<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/NCT02263898</url>
  </required_header>
  <id_info>
    <org_study_id>14-000616</org_study_id>
    <secondary_id>NCI-2014-01971</secondary_id>
    <secondary_id>14-000616</secondary_id>
    <secondary_id>P01CA168585</secondary_id>
    <nct_id>NCT02263898</nct_id>
  </id_info>
  <brief_title>Intermittent LGX818 and MEK162 in Treating Patients With Metastatic Melanoma Who Have BRAFV600 Mutations</brief_title>
  <official_title>Biomarkers of Durable Response With Intermittent Therapy With LGX818 and MEK162 Combined Therapy in Patients With BRAF Mutant Metastatic Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Jonsson Comprehensive Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Jonsson Comprehensive Cancer Center</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase II trial studies intermittent dosing of BRAF inhibitor LGX818 (encorafenib) and&#xD;
      MEK inhibitor MEK 162 (binimetinib) in treating patients with melanoma that has spread to&#xD;
      other parts of the body (metastatic) and have a BRAF V600 mutation. LGX818 and MEK162 may&#xD;
      stop the growth of tumor cells by blocking different enzymes needed for cell growth. Giving&#xD;
      LGX818 and MEK162 with breaks between each course (intermittently) may help delay the time&#xD;
      when tumors become resistant to the drugs.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. One year progression free survival (PFS) rate.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. Obtain biopsy samples from patients treated with an intermittent schedule of LGX818 and&#xD;
      MEK162 to study adaptive and acquired resistance as well as melanoma evolutionary patterns.&#xD;
&#xD;
      II. Study molecular changes of adaptive resistance and acquired resistance to LGX818 and&#xD;
      MEK162 in circulating melanoma cells.&#xD;
&#xD;
      III. Study plasma samples for circulating deoxyribonucleic acid (DNA), microribonucleic acid&#xD;
      (microRNA) and protein signatures of adaptive resistance and acquired resistance.&#xD;
&#xD;
      IV. Explore the median progression free survival and overall survival of patients receiving&#xD;
      an intermittent schedule of LGX818 and MEK162.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive LGX818 orally (PO) once daily (QD) and MEK162 PO twice daily (BID)&#xD;
      continuously for 8 weeks, followed by intermittent dosing in subsequent cycles (3 weeks off&#xD;
      therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease&#xD;
      progression or unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days and then every 6&#xD;
      months thereafter.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    closed without enrollment&#xD;
  </why_stopped>
  <start_date>January 2015</start_date>
  <completion_date type="Anticipated">December 2020</completion_date>
  <primary_completion_date type="Anticipated">December 2019</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>PFS rate</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Recurrent Melanoma</condition>
  <condition>Stage IV Melanoma</condition>
  <arm_group>
    <arm_group_label>Treatment (LGX818, MEK162)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive LGX818 PO QD and MEK162 PO BID continuously for 8 weeks followed by intermittent dosing in subsequent cycles (3 weeks off therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Raf kinase inhibitor LGX818</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (LGX818, MEK162)</arm_group_label>
    <other_name>LGX818</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>binimetinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (LGX818, MEK162)</arm_group_label>
    <other_name>ARRY-162</other_name>
    <other_name>ARRY-438162</other_name>
    <other_name>MEK inhibitor ARRY-438162</other_name>
    <other_name>MEK162</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>laboratory biomarker analysis</intervention_name>
    <description>Correlative studies</description>
    <arm_group_label>Treatment (LGX818, MEK162)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Signed written informed consent&#xD;
&#xD;
          -  Histologically confirmed diagnosis of metastatic melanoma with the presence of the&#xD;
             B-Raf proto-oncogene, serine/threonine kinase (BRAFV600) mutation&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status &lt; 3&#xD;
&#xD;
          -  Absolute neutrophil count (ANC) &gt;= 1.0 x 10^9/L&#xD;
&#xD;
          -  Hemoglobin (Hgb) &gt;= 9 g/dL without transfusions&#xD;
&#xD;
          -  Platelets (PLT) &gt;= 90 x 10^9/L without transfusions&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) =&lt; 2.5 x upper&#xD;
             limit of normal (ULN); patient with liver metastases =&lt; 5 x ULN&#xD;
&#xD;
          -  Total bilirubin =&lt; 2 x ULN, or &lt; 5 ULN if Gilbertâ€™s disease&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 mg/dL, or calculated creatinine clearance (determined as per&#xD;
             Cockcroft-Gault) &gt;= 50 mL/min&#xD;
&#xD;
          -  Left ventricular ejection fraction (LVEF) &gt;= 50% as determined by a multigated&#xD;
             acquisition (MUGA) scan or echocardiogram (ECHO)&#xD;
&#xD;
          -  Corrected QT (QTc) interval =&lt; 480 ms&#xD;
&#xD;
          -  Able to take oral medications&#xD;
&#xD;
          -  Patient is deemed by the Investigator to have the initiative and means to be compliant&#xD;
             with the protocol (treatment and follow-up)&#xD;
&#xD;
          -  Negative serum beta (Î²) human chorionic gonadotropin (HCG) test (female patient of&#xD;
             childbearing potential only) within 72 hours prior to first dose&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior exposure to BRAF or MEK inhibitors&#xD;
&#xD;
          -  Any active central nervous system (CNS) lesion (i.e., those with radiographically&#xD;
             unstable, symptomatic lesions) and/or leptomeningeal metastases; however, patient&#xD;
             treated with stereotactic radiotherapy, whole brain radiation or surgery are eligible&#xD;
             if patient remained without evidence of CNS disease progression &gt;= 4 weeks; patients&#xD;
             must be off corticosteroid therapy for &gt;= 2 weeks&#xD;
&#xD;
          -  History or current evidence of retinal vein occlusion (RVO) or predisposing factors to&#xD;
             RVO (e.g. uncontrolled glaucoma or ocular hypertension, history of hyperviscosity or&#xD;
             hypercoagulability syndromes)&#xD;
&#xD;
          -  History of retinal degenerative disease&#xD;
&#xD;
          -  History of Gilbertâ€™s syndrome&#xD;
&#xD;
          -  Previous or concurrent malignancy is not an exclusion provided that the other&#xD;
             malignancy is considered under control and target lesions from melanoma are clearly&#xD;
             defined for response assessment&#xD;
&#xD;
          -  Impaired cardiovascular function or clinically significant cardiovascular diseases,&#xD;
             including any of the following:&#xD;
&#xD;
               -  History of acute coronary syndromes (including myocardial infarction, unstable&#xD;
                  angina, coronary artery bypass grafting, coronary angioplasty, or stenting) &lt; 6&#xD;
                  months prior to screening,&#xD;
&#xD;
               -  Symptomatic chronic heart failure, history or current evidence of clinically&#xD;
                  significant cardiac arrhythmia and/or conduction abnormality &lt; 6 months prior to&#xD;
                  screening except atrial fibrillation and paroxysmal supraventricular tachycardia&#xD;
&#xD;
          -  Uncontrolled arterial hypertension despite medical treatment&#xD;
&#xD;
          -  Known positive serology for HIV (human immunodeficiency virus), active hepatitis B,&#xD;
             and/or active hepatitis C infection&#xD;
&#xD;
          -  Patients who have neuromuscular disorders that are associated with elevated creatine&#xD;
             kinase (CK) (e.g., inflammatory myopathies, muscular dystrophy, amyotrophic lateral&#xD;
             sclerosis, spinal muscular atrophy)&#xD;
&#xD;
          -  Patients who are planning on embarking on a new strenuous exercise regimen after first&#xD;
             dose of study treatment; muscular activities, such as strenuous exercise, that can&#xD;
             result in significant increases in plasma CK levels should be avoided while on MEK162&#xD;
             treatment&#xD;
&#xD;
          -  Impairment of gastrointestinal function or gastrointestinal disease (e.g., ulcerative&#xD;
             disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel&#xD;
             resection)&#xD;
&#xD;
          -  Patients taking non-topical medication known to be a strong inhibitor of cytochrome&#xD;
             P450, family 3, subfamily A, polypeptide 4 (CYP3A4); however patients who either&#xD;
             discontinue their treatment or switch to another medication at least three days prior&#xD;
             to randomization are eligible&#xD;
&#xD;
          -  Any other condition that would, in the Investigatorâ€™s judgment, contraindicate the&#xD;
             patientâ€™s participation in the clinical study due to safety concerns or compliance&#xD;
             with clinical study procedures, e.g., infection/inflammation, intestinal obstruction,&#xD;
             unable to swallow medication, social/psychological issues, etc.&#xD;
&#xD;
          -  Patients who have undergone major surgery =&lt; 3 weeks prior to starting study drug or&#xD;
             who have not recovered from side effects of such procedure&#xD;
&#xD;
          -  Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a&#xD;
             female after conception and until the termination of gestation, confirmed by a&#xD;
             positive hCG laboratory test&#xD;
&#xD;
          -  Women of child-bearing potential, defined as all women physiologically capable of&#xD;
             becoming pregnant, unless they are using highly effective methods of contraception&#xD;
             throughout the study and for 8 weeks after study drug discontinuation; highly&#xD;
             effective contraception methods include:&#xD;
&#xD;
               -  Total abstinence when this is in line with the preferred and usual lifestyle of&#xD;
                  the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal,&#xD;
                  post-ovulation methods) and withdrawal are not acceptable methods of&#xD;
                  contraception&#xD;
&#xD;
               -  Female sterilization (have had surgical bilateral oophorectomy with or without&#xD;
                  hysterectomy) or tubal ligation at least six weeks before taking study treatment;&#xD;
                  in case of oophorectomy alone, only when the reproductive status of the woman has&#xD;
                  been confirmed by follow up hormone level assessment&#xD;
&#xD;
               -  Male sterilization (at least 6 months prior to screening); for female patients on&#xD;
                  the study, the vasectomized male partner should be the sole partner for that&#xD;
                  patient&#xD;
&#xD;
               -  Combination of any of the two following (a+b or a+c or b+c)&#xD;
&#xD;
                    -  a. Use of oral, injected or implanted hormonal methods of contraception or&#xD;
                       other forms of hormonal contraception that have comparable efficacy (failure&#xD;
                       rate &lt; 1%), for example hormone vaginal ring or transdermal hormone&#xD;
                       contraception&#xD;
&#xD;
                    -  b. Placement of an intrauterine device (IUD) or intrauterine system (IUS)&#xD;
&#xD;
                    -  c. Barrier methods of contraception: Condom or occlusive cap (diaphragm or&#xD;
                       cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal&#xD;
                       suppository&#xD;
&#xD;
               -  In case of use of oral contraception, women should have been stable on the same&#xD;
                  pill before taking study treatment&#xD;
&#xD;
               -  Note: Oral contraceptives are allowed but should be used in conjunction with a&#xD;
                  barrier method of contraception&#xD;
&#xD;
               -  Women are considered post-menopausal and not of child bearing potential if they&#xD;
                  have had 12 months of natural (spontaneous) amenorrhea with an appropriate&#xD;
                  clinical profile (e.g. age appropriate, history of vasomotor symptoms) or have&#xD;
                  had surgical bilateral oophorectomy (with or without hysterectomy) or tubal&#xD;
                  ligation at least six weeks ago; in the case of oophorectomy alone, only when the&#xD;
                  reproductive status of the woman has been confirmed by follow up hormone level&#xD;
                  assessment is she considered not of child bearing potential&#xD;
&#xD;
          -  Sexually active males unless they use a condom during intercourse while taking the&#xD;
             drug and for 8 weeks after stopping treatment and should not father a child in this&#xD;
             period; a condom is required to be used also by vasectomized men&#xD;
&#xD;
          -  Medical, psychiatric, cognitive or other conditions that may compromise the patient's&#xD;
             ability to understand the patient information, give informed consent, comply with the&#xD;
             study protocol or complete the study&#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>Antoni Ribas</last_name>
    <role>Principal Investigator</role>
    <affiliation>Jonsson Comprehensive Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Jonsson Comprehensive Cancer Center</name>
      <address>
        <city>Los Angeles</city>
        <state>California</state>
        <zip>90095</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>October 8, 2014</study_first_submitted>
  <study_first_submitted_qc>October 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>July 23, 2020</last_update_submitted>
  <last_update_submitted_qc>July 23, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 27, 2020</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>Melanoma</mesh_term>
  </condition_browse>
  <!-- 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/NCT02263898
org study id: 14-000616
secondary id: NCI-2014-01971
secondary id: 14-000616
secondary id: P01CA168585
nct id: NCT02263898
lead sponsor: 
collaborator: 
has dmc: Yes
This phase II trial studies intermittent dosing of BRAF inhibitor LGX818 (encorafenib) and
      MEK inhibitor MEK 162 (binimetinib) in treating patients with melanoma that has spread to
      other parts of the body (metastatic) and have a BRAF V600 mutation. LGX818 and MEK162 may
      stop the growth of tumor cells by blocking different enzymes needed for cell growth. Giving
      LGX818 and MEK162 with breaks between each course (intermittently) may help delay the time
      when tumors become resistant to the drugs.
PRIMARY OBJECTIVES:

      I. One year progression free survival (PFS) rate.

      SECONDARY OBJECTIVES:

      I. Obtain biopsy samples from patients treated with an intermittent schedule of LGX818 and
      MEK162 to study adaptive and acquired resistance as well as melanoma evolutionary patterns.

      II. Study molecular changes of adaptive resistance and acquired resistance to LGX818 and
      MEK162 in circulating melanoma cells.

      III. Study plasma samples for circulating deoxyribonucleic acid (DNA), microribonucleic acid
      (microRNA) and protein signatures of adaptive resistance and acquired resistance.

      IV. Explore the median progression free survival and overall survival of patients receiving
      an intermittent schedule of LGX818 and MEK162.

      OUTLINE:

      Patients receive LGX818 orally (PO) once daily (QD) and MEK162 PO twice daily (BID)
      continuously for 8 weeks, followed by intermittent dosing in subsequent cycles (3 weeks off
      therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease
      progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 6
      months thereafter.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: PFS rate
time frame: 1 year
arm group label: Treatment (LGX818, MEK162)
arm group type: Experimental
description: Patients receive LGX818 PO QD and MEK162 PO BID continuously for 8 weeks followed by intermittent dosing in subsequent cycles (3 weeks off therapy, 5 weeks on therapy). Cycles repeat every 8 weeks in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Raf kinase inhibitor LGX818
description: Given PO
arm group label: Treatment (LGX818, MEK162)
other name: LGX818
intervention type: Drug
intervention name: binimetinib
description: Given PO
arm group label: Treatment (LGX818, MEK162)
other name: ARRY-162
other name: ARRY-438162
other name: MEK inhibitor ARRY-438162
other name: MEK162
intervention type: Other
intervention name: laboratory biomarker analysis
description: Correlative studies
arm group label: Treatment (LGX818, MEK162)
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Antoni Ribas
role: Principal Investigator
affiliation: Jonsson Comprehensive Cancer Center
facility: 
country: United States
responsible party type: Sponsor
mesh term: Melanoma