<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03794297</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2018-03659</org_study_id>
    <secondary_id>NCI-2018-03659</secondary_id>
    <secondary_id>NCI9598B</secondary_id>
    <secondary_id>9598B</secondary_id>
    <secondary_id>9598B</secondary_id>
    <secondary_id>P30CA016672</secondary_id>
    <nct_id>NCT03794297</nct_id>
  </id_info>
  <brief_title>Dabrafenib and Trametinib in Treating Patients With Erdheim Chester Disease With BRAF V600 Mutations</brief_title>
  <official_title>A Phase II Therapeutic Trial of the Use of Dabrafenib and Trametinib in Patients With BRAF V600 Mutation Positive Lesions in Erdheim Chester Disease</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies the side effects and how well dabrafenib and trametinib work in&#xD;
      treating patients with Erdheim Chester disease that have BRAF V600 gene mutations. Dabrafenib&#xD;
      and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for&#xD;
      cell growth.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To study the efficacy and safety of dabrafenib mesylate (dabrafenib) and trametinib&#xD;
      dimethyl sulfoxide (trametinib) as combination therapy in patients with BRAF V600E positive&#xD;
      Erdheim Chester disease.&#xD;
&#xD;
      II. To determine the clinical response rate to dabrafenib and trametinib combination therapy&#xD;
      in patients with BRAF V600E positive Erdheim Chester disease.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine time response, progression free survival and overall survival. II. To assess&#xD;
      disease resistance to this combination therapy.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To monitor the degree of histiocytic infiltration-fibrosis progression, stability and&#xD;
      regression under combination therapy using fludeoxyglucose F 18 (FDG)-positron emission&#xD;
      tomography (PET) scan, magnetic resonance imaging (MRI) scans, computed tomography (CT) scans&#xD;
      and technetium (T)-99m bone scans.&#xD;
&#xD;
      II. To monitor serum C-reactive protein (CRP), estrogen receptor (ESR), and cytokine levels&#xD;
      as inflammatory markers prior to and during combination therapy.&#xD;
&#xD;
      III. To monitor renal function prior to and during combination therapy in order to assess for&#xD;
      functional improvement.&#xD;
&#xD;
      IV. To evaluate the level of functioning, fatigue, motor skills and ability to perform&#xD;
      routine daily activities prior to and during therapy in order to assess for improvements in&#xD;
      these areas as well as quality of life improvement.&#xD;
&#xD;
      V. To establish duration of treatment-endpoints in patients with BRAF V600E positive&#xD;
      Erdheim-Chester disease (ECD) lesions.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl&#xD;
      sulfoxide PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12&#xD;
      cycles in the absence of disease progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up for 48 weeks.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Inadequate accrual rate&#xD;
  </why_stopped>
  <start_date type="Actual">January 4, 2019</start_date>
  <completion_date type="Actual">February 18, 2021</completion_date>
  <primary_completion_date type="Actual">February 18, 2021</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Clinical response rate</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
    <description>Measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. 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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Incidence of toxicities</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
    <description>Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to response</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
    <description>Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response</measure>
    <time_frame>From the time measurement criteria are met for complete or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 48 weeks after completion of study treatment</time_frame>
    <description>Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>From start of treatment to time of progression or death, whichever occurs first, assessed up to 48 weeks after completion of study treatment</time_frame>
    <description>Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
    <description>Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Degree of histiocytic infiltration using fludeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and bone scans</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of C-reactive protein</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of estrogen receptor (ESR)</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Levels of cytokines</measure>
    <time_frame>Up to 48 weeks after completion of study treatment</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fatigue</measure>
    <time_frame>Baseline up to 48 weeks after completion of study treatment</time_frame>
    <description>Patients will be evaluated using the multi-dimensional fatigue inventory.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in level of functioning</measure>
    <time_frame>Baseline up to 48 weeks after completion of study treatment</time_frame>
    <description>Patients will be evaluated using the 6 minute walk test, single leg stance, and functional reach and grip strength using a dynamometer.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in ability to perform routine activities</measure>
    <time_frame>Baseline up to 48 weeks after completion of study treatment</time_frame>
    <description>Patients will be evaluated using the human activity profile and activity card sort.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in pain</measure>
    <time_frame>Baseline up to 48 weeks after completion of study treatment</time_frame>
    <description>Patients will be evaluated using the comparative pain scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in fine motor dexterity</measure>
    <time_frame>Baseline up to 48 weeks after completion of study treatment</time_frame>
    <description>Patients will be evaluated using the the group peg board test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in overall quality of life</measure>
    <time_frame>Baseline up to 48 weeks after completion of study treatment</time_frame>
    <description>Improvement of patients' 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. Patients will be evaluated using the National Institute of Neurological Disorders and Stroke-Neuro-Quality of Life scale.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Resistance to therapy</measure>
    <time_frame>Up to 1 year</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Erdheim-Chester Disease</condition>
  <arm_group>
    <arm_group_label>Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dabrafenib Mesylate</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)</arm_group_label>
    <other_name>Dabrafenib Methanesulfonate</other_name>
    <other_name>GSK2118436 Methane Sulfonate Salt</other_name>
    <other_name>GSK2118436B</other_name>
    <other_name>Tafinlar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Quality-of-Life Assessment</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)</arm_group_label>
    <other_name>Quality of Life Assessment</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Questionnaire Administration</intervention_name>
    <description>Ancillary studies</description>
    <arm_group_label>Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trametinib Dimethyl Sulfoxide</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)</arm_group_label>
    <other_name>Mekinist</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients can be previously or simultaneously enrolled in the natural history ECD&#xD;
             protocol #11-HG-0207, &quot;Clinical and Basic Investigations into Erdheim Chester&#xD;
             disease&quot;. Eligible patients must have been diagnosed with Erdheim Chester disease,&#xD;
             confirmed by pathological evaluation of the affected tissue with adequate staining.&#xD;
             Affected tissue must harbor the BRAF V600 mutation&#xD;
&#xD;
          -  Patients must have measurable or evaluable disease according to Response Evaluation&#xD;
             Criteria in Solid Tumors 1.1&#xD;
&#xD;
          -  Prior treatment, involving interferon, anakinra, imatinib, steroids, chemotherapy&#xD;
             with, but not limited to cladribine, vinblastine, 6-mercaptopurine and etoposide, or&#xD;
             other medications used empirically for the treatment of ECD, will be acceptable. These&#xD;
             therapies should have been completed and discontinued 4 weeks or for biologic agents 4&#xD;
             weeks or 5 half-lives (whichever comes shorter) prior to enrollment in this study&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status =&lt; 2 (Karnofsky &gt;= 60%)&#xD;
&#xD;
               -  Exception will be made for patients with ECOG performance status =&lt; 3 and&#xD;
                  Karnofsky performance scale &gt;= 50%, who require the use of wheelchairs, walkers&#xD;
                  or canes as well as assistance with daily routines secondary to disabilities&#xD;
                  caused by ECD cerebellar or brain disease that has been stable for &gt;= 3 months&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  Able to swallow and retain oral medication and must not have any clinically&#xD;
             significant gastrointestinal abnormalities that may alter absorption such as&#xD;
             malabsorption syndrome or major resection of the stomach or bowels&#xD;
&#xD;
          -  Patients must have BRAF V600 mutation in the tumor tissue and/or cell-free&#xD;
             deoxyribonucleic acid (DNA), identified by a Clinical Laboratory Improvement Act&#xD;
             (CLIA)-certified lab&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1.0 x 10^9/L&#xD;
&#xD;
          -  Hemoglobin &gt;= 8 g/dL&#xD;
&#xD;
          -  Platelets &gt;= 75 x 10^9/L&#xD;
&#xD;
          -  Serum bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN) except subjects&#xD;
             with known Gilbert's syndrome&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =&lt; 3 x&#xD;
             institutional ULN&#xD;
&#xD;
          -  Serum creatinine =&lt; 1.5 x institutional ULN&#xD;
&#xD;
          -  Left ventricular ejection fraction &gt;= institutional lower limit of normal (LLN) by&#xD;
             echocardiogram (ECHO)&#xD;
&#xD;
          -  Women of childbearing potential must have a negative serum pregnancy test within 14&#xD;
             days prior to registration or randomization&#xD;
&#xD;
          -  Pregnancy and breast feeding. The effects of dabrafenib and trametinib on the&#xD;
             developing human fetus are unknown. For this reason women of child-bearing potential&#xD;
             must agree to use adequate contraception (barrier method of birth control, or&#xD;
             abstinence; hormonal contraception is not allowed due to drug-drug interactions which&#xD;
             can render hormonal contraceptives ineffective) for the duration of study&#xD;
             participation, and for at least 2 weeks after treatment with dabrafenib or for 4&#xD;
             months after dabrafenib in combination with trametinib. Should a woman become pregnant&#xD;
             or suspect she is pregnant while she is participating in this study, she should inform&#xD;
             her treating physician immediately. Based on studies in animals, it is also known that&#xD;
             dabrafenib may cause damage to the tissue that makes sperm. This may cause sperm to be&#xD;
             abnormal in shape and size and could lead to infertility, which may be irreversible.&#xD;
             Safety and efficacy of the combination of dabrafenib and trametinib in pediatric&#xD;
             populations have not been investigated. Dabrafenib or trametinib-dabrafenib&#xD;
             combination should not be administered to pediatric populations outside clinical&#xD;
             trials&#xD;
&#xD;
          -  Therapeutic level dosing of warfarin can be used with close monitoring of prothrombin&#xD;
             time (PT)/international normalized ratio (INR) by the site. Exposure may be decreased&#xD;
             due to enzyme induction when on treatment, thus warfarin dosing may need to be&#xD;
             adjusted based upon PT/INR. Consequently, when discontinuing dabrafenib, warfarin&#xD;
             exposure may be increased and thus close monitoring via PT/INR and warfarin dose&#xD;
             adjustments must be made as clinically appropriate. Prophylactic low dose warfarin may&#xD;
             be given to maintain central catheter patency&#xD;
&#xD;
          -  Ability to understand and the willingness to sign a written informed consent document&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Inability to provide informed consent&#xD;
&#xD;
          -  Patients treated with prior BRAF and/or MEK inhibitors&#xD;
&#xD;
          -  Current use of a prohibited medication. Patients receiving any medications or&#xD;
             substances that are strong inhibitors or inducers of CYP3A or CYP2C8 are ineligible.&#xD;
             Current use of, or intended ongoing treatment with: herbal remedies (e.g., St. John's&#xD;
             wort), or strong inhibitors or inducers of P-glycoprotein (Pgp) or breast cancer&#xD;
             resistance protein 1 (Bcrp1) should also be excluded&#xD;
&#xD;
          -  Unresolved toxicity of National Cancer Institute Common Terminology Criteria for&#xD;
             Adverse Events, version 5.0 (NCI CTCAE v5.0) grade 2 or higher from previous&#xD;
             anti-cancer therapy, except alopecia, at the time of randomization&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral&#xD;
             therapy are ineligible because of the potential for pharmacokinetic interactions with&#xD;
             dabrafenib&#xD;
&#xD;
          -  A history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (with the&#xD;
             exception of cleared HBV and HCV infection, which will be allowed)&#xD;
&#xD;
          -  Presence of active malignancy other than the study indication&#xD;
&#xD;
          -  Patients with known RAS in ECD, or history of other malignancies with RAS mutations&#xD;
&#xD;
          -  Leptomeningeal or brain metastases are allowed. Subjects on a stable dose of&#xD;
             corticosteroids can be enrolled with approval of the principal investigator (PI) and&#xD;
             Cancer Therapy Evaluation Program (CTEP) medical monitor. Subjects must not receive&#xD;
             enzyme-inducing anticonvulsants&#xD;
&#xD;
          -  History or evidence of cardiovascular risks, except stable ECD cardiac lesion,&#xD;
             including any of the following:&#xD;
&#xD;
               -  QT interval corrected for heart rate using the Bazett's formula (QTcB) &gt;= 480&#xD;
                  msec&#xD;
&#xD;
               -  History of acute coronary syndromes (including myocardial infarction or unstable&#xD;
                  angina), coronary angioplasty, or stenting within the past 24 weeks prior to&#xD;
                  randomization&#xD;
&#xD;
               -  History or evidence of current class II, III, or IV heart failure as defined by&#xD;
                  the New York Heart Association (NYHA) functional classification system&#xD;
&#xD;
               -  Intra-cardiac defibrillators&#xD;
&#xD;
               -  Abnormal cardiac valve morphology (&gt;= grade 2) documented by ECHO; (subjects with&#xD;
                  grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered on&#xD;
                  study). Subjects with moderate valvular thickening should not be entered on study&#xD;
&#xD;
               -  History or evidence of current clinically significant uncontrolled cardiac&#xD;
                  arrhythmias; clarification: subjects with atrial fibrillation controlled for &gt; 30&#xD;
                  days prior to dosing are eligible&#xD;
&#xD;
               -  Treatment refractory hypertension defined as a blood pressure of systolic &gt; 140&#xD;
                  mmHg and/or diastolic &gt; 90 mm Hg which cannot be controlled by anti-hypertensive&#xD;
                  therapy&#xD;
&#xD;
          -  Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs&#xD;
             chemically related to the study treatments, their excipients, and/or dimethyl&#xD;
             sulfoxide (DMSO)&#xD;
&#xD;
          -  Any serious or unstable pre-existing medical conditions (aside from malignancy&#xD;
             exceptions specified above), psychiatric disorders, or other conditions that could&#xD;
             interfere with the subject's safety, obtaining informed consent, or compliance with&#xD;
             study procedures&#xD;
&#xD;
          -  Pregnant women are excluded from this study because of the potential for teratogenic&#xD;
             or abortifacient effects. Because there is an unknown but potential risk for adverse&#xD;
             events in nursing infants secondary to treatment of the mother with&#xD;
             dabrafenib/trametinib, breastfeeding should be discontinued prior to treatment with&#xD;
             dabrafenib/trametinib. These potential risks may also apply to other agents used in&#xD;
             this study&#xD;
&#xD;
          -  History of retinal vein occlusion (RVO)&#xD;
&#xD;
          -  Interstitial lung disease or pneumonitis not secondary to ECD&#xD;
&#xD;
          -  Central serous retinopathy (CSR) including presence of predisposing factors to RVO or&#xD;
             CSR (e.g., uncontrolled glaucoma or ocular hypertension, uncontrolled diabetes&#xD;
             mellitus, or a history of hyperviscosity or hypercoagulability syndromes); or visible&#xD;
             pathology (e.g., evidence of optic disc cupping, evidence of new visual field defects&#xD;
             on automated perimetry, or intraocular pressure &gt; 21 mmHg as measured by tonography)&#xD;
             as assessed by ophthalmic examination&#xD;
&#xD;
          -  Inability to travel to the treating center&#xD;
&#xD;
          -  Patients with confirmed diagnosis of ECD that are asymptomatic and with no visceral&#xD;
             involvement are not eligible for this trial (patients with no target lesions as per&#xD;
             RECIST 1.1 criteria)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Filip Janku</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2021</verification_date>
  <study_first_submitted>January 1, 2019</study_first_submitted>
  <study_first_submitted_qc>January 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 7, 2019</study_first_posted>
  <last_update_submitted>March 16, 2021</last_update_submitted>
  <last_update_submitted_qc>March 16, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 17, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Erdheim-Chester Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trametinib</mesh_term>
    <mesh_term>Dabrafenib</mesh_term>
    <mesh_term>Dimethyl Sulfoxide</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page</ipd_description>
    <ipd_url>https://grants.nih.gov/policy/sharing.htm</ipd_url>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03794297
org study id: NCI-2018-03659
secondary id: NCI-2018-03659
secondary id: NCI9598B
secondary id: 9598B
secondary id: 9598B
secondary id: P30CA016672
nct id: NCT03794297
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial studies the side effects and how well dabrafenib and trametinib work in
      treating patients with Erdheim Chester disease that have BRAF V600 gene mutations. Dabrafenib
      and trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for
      cell growth.
PRIMARY OBJECTIVES:

      I. To study the efficacy and safety of dabrafenib mesylate (dabrafenib) and trametinib
      dimethyl sulfoxide (trametinib) as combination therapy in patients with BRAF V600E positive
      Erdheim Chester disease.

      II. To determine the clinical response rate to dabrafenib and trametinib combination therapy
      in patients with BRAF V600E positive Erdheim Chester disease.

      SECONDARY OBJECTIVES:

      I. To determine time response, progression free survival and overall survival. II. To assess
      disease resistance to this combination therapy.

      EXPLORATORY OBJECTIVES:

      I. To monitor the degree of histiocytic infiltration-fibrosis progression, stability and
      regression under combination therapy using fludeoxyglucose F 18 (FDG)-positron emission
      tomography (PET) scan, magnetic resonance imaging (MRI) scans, computed tomography (CT) scans
      and technetium (T)-99m bone scans.

      II. To monitor serum C-reactive protein (CRP), estrogen receptor (ESR), and cytokine levels
      as inflammatory markers prior to and during combination therapy.

      III. To monitor renal function prior to and during combination therapy in order to assess for
      functional improvement.

      IV. 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.

      V. To establish duration of treatment-endpoints in patients with BRAF V600E positive
      Erdheim-Chester disease (ECD) lesions.

      OUTLINE:

      Patients receive dabrafenib mesylate orally (PO) twice daily (BID) and trametinib dimethyl
      sulfoxide PO once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 12
      cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 48 weeks.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Clinical response rate
time frame: Up to 48 weeks after completion of study treatment
description: Measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. 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.
measure: Incidence of toxicities
time frame: Up to 48 weeks after completion of study treatment
description: Assessed using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
measure: Time to response
time frame: Up to 48 weeks after completion of study treatment
description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.
measure: Duration of response
time frame: From the time measurement criteria are met for complete or partial response (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 48 weeks after completion of study treatment
description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.
measure: Progression-free survival
time frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 48 weeks after completion of study treatment
description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.
measure: Overall survival
time frame: Up to 48 weeks after completion of study treatment
description: Will be reported using Kaplan-Meier curves and appropriate 95% confidence intervals.
measure: Degree of histiocytic infiltration using fludeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and bone scans
time frame: Up to 48 weeks after completion of study treatment
measure: Levels of C-reactive protein
time frame: Up to 48 weeks after completion of study treatment
measure: Levels of estrogen receptor (ESR)
time frame: Up to 48 weeks after completion of study treatment
measure: Levels of cytokines
time frame: Up to 48 weeks after completion of study treatment
measure: Change in fatigue
time frame: Baseline up to 48 weeks after completion of study treatment
description: Patients will be evaluated using the multi-dimensional fatigue inventory.
measure: Change in level of functioning
time frame: Baseline up to 48 weeks after completion of study treatment
description: Patients will be evaluated using the 6 minute walk test, single leg stance, and functional reach and grip strength using a dynamometer.
measure: Change in ability to perform routine activities
time frame: Baseline up to 48 weeks after completion of study treatment
description: Patients will be evaluated using the human activity profile and activity card sort.
measure: Change in pain
time frame: Baseline up to 48 weeks after completion of study treatment
description: Patients will be evaluated using the comparative pain scale.
measure: Change in fine motor dexterity
time frame: Baseline up to 48 weeks after completion of study treatment
description: Patients will be evaluated using the the group peg board test.
measure: Change in overall quality of life
time frame: Baseline up to 48 weeks after completion of study treatment
description: Improvement of patients' 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. Patients will be evaluated using the National Institute of Neurological Disorders and Stroke-Neuro-Quality of Life scale.
measure: Resistance to therapy
time frame: Up to 1 year
description: 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.
arm group label: Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
arm group type: Experimental
description: Patients receive dabrafenib mesylate PO BID and trametinib dimethyl sulfoxide PO QD on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Dabrafenib Mesylate
description: Given PO
arm group label: Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
other name: Dabrafenib Methanesulfonate
other name: GSK2118436 Methane Sulfonate Salt
other name: GSK2118436B
other name: Tafinlar
intervention type: Other
intervention name: Quality-of-Life Assessment
description: Ancillary studies
arm group label: Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
other name: Quality of Life Assessment
intervention type: Other
intervention name: Questionnaire Administration
description: Ancillary studies
arm group label: Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
intervention type: Drug
intervention name: Trametinib Dimethyl Sulfoxide
description: Given PO
arm group label: Treatment (dabrafenib mesylate, trametinib dimethyl sulfoxide)
other name: Mekinist
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Filip Janku
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Erdheim-Chester Disease
mesh term: Trametinib
mesh term: Dabrafenib
mesh term: Dimethyl Sulfoxide
sharing ipd: Yes
ipd description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
ipd url: https://grants.nih.gov/policy/sharing.htm