%). 
In a multicenter phase 2 study, NSCLC patients with KRAS mutant tumors were randomized 
2:1 to receive trametinib (2 mg QD) or docetaxel (75 mg/m2 IV every 3 weeks) (Blumenschein 
et al., 2013).  A total of 134 pts were randomized to trametinib (89) or docetaxel (45); 129 
patients had KRAS-mutant NSCLC.  The hazard ratio for PFS was 1.14 (95% CI, 0.75-1.75; 
P=0.5197) with a median PFS of 11.7 versus 11.4 weeks for trametinib versus docetaxel.  The 
overall response rate (ORR) was 12% for trametinib and 12% for docetaxel. 
In a double-blind, phase 2 study evaluating the combination of gemcitabine with trametinib, 
untreated pancreatic cancer patients were randomized to receive gemcitabine (1000 mg/m2 
weekly 7 for 8 weeks, then weekly 3 every 4 weeks) plus either trametinib 2mg or placebo 
QD (Infante et al., 2013).  Median OS was 8.4 months with trametinib compared to 6.7 months 
with placebo.  Median PFS was 16 weeks versus 15 weeks, and ORRs and median duration of 
responses were 22% and 23.9 weeks and 18% and 16.1 weeks on trametinib and placebo; the 
median OS and ORR in the subgroup of patients with KRAS mutations (143/160) was similar 
to OS and ORR for all randomized patients.   
Efficacy and safety data for trametinib in patients with Erdheim Chester disease are not 
available. This will be the first therapeutic trial that will address this. 
 
5.6.1.3.3- Trametinib Safety Profile 
A Comprehensive Adverse Events and Potential Risks (CAEPR) list using NCI Common 
Terminology Criteria for Adverse Events (CTCAE) terms is included in appendix 2. 
Based on available AE data from clinical studies involving trametinib to date, the most 
common toxicities are rash and diarrhea.  Rash and diarrhea are common, class-effect toxicities 
for MEK inhibitors.  In addition, visual impairment and left ventricular ejection fraction 
(LVEF) reduction, although observed at lower frequencies, are also considered class-effect 
toxicities as they have been observed with trametinib as well as other MEK inhibitors. 
AEs of special interest: 
Rash, diarrhea, visual disorders, hepatic disorders, cardiac-related AEs, and pneumonitis 
are considered AEs of special interest because they are either known class effects (i.e., have 
been observed with other MEK inhibitors) or are potentially life-threatening (Investigator’s 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 37 of 77 
Brochure, 2012a). 
Skin Toxicities:  Rash was a common AE observed across different dose levels and in 
different combinations.  The majority of rash observed with trametinib was acneiform and 
occur most frequently on the face, scalp, chest, and upper back.  However, serious skin 
toxicities can occur and lead to infection and hospitalization.  At the 2 mg dose, rash was 
seen in 48% to 91% of patients in different trials.  The majority of rash AEs were grades 1 
or 2 (68% to 80%); 1% to 18% of patients experienced grade 3 rash AEs, and one patient 
had a grade 4 rash AE. 
In a randomized phase 3 trial of trametinib vs. chemotherapy, the overall incidence of skin 
toxicity (including rash, dermatitis, acneiform rash, palmar-plantar erythrodysesthesia 
syndrome, and erythema) was 87% in patients treated with trametinib and 13% in 
chemotherapy-treated patients.  Severe skin toxicity occurred in 12% of patients on the 
trametinib arm, most commonly for secondary infections of the skin.  The median time to 
onset of skin toxicity was 15 days (range:  1 to 221 days), and median time to resolution 
was 48 days (range:  1 to 282 days).  Dose reduction was required in 12% for skin toxicities, 
and permanent discontinuation of trametinib was required in 1% of patients.  
Refer to dose modification guidelines for skin toxicities. 
Diarrhea:  At the 2 mg monotherapy dose, 28% to 58% of patients in three trials had 
diarrhea.  Of 219 patients with diarrhea at this dose, the majority of diarrhea AEs were 
grade 1 or 2 in severity (28% to 56% of all study patients); 6 patients had grade 3 diarrhea, 
and none had grade 4 diarrhea. 
Visual disorders:  At the 2 mg monotherapy dose, 6% to 21% of the patients in three trials 
experienced visual disorders.  Of the 62 total patients experiencing visual disorders at this 
dose level, the majority of visual disorders were grades 1 or 2 (6% to 20% of all study 
patients); five patients experienced grade 3 visual disorders, and one patient experienced a 
grade 4 visual disorder. 
− 
Central serous retinopathy (CSR) with Retinal Pigment Epithelial Detachment 
(RPED):  CSR is a class side effect of MEK inhibitors.  Across all clinical trials, the 
incidence of RPED was 0.8% (14/1749).  In the randomized trial with trametinib vs. 
chemotherapy where ophthalmologic examinations including retinal evaluation 
pretreatment and at regular intervals during treatment, one patient (0.5%) receiving 
trametinib developed RPED. 
 
Retinal detachments were often bilateral and multifocal, occurring in the macular 
region of the retina.  RPED led to reduction in visual acuity that resolved after a median 
of 11.5 days (range:  3 to 71 days) following the interruption of trametinib, although 
Ocular Coherence Tomography (OCT) abnormalities persisted beyond a month in at 
least several cases.  Perform ophthalmological evaluation at any time a patient reports 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 38 of 77 
visual disturbances and compare to baseline.  Refer to dose modification guidelines for 
visual disturbance for management and dose interruption/discontinuation. 
− 
Retinal vein occlusion (RVO):  Across all clinical trials, the incidence of RVO was 
0.2% (4/1749).  An RVO may lead to macular edema, decreased visual function, 
neovascularization, and glaucoma. It is recommended to urgently (within 24 hours) 
perform ophthalmological evaluation for patient-reported loss of vision or other visual 
disturbances, and permanently discontinue trametinib in patients with documented 
retinal vein occlusion (see Dosage Modification guidelines). 
 
Hepatic disorders:  Abnormalities of liver enzymes and bilirubin have been observed with 
administration of trametinib.  However, assessment of these cases was often confounded 
by co-morbid conditions (such as biliary obstruction), concomitant use of other potentially 
hepatotoxic drugs, and liver metastases.  At the 2 mg monotherapy dose, 10% to 19% of 
patients in three trials had LFT abnormalities.  Of the 56 total patients with LFT changes, 
the majority were grade 1 or 2 in severity (7% to 15% of all study patients); 12 had grade 
3 events, and 3 patients had grade 4 events. 
Cardiac-related AEs:  At the 2 mg monotherapy dose across trials, 11% of patients 
developed evidence of cardiomyopathy (decrease in LVEF below institutional lower limits 
of normal with an absolute decrease in LVEF ≥10% below baseline), and 5% demonstrated 
a decrease in LVEF below institutional lower limits of normal with an absolute decrease 
in LVEF of ≥20% below baseline.  Most cardiac AEs are grade 1 or grade 2, but grade 4 
or 5 cardiac AEs have rarely been reported. 
In the phase 3 trial of trametinib vs. chemotherapy in patients with melanoma 
(MEK114267), cardiomyopathy (defined as cardiac failure, left ventricular dysfunction, or 
decreased LVEF) occurred in 7% (14/211) of patients treated with trametinib, and in no 
patients in the chemotherapy arm.  Cardiomyopathy was identified within the first month 
of treatment in five of these 14 patients; median onset of cardiomyopathy was 63 days 
(range: 16 to 156 days). Cardiomyopathy resolved in 10 of these 14 (71%) patients.  
Cardiac monitoring should be included in trametinib protocols, to include LVEF 
assessment by echocardiogram or MUGA scan at baseline, one month after initiation of 
trametinib and then at 2- to 3-month intervals while on treatment. Dose modification 
guidelines for cardiac AEs should be followed in the event of LVEF decline or 
symptomatic cardiac AEs. 
Pneumonitis (interstitial lung disease):  Pneumonitis or interstitial lung disease was 
reported in 1.8% of patients.  In the randomized phase III trial for trametinib vs. 
chemotherapy, 2.4% patients (5/211) developed pneumonitis, all of whom required 
hospitalization.  Median onset of the first presentation of pneumonitis was 160 days (range:  
60-172 days). 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 39 of 77 
Embryofetal toxicity:  Based on its mechanism of action, trametinib can cause fetal harm 
when administered to a pregnant woman.  Trametinib was embryotoxic and abortifacient 
in rabbits at doses greater than or equal to those resulting in exposures approximately 0.3 
times the human exposure at the recommended clinical dose.  If this drug is used during 
pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be 
apprised of the potential hazard to a fetus. 
Incidence of common AEs reported from a phase III trial of trametinib vs. chemotherapy 
in patients with advanced melanoma: 
Patients with abnormal LVEF, history of acute coronary syndrome within 6 months, or 
current evidence of Class II or greater congestive heart failure (New York Heart 
Association) were excluded from this trial.  Selected adverse reactions (AR) occurring in 
patients receiving trametinib as compared to patients in the chemotherapy arm are listed as 
below: 
Table 11. Selected Adverse Reactions (ARs) Occurring in ≥10% of Patients Receiving 
Trametinib AND at a Higher Incidence than in the Chemotherapy Arm. 
Events are listed only if they were high in the trametinib arm compared with chemotherapy by 
≥5% in overall incidence or by ≥2% grade 3 or 4 AEs. 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Adverse Reactions 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Skin and subcutaneous tissue 
disorders 
 
 
 
 
Rash 
57 
8 
10 
0 
Dermatitis acneiform 
19 
<1 
1 
0 
Dry skin 
11 
0 
0 
0 
Pruritis 
10 
2 
1 
0 
Paronychia 
10 
0 
1 
0 
Gastrointestinal disorders 
 
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 40 of 77 
Diarrhea 
43 
0 
16 
2 
Stomatitis 
15 
2 
2 
0 
Abdominal pain 
13 
1 
5 
1 
Vascular disorders 
 
 
 
 
Lymphedema 
32 
1 
4 
0 
Hypertension 
15 
12 
7 
3 
Hemorrhage 
13 
<1 
0 
0 
 
Table 12.   Percent-patient Incidence of Laboratory Abnormalities Occurring at a Higher 
Incidence in Patients Treated with Trametinib Versus Chemotherapy.  
Events are listed only if between-arm differences were ≥5% [all grades] or ≥2% [grades 3 or 4]. 
 
Trametinib 
(n=211) 
Chemotherapy 
(n=99) 
Preferred term 
All Grades 
Grades 
3 and 4 
All Grades 
Grades 
3 and 4 
Increased aspartate 
aminotransferase (AST) 
60 
2 
16 
1 
Increased alanine aminotransferase 
(ALT) 
39 
3 
20 
3 
Hypoalbuminemia 
42 
2 
23 
1 
Anemia 
38 
2 
26 
3 
Increased alkaline phosphatase 
24 
2 
18 
3 
 
Other clinically important adverse reactions observed in ≤10% of patients (n=329) treated 
with trametinib were: nervous system disorders (dizziness, dysgeusia), ocular disorders 
(blurred vision, dry eye), infections and infestations (folliculitis, rash pustular, cellulitis), 
cardiac 
disorders 
(bradycardia), 
gastrointestinal 
disorders 
(xerostomia), 
and 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 41 of 77 
musculoskeletal and connective tissue disorders (rhabdomyolysis).   
5.6.1.4- Clinical Experience and Safety Profile with the Combination of Trametinib + 
Dabrafenib 
Comprehensive Adverse Events and Potential Risks (CAEPR) lists using NCI 
Common Terminology Criteria for Adverse Events (CTCAE) terms for dabrafenib and 
for trametinib are included in Appendix 2 of the protocol. 
Based on available AE data from clinical studies involving dabrafenib to date, the most 
common drug-related AE was hyperkeratosis (29%). Other commonly reported (>15%) 
drug-related AEs included alopecia, arthralgia, fatigue, skin papilloma, pyrexia, and rash 
(IB, 2013). 
Based on available AE data from clinical studies involving trametinib to date, the most 
common toxicities are rash and diarrhea.  Rash and diarrhea are common, class-effect 
toxicities for MEK inhibitors.  In addition, visual impairment and left ventricular ejection 
fraction (LVEF) reduction, although observed at lower frequencies, are also considered 
class-effect toxicities as they have been observed with trametinib as well as other MEK 
inhibitors. 
Common Adverse Events of Dabrafenib-Trametinib Combination vs. Dabrafenib 
Monotherapy.  The phase 2 portion of study BRF113220 (referred to as Part C) included 
3 arms:  dabrafenib 150 mg BID + trametinib 2 mg QD, dabrafenib 150 mg BID + 
trametinib 1 mg QD, and single-agent dabrafenib 150 mg BID.  The most common AE 
resulting in permanent discontinuation was pyrexia (4%).  AEs led to dose reductions in 
49% and dose interruptions in 67% of patients treated with dabrafenib in combination with 
trametinib.  The table below presents selected adverse reactions and treatment-emergent 
laboratory abnormalities in this study. 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 42 of 77 
Table 13-Selected AEs and Laboratory Abnormalities Occurring in ≥10% at (All Grades) 
or ≥5% (Grades 3 or 4) of Patients Treated With Dabrafenib in Combination With 
Trametinib 
Adverse 
Reaction 
or 
Laboratory Abnormality 
Dabrafenib + 
Trametinib 2mg 
(n=55) 
Dabrafenib + 
Trametinib 1mg 
(n=54) 
Dabrafenib 
(n=53) 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
General disorders and administrative site conditions 
Pyrexia 
71 
5 
69 
9 
26 
0 
Chills 
58 
2 
50 
2 
17 
0 
Fatigue 
53 
4 
57 
2 
40 
6 
Edema peripheralb 
31 
0 
28 
0 
17 
0 
Skin and subcutaneous tissue disorders 
Rashc 
45 
0 
43 
2 
53 
0 
Night sweats 
24 
0 
15 
0 
6 
0 
Dry skin 
18 
0 
9 
0 
6 
0 
Dermatitis acneiform 
16 
0 
11 
0 
4 
0 
Actinic keratosis 
15 
0 
7 
0 
9 
0 
Erythema 
15 
0 
6 
0 
2 
0 
Pruritis 
11 
0 
11 
0 
13 
0 
Gastrointestinal disorders 
Nausea 
44 
2 
46 
6 
21 
0 
Vomiting 
40 
2 
43 
4 
15 
0 
Diarrhea 
36 
2 
26 
0 
28 
0 
Metabolism and nutritional disorders 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 43 of 77 
Table 13-Selected AEs and Laboratory Abnormalities Occurring in ≥10% at (All Grades) 
or ≥5% (Grades 3 or 4) of Patients Treated With Dabrafenib in Combination With 
Trametinib 
Adverse 
Reaction 
or 
Laboratory Abnormality 
Dabrafenib + 
Trametinib 2mg 
(n=55) 
Dabrafenib + 
Trametinib 1mg 
(n=54) 
Dabrafenib 
(n=53) 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
Decreased appetite 
22 
0 
30 
0 
19 
0 
Dehydration 
11 
0 
6 
2 
2 
0 
Vascular disorders 
Hemorrhaged 
16 
5 
11 
0 
8 
2 
Renal and urinary disorders 
Renal failuree 
7 
7 
2 
0 
0 
0 
Hematology 
Leukopenia 
62 
5 
46 
4 
21 
0 
Neutropenia 
55 
13 
37 
2 
9 
2 
Liver function tests 
Increased AST 
60 
5 
54 
0 
15 
0 
Increased 
alkaline 
phosphatase 
60 
2 
67 
6 
26 
2 
Increased ALT 
42 
4 
35 
4 
11 
0 
Hyperbilirubinemia 
15 
0 
7 
4 
0 
0 
Chemistry 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 44 of 77 
Table 13-Selected AEs and Laboratory Abnormalities Occurring in ≥10% at (All Grades) 
or ≥5% (Grades 3 or 4) of Patients Treated With Dabrafenib in Combination With 
Trametinib 
Adverse 
Reaction 
or 
Laboratory Abnormality 
Dabrafenib + 
Trametinib 2mg 
(n=55) 
Dabrafenib + 
Trametinib 1mg 
(n=54) 
Dabrafenib 
(n=53) 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
All 
Gradesa 
Grades 
3 and 4 
Hyperglycemia 
58 
5 
67 
6 
49 
2 
Hyponatremia 
55 
11 
48 
15 
36 
2 
Hypophosphatemia 
47 
5 
41 
11 
40 
0 
Increased creatinine 
24 
5 
20 
2 
9 
0 
a NCI CTCAE v4. 
b Includes the following terms:  peripheral edema, edema, and lymphedema. 
c Includes the following terms:  rash, rash generalized, rash pruritic, rash erythematous, rash popular, rash 
vesicular, rash macular, rash maculo-papular. 
d Includes the following terms:  brain stem hemorrhage, cerebral hemorrhage, gastric hemorrhage, 
epistaxis, gingival hemorrhage, hematuria, vaginal hemorrhage, hemorrhage intracranial, eye hemorrhage, 
and vitreous hemorrhage. 
e Includes the following terms:  renal failure and renal failure acute. 
 
AEs of special interest: 
The following events observed with dabrafenib monotherapy and for dabrafenib plus 
trametinib are discussed in further detail because they may represent a class effect of 
BRAF and/or MEK inhibitor compounds, and/or are potentially life-threatening.  AEs of 
special interest associated with dabrafenib or trametinib individually are listed in the table 
below: 
Table 14 
AEs of special interest that are associated 
with dabrafenib (BRAF category AEs) 
are: 
• 
Skin-related toxicities 
• 
Pyrexia 
AEs of special interest that are associated with trametinib 
(MEK category AEs) 
• 
Skin-related toxicities (e.g., rash – generalized, 
macular, maculopapular, 
pruritic, erythematous, etc; dermatitis acneiform; 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 45 of 77 
• 
Malignancies 
• 
Renal failure (renal failure, 
renal failure acute) 
• 
Uveitis 
• 
Hyperglycemia 
• 
Pancreatitis 
 
erythema; skin exfoliation 
• 
Diarrhea 
• 
Ocular events (e.g., RVO, RPED (previously termed 
CSR)) 
• 
Hepatic events (e.g., aspartate aminotransferase 
[AST], ALT, and blood 
bilirubin increased) 
• 
Cardiac-related events (e.g., LVEF decreased and 
left ventricular dysfunction) 
• 
Hypertension 
• 
Pneumonitis (pneumonitis, interstitial lung disease) 
• 
Hemorrhages 
 
In general, the overall profile of “AEs of special interest” observed with the combination 
of trametinib-dabrafenib is consistent with the known profiles of each separate drug, the 
most notable differences being the increase in pyrexia and the decrease in skin-related 
toxicities with combination therapy relative to monotherapy.    
For “MEK-related AEs of special interest,” the overall incidence in the dabrafenib-
trametinib combination arm in trial BRF113220 was 91%, which was similar to the 
incidence reported with trametinib ISS monotherapy  (94%), but higher than the incidence 
in the dabrafenib alone arm.  However, MEK-related skin toxicities, diarrhea and 
hypertension appeared to be lower in the combination arm, as compared with the 
trametinib-only treated population.  The incidence rate of ocular events was higher relative 
to the trametinib ISS population.  
For “BRAF-related AEs of special interest,” the incidence of any event in combination 
arm was higher (84%) than either the Dabrafenib ISS population (49%) or the trametinib 
ISS population (19%).  This increase is predominantly due to the increased incidence of 
pyrexia observed with combination treatment.  Also noted were an increase in renal failure 
and a decrease in cuSCC and PPES when comparing the combination to dabrafenib ISS 
population. 
The following sections provide more detailed description of the AEs of Special Interest.   
Dermatologic toxicities (dabrafenib or dabrafenib-trametinib):   
Dabrafenib monotherapy has been associated with skin-related toxicities including 
hyperkeratosis, skin papilloma, rash, seborrheic keratosis, acrochordon as well as rash and 
pruritis and cutaneous squamous cell carcinoma.    
With the combination of dabrafenib-trametinib at 150/2 (Part C of the phase II trial), skin-
related toxicity occurred in 65% of subjects (IB, 2013). This incidence was lower than 
observed in the trametinib ISS population (88%, 288 out of 329 subjects).  The most 
frequent skin-related toxicities (affecting >10% treated with combination) were rash, 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 46 of 77 
dermatitis acneiform, erythema, and rash generalized.  The incidence and severity of the 
majority of skin-related toxicities and especially those most often seen with either 
trametinib- or dabrafenib therapy alone appear to be reduced when both compounds are 
combined. 
Malignancies (dabrafenib or dabrafenib-trametinib): 
Cutaneous SCC and keratoacanthomas:  SCC and proliferative skin toxicities are 
considered a class effect of BRAF inhibitors such as vemurafenib and sorafenib (Long 
et al., 2011).  SCC was treated with local excision, and treatment with dabrafenib was 
continued.  Most SCCs of the skin have been localized and generally treated with 
curettage, and have been without significant clinical sequelae. 
Across clinical trials of dabrafenib monotherapy (n=586), the incidence of cutaneous 
SCC was 11%.  Of those patients who developed new SCC, approximately 33% 
developed one or more SCC with continued administration of dabrafenib.   
In randomized trial with dabrafenib vs. dabrafenib-trametinib combination 
(BRF113220), the incidence of cutaneous SCC/keratocanthoma was statistically 
lower with150/2 combination therapy relative to dabrafenib alone (7 vs. 19%).  The 
median time to the first occurrence of keratoacanthoma/cuSCC was 152 days in the 
combination treatment group as compared to 30.5 days in the dabrafenib alone arm. 
New primary malignant melanoma:  In the randomized trial for dabrafenib-
trametinib combination (BRF113220), new primary melanoma occurred in 2% (1/53) 
on dabrafenib monotherapy [similar to the dabrafenib ISS population (1%)] and in 
none of 55 patients receiving dabrafenib + trametinib (IB, 2013).  The overall 
frequency of new primary melanomas observed with dabrafenib treatment 
approximates that expected for untreated subjects with antecedent melanoma. 
Other treatment-emergent malignancies:  Non-cutaneous secondary malignancies 
have also been reported in patients receiving dabrafenib or dabrafenib-trametinib 
combination.  In patients receiving dabrafenib-trametinib combination, five cases out 
of 365 subjects (1%) were identified as having non-cutaneous malignancies:  KRAS 
mutation-positive pancreatic adenocarcinoma (n=1), recurrent NRAS mutation-
positive CRC (n=1), head and neck carcinoma (n=1), glioblastoma (n=1), and pre-
existing renal cell carcinoma (n=1) (FDA label).  No increase was detected in the 
overall frequency of treatment emergent malignancies in melanoma subjects receiving 
dabrafenib and trametinib treatment in Study BRF113220 as compared to the 
dabrafenib safety population.  Dabrafenib should be permanently discontinued for 
RAS mutation-positive non-cutaneous malignancies. 
Pyrexia (dabrafenib or dabrafenib-trametinib):  Pyrexia and pyrexia-related events, 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 47 of 77 
including influenza-like illness, cytokine release syndrome, and systemic 
inflammatory response syndrome are common side effects associated with dabrafenib.  
In dabrafenib- trametinib combination study BRAF113220 Part C, pyrexia and related 
events in the combination arm (150/2) were increased in frequency and severity (76%; 
5% grade 3, no grade 4), as compared with dabrafenib monotherapy ISS population 
(33%; 2% grade 3, no grade 4).  Eleven percent of subjects in the combination group 
required hospitalization for episodes of serious pyrexia (IB, 2013).  Approximately 
50% of the pyrexia-related events in the Part C 150/2 arm resulted in dose interruption 
and/or dose reduction, a higher proportion than in the dabrafenib ISS population (15% 
to 30%).  The majority of subjects (>80%) who dose-reduced dabrafenib due to AEs 
were able to be dose re-escalated.  
All SAEs of pyrexia-related events (pyrexia, influenza-like illness, cytokine release 
syndrome, and systemic inflammatory response syndrome) were manually reviewed 
to identify cases described as having experienced serious non-infectious febrile 
events with complications of hypotension, dehydration, severe rigors/chills, or renal 
failure in the absence of another identifiable etiology (e.g., infection).  Ten such 
subjects were identified among 404 subjects (2.5%) in the entire combination therapy 
population as compared to 1% in the dabrafenib ISS population; 9 of these subjects 
were hospitalized.  All of these subjects required dose interruption(s) and/or dose 
modification(s); one subject permanently discontinued study drug after experiencing 
fever, muscle weakness, dehydration, and hyponatremia.  All subjects responded to 
symptomatic therapy with either NSAIDs, paracetamol, or corticosteroids and best 
supportive care including IV fluids. 
Renal failure (dabrafenib or dabrafenib-trametinib):  Renal failure was observed in 
the dabrafenib ISS population (<1%; <1% grade 3/4) and trametinib ISS population 
(2%; no grade 3, <1% grade 4), and was increased in incidence and severity in the 
combination arm in study BRF113220 (7%, all grade 3) (IB, 2013).  Most cases of 
acute renal failure presented as a secondary event in the setting of pyrexia where 
dehydration appeared to be a contributing factor and/or in concert with other risk 
factors such as hemolytic uremic syndrome (HUS), antibiotic toxicity, or 
hypercalcemia.  There was one case of advanced renal failure which may have been 
drug-induced but whose precise etiology was not clear.  The renal events led to 
permanent discontinuation of study drugs in one subject, and to dose interruptions in 
three subjects. 
Hypertension (dabrafenib-trametinib): Hypertension has been associated with 
trametinib therapy.  In the combination study of dabrafenib-trametinib, the 
combination arm had a higher rate of hypertension compared to the dabrafenib ISS 
population (9% vs. 2%); however, this rate was lower than that in the trametinib ISS 
population (15%) (IB, 2013).   


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 48 of 77 
In either the combination or the dabrafenib monotherapy population, there were no 
SAEs related to hypertension, and hypertension did not lead to treatment 
discontinuation, dose reduction or dose interruption in any of the patients.   
Cardiac valvular abnormalities (dabrafenib or dabrafenib-trametinib):  Data from 
preclinical studies suggested that dabrafenib has the potential to cause cardiac valve 
abnormalities.  In a 28-day dog toxicology study, high doses (50 mg/kg/day; 
approximately 40-fold over the therapeutic dose) of dabrafenib in 1 dog (n=10) 
resulted in hypertrophy of the right atrio-ventricular valve (tricuspid valve).  
Therefore, this was monitored in clinical trials with echocardiograms. 
Cardiomyopathy (dabrafenib-trametinib):  Cardiomyopathy has been associated 
with trametinib use and therefore the incidence was increased in the dabrafenib-
trametinib combination compared to dabrafenib alone.  Cardiac-related AEs occurred 
in 9% of subjects in the Part C 150/2 group, which is the same incidence as in the 
Trametinib ISS population (9%), but a higher incidence compared with the Dabrafenib 
ISS population (2%) (IB, 2013).  Decreased ejection fraction was the only AE reported 
in the Part C 150/2 group, and all reports were either grade 1 or 2. 
Ocular adverse events:  Ocular events occurred at a higher frequency in study 
BRF113220 Part C 150/2 combination group (25%) compared to trametinib (13%) 
and dabrafenib (8%) monotherapy ISS populations (IB, 2013).  Blurred vision, dry 
eye, and visual impairment were the most commonly reported ocular events in the Part 
C 150/2 group.  All ocular events in Part C 150/2 were grade 1 to 2 with the exception 
of one case of grade 3 retinal pigment epithelial detachment (RPED). 
RPED and RVO (dabrafenib-trametinib):  These two events are associated with 
trametinib therapy and therefore were observed in the combination of dabrafenib and 
trametinib.  Of 365 subjects in Study BRF113220, the incidence of RPED remained 
at 1% and is thus similar to the frequency observed in the overall trametinib 
development program so far. Thus, the addition of dabrafenib appears to have no 
impact on the frequency or severity of RPED previously reported for trametinib.  
RVO has not been reported as an AE in the dabrafenib ISS population of 586 subjects. 
Addition of dabrafenib to trametinib in the combination treatment regimen in Study 
BRF113220 did not increase the frequency of RVO observed thus far with trametinib 
monotherapy.  
Uveitis, iritis, and iridocyclitis (dabrafenib or dabrafenib-trametinib):  Uveitis and 
iritis can occur when dabrafenib is administered as a single agent or in combination 
with trametinib.  In the 365 subjects with melanoma treated on the dabrafenib-
trametinib combination arm in Study BRF113220, the incidence of ocular events 
including uveitis, iritis, or iridocyclitis was 2%, and responded to symptomatic 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 49 of 77 
therapy, which included primarily the use of topical corticosteroids.  This rate is 
slightly higher than in the dabrafenib ISS population (1%).  In addition, the severity 
of the inflammatory ocular events also appeared to be slightly increased, with 2 cases 
of uveitis Grade 3 and 1 case of Grade 4. 
Hyperglycemia (dabrafenib or dabrafenib-trametinib):  Hyperglycemia can occur 
when dabrafenib is used as a monotherapy or in combination with trametinib.  In study 
BRF112680 (dabrafenib monotherapy), 5/12 patients with a history of diabetes 
required more intensive hypoglycemic therapy while taking dabrafenib; the incidence 
of grade 3 hyperglycemia was 6% (12/187) in patients treated with dabrafenib 
compared with none of the dacarbazine-treated patients.  In study BRF113220 
(combination with trametinib), the incidence of hyperglycemia was 5% (3/55) in 
patients treated with dabrafenib-trametinib compared with 2% (1/53) in patients 
treated with dabrafenib (FDA label).  
Pancreatitis (dabrafenib or dabrafenib-trametinib):  Pancreatitis (<1%) and/or 
increased lipase/amylase (2%) have been reported at low frequency with dabrafenib.  
In the phase 2 combination study BRAF113229, AEs of acute pancreatitis or 
pancreatitis occurred in six (1%) subjects on the dabrafenib-trametinib arm (IB, 2013), 
and none with dabrafenib monotherapy.  The time to onset of pancreatitis ranged from 
Study Day 21 to 292 (median:  138 days).  At the data cut-off, 4 subjects had recovered 
from the event of pancreatitis.  Discontinuation of study drugs due to pancreatitis was 
not deemed necessary by the investigators in any of the 6 cases.  The incidence of 
pancreatitis was <1% in the dabrafenib ISS population (2 subjects) and in the 
trametinib ISS population (1 subject). 
Hepatic events (dabrafenib-trametinib combination):  In the Part C 150/2 group, 15% 
of subjects experienced hepatic AEs as compared to 13% of subjects in the trametinib 
ISS population and 6% of subjects in the dabrafenib ISS population (IB, 2013).  Of 
the hepatic AEs, increased ALT and AST were the most common events in all groups, 
and most were either grade 1 or 2.  No cases of Hy’s law were observed among any 
of the subjects in the BRF113220 study. 
Diarrhea (dabrafenib-trametinib combination):  The proportion of subjects in the Part 
C 150/2 group who experienced diarrhea was 36% compared with 49% in the 
trametinib ISS population and 16% in the dabrafenib ISS population (IB, 2013).  Most 
subjects across the monotherapy and combination therapy dabrafenib and trametinib 
clinical programs reported grade 1 or grade 2 diarrhea. 
Pneumonitis (dabrafenib-trametinib combination):  Pneumonitis was not reported as 
an AE in the 365 subjects enrolled in Study BRF113220 (Investigators Brochure, 
2013).  However, pneumonitis was the most common drug-related SAE (1% of 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 50 of 77 
subjects) Trametinib ISS population.  Overall, the addition of dabrafenib to trametinib 
does not appear to increase the frequency or severity of pneumonitis previously 
observed with trametinib monotherapy. 
Hypersensitivity:  There has been a single report of hypersensitivity (blisters) to 
dabrafenib, occurring on the same day as the 1st dose of study drug as well as upon 
rechallenge (IB, 2013).  The subject recovered after interruption and then 
discontinuation of dabrafenib.  Grade 1 AEs of blisters on limbs (4 subjects) and drug 
hypersensitivity (rash, 1 subject) have been reported in previous studies with 
dabrafenib.  However, the precise etiology of these events is unclear. 
Hypersensitivity to trametinib was reported by one subject 7 days after starting 
trametinib who experienced fever, asthenia, visual disturbance, and symptoms 
suggestive of a hypersensitivity reaction described by the investigator as “vascularity.”  
This subject also developed LFT elevations, lower limb nodules that by biopsy showed 
“dermo-hypodermatitis with plasmocyte and lymphocyte infiltrate.”  The subject 
recovered after discontinuation of trametinib. 
Hemorrhages (dabrafenib-trametinib combination):  Hemorrahge is an AE identified 
with the dabrafenib-trametinib combination therapy.  Hemorrhages, including major 
hemorrhages defined as symptomatic bleeding in a critical area or organ, can occur 
with dabrafenib plus trametinib combination therapy (FDA label).  In study 
BRF113220, treatment with dabrafenib in combination with trametinib resulted in an 
increased incidence and severity of any hemorrhagic event:  16% (9/55) of patients 
treated with trametinib in combination with dabrafenib compared with 2% (1/53) of 
patients treated with dabrafenib as a single agent.  The major hemorrhagic events of 
intracranial or gastric hemorrhage occurred in 5% (3/55) of patients treated with 
trametinib in combination with dabrafenib compared with none of the 53 patients 
treated with dabrafenib as a single agent.  Intracranial hemorrhage was fatal in two 
(4%) patients receiving the combination of trametinib and dabrafenib.  
Glucose-6-phosphate dehydrogenase (G6PD) deficiency (dabrafenib or dabrafenib-
trametinib combination):  Dabrafenib, which contains a sulfonamide moiety, confers 
a potential risk of hemolytic anemia in patients with G6PD deficiency; these patients 
should be closely observed for signs of hemolytic anemia.   
Embryofetal toxicity:  Based on the mechanisms of action, dabrafenib and/or 
trametinib can cause fetal harm when administered to a pregnant woman.  Dabrafenib 
was teratogenic and embryotoxic in rats at doses three times greater than the human 
exposure at the recommended clinical dose.  Trametinib was embryotoxic and 
abortifacient in rabbits at doses greater than or equal to those resulting in exposures 
approximately 0.3 times the human exposure at the recommended clinical dose.  


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 51 of 77 
5.6.2  Additional information for trametinib. 
5.6.2.1 Clinical pharmacology of trametinib: 
Trametinib is absorbed rapidly with median Tmax generally occurring 1.50 hours after 
single oral administration of trametinib under fasting conditions.  The absolute oral 
bioavailability of a single trametinib 2 mg tablet is moderate to high (72%) relative to 
a co-administered IV microdose.  
Following repeat-dosing the mean area under the curve (AUC0-) and maximum 
concentrations (Cmax) increased in an approximately dose proportional manner.  
Trametinib accumulates with repeat dosing with a mean accumulation ratio at the 
recommended dose of 2 mg once daily of 5.97 and a terminal half-life of 5.3 days.  
Steady state is achieved by Day 15.   
Trametinib has a high volume of distribution (Vd) of 1060 L.  Fecal excretion is the 
major route of elimination after [14C] trametinib oral dose, accounting for >80% of 
excreted radioactivity recovered (or 39.2 and 35.0% of the radioactive dose in 2 
subjects) while urinary excretion accounted for <19% of excreted radioactivity 
recovered (<10% of the radioactive dose).   
In vitro and in vivo data suggest that trametinib is unlikely to affect the PK of other 
drugs and that the PK of trametinib12 is unlikely to be affected by other drugs.  
Trametinib is metabolized predominantly via deacetylation which is likely mediated by 
hydrolytic esterases which are not generally associated with drug interaction risk, nor 
is it a substrate of P-gp or BCRP. 
5.6.3- Other Agent(s): 
 
      N/A, no other agents will be used in this trial. 
5.7 - Specific results that will be given to participants or their health care providers. 
Medically relevant results will be transmitted to patients or the legal guardian, not to the 
patient’s minor son or daughter. Incidental results will be given only if medically critical, 
i.e., severe, urgent, or actionable.  Research results will not be revealed to patients unless 
there are medically important implications for the patient or the patient’s family members. 
Participants are encouraged to remain in contact with the principal investigator regarding 
advances in the field, and will be invited to enroll in pertinent future studies. Results from 
routine and diagnostic studies will be given to participants prior to their discharge from the 
NIHCC. These results will be discussed in wrap up sessions at the end of the visit or earlier 
if medical action is required for any given result. Participant’s healthcare providers will 
obtain a copy of these routine tests and procedures upon participant’s request. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 52 of 77 
5.8 Describe questionnaires or other psychological instruments and estimate how 
long they will take to complete, and whether they address sensitive topics. 
Questionnaires and other psychological tools are described on section 5.1.2 and are 
attached separately.  
5.9 Genetic counseling. 
Genetic counseling will be performed in person by the principal investigator Dr Juvianee 
I. Estrada-Veras or by Kevin J. O’Brien NP during the inpatient or outpatient evaluations.  
5.10 Description of criteria for withdrawal from study. 
For description of criteria for withdrawal from the study, please see descriptions on Section 
4.4. 
6.0 Description of study population 
6.1 Estimated number of participants, enrollment ceiling, and anticipated 
enrollment by year. 
Eighteen patients with a monthly enrollment of 1 or 2. Patients from both genders will be 
enrolled as well as from any ethnic background. 
Table 15. Accrual Targets. 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
2 
= 
3 
Not Hispanic or Latino 
6 
+ 
9 
= 
15 
Ethnic Category: Total of all subjects 
                7 
(A1) + 
             11 
(B1) = 
             18 
(C1) 
Racial Category 
 
American Indian or Alaskan Native 
1 
+ 
1 
= 
2 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
1 
= 
2 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 53 of 77 
Native Hawaiian or other Pacific 
Islander 
1 
+ 
1 
= 
2 
White 
3 
+ 
7 
= 
10 
Racial Category: Total of all subjects 
                7 
(A2) + 
             11 
(B2) = 
              18 
(C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
 
6.2 Description and justification of clinical inclusion/exclusion criteria. 
  
6.2.1- Eligibility Criteria  
See Figure 1 above for a flowchart regarding eligibility and enrollment procedures. 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 54 of 77 
All patients will be previously or simultaneously enrolled in the natural history ECD 
protocol #11-HG-0207, “Clinical and Basic Investigations into Erdheim-Chester Disease”. 
Eligible patients must have been diagnosed with Erdheim Chester disease, confirmed by 
pathological evaluation of the affected tissue with adequate staining. Affected tissue must 
harbor the BRAF V600E or V600K mutation. Patients must have measurable disease, 
defined as at least one lesion that can be accurately measured in at least one dimension  
(longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as 
≥20 mm with conventional techniques or as ≥10 mm with spiral CT scan, MRI, or calipers 
by clinical exam.  See Section 11 for the evaluation of measurable disease. 
- 
Patients must have BRAFV600E or BRAFV600K mutations, identified by an FDA-
approved test at a CLIA-certified lab.  If test at CLIA-certified lab used a non-FDA 
approved method, information about the assay must be provided.  (FDA approved tests 
for BRAF V600 mutations in melanoma include:  THxID BRAF Detection Kit and 
Cobas 4800 BRAF V600 Mutation Test). 
- 
Prior treatment, involving interferon, anakinra, imatinib, steroids, chemotherapy with, 
but not limited to cladribine, vinblastine, 6-mercaptopurine and etoposide, or other 
medications used empirically for the treatment of ECD, will be acceptable. These 
therapies should have been completed and discontinued 4 weeks or more prior to 
enrollment in this study. 
- 
Age ≥18 years. Because no dosing or adverse event data are currently available on the 
use of dabrafenib in combination with trametinib in patients <18 years of age, children 
are excluded from this study, but will be eligible for future pediatric trials. 
- 
Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 (Karnofsky 
≥70%, see Appendix A). Exception will be made for patients with ECOG performance 
status ≤ 3 and Karnosfky performance scale ≥ 50%, who require the use of wheelchairs, 
walkers or canes as well as assistance with daily routines secondary to disabilities 
caused by ECD cerebellar or brain disease that has been stable for ≥ 3 months. 
- 
Life expectancy of greater than 3 months. 
- 
Able to swallow and retain oral medication and must not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption 
syndrome or major resection of the stomach or bowels. 
- 
Patients must have normal organ and marrow function as defined below: 
− 
Absolute neutrophil count (ANC) ≥1.2x109/L 
− 
Hemoglobin ≥9 g/dL 
− 
Platelets ≥100x109/L  
− 
Albumin ≥2.5 g/dL 
− 
Serum bilirubin ≤1.5x institutional upper limit of normal (ULN) except subjects 
with known Gilbert’s syndrome 
− 
Aspartate aminostransferase (AST) and alanine aminotransferase (ALT) ≤2.5x 
institutional ULN 
− 
Serum creatinine ≤1.5 mg/dL OR calculated creatinine clearance (Cockroft-Gault 
formula) ≥50 mL/min  
− 
Prothrombin time (PT)/International normalized ratio (INR) and partial 
thromboplastin time (PTT) ≤1.3x institutional ULN; subjects receiving 
anticoagulation treatment may be allowed to participate with INR established 
within the therapeutic range prior to randomization. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 55 of 77 
− 
Left ventricular ejection fraction ≥ institutional lower limit of normal (LLN) by 
ECHO 
- 
Women of childbearing potential must have a negative serum pregnancy test within 14 
days of the first dose of study treatment. 
- 
Pregnancy and breast feeding: The effects of dabrafenib and trametinib on the 
developing human fetus are unknown.  For this reason women of child-bearing 
potential must agree to use adequate contraception (barrier method of birth control, or 
abstinence; hormonal contraception is not allowed due to drug-drug interactions which 
can render hormonal contraceptives ineffective) for the duration of study participation, 
and for at least 2 weeks after treatment with dabrafenib or for 4 months after dabrafenib 
in combination with trametinib.  Should a woman become pregnant or suspect she is 
pregnant while she is participating in this study, she should inform her treating 
physician immediately.   
 
Based on studies in animals, it is also known that dabrafenib may cause damage to the 
tissue that makes sperm.  This may cause sperm to be abnormal in shape and size and could 
lead to infertility, which may be irreversible. 
Safety and efficacy of the combination of dabrafenib and trametinib in pediatric 
populations have not been investigated.  Dabrafenib or trametinib-dabrafenib combination 
should not be administered to pediatric populations outside clinical trials. 
 
- 
Based on studies in animals, it is known that dabrafenib may cause damage to the tissue 
that makes sperm.  This may cause sperm to be abnormal in shape and size and could 
lead to infertility, which may be irreversible. Therefore, male patients should avoid 
impregnating their partners for the duration of treatment. 
- 
Safety and efficacy of the combination of dabrafenib and trametinib in the pediatric 
populations have not been investigated.  Trametinib and dabrafenib should not be 
administered to pediatric populations outside clinical trials.  
- 
Therapeutic level dosing of warfarin can be used with close monitoring of PT/INR by 
the site.  Exposure may be decreased due to enzyme induction when on treatment, thus 
warfarin dosing may need to be adjusted based upon PT/INR.  Consequently, when 
discontinuing dabrafenib, warfarin exposure may be increased and thus close 
monitoring via PT/INR and warfarin dose adjustments must be made as clinically 
appropriate.  Prophylactic low dose warfarin may be given to maintain central catheter 
patency. 
- 
Ability to understand and willingness to sign a written informed consent document. 
 
6.2.2 - Exclusion Criteria 
- 
Inability to provide informed consent. 
- 
Prior systemic anti-cancer therapy (chemotherapy with delayed toxicity, extensive 
radiation therapy, immunotherapy, biologic therapy, or vaccine therapy) within the last 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 56 of 77 
3 weeks; chemotherapy regimens without delayed toxicity within the last 2 weeks 
preceding the first dose of study treatment.   
- 
Use of other investigational drugs within 28 days (or five half-lives, whichever is 
shorter; with a minimum of 14 days from the last dose) preceding the first dose of study 
treatment and during the study. Patients that have used other BRAF or MEK inhibitor 
are excluded. 
- 
Current use of a prohibited medication.  Patients receiving any medications or 
substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible.  
Current use of, or intended ongoing treatment with:  herbal remedies (e.g., St. John’s 
wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer 
resistance protein 1 (Bcrp1) should also be excluded.  Below are a few examples of the 
agents. 
 
Table 16. Prohibited Drugs  
Strong inducers/inhibitors of CYP3A, CYP2C8, Pgp, and Bcrp are prohibited since they 
can affect the concentrations of dabrafenib. 
The following medications or non-drug therapies are prohibited: 
− 
Other anti-cancer therapy while on study treatment.  (Megestrol [Megace], if used as 
an appetite stimulant, is allowed.) 
− 
Concurrent treatment with bisphosphonates is permitted; however, treatment must be 
initiated prior to the first dose of study therapy.  Prophylactic use of bisphosphonates 
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be 
decreased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Rifamycin class agents (e.g., rifampin, rifabutin, rifapentine),  
Anticonvulsant 
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin  
Miscellaneous 
bosentan, St. John’s wort 
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may 
be increased 
Class/Therapeutic Area 
Drugs/Agents 
Antibiotics 
Clarithromycin, telithromycin, troleandomycin 
Antidepressant 
Nefazodone 
Antifungals 
Itraconazole, ketoconazole, posaconazole, voriconazole 
Hyperlipidemia 
Gemfibrozil  
Antiretroviral 
ritonavir, saquinavir, atazanavir 
Miscellaneous 
Conivaptan  


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 57 of 77 
in patients without bone disease is not permitted, except for the treatment of 
osteoporosis. 
− 
Because the composition, PK, and metabolism of many herbal supplements are 
unknown, the concurrent use of all herbal supplements is prohibited during the study 
(including, but not limited to, St. John’s wort, kava, ephedra [ma huang], ginkgo biloba, 
dehydroepiandrosterone [DHEA], yohimbe, saw palmetto, or ginseng). 
 
Because the lists of these agents are constantly changing, it is important to regularly consult 
a frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/main-table/; 
medical reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient will be 
counseled on the risk of interactions with other agents, and what to do if new medications 
need to be prescribed or if the patient is considering a new over-the-counter medicine or 
herbal product.  Appendix C is a patient information sheet that can be used for this specific 
protocol and presented to the patient. 
-Unresolved toxicity of National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.0 (NCI CTCAE v4.0) grade 2 or higher from previous anti-
cancer therapy, except alopecia. 
-Human Immunodeficiency Virus (HIV)-positive patients on combination antiretroviral 
therapy are ineligible because of the potential for pharmacokinetic interactions with 
dabrafenib. 
 
- A history of Hepatitis B Virus (HBV) or Hepatitis C Virus (HCV) infection (with the 
exception of cleared HBV and HCV infection, which will be allowed). 
- Presence of malignancy other than the study indication under this trial within 3 years of 
study enrollment. 
- Patients with history of RAS mutation-positive tumors are not eligible regardless of 
interval from the current study.  Note: RAS testing and absence of RAS mutation are 
required for eligibility.  
- Leptomeningeal or brain metastases or metastases causing spinal cord compression that 
are symptomatic or untreated or not stable for ≥3 months (must be documented by imaging) 
or requiring corticosteroids.  Subjects on a stable dose of corticosteroids >1 month or who 
have been off of corticosteroids for at least 2 weeks can be enrolled with approval of the 
CTEP medical monitor.  Subjects must also be off of enzyme-inducing anticonvulsants for 
>4 weeks. 
- History or evidence of cardiovascular risk including any of the following: 
• QT interval corrected for heart rate using the Bazett’s formula QTcB ≥480 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 58 of 77 
msec. 
• History of acute coronary syndromes (including myocardial infarction or 
unstable angina), coronary angioplasty, or stenting within the past 24 weeks 
prior to randomization. 
• History or evidence of current Class II, III, or IV heart failure as defined by the 
New York Heart Association (NYHA) functional classification system. 
• Intra-cardiac defibrillators. 
• Abnormal cardiac valve morphology (≥ grade 2) documented by ECHO; 
(subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be 
entered on study).  Subjects with moderate valvular thickening should not be 
entered on study. 
• History or evidence of current clinically significant uncontrolled cardiac 
arrhythmias; clarification:  Subjects with atrial fibrillation controlled for >30 
days prior to dosing are eligible. 
• Treatment refractory hypertension defined as a blood pressure of systolic >140 
mmHg and/or diastolic > 90 mm Hg which cannot be controlled by anti-
hypertensive therapy 
 
- 
History of interstitial lung disease or pneumonitis not due to ECD. 
- 
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO). 
- 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, diabetes mellitus, hypertension, or psychiatric illness/social situations that 
would limit compliance with study requirements. 
- 
History or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR) including presence of predisposing factors to RVO or CSR (e.g., 
uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes mellitus, or a 
history of hyperviscosity or hypercoagulability syndromes); or visible pathology (e.g., 
evidence of optic disc cupping, evidence of new visual field defects on automated 
perimetry, or intraocular pressure >21 mmHg as measured by tonography) as assessed 
by ophthalmic examination. 
- 
Pregnant women are excluded from this study because of the potential for teratogenic 
or abortifacient effects.  Because there is an unknown but potential risk for adverse 
events in nursing infants secondary to treatment of the mother with dabrafenib, 
breastfeeding should be discontinued if the mother is treated with dabrafenib.  These 
potential risks may also apply to other agents used in this study. 
- 
Inability to travel to the NIH Clinical Center. 
- 
Patients with wild type BRAF gene molecular results on Erdheim Chester disease 
affected tissue. 
- 
Patients with confirmed diagnosis of ECD that are asymptomatic and with no visceral 
involvement are not eligible for this trial (Patients with no target lesions as per RECIST 
1.1 criteria. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 59 of 77 
 
6.2.3 Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial.   
6.3 Location of study  
Patient will be seen and evaluated at the NIH Clinical Center inpatient unit or outpatient 
clinic according to the study calendar. 
6.4 Description of recruitment strategies 
Most often, patients call the Principal Investigator at the suggestion of the ECD Global 
Alliance, a family-patient organization that has its own web site and contact information. 
In addition, the medical community knows of the Principal Investigator’s interest in ECD, 
and refers patients. Patients with the pathologic findings of ECD and BRAFV600E 
mutation are immediately accepted for possible enrollment. See figure 1 on section 6.2.1 
for a flowchart explaining the recruitment strategies. 
6.5 For existing sample/data sets, note whether samples were originally collected for 
research or clinical practice. If obtained for research, include a description of 
the original purpose of study and prior plans for sample storage. Was consent 
obtained that would be applicable to this study?  
 
Patients enrolled on NHGRI Protocol 11-HG-0207 are potential candidates for this trial as 
long as the BRAF mutations V600E or V600K were detected in their samples. These 
samples were collected for clinical diagnostic as well as research purposes and consent was 
obtained at moment of enrollment to the natural history study. The clinical use of these 
samples was to confirm the pathological diagnosis of ECD. These samples were then 
analyzed under research for BRAF mutation testing which was then CLIA certified. 
Patients that will be considered as enrollees to this trial, but are unknown to our natural 
history study, will be enrolled on study 11-HG-0207 and tissue will be collected for 
confirmation of BRAF status prior to enrollment into this clinical trial. The 11-HG-0207 
patient subject consent form is attached as Appendix 3. 
6.6 Description of any financial compensation. If participant withdraws early, 
describe whether compensation will be modified. 
NA. 
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 60 of 77 
7.0 Description of study statistical considerations and/or analytic plan: 
7.1- STATISTICAL CONSIDERATIONS 
7.1.1- Study Design/Endpoints 
Patients with BRAFV600E positive Erdheim Chester disease will be enrolled in this study 
and will be evaluated at the NIH Clinical Center in Bethesda, Maryland. Patients will be 
referred to this trial from NHGRI protocol 11-HG-0207, which performs clinical and basic 
investigations into Erdheim Chester disease. Referrals will also be accepted from treating 
physicians, the ECD Global Alliance and patients themselves. Patient will be admitted for 
4-5 days at the NIH Clinical Center and baseline testing will be performed prior to the first 
dose administration. Patients without progression or significant AEs may continue therapy 
for a maximum of 12 months. At six months, patients without RECIST- defined response 
or major clinical improvement may elect to discontinue therapy.  There will be no 
randomization due to the rarity of the disease and small patient population. Patients will be 
seen once at the start of their participation in the trial, and again 1 week, 1 month, 2 months, 
4 months, and 6 months, 8 months, 10 months and 12 months after the initial admission. 
At 12 months, therapy will be stopped and follow up will be for one year after completion 
of therapy at 15 months, 18 months and 24 months, but for proper analysis of treatment 
response and other variants, follow up could be prolonged. It is our intention to recruit at 
least 18 patients within approximately one year. In addition, we have access to 
approximately 100 cases in the USA and worldwide through the ECD Global Alliance. No 
placebo will be used and patients must stop their current ECD treatment at least 4 weeks 
before enrollment; this applies to cases in which the patient is not responding to current 
treatment. 
To determine the clinical response rate, baseline measurable disease, as per RECIST 1.1 
criteria, will be determined less than 4 weeks prior to the start of treatment or at the baseline 
visit. Patients with ECD must have measurable or evaluable disease in one or more 
systems. These can include, but are not limited to, the retro-orbital space, pituitary stalk, 
cerebellum, brainstem, heart, retroperitoneal space causing renal and aortic encasement 
and long bones of upper and lower extremities. Complete response can be determined 
through imaging studies of these areas. As described in the treatment plan, imaging studies 
will be performed including retro-orbital/pituitary/brain/cerebellar MRI, abdomen and 
pelvis CT, and cardiac CT and MRI. FDG PET scan and T-99m bone scan will also be 
performed as exploratory outcome measures. The required imaging study will be selected 
on a case-by-case basis since the disease is heterogeneous in its presentation. Response to 
therapy will be evident on follow up imaging studies revealing a decrease in lesion size of 
30% or more, which is defined as a partial response as per RECIST Criteria, when 
compared to baseline studies. After 12 months of therapy have been completed, patients 
will go to an off therapy follow up period that will have follow up visits at 15 months, 18 
months and 24 months. During this period, duration of response will be assessed through 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 61 of 77 
imaging studies of the patient’s target lesions. If these target lesions show an increase, in 
at least one diameter, of 20% or more when compared to that target lesion measurement 
when they completed 12 months of therapy, this will be considered recurrence/progession 
of disease. Patients with disease recurrence will be considered for therapy resumption at 
the dose they were on when they completed therapy. Patients considered for therapy 
resumption will need to meet all inclusion and exclusion criteria and have new registration 
and TAC. They will also follow the safety guidelines for toxicity and dose modifications.  
Besides imaging follow up, duration of response will be also assessed through patient’s 
report of symptoms according to the MD Anderson symptom inventory, quality of life 
measures and SUV values on PET scan. Cytokines will also be followed during this period. 
All these parameters will help us determine disease recurrence-progression on each case.       
The study will be conducted as an optimal Simon two-stage phase II trial in order to rule 
out an unacceptably low 10% clinical response rate  (PR+CR: p0=0.10) in favor of a 
targeted  rate consistent with 40% (p1=0.40). Maximum trial size would be set at 18 
evaluable patients.  If at least 4 responses (at least 22%) were observed among the 18 
evaluable patients, this regimen would be considered worthy of further testing in this 
disease.  If no responses were observed among the initial 6 patients, the study would be 
terminated early and declared negative. This design yields at least 90% power to detect a 
true response rate of at least 40%.  It yields at least .90 probability of a negative result if 
the true response rate is no more than 10%, with at least .59 probability of early negative 
stopping. A temporary pause in the accrual to the trial may be necessary to ensure that 
enrollment to the second stage is warranted.  
To ensure safety and feasibility of the selected dose for patients with ECD, we will assess 
the toxicity profile and dose delivery after the first 6 subjects have completed 3 months of 
therapy. If 3 or more individuals do not take at least 80% of the full doses of both drugs 
over 3 months due to dose modification for toxicity, revision of the dose schedule should 
be considered.  Safety will be monitored on a continuous basis and feasibility of drug 
administration will be reviewed after 12 patients and then 18 patients have completed the 
3 months of therapy.   
All patients who receive any amount of the study drug will be evaluable for toxicity. 
Toxicity and doses adjustment will be perform as per the guidelines discussed on sessions 
4.7 and 9 where dosing modifications and adverse events are discussed. Reassessment of 
the dose-schedule when 3 months or 12 cycles of therapy are completed will be performed 
by collecting the patient’s medication diary information. This information will be collected 
by the study PI or the study coordinator by direct communication with the patient.  
Besides response measured through imaging studies, physical and emotional well-being 
will be evaluated to assess improvement in daily living as exploratory endpoints. These 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 62 of 77 
evaluations will be performed by the rehabilitation medicine and pain and palliative care 
teams during the treatment part of this trial as well as the off therapy follow up period.  The 
list of tools and evaluations is available on sections 4.1.2 and 11.3.  
7.1.2- Stratification Factors 
N/A 
7.1.3- Analysis of Secondary Endpoints 
As secondary evaluations, time to response, duration of response, PFS and OS will be 
reported separately using Kaplan-Meier curves and appropriate 95% confidence intervals. 
Every report will contain all patients included in the study. These findings will be compared 
informally to other similar published results in patients with the same disease. 
Other exploratory analyses will include FDG-PET, CT, bone scans, and levels of C-
reactive protein, ESR, and cytokines. There are no specific ECD biomarkers that can be 
measured in blood, urine or tissue in order to assess disease activity. 
In patients affected by central nervous system disease (mainly cerebellar and brain stem 
disease), improvement in overall physical function and conditioning will be assessed. 
Patients will be evaluated by rehabilitation medicine and neurology. Improvement of their 
overall quality of life will be evidence of response, and assessments will be made at 
baseline and throughout the trial, as well as at the conclusion of the trial, to evaluate for 
any improvement in quality of life. 
Resistance to therapy will be evaluated through imaging studies and patient follow up for 
at least one year, but this is not expected with the combination therapy.   
7.1.4- Reporting and Exclusions 
Evaluation of Toxicity 
All patients will be evaluable for toxicity from the time of their first treatment with 
Dabrafenib mesylate (GSK2118436B, NSC 763760) and Trametinib dimethyl sulfoxide 
(GSK1120212B) (NSC 763093). 
CTEP is the sponsor of the trial. The principial investigator and study data manager will 
monitor the safety data. CTEP will be notified of serious adverse events as soon as the PI, 
associate investigator or study data manager are aware of them through the expedited 
reporting systems and all AEs through the routine reporting to CDS. The National Human 
Genome Research Institute Intramural Data Safety and Monitoring Board (DSMB) will 
also monitor this trial. Monitoring by the DSMB will include receipt of quarterly updates 
regarding the trial status and accrual with a report every 6 months summarizing safety data 
as provided by the investigational staff. The DSMB will follow the protocols stopping 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 63 of 77 
guidelines for serious adverse event as described in sections 4.7 and 9. Timing of the 
reports may be adjusted based on the rate of enrollment or any other circumstance that 
might warrant increased monitoring, for example if more than expected adverse events are 
reported on the quarterly updates, safety data reports may be available sooner than 6 
months. 
The NHGRI DSMB is led by Pamela West, executive secretary, NHGRI DSMB. Other 
DSMB members include physicians and ethicists. Three members of the DSMB are from 
outside NIH and one is from within the NIH. 
 
Evaluation of Response 
All patients included in the study must be assessed for response to treatment, even if there 
are major protocol treatment deviations or if they are ineligible.  Each patient will be 
assigned one of the following categories:  1) complete response, 2) partial response, 3) 
stable disease, 4) progressive disease, 5) early death from malignant disease, 6) early death 
from toxicity, 7) early death because of other cause, or 9) unknown (not assessable, 
insufficient data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
All the patients who met the eligibility criteria (with the possible exception of those who 
received no study medication) will be included in the main analysis of the response rate.  
Patients in response categories 4-9 will be considered to have a treatment failure (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result 
in exclusion from the analysis of the response rate.  Precise definitions for categories 4-9 
will be protocol specific.  
All conclusions will be based on all eligible patients.  Subanalyses will be performed on 
the basis of a subset of patients, excluding those for whom major protocol deviations have 
been identified (e.g., early death due to other reasons, early discontinuation of treatment, 
major protocol violations, etc.).  However, these subanalyses will not serve as the basis for 
drawing conclusions concerning treatment efficacy, and the reasons for excluding patients 
from the analysis will be clearly reported.  The 95% confidence intervals will also be 
provided.  
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 64 of 77 
  
8.0 Description of potential benefits of study: 
8.1 Direct benefits to participants  
This study has only a small chance of a direct benefit for the participant because we do not 
know if the study drug/study approach is effective. This study may help researchers learn 
things that may help other people in the future. 
8.2 Collateral benefit to participants 
Individual patients will have the benefit of improved accuracy of diagnosis and prognosis 
due to greater experience and knowledge by a physician caring for a large number of ECD 
patients. The results of testing performed at the Clinical Center will provide baseline or 
follow up medical data for each patient. The Principal Investigator serves as a resource for 
consultation with referring physicians. 
8.3 Benefits to society 
This protocol should elucidate the clinical breadth of ECD, and provide new approach to 
treatment of this rare disorder 
9.0  Description of likelihood and seriousness of harms and how safety   will be 
maximized: 
9.1 Therapeutic Interventions – Adverse Events: List and Reporting Requirements 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 9.1.1) and the characteristics of an observed AE (Section 
9.1.2) will determine whether the event requires expedited reporting (via CTEP-AERS) in 
addition to routine reporting.   
9.1.1- Comprehensive Adverse Events and Potential Risks List(s) (CAEPRs) 
CAEPRs for CTEP IND Agent(s) 
CAEPR for Dabrafenib and Trametinib. 
9.1.1.1- Comprehensive Adverse Events and Potential Risks list (CAEPR) for 
Dabrafenib mesylate (GSK2118436B, NSC 763760) and Trametinib dimethyl 
sulfoxide (GSK1120212B, NSC 763093) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate 
column and is identified with bold and italicized text. This subset of AEs (SPEER) is a list 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 65 of 77 
of events that are protocol specific exceptions to expedited reporting to NCI via CTEP-
AERS (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event 
Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 691 patients for Dabrafenib 
Mesylate and 968 for Trametinib dimethyl sulfoxide . CAEPR for Dabrafenib mesylate 
(GSK2118436B) and Trametinib dimethyl sulfoxide (GSK1120212B) are available on 
Appendix 2.  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
9.1.2- Adverse Event List(s) for [Other Investigational Agent(s)] 
N/A 
9.1.2.1- Adverse Event List(s) for Commercial Agent(s) 
N/A 
9.1.2.2- CAEPR for [CIP IND Agent #1)] 
N/A 
9.1.2.3- Adverse Event List(s) for CIP (e.g. Study-Specific) Commercial Imaging 
Agents 
N/A 
9.1.3- Adverse Event Characteristics  
CTCAE term (AE description) and grade:  The descriptions and grading scales found 
in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 
4.0 will be utilized for AE reporting.  All appropriate treatment areas should have access 
to a copy of the CTCAE version 4.0.  A copy of the CTCAE version 4.0 can be downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed in the 
SPEER column, Section 9.1.1.1) should be reported through CTEP-AERS only if the 
grade is above the grade provided in the SPEER. 
o Other AEs for the protocol that do not require expedited reporting are outlined in 
section 9.1.1.1 and 9.1.4 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 66 of 77 
 
• Attribution of the AE: 
Definite – The AE is clearly related to the study treatment. 
Probable – The AE is likely related to the study treatment. 
  Possible – The AE may be related to the study treatment. 
Unlikely – The AE is doubtfully related to the study treatment. 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
9.1.4- Expedited Adverse Event Reporting 
Expedited AE reporting for this study must use CTEP-AERS (Adverse Event Expedited 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for Investigators: 
Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and DCP INDs and 
IDEs” which can be downloaded from the CTEP Web site (http://ctep.cancer.gov).  These 
requirements are briefly outlined in the tables below (Section 9.1.4.1). 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site. 
9.1.4.1- Expedited Reporting Guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
Death due to progressive disease should be reported as Grade 5 “Neoplasms benign, 
malignant and unspecified (incl cysts and polyps) - Other (Progressive Disease)” under 
the system organ class (SOC) of the same name.  Evidence that the death was a 
manifestation of underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be submitted.  
 
 
 
 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 67 of 77 
Table 17. Expedited Reporting Requirements for Adverse Events that Occur on Studies 
under an IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR 
Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious 
Adverse Events, whether or not they are considered related to the 
investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of 
existing hospitalization for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered serious when, based upon medical 
judgment, they may jeopardize the patient or subject and may require medical 
or surgical intervention to prevent one of the outcomes listed in this definition. 
(FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately 
reported to the NCI via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalizatio
n 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization  
≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 68 of 77 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events 
are found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion 
of the CAEPR 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS 
within 24 hours of learning of the AE, followed by a complete expedited report 
within 5 calendar days of the initial 24-hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted 
within 10 calendar days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of 
investigational agent/intervention and have an attribution of possible, probable, or 
definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar 
days for: 
• All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of 
hospitalization  
• Grade 3 adverse events 
2For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the 
agent/intervention was last administered.  Footnote “1” above applies after this 
reporting period. 
Effective Date:  May 5, 2011 
 
Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
Not Applicable. 
9.1.5- Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
through CTEP-AERS must also be reported in routine study data submissions. 
9.1.6- Secondary Malignancy Due to Prior Treatment or Interventional Therapy 
In these cases, a secondary malignancy is a cancer caused by treatment for a previous 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 69 of 77 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). In these cases, a secondary malignancy is not considered a metastasis of 
the initial neoplasm.  
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event:  
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
9.1.7- Second Malignancy Unrelated to Prior Treatment or Interventional Therapy 
In these cases, a second malignancy is one unrelated to the treatment of a prior malignancy 
(and is NOT a metastasis from the initial malignancy). CTEP requires all second 
malignancies that occur following treatment with an agent under an NCI IND/IDE be 
reported expeditiously via CTEP-AERS.  
9.2 Diagnostic interventions  
Risks from diagnostic interventions are minimal. A physical risk of this study consists of 
the phlebotomy requirement. Blood drawing can cause a small amount of discomfort and 
possible bruising or redness from a small needle puncture.  Rarely, some people faint from 
blood drawing.   
Electrocardiogram and echocardiogram do not involve radiation and are minimal risk. 
However, these studies may be uncomfortable for the patient, due to the use of probes and 
instruments placed on the patient’s skin. In the heart tracing, electric signals produced by 
the heart are measured by probes that are placed on the skin surface.  There are times when 
shaving of chest hair is needed for this test.  The echocardiogram uses soundwaves to show 
pictures of the heart using an instrument called a transducer placed on the skin of the 
patient’s chest. 
Discomforts also include the venipunctures themselves (usually 2 per admission) and 
24-hour urine collections 
 
9.3 Radiation 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 70 of 77 
  
The imaging studies proposed for staging and follow up of target lesions in this trial are all 
clinically indicated in the diagnosis of Erdheim Chester disease and are also indicated for 
the proper follow up of patients undergoing active therapy. 
For cancer, it is necessary to do the imaging for proper evaluation of treatment efficacy 
and since these treatments are also toxic, serial radiological assessments are needed in order 
to discontinue treatments that are ineffective. CT scan as well as PET/CT scan and other 
nuclear medicine studies are common clinical practice in cancer care. ECD is not yet 
considered a malignancy, but emerging research indicates that besides BRAF, other RAS 
genes are involved and some researchers postulate oncogene-induced senescence as a 
possible pathophysiological mechanism making this disease to behave as a low grade 
malignancy. Having multiple tests using radiation, increases the possibility of cancer 
induction due to radiation exposure; this will be discussed at the time of recruitment. 
9.4 Sedation 
The use of sedation will be primarily for clinical purposes. However, there may be 
circumstances where sedation is required for procedures that are strictly for research. For 
example, procedures such as the tissue biopsy (including, but not limited to, bone marrow, 
core bone, and perirenal biopsy) or imaging studies will require sedation. The tissue 
biopsies will be clinically indicated procedures (e.g., tissue collection for mutant BRAF 
status) and research procedures (e.g., tissue collection for proteomic analysis). It is our 
intention to use sedation primarily when clinically indicated, but there may be times when 
the use of sedation for tissue collection will be needed for the purpose of research, (e.g., 
tissue collection to evaluate regression of hisiocytic infiltration and proteomic analysis).   
This will help the participant tolerate the procedure with minimal or no discomfort. The 
risks associated with this include, but are not limited to, allergic reaction to the sedative 
used, amnesia, airway obstruction, apnea, hypotension and hallucinations. Healthcare 
professionals trained to respond to these events, as well as the necessary medical 
equipment, will be available at the bedside. This will be discussed with the participant prior 
to consent signature. 
9.5 Psychological harms 
The main psychological issues will be the acquisition by the patient of a new awareness 
concerning ECD and new hope for a cure. Learning the likelihood of other complications 
is usually part of the motivation behind a patient’s enrolling in this protocol. Lack of 
therapeutic efficacy will be a challenging situation for the patient. Facing this reality can 
be besides challenging, depressing, so counseling will be available. Incomplete 
understanding is always a risk, but should be minimized by the availability of counseling 
and consultation through the principal investigator.  


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 71 of 77 
 
Also, some people have had problems getting jobs or life insurance policies as a result of 
participating in genetic studies.  These situations might cause emotional and financial 
stress.  While it is our policy to protect privacy and confidentiality and not to disclose 
genetic information, we cannot guarantee complete confidentiality.  There may be rare 
instances when we are required by law to release information without permission.  If such 
an instance occurs, we will attempt to notify the patient. 
 
 
9.6 Risks to family relationships. 
This protocol may reveal unexpected family relationships such as adoption or misattributed 
parentage, but if these issues do arise, we will not mention them to the patient or family 
members, unless medically or genetically significant information is found. Every attempt 
will be made to uphold the objective of privacy and subject autonomy. 
9.7 Discrimination. 
Patients enrolled in this protocol already have ECD. However, the hematologic and 
pulmonary complications among others may create additional issues vis-à-vis insurability 
and employment. To the fullest extent possible, the investigators will not disclose to third 
parties any information about the participants without their expressed consent. The risks of 
genetic (DNA) testing include concern over the specific DNA results found and failure to 
keep the genetic information private.  However, medical data collected for this protocol 
will be treated confidentially, as is standard for patient-related information. 
10 Description of how privacy and confidentiality of medical information/biological 
specimens will be maximized  
10.1 Will participant identifiers be attached to data, or will samples/data be coded 
or unlinked? 
  
Patient samples will be coded on arrival. However, the identifier will be attached to the data, 
all of which will be maintained in records in a locked file cabinet and a research database 
such as Lab Matrix within a secured laboratory on the NIH main campus in Bethesda, MD. 
Besides LabMatrix and after the approval of amendment E, the research team will be using 
the NICHD electronic data capture system, the Clinical Trials Database (CTDB) as a 
complimentary data base. Data entered directly in CTDB will be considered digital source 
documentation. The Clinical Trials Database Project (CTDB) assists Investigators with the 
management of natural history and clinical trial research projects.  Associated with the 
project are two major components: (1) a set of information technology systems based upon 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 72 of 77 
industry standard technologies and best practices (e.g. Java, XML, UML); and (2) a team of 
support staff that assist investigators with designing and executing research projects. CTDB 
is 21 CFR Part 11 Compliance certified. The CTDB is a web-based application that supports 
flexible data capture, and reporting. The system is hosted at the NIH in Bethesda, MD and 
was pushed to production in 2004.  It is accessible via the Internet through the NIH firewall, 
on both Mac and Windows based computers.  An Oracle relational database is utilized to 
capture and secure data entered through the web interface. 
 
Access to this research databases will be limited to the investigators and laboratory staff 
involved in this project. Patients’ medical summaries and other documents sent to us upon 
referral to this study will be kept in a locked file cabinet on the NIH campus. 
10.2 Description of any clinical/demographic information that will be included.  
This will be part of the clinical data kept in a locked file within a secured laboratory on the 
NIH campus. 
10.3   How might this information make specific individuals or families identifiable? 
Patients enrolled in this study are from all over the world. It is doubtful that any 
demographic information could identify an individual. However, if an ECD patient lived 
in a small town, and information revealed that the person was enrolled in this study, the 
patient might be identified as having ECD. 
10.4   If research data will be coded, how will access to the “key” for the code be  
limited? Include description of security measures (e.g., password-protected database, 
other).  List names or positions of persons with access to the "key" for the code. 
The code to patient identities, as well as other patient data, will be kept in a password 
protected database. Access to the code will be restricted to the principal investigator, Dr. 
William A. Gahl. This protected database will contain patient’s information obtained at the 
NIH visit. The results of research and relevant tests and procedures done at the NIH will 
also be kept in this protected database. 
10.5 Will pedigrees be published?  Include description of measures to minimize the 
chance of identifying specific families. 
Partial pedigrees or pedigrees that are not identifiable may be published. Elements that 
could uniquely identify a pedigree will be disguised by, for example, not specifying the 
genders of certain members. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 73 of 77 
10.6 Will results be provided to participants? 
All clinical data will be given directly to the patients at a debriefing session just prior to                      
discharge. 
10.7 Will personally identifiable information be released to third parties? 
The investigators will not disclose to third parties any information about the participants 
without their expressed consent, unless required by law. 
10.8 Under what circumstances will data/samples be shared with other researchers 
or deposited in various repositories, biobanks, and/or databases voluntarily or as 
mandated by NIH policies (e.g. dbGaP)? 
Biologicals and data may be shared with collaborators within NIH, but will not be 
transferred to another site with any identifiers. Patient’s biologicals and data can be shared 
with ECD investigators outside of the NIH, but these samples and data will be de-identified 
and patients will provide permission to allow for their samples and data to be shared. Also, 
requests by the patient to transfer samples to another laboratory will be honored if 
reasonable, e.g., if another investigator offers a diagnostic test not offered by this protocol. 
Questionable requests will be referred for IRB or ethics review. 
10.9 Describe any additional features to protect confidentiality. 
  No other features will be used to protect confidentiality at the moment 
11.0  Assessment of risk/benefit ratio 
This is a phase II, interventional study enrolling adults with Erdheim Chester Disease. This 
study will not enroll children or adults who are or may be unable to provide consent. This 
study involves greater than minimal risk, but presents the prospect of direct benefit to 
individual subjects from the intervention being tested. This study also presents the 
possibility of yielding generalizable knowledge about the disease under study, Erdheim 
Chester Disease, which could directly or indirectly influence the care of patients with ECD 
in the future. 
12.0 Unanticipated Problems:  Collection, monitoring, analysis and reporting of 
adverse events and protocol deviations  
12.1 Exclusion of adverse event reporting for a natural history protocol. 
N/A 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 74 of 77 
12.2 Monitoring of adverse events related to this protocol. 
Adverse events, protocol deviations, unanticipated problems (UP), Unanticipated Adverse 
Device Effects (UADEs), serious adverse events, sponsor and serious, are defined as 
described in NIH HRPP SOP 16 ("Reporting Requirements for Unanticipated Problems, 
Adverse Events and Protocol Deviations").  All adverse events occurring during the study, 
including those observed by or reported to the research team, will be recorded.  Serious 
unanticipated problems, Unanticipated Adverse Device Effects and serious protocol 
deviations, will be reported to the IRB and CD (Clinical Director) as soon as possible but 
not more than 7 days after the PI first learns of the event.  Not serious unanticipated 
problems will be reported to the IRB and CD as soon as possible but not more than 14 days 
after the PI first learns of the event.  Not serious protocol deviations will be reported to the 
IRB as soon as possible but not more than 14 days after the PI first learns of the event. 
Deaths will be reported to the Clinical Director within 7 days after the PI first learns of the 
event. 
12.3 Data Safety and Monitoring Board. 
This protocol offers therapeutic interventions and a DSMB is indicated, but CTEP will lead 
the monitoring of this trial.  
13.0 Description of alternatives to participation  
We know of no other therapeutic clinical trial studying exclusively the efficacy of targeted 
therapy on BRAF V600E mutated ECD. Patients are welcome to participate in other research 
studies in ECD that are available in the USA and Europe. Currently, this is the only study 
that is treating ECD patients without having patients with other malignancies in the cohort. 
14.0 Description of consent process  
14.1 Who will obtain consent? 
 
 Either the Principal Investigator or an Associate Investigator will obtain consent. 
14.2 Setting where consent will be obtained. 
Consent will be obtained on the inpatient ward or outpatient clinics of the NIH Clinical 
Center. 
14.3 What information will be provided to participants? 
 
 A copy of the consent form will be given to each participant for their records. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 75 of 77 
14.4 Protections for participants who may be vulnerable to coercion or undue 
influences. 
This study will enroll adults with Erdheim Chester Disease. We will not enroll children, 
pregnant women, prisoners, healthy volunteers, or adults with impaired decision-making 
ability. Children are excluded from this study, because no dosing or adverse event data are 
currently available on the use of dabrafenib in combination with trametinib in patients 
under 18 years of age. Pregnant women and fetuses are excluded from this study, because 
BRAF inhibitors, as well as other therapeutic agents used in this trial, are known to be 
teratogenic (causing physiological abnormalities during development) to fetuses. Prisoners 
will not be enrolled, because of their inability to comply with the requirement to visit the 
NIH Clinical Center on a regular basis for study visits. Adults who are or may be unable 
to provide informed consent and adults with impaired decision-making ability, will not be 
enrolled to the study, because of their anticipated inability to comply with the complex and 
rigorous study procedure requirements. If at any time during the study a subject loses the 
ability to provide informed consent or develops impaired decision-making ability, the 
subject will be withdrawn from the study. 
Potential participants who are also NIH employees will not be excluded based solely upon 
their affiliation with NIH. However, due to the rare nature of the disease being studied, the 
disabling course of the disease, and the small number of subjects to be enrolled, it is 
extremely unlikely that any potential subjects we enroll will also be NIH employees. At 
this time, we do not anticipate enrolling any NIH employees into this study. 
14.5 Are there special circumstances regarding obtaining consent?  
We anticipate that all potential participants will be proficient with the English language and 
will be consented in English. However, we will not exclude potential participants, who are 
otherwise eligible, based upon their inability to be consented in English. In those cases, we 
will submit an action to the IRB for the use of the short form and will use an interpreter to 
conduct the informed consent with one of the study investigators present. We also anticipate 
that all potential participants will undergo all studies and procedures in order to meet our 
objectives and successfully conclude our trial.   
15.0  Description of any financial compensation  
N/A 
16.0  References 
1- 
Adam Z, Szturz P et al. “Cladribine is a highly effective in the treatment of Langerhans cell 
histiocytosis and rare histiocytic disorders of the Juvenile Xanthogranuloma group” Vnitr Lek, 
58(6): 455-65, June 2012. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 76 of 77 
2- 
Adam Z, Koukalova R, Sprlakova A “Successful treatment of Erdheim Chester disease by 2-
chlorodeoxyadenosine based chemotherapy: Two cases and review of the literature” Vnitr Lek 
57(6): 1576-89.  
3- 
Aouba, A., Georgin-Lavialle, S., Pagnoux, C., et al. (2010). Rationale and efficacy of 
interleukin-1 targeting in Erdheim Chester disease. Blood, 116(20), 4070-6. 
4- 
Balagula, Y., K. Barth Huston, K.J. Busam, et al.  (2010).  Dermatologic side effects associated 
with the MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886).  Invest New Drugs.  
29:1114-1121. 
5- 
Bassou, D., El Kharras, A., Taoufik, A.T., EN Nouali, H., Elbaaj, M., Benameur, M., et al. 
(2009). Cardiac Erdheim Chester. Intern Med, 48(1), 83-84. 
6- 
Bianco, F., Iacovelli, E., Tinelli, E., Locuratolo, N., Pauri, F., & Fattapposta, F. (2009). 
Characteristic brain MRI appereance of Erdheim Chester disease. Neurology, 73(24), 2120-
2122. 
7- 
Bjelland I., Dahl, AA., Haug TT., The Validity of the Hospital Anxiety and Depression Scale. 
An Updated Literature Review. J Psychosom Res. 2002 Feb;52(2): 69-77  
8- 
Bogats, G., Piros, G., Tiszlavicz, L., Ivanyi, B., Sasi, V., Csepregil, L., et al. (2006). Erdheim 
Chester’s disease of the heart: a diagnostic conundrum and collision with the same mass in the 
orbit. Heart Surg Forum, 9(1), E549-554. 
9- 
Braiteh, F., Boxrud, C., Esmaeli, B., &Kurzrock, R. (2005). Successful treatment of Erdheim 
Chester disease, a non-langerhans-cell histiocytosis, with interferon-alpha. Blood, 106(9), 
2992-2994. 
10- 
Chang VT., Hwang SS., Feuerman M., The Memorial Symptom Assessment Scale Short Form 
(MSAS-SF), Cancer, 2000 Sep 1;89(5): 1162-71 
11- 
Chapman, P.B., A. Hauschild, C. Robert, et al.  (2011).  Improved survival with vemurafenib 
in melanoma with BRAF V600E mutation.  N Engl J Med.  364:2507-2516. 
12- 
Chester W. Uber Lipoidgranulomatose. Virchows Arch Pathol, Anat 1930; 279:561-602. 
13- 
Clerico, Anna., et al (2003). Erdheim Chester Disease in a child. Med Pediatr Oncol, 41(6), 
575-577. 
14- 
Drier, A., Haroche, J., Savatovsky, J., et al (2010). Cerebral, facial, and orbital involvement in 
Erdheim Chester disease: CT and MR Imaging findings. Radiology, 255(2) 
15- 
Flaherty, K.T., J.R. Infante, A. Daud, et al.  (2012).  Combined BRAF and MEK inhibition in 
melanoma with BRAF V600 mutations.  N Engl J Med.  367:1694-1703. 
16- 
Force, T., D.S. Krause, and R.A. Van Etten.  (2007). Molecular mechanisms of cardiotoxicity 
of tyrosine kinase inhibition.  Nat Rev Cancer.  7:332-344. 
17- 
Haroche, J., Amoura, Z., Touraine, P., Seilhean, D., Graef, C., Birmele, B., et al. (2007). 
Bilateral adrenal infiltration in Erdheim Chester disease. Report of seven cases and literature 
review. J Clin Endocrinol Metab, 92(6), 2007-2012. 
18- 
Haroche, J, Arnoud, L “Erdheim Chester Disease” Curr Opin Rheumatol, 2012. 
19- 
Haroche J, Charlotte F, Arnoud L et al, . High prevalence of BRAF V600E mutations in 
Erdheim-Chester disease but not in other non-Langerhans cell histiocytoses. Blood. 2012 Sep 
27;120(13):2700-3  
20- 
Haroche, J; Cohen-Aubart, F. et al “Dramatic efficacy of Vemurafenib in both multisystemic 
and refractory Erdheim Chester disease and Langerhans cell histiocytosis harboring the BRAF 
V600E mutation” Blood, December 2012. 
21- 
Hauschild, A., J.J. Grob, L.V. Demidov, et al.  (2012).  Phase III, randomized, open-label, 
multicenter trial (BREAK-3) comparing the BRAF kinase inhibitor dabrafenib (GSK2118436) 
with dacarbazine (DTIC) in patients with BRAFV600E-mutated melanoma.  J Clin Oncol.  
30:Abstract LBA8500. 
22- 
Herth K., Abbreviated Instrument to Measure HOPE: Development and Psychometric 
Evaluation, Journal of Advanced Nursing, 1992, 17, 1251-1259. 
23- 
Hervier, B; Arnoud, L; Charlotte, F et al. “Treatment of Erdheim Chester disease with long 
term high dose IFN Alpha” Semin Arthritis Rheum, 2011.  
24- 
Investigator’s Brochure (2012a).  GSK2118436.  GlaxoSmithKline.  Version 04.  May 15, 
2012. 
25- 
Investigator’s Brochure.  (2012b).  GSK1120212 + GSK2118436.  GlaxoSmithKline.  Version 
01.  February 15, 2012. 


• 
NHGRI IRB Protocol - June 26, 2017   
NHGRI Template Version 9/26/2016 
 
Page 77 of 77 
26- 
Ironson, G., Solomon B., et al, The Ironson-Woods Spirituality/Religiousness Index is 
Associated with Long Survival, Health Behaviors, Less Distress, and Low Cortisol in People 
with HIV/AIDS, Ann Behav Med 2002, 24(1): 34-48. 
27- 
Jaffe, Ronald “The Histiocytoses” Clinics in Laboratory Medicine” 19(1): March 1999. 
28- 
Janku, Filip et al “ Response of histiocytoses to imatinib mesylate: fire to ashes” Journal of 
Clinical Oncology, Vol 28, No 31, Nov. 2010. 
29- 
Kopetz, S., J. Desai, E. Chan, et al.  (2010).  PLX4032 in metastatic colorectal cancer patients 
with mutant BRAF tumors.  J Clin Oncol.  28:Abstract 3534. 
30- 
Lachenal, F., Cotton, F., Desmurs-Clavel, H., Haroche, J., Taillia, H., Magy, N., et al. (2006). 
Neurological manifestations and neuroradiological presentation of Erdheim Chester disease: 
report of 6 cases and systematic review of the literature. J Neurol, 253(10), 1267-1277. 
31- 
Lacouture, M.E., M.J. Anadkat, R.J. Bensadoun, et al.  (2011).  Clinical practice guidelines for 
the prevention and treatment of EGFR inhibitor-associated dermatologic toxicities.  Support 
Care Cancer.  19:1079-1095. 
32- 
Lau, W. W., Chan, E., & Chan, C. W. (2007). Orbital involvement in Erdheim Chester disease. 
Hong Kong Med J, 13(3), 238-240. 
33- 
Long, G.V., A.M. Menzies, A.M. Nagrial, et al.  (2011).  Prognostic and clinicopathologic 
associations of oncogenic BRAF in metastatic melanoma.  J Clin Oncol.  29:1239-1246. 
34- 
Lyders, E. M., Kaushik, S., Perez-Berenguer, J., & Henry, D. A. (2003). Aggressive and 
atypical manifestations of Erdheim Chester disease. Clin Rheumatol, 22(6), 464-466 
35- 
Namwongprom, S., Nunez, R., Kim. E. E., & Macapinlac, H.A. (2007). Tc-99m MDP bone 
scintigraphy and positron emission tomography/computed tomography(PET/CT) imaging in 
Erdheim Chester disease. Clin Nucl Med, 32(1), 35-38. 
36- 
Nathanson, K.L., A. Martin, R. Letrero, et al. (2011).  Tumor genetic analyses of patients with 
metastatic melanoma treated with the BRAF inhibitor GSK2118436 (GSK436).  J Clin Oncol.  
29:Abstract 8501. 
37- 
Salama, April; Flaherty, Keith “BRAF in Melanoma: Current strategies and future directions” 
Clin Cancer Rs, June 14, 2013. Published Online. 
38- 
Shamburek, R., Brewer, B., Gochuico, B., (2001). Erdheim-Chester disease: a rare multisystem 
histiocytic disorder associated with interstitial lung disease. Am J Med Sci;321(1): 66-75. 
39- 
Skeath, P., Norris, S., Katheria, V., The Nature of Life-Transforming Changes Among Cancer 
Survivors, Qualitative Health Research, 23(9): 1155-1167, 2013 
40- 
Sosman, J., K. Kim, L. Schuchter, et al.  (2010).  An open-label, multicenter Phase II study of 
continuous oral dosing of RG7204 (PLX4032) in previously treated patients with BRAF 
V600E mutation-positive metastatic melanoma.  Pigment Cell Melanoma Res.  23:886. 
41- 
Tertemiz, K. C., Sevinc, C., Tuna, B., Karatosun, V., Yilmaz, E., & Celik, A. (2008). Erdheim 
Chester disease multisystemic manifestations and long term survival with corticosteroid 
therapy. Respiratory Medicine CME, 1(2), 126-130. 
42- 
Tran, T. A., Fabre, M., Pariente, D., Craiu, I., Haroche, J., Charlotte, F., et al. (2009). Erdheim 
Chester disease in childhood: a challenging diagnosis and treatment. J Pediatr Hematol Oncol, 
31(10), 782-786. 
43- 
Trab, T; Pariente, D; Lecron, JC, et al. “Treatment of Pediatric Erdheim Chester Disease with 
Interleukin-1 Targeting Drugs” Arthritis and Rheumatology, 63(12): 4031-32, 12/2011.  
44- 
Zelboraf. 
 
(2011).  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/202429s000lbl.pdf  (last accessed 
26 April 2013).