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

NCT02281760 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: 15000615-HG-0006
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

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.

Conditions

BRAF V600E Mutation

Keywords

Histiocytosis; Non Langerhans Cell Histiocytosis; BRAF Inhibitor

Outcome Measures

Primary Outcomes (3)

• Number of Participants With Partial Response to Dabrafenib and Trametinib

  Efficacy of dabrafenib and trametinib as combination therapy in patients with BRAFV600E positive Erdheim Chester Disease based on RECIST 1.1 criteria of a partial response greater than or equal to 30% decrease in at least one target lesion size.

  24 months

• Number of Participants With Adverse Events to Dabrafenib and/or Trametinib

  Safety of dabrafenib and trametinib as combination therapy, or either drug as single-agent therapy among participants, as measured by the adverse event characteristics of participants. See the adverse event table for list of specific adverse events experienced.

  24 months

• Clinical Response Rate to Dabrafenib/Trametinib Combination Therapy in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease.

  Clinical response rate to dabrafenib and trametinib combination therapy in patients as measured by the percentage of patients who met RECIST 1.1 criteria for a partial response.

  24 months

Secondary Outcomes (4)

• Progression-free Survival in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease

  24 months

• Overall Survival in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease

  24 months

• Disease Resistance to Dabrafenib/Trametinib Combination Therapy in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease

  12 months

• Time Response to Dabrafenib/Trametinib Combination Therapy in a Cohort of Patients With BRAFV600E Positive Erdheim Chester Disease.

  12 months

Study Arms (1)

Combination therapy with dabrafenib and trametinib in patients with ECD

EXPERIMENTAL

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.

Drug: Dabrafenib Mesylate; Drug: Trametinib Dimethyl Sulfoxide

Interventions

Dabrafenib Mesylate DRUG

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.

Combination therapy with dabrafenib and trametinib in patients with ECD

Trametinib Dimethyl Sulfoxide DRUG

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.

Combination therapy with dabrafenib and trametinib in patients with ECD

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT scan, MRI, or calipers by clinical exam.
• Patients must have BRAFV600E or BRAFV600K mutations, identified by an FDAapproved test at a CLIAcertified lab. If test at CLIAcertified lab used a nonFDA 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 greater than or equal to18 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 greater than or equal to 70%).
• Exception will be made for patients with ECOG performance status less than or equal to 3 and Karnofsky performance scale greater than or equal to 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 greater than or equal to 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) greater than or equal to1.2x10(9)/L
• Hemoglobin greater than or equal to 9 g/dL
• Platelets greater than or equal to100x10(9)/L
• Albumin greater than or equal to2.5 g/dL
• Serum bilirubin less than or equal to1.5x institutional upper limit of normal (ULN) except subjects with known Gilbert s syndrome

You may not qualify if:

• 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 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.
• 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 greater than or equal to 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 risks, except stable ECD cardiac lesion, including any of the following:
• QT interval corrected for heart rate using the Bazett s formula QTcB greater than or equal to 480 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.

Sponsors & Collaborators

• National Human Genome Research Institute (NHGRI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (3)

• Haroche J, Arnaud L, Cohen-Aubart F, Hervier B, Charlotte F, Emile JF, Amoura Z. Erdheim-Chester disease. Curr Rheumatol Rep. 2014 Apr;16(4):412. doi: 10.1007/s11926-014-0412-0.

  PMID: 24532298 BACKGROUND

• Haroche J, Cohen-Aubart F, Emile JF, Arnaud L, Maksud P, Charlotte F, Cluzel P, Drier A, Hervier B, Benameur N, Besnard S, Donadieu J, Amoura Z. Dramatic efficacy of vemurafenib in both multisystemic and refractory Erdheim-Chester disease and Langerhans cell histiocytosis harboring the BRAF V600E mutation. Blood. 2013 Feb 28;121(9):1495-500. doi: 10.1182/blood-2012-07-446286. Epub 2012 Dec 20.

  PMID: 23258922 BACKGROUND

• Yeager LB, Grimes JM, Dal Col AK, Shah NV, Bogomolny D, Debelenko L, Marr BP. Ophthalmologic Findings in Pediatric Erdheim-Chester Disease: A Literature Review With a Novel Case Report. Ophthalmic Plast Reconstr Surg. 2023 Sep-Oct 01;39(5):419-426. doi: 10.1097/IOP.0000000000002356. Epub 2023 Mar 3.

  PMID: 36877575 DERIVED

MeSH Terms

Conditions

Histiocytosis; Histiocytosis, Non-Langerhans-Cell

Condition Hierarchy (Ancestors)

Lymphatic Diseases; Hemic and Lymphatic Diseases

Results Point of Contact

• Title: Gahl, William
• Organization: National Human Genome Research Institute

gahlw@mail.nih.gov

+1 301 402 2739

Study Officials

• William A Gahl, M.D.

  National Human Genome Research Institute (NHGRI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 1, 2014
• First Posted: November 4, 2014
• Study Start: November 1, 2014
• Primary Completion: August 29, 2018
• Study Completion: August 29, 2018
• Last Updated: August 31, 2021
• Results First Posted: June 7, 2021

Record last verified: 2018-08-29

Locations

US (1)