Dabrafenib and Trametinib in People With BRAF V600E Mutation Positive Lesions in Erdheim Chester Disease
Condition: BRAF V600E Mutation
MeSH terms: Erdheim-Chester Disease
Intervention: Dabrafenib Mesylate; Trametinib Dimethyl Sulfoxide
Intervention description: Description: Dabrafenib mesylate (GSK2118436B) is a potent and selective BRAF kinase inhibitor. This inhibition suppresses downstream activity of pERK, a biomarker, and has antiproliferative activity against BRAF mutant tumors.The mode of action is consistent with ATP competitive inhibition.; Trametinib dimethyl sulfoxide is a reversible, highly selective, allosteric inhibitor of mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2. Tumor cells commonly have hyperactivated extracellular signal-related kinase (ERK) pathways in which MEK is a critical component. Trametinib dimethyl sulfoxide inhibits activation of MEK by RAF kinases and MEK kinases.
Intervention MeSH terms: Trametinib; Dabrafenib; Dimethyl Sulfoxide
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 9.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Histiocytosis; Non Langerhans Cell Histiocytosis; BRAF Inhibitor

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.
    

Eligibility criteria:

        -  INCLUSION CRITERIA:

          -  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

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than or
                  equal to2.5x institutional ULN

               -  Serum creatinine less than or equal to1.5 mg/dL OR calculated creatinine
                  clearance (Cockcroft-Gault formula) greater than or equal to 50 mL/min

               -  Prothrombin time (PT)/International normalized ratio (INR) and partial
                  thromboplastin time (PTT) less than or equal to1.3x institutional ULN; subjects
                  receiving anticoagulation treatment may be allowed to participate with INR
                  established within the therapeutic range prior to randomization.

               -  Left ventricular ejection fraction greater than or equal to institutional lower
                  limit of normal (LLN) by ECHO

          -  Women of childbearing potential must have a negative serum pregnancy test within 14
             days prior to registration or randomization.

          -  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.

          -  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 the willingness to sign a written informed consent document.

        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 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.

        Abnormal cardiac valve morphology (greater than or equal to 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

          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
             chemically related to the study treatments, their excipients, and/or dimethyl
             sulfoxide (DMSO).

          -  Any serious or unstable pre-existing medical conditions (aside from malignancy
             exceptions specified above), psychiatric disorders, or other conditions that could
             interfere with the subject s safety, obtaining informed consent, or compliance with
             study procedures.

          -  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/trametinib, breastfeeding should be discontinued prior to treatment with
             dabrafenib/trametinib. These potential risks may also apply to other agents used in
             this study.

          -  History of retinal vein occlusion (RVO).

          -  Interstitial lung disease or pneumonitis not secondary to ECD.

          -  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.

          -  Inability to travel to the NIH Clinical Center.

          -  Patients with wild type BRAF gene molecular results on ECD 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.