<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/NCT02974725</url>
  </required_header>
  <id_info>
    <org_study_id>CLXH254X2102</org_study_id>
    <secondary_id>2016-004293-18</secondary_id>
    <nct_id>NCT02974725</nct_id>
  </id_info>
  <brief_title>A Phase Ib Study of LXH254-centric Combinations in NSCLC or Melanoma</brief_title>
  <official_title>A Phase Ib, Open-label, Multicenter Study of Oral LXH254-centric Combinations in Adult Patients With Advanced or Metastatic KRAS or BRAF Mutant Non-Small Cell Lung Cancer or NRAS Mutant Melanoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Novartis</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>
      To characterize safety and tolerability and identify a recommended dose and regimen for the&#xD;
      LXH254 in combination with LTT462 or trametinib or ribociclib.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">February 24, 2017</start_date>
  <completion_date type="Anticipated">December 29, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 29, 2023</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of participants with Adverse Events (AEs) as a measure of safety and tolerability</measure>
    <time_frame>up to 5 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Dose limiting toxicities (DLTs) (dose escalation only)</measure>
    <time_frame>up to 3 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Tolerability measured by the number of subjects who have interruptions/reductions of study treatment and reason for interruptions/reductions</measure>
    <time_frame>up to 5 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Tolerability measured by the dose intensity of study drug, Relative Dose intensity for subjects with non-zero duration of exposure is computed as the ratio of dose intensity and planned dose intentity</measure>
    <time_frame>Up to 5 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DOR)</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR)</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS) - (dose expansion part only)</measure>
    <time_frame>Up to 6 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Derived PK parameter (Cmax) for LXH254 &amp; LTT462:</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Derived PK parameter (AUC) for LXH254 &amp; LTT462</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor samples</measure>
    <time_frame>up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Derived PK parameter (Cmax) for LXH254 &amp; trametinib</measure>
    <time_frame>up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Derived PK parameter (AUC) for LXH254 &amp; trametinib</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Derived PK parameter (Cmax) for LXH254 &amp; ribociclib</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Derived PK parameter (AUC) for LXH254 &amp; ribociclib</measure>
    <time_frame>Up to 5 years</time_frame>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">242</enrollment>
  <condition>Non-Small Cell Lung Cancer</condition>
  <condition>Melanoma</condition>
  <arm_group>
    <arm_group_label>LXH254+LTT462</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>LXH254+Trametinib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>LXH254+Ribociclib</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LXH254</intervention_name>
    <description>LXH254 will be supplied as tablet for oral use.</description>
    <arm_group_label>LXH254+LTT462</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LTT462</intervention_name>
    <description>LTT462 will be supplied as hard gelatin capsule for oral use.</description>
    <arm_group_label>LXH254+LTT462</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Trametinib</intervention_name>
    <description>Trametinib will be supplied as film-coated tablet for oral use</description>
    <arm_group_label>LXH254+Trametinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>LXH254</intervention_name>
    <description>Trametinib will be supplied as film-coated tablet for oral use</description>
    <arm_group_label>LXH254+Trametinib</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ribociclib</intervention_name>
    <description>Ribociclib will be supplied in tablets and hard gelatin capsules.</description>
    <arm_group_label>LXH254+Ribociclib</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have advanced or metastatic NSCLC or cutaneous melanoma&#xD;
&#xD;
          -  Presence of KRAS or BRAF mutation (NSCLC) or NRAS mutation (cutaneous melanoma) in&#xD;
             tumor tissue&#xD;
&#xD;
          -  All patients participating in this clinical trial must have progressed following&#xD;
             standard therapy or, in the opinion of the Investigator, no effective standard therapy&#xD;
             exists, is tolerated, appropriate or is considered equivalent to study treatment.&#xD;
&#xD;
          -  ECOG (Eastern Cooperative Oncology Group) performance status ≤ 2&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        -Dose expansion - KRAS or NRAS mutant patients groups: Prior treatment with a RAFi&#xD;
        (including any BRAFi and pan-RAFi), MEKi and/or ERKi. (Patients with KRAS mutant NSCLC with&#xD;
        prior G12C inhibitor treatments are also excluded in the LXH254+trametinib expansion part).&#xD;
        BRAF mutant patients group: Prior treatment with any EGFR, ALK, ROS1, KRAS, RAF (both&#xD;
        BRAFV600 selective and pan-RAF), MEK1/2 and/or ERK1/2 inhibitors (for patients with BRAF&#xD;
        V600 mutant NSCLC, prior treatments with BRAF and MEK1/2 inhibitors are allowed).&#xD;
&#xD;
        Patients who have received more than 3 lines of anti-cancer therapy are excluded.&#xD;
&#xD;
          -  History or current evidence of retinal vein occlusion (RVO) or current risk factors&#xD;
             for RVO.&#xD;
&#xD;
          -  Any medical condition that would, in the investigator's judgment, prevent the&#xD;
             patient's participation in the clinical study due to safety concerns or compliance&#xD;
             with clinical study procedures.&#xD;
&#xD;
          -  Patients receiving proton pump inhibitors (PPI) which cannot be discontinued 3 days&#xD;
             prior to the start study treatment and for the duration of the study.&#xD;
&#xD;
          -  Patients with Gilbert's syndrome or other heritable diseases of bile processing.&#xD;
&#xD;
        Other protocol-defined inclusion/exclusion criteria may apply&#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>Novartis Pharmaceuticals</last_name>
    <role>Study Director</role>
    <affiliation>Novartis Pharmaceuticals</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of California San Diego .</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92103</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>UCSF Medical Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts General Hospital SC</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center .</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sarah Cannon Research Institute Tennessee Oncology</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37203</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Uni of TX MD Anderson Cancer Cntr</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Westmead</city>
        <state>New South Wales</state>
        <zip>2145</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Leuven</city>
        <zip>3000</zip>
        <country>Belgium</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Lyon</city>
        <zip>69373</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Paris Cedex 10</city>
        <zip>75475</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Villejuif Cedex</city>
        <zip>94800</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Dresden</city>
        <zip>01307</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Essen</city>
        <zip>45147</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Frankfurt</city>
        <zip>60590</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Koeln</city>
        <zip>50937</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Tel Aviv</city>
        <zip>6423906</zip>
        <country>Israel</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20133</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Milano</city>
        <state>MI</state>
        <zip>20162</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Rozzano</city>
        <state>MI</state>
        <zip>20089</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Verona</city>
        <state>VR</state>
        <zip>37126</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Napoli</city>
        <zip>80131</zip>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>03080</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Seoul</city>
        <zip>06351</zip>
        <country>Korea, Republic of</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Warszawa</city>
        <zip>02 781</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Sevilla</city>
        <state>Andalucia</state>
        <zip>41013</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <state>Catalunya</state>
        <zip>08035</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Barcelona</city>
        <state>Catalunya</state>
        <zip>08036</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Valencia</city>
        <state>Comunidad Valenciana</state>
        <zip>46010</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Pamplona</city>
        <state>Navarra</state>
        <zip>31008</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Madrid</city>
        <zip>28034</zip>
        <country>Spain</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Novartis Investigative Site</name>
      <address>
        <city>Stockholm</city>
        <zip>171 76</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>Belgium</country>
    <country>France</country>
    <country>Germany</country>
    <country>Israel</country>
    <country>Italy</country>
    <country>Korea, Republic of</country>
    <country>Poland</country>
    <country>Spain</country>
    <country>Sweden</country>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>November 23, 2016</study_first_submitted>
  <study_first_submitted_qc>November 23, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">November 28, 2016</study_first_posted>
  <last_update_submitted>June 2, 2023</last_update_submitted>
  <last_update_submitted_qc>June 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 5, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>NSCLC</keyword>
  <keyword>Melanoma</keyword>
  <keyword>NRAS</keyword>
  <keyword>KRAS</keyword>
  <keyword>BRAF</keyword>
  <keyword>LXH254</keyword>
  <keyword>LTT462</keyword>
  <keyword>Trametinib</keyword>
  <keyword>Ribocliclib</keyword>
  <keyword>Non-small cell lung carcinoma (NSCLC)</keyword>
  <keyword>treatment of lung cancer after first metastasis</keyword>
  <keyword>lung cancer</keyword>
  <keyword>lung adenocarcinoma</keyword>
  <keyword>Large-cell lung carcinoma</keyword>
  <keyword>Non small cell lung carcinoma</keyword>
  <keyword>Non small cell lung cancer</keyword>
  <keyword>Large cell lung carcinoma</keyword>
  <keyword>Large cell lung cancer</keyword>
  <keyword>squamous cell lung carcinoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
    <mesh_term>Melanoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Trametinib</mesh_term>
    <mesh_term>Naporafenib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </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/NCT02974725
org study id: CLXH254X2102
secondary id: 2016-004293-18
nct id: NCT02974725
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
To characterize safety and tolerability and identify a recommended dose and regimen for the
      LXH254 in combination with LTT462 or trametinib or ribociclib.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of participants with Adverse Events (AEs) as a measure of safety and tolerability
time frame: up to 5 years
measure: Dose limiting toxicities (DLTs) (dose escalation only)
time frame: up to 3 years
measure: Tolerability measured by the number of subjects who have interruptions/reductions of study treatment and reason for interruptions/reductions
time frame: up to 5 years
measure: Tolerability measured by the dose intensity of study drug, Relative Dose intensity for subjects with non-zero duration of exposure is computed as the ratio of dose intensity and planned dose intentity
time frame: Up to 5 years
measure: Overall Response Rate (ORR)
time frame: Up to 5 years
measure: Duration of response (DOR)
time frame: Up to 5 years
measure: Disease Control Rate (DCR)
time frame: Up to 5 years
measure: Progression Free Survival (PFS)
time frame: Up to 5 years
measure: Overall Survival (OS) - (dose expansion part only)
time frame: Up to 6 years
measure: Derived PK parameter (Cmax) for LXH254 & LTT462:
time frame: Up to 5 years
measure: Derived PK parameter (AUC) for LXH254 & LTT462
time frame: Up to 5 years
measure: Changes from baseline of pharmacodynamics (PD) marker DUSP6 in tumor samples
time frame: up to 5 years
measure: Derived PK parameter (Cmax) for LXH254 & trametinib
time frame: up to 5 years
measure: Derived PK parameter (AUC) for LXH254 & trametinib
time frame: Up to 5 years
measure: Derived PK parameter (Cmax) for LXH254 & ribociclib
time frame: Up to 5 years
measure: Derived PK parameter (AUC) for LXH254 & ribociclib
time frame: Up to 5 years
arm group label: LXH254+LTT462
arm group type: Experimental
arm group label: LXH254+Trametinib
arm group type: Experimental
arm group label: LXH254+Ribociclib
arm group type: Experimental
intervention type: Drug
intervention name: LXH254
description: LXH254 will be supplied as tablet for oral use.
arm group label: LXH254+LTT462
intervention type: Drug
intervention name: LTT462
description: LTT462 will be supplied as hard gelatin capsule for oral use.
arm group label: LXH254+LTT462
intervention type: Drug
intervention name: Trametinib
description: Trametinib will be supplied as film-coated tablet for oral use
arm group label: LXH254+Trametinib
intervention type: Drug
intervention name: LXH254
description: Trametinib will be supplied as film-coated tablet for oral use
arm group label: LXH254+Trametinib
intervention type: Drug
intervention name: Ribociclib
description: Ribociclib will be supplied in tablets and hard gelatin capsules.
arm group label: LXH254+Ribociclib
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Novartis Pharmaceuticals
role: Study Director
affiliation: Novartis Pharmaceuticals
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country: Australia
country: Belgium
country: France
country: Germany
country: Israel
country: Italy
country: Korea, Republic of
country: Poland
country: Spain
country: Sweden
country: United States
responsible party type: Sponsor
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Melanoma
mesh term: Trametinib
mesh term: Naporafenib
sharing ipd: No