<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/NCT02185690</url>
  </required_header>
  <id_info>
    <org_study_id>CMEK162ACA02T</org_study_id>
    <secondary_id>CMEK162ACA02T</secondary_id>
    <nct_id>NCT02185690</nct_id>
  </id_info>
  <brief_title>A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung</brief_title>
  <acronym>MEK162</acronym>
  <official_title>A Phase I/Ib Study of MEK162, a MEK Inhibitor, in Combination With Carboplatin and Pemetrexed in Patients With Non-squamous Carcinoma of the Lung</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Health Network, Toronto</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Novartis Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>University Health Network, Toronto</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>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft&#xD;
      models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These&#xD;
      data suggest that MEK162 may provide a potential benefit in cancer indications harboring&#xD;
      these mutations. MEK162 is currently being investigated in phase I clinical testing and has&#xD;
      been well tolerated up to an MTD of 45mg BID in cancer patients.&#xD;
&#xD;
      There has been little change in survival benefit for patients with non-small cell lung cancer&#xD;
      in recent years. Emerging new treatment options relying on molecular and genetic markers are&#xD;
      being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer&#xD;
      with molecular targeted therapies in combination with standard chemotherapy. This study will&#xD;
      be targeting patients with KRAS mutations.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      OBJECTIVES&#xD;
&#xD;
      1.1 Primary Objectives&#xD;
&#xD;
        -  To assess the safety of MEK162 administered in combination with carboplatin and&#xD;
           pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC).&#xD;
&#xD;
        -  To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a&#xD;
           continuous dosing schedule together with pemetrexed and carboplatin administered on a&#xD;
           3-weekly schedule as first line treatment in advanced NSCLC.&#xD;
&#xD;
        -  To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the&#xD;
           combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve&#xD;
           patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung.&#xD;
&#xD;
      1.2 Secondary Objectives&#xD;
&#xD;
        -  To characterize the population pharmacokinetics of MEK162 administered in combination&#xD;
           with carboplatin and pemetrexed (Phase I).&#xD;
&#xD;
        -  To explore relationships between KRAS mutation (and sub-types) and additional genomic&#xD;
           mutations and objective clinical response.&#xD;
&#xD;
      1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined&#xD;
      in section 4.3) as measured with NCI CTC AE v4.&#xD;
&#xD;
      Phase Ib&#xD;
&#xD;
      • Objective response rate (ORR) as per RECIST v1.1.&#xD;
&#xD;
      Secondary Phase I • Adverse events, serious adverse events, changes in hematology and&#xD;
      chemistry values, vital signs, ECGs.&#xD;
&#xD;
      Phase Ib&#xD;
&#xD;
        -  Evaluation of response rate (RR), progression-free survival (PFS) and disease control&#xD;
           rate (DCR) for patients with and without KRAS mutation in tumor tissue.&#xD;
&#xD;
        -  Exploratory analysis of KRAS mutation sub-type.&#xD;
&#xD;
      Exploratory end-points&#xD;
&#xD;
      • A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance&#xD;
      of MEK162 is not influenced by the concurrent administration of pemetrexed-based&#xD;
      chemotherapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 11, 2018</start_date>
  <completion_date type="Actual">July 4, 2019</completion_date>
  <primary_completion_date type="Actual">July 4, 2019</primary_completion_date>
  <phase>Phase 1</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>Development of dose-limiting toxicity (DLT) in milligrams per day.</measure>
    <time_frame>18 weeks of treatment</time_frame>
    <description>To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Objective response rate (ORR) as per RECIST v1.1.</measure>
    <time_frame>18 weeks of treatment &amp; 30 days followup</time_frame>
    <description>The size of tumours in centimetres before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Clearance (millilitres per minute)of MEK162</measure>
    <time_frame>18 weeks of treatment</time_frame>
    <description>Exploratory end-points&#xD;
• A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.</description>
  </other_outcome>
  <other_outcome>
    <measure>Progression Free Survival measured in weeks.</measure>
    <time_frame>18 weeks of treatment and 30 days of Follow up</time_frame>
    <description>• Evaluation progression-free survival (PFS) for patients with and without KRAS mutation in tumor tissue.&#xD;
Number of weeks survived before progression or death.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">13</enrollment>
  <condition>Lungcancer</condition>
  <arm_group>
    <arm_group_label>Binimetinib efficacy/safety</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>This is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed.&#xD;
Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma.&#xD;
Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype.&#xD;
The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Binimetinib</intervention_name>
    <description>Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease.&#xD;
MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule.</description>
    <arm_group_label>Binimetinib efficacy/safety</arm_group_label>
    <other_name>MEK162</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Pemetrexed</intervention_name>
    <description>4-6 cycles given intravenously in combination with carboplatin as per standard therapy.</description>
    <arm_group_label>Binimetinib efficacy/safety</arm_group_label>
    <other_name>Alimta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.</description>
    <arm_group_label>Binimetinib efficacy/safety</arm_group_label>
    <other_name>Paraplatin AG</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subjects eligible for enrolment on the study must meet all of the following criteria:&#xD;
&#xD;
          -  Patients with histologically confirmed non-squamous EGFR wild-type, ALK-rearrangement&#xD;
             negative carcinoma of lung. Patients with neuroendocrine carcinoma, mixed small and&#xD;
             non-small cell carcinoma or squamous carcinoma are not eligible.&#xD;
&#xD;
          -  Tissue available for KRAS mutation status analysis.&#xD;
&#xD;
          -  Patients must have metastatic disease (Incurable stage IIIB/stage IV).&#xD;
&#xD;
          -  Patients must have clinically and/or radiographically documented measurable disease.&#xD;
             At least one site of disease must be unidimensionally measurable by RECIST v1.1 as&#xD;
             follows (Eisenhauer et al.):&#xD;
&#xD;
        CT-scan, physical exam ≥10 mm Chest X-ray ≥20 mm Lymph node short axis ≥15 mm&#xD;
&#xD;
          -  All radiology studies must be performed within 28 days prior to registration (35 days&#xD;
             if negative).&#xD;
&#xD;
          -  Lesions in previously irradiated areas should not be selected unless there is clear&#xD;
             evidence of progression in such lesions.&#xD;
&#xD;
          -  Patients may not have received any prior systemic treatment for metastatic NSCLC.&#xD;
             Patients who have received adjuvant treatment or chemoradiation for stage III disease&#xD;
             should have completed this ≥12 months prior to study enrollment.&#xD;
&#xD;
          -  Patients with stable CNS metastases are permitted if stability of disease is&#xD;
             documented with imaging ≥28 days after treatment completion, are and off&#xD;
             corticosteroids by day 1 of study treatment.&#xD;
&#xD;
          -  Patients may have had prior malignancy if definitively treated and/or, in the opinion&#xD;
             of the investigator, the only active malignancy is NSCLC. Patients with mixed small&#xD;
             cell lung cancer histology are excluded. Patients who have received radiotherapy to&#xD;
             &gt;30% bone marrow are excluded. Consult PI if unsure whether second malignancies meet&#xD;
             requirements specified above.&#xD;
&#xD;
          -  In patients treated for other malignancy, all prior treatment-related toxicities must&#xD;
             be CTCAE v4.0 ≤ Grade 1 (except alopecia) at the time of enrollment.&#xD;
&#xD;
          -  Able to swallow and retain oral medication and does 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 receiving medications or substances that are inhibitors or inducers of&#xD;
             CYP1A2, CYP2A19, CYP2B6, CYP3A4 and/or UGT1A1 and UGT1A9 are eligible but these drugs&#xD;
             must be used with caution (Appendix C).&#xD;
&#xD;
        Because the lists of these agents are constantly changing, it is important to regularly&#xD;
        consult a frequently-updated list such as&#xD;
        http://medicine.iupui.edu/clinpharm/ddis/table.aspx;&#xD;
&#xD;
          -  Patients must be aged ≥18 years.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤1&#xD;
&#xD;
          -  Adequate organ and laboratory parameters, defined below.&#xD;
&#xD;
          -  Laboratory Requirements - within 7 days prior to enrollment:&#xD;
&#xD;
        Haematology: absolute granulocytes ≥1.5 × 109/L platelets ≥100 × 109/L Biochemistry:&#xD;
        bilirubin ≤1.25 × institutional upper limit of normal AST(SGOT) ≤2.5 × institutional upper&#xD;
        limit of normal /ALT(SGPT) or ≤5 × institutional upper limit of normal in the presence of&#xD;
        liver metastases&#xD;
&#xD;
        creatinine clearance ≥45 mL/min/1.73 m2&#xD;
&#xD;
        -Patients must be able to provide Informed Consent based on the details below:&#xD;
&#xD;
          -  absence of any psychological, familial, sociological or geographical condition&#xD;
             potentially hampering compliance with the study protocol and follow-up schedule; those&#xD;
             conditions should be discussed with the patient before registration in the trial&#xD;
&#xD;
          -  before patient registration/randomization, written informed consent must be given&#xD;
             according to ICH/GCP, and national/local regulations.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  History or current evidence/risk of retinal vein occlusion (RVO) or central serous&#xD;
             retinopathy (CSR):&#xD;
&#xD;
               -  History of RVO or CSR, or predisposing factors to RVO or CSR (e.g., uncontrolled&#xD;
                  glaucoma or ocular hypertension, uncontrolled systemic disease such as&#xD;
                  hypertension, diabetes mellitus, or history of hyperviscosity or&#xD;
                  hypercoagulability syndromes). Patients with prior deep venous thrombosis or&#xD;
                  pulmonary embolism are permitted.&#xD;
&#xD;
               -  Visible retinal pathology as assessed by ophthalmologic exam that is considered a&#xD;
                  risk factor for RVO or CSR such as:&#xD;
&#xD;
          -  Evidence of new optic disc cupping&#xD;
&#xD;
          -  Evidence of new visual field defects on automated perimetry&#xD;
&#xD;
          -  Intraocular pressure &gt;21mmHg as measured by tonography&#xD;
&#xD;
          -  Any serious and/or unstable pre-existing medical (aside from malignancy exception),&#xD;
             psychiatric disorder, or other conditions that could interfere with subjects' safety,&#xD;
             obtaining informed consent or compliance to the study procedures, in the opinion of&#xD;
             the PI.&#xD;
&#xD;
          -  History of interstitial lung disease or pneumonitis.&#xD;
&#xD;
          -  Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated&#xD;
             respiratory, hepatic, renal metabolic or cardiac disease).&#xD;
&#xD;
          -  Any factors that increase the risk of QTc prolongation or risk of arrhythmic events&#xD;
             (e.g. congenital long QT syndrome, family history of long QT syndrome, hypokalemia) or&#xD;
             baseline QTcB interval ≥480 msec.&#xD;
&#xD;
          -  History of acute coronary syndromes (including myocardial infarction and unstable&#xD;
             angina), coronary angioplasty, or stenting within the past 6 months or cardiac&#xD;
             metastases.&#xD;
&#xD;
          -  History or evidence of current clinically significant uncontrolled arrhythmias.&#xD;
&#xD;
          -  History or evidence of current ≥Class II congestive heart failure as defined by New&#xD;
             York Heart Association (NYHA).&#xD;
&#xD;
          -  Known positivity for Hepatitis B surface antigen or Hepatitis C antibody.&#xD;
&#xD;
          -  Known Human Immunodeficiency Virus (HIV) infection.&#xD;
&#xD;
          -  Treatment refractory hypertension defined as a blood pressure systolic &gt;140 mmHg&#xD;
             and/or diastolic &gt;90 mmHg which cannot be controlled by anti-hypertensive therapy.&#xD;
&#xD;
          -  Subjects with intra-cardiac defibrillators or permanent pacemakers.&#xD;
&#xD;
          -  Pregnant or nursing (lactating) women are excluded.&#xD;
&#xD;
          -  Female patient of child bearing potential must have a negative serum or urine&#xD;
             pregnancy test.&#xD;
&#xD;
          -  Women of child-bearing potential must agree to use of appropriate contraceptive&#xD;
             methods throughout the study and for 120 days after, These methods include&#xD;
&#xD;
          -  Total abstinence or 2 barrier methods or a barrier method plus hormonal method from&#xD;
             visit 1 to 120 days after the last dose of treatment.&#xD;
&#xD;
          -  Men must agree to use an appropriate method of contraception starting with first dose&#xD;
             of study drug through 120 days after the last dose of treatment (see above).&#xD;
&#xD;
          -  Whilst not excluded, patients with significant impaired hearing must be made aware of&#xD;
             potential ototoxicity and may choose not to be included. If included, baseline&#xD;
             audiograms are recommended and should be followed by repeat audiograms prior to cycle&#xD;
             2.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>90 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Natasha Leighl, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>UHN - Princess Margaret Cancer Centre</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Amit Oza, MD</last_name>
    <role>Study Director</role>
    <affiliation>Princess Margaret Cancer Centre Drug Development Program</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Cross Cancer Institute</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T6G1Z2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Juravinski Cancer Centre</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8V 5C2</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Ottawa Hospital Regional Cancer Centre</name>
      <address>
        <city>Ottawa</city>
        <state>Ontario</state>
        <zip>K1G 3Y9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Princess Margaret Cancer Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <zip>M5G2M9</zip>
        <country>Canada</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
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  </reference>
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  </reference>
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    <citation>Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. doi: 10.1056/NEJMoa011954.</citation>
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    <citation>Schuette WH, Groschel A, Sebastian M, Andreas S, Muller T, Schneller F, Guetz S, Eschbach C, Bohnet S, Leschinger MI, Reck M. A randomized phase II study of pemetrexed in combination with cisplatin or carboplatin as first-line therapy for patients with locally advanced or metastatic non-small-cell lung cancer. Clin Lung Cancer. 2013 May;14(3):215-23. doi: 10.1016/j.cllc.2012.10.001. Epub 2013 Jan 16.</citation>
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  <verification_date>April 2021</verification_date>
  <study_first_submitted>April 9, 2014</study_first_submitted>
  <study_first_submitted_qc>July 3, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 9, 2014</study_first_posted>
  <last_update_submitted>April 1, 2021</last_update_submitted>
  <last_update_submitted_qc>April 1, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">April 2, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Lung cancer</keyword>
  <keyword>Non small cell lung cancer</keyword>
  <keyword>non squamous</keyword>
  <keyword>pemetrexed</keyword>
  <keyword>carboplatin</keyword>
  <keyword>binimetinib</keyword>
  <keyword>chemotherapy</keyword>
  <keyword>combination chemotherapy</keyword>
  <keyword>Phase 1</keyword>
  <keyword>Princess Margaret Cancer Centre</keyword>
  <keyword>carcinoma</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carboplatin</mesh_term>
    <mesh_term>Pemetrexed</mesh_term>
  </intervention_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/NCT02185690
org study id: CMEK162ACA02T
secondary id: CMEK162ACA02T
nct id: NCT02185690
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
MEK162 has shown significant inhibition of tumor growth as a single agent in NSCLC xenograft
      models in mice and human cancer cells in vitro, which have KRAS and/or other mutations. These
      data suggest that MEK162 may provide a potential benefit in cancer indications harboring
      these mutations. MEK162 is currently being investigated in phase I clinical testing and has
      been well tolerated up to an MTD of 45mg BID in cancer patients.

      There has been little change in survival benefit for patients with non-small cell lung cancer
      in recent years. Emerging new treatment options relying on molecular and genetic markers are
      being studied extensively. Thus, there has been a shift to manage non-small cell lung cancer
      with molecular targeted therapies in combination with standard chemotherapy. This study will
      be targeting patients with KRAS mutations.
OBJECTIVES

      1.1 Primary Objectives

        -  To assess the safety of MEK162 administered in combination with carboplatin and
           pemetrexed as first line treatment in advanced non-small cell lung cancer (NSCLC).

        -  To determine the recommended phase II dose (RP2D) of MEK162 to be used when given in a
           continuous dosing schedule together with pemetrexed and carboplatin administered on a
           3-weekly schedule as first line treatment in advanced NSCLC.

        -  To explore the efficacy (as measured by tumor response in the Phase Ib portion) of the
           combination of MEK162 in addition to pemetrexed and carboplatin in treatment-naïve
           patients with EGFR wild-type, ALK-rearrangement negative NSCLC of the lung.

      1.2 Secondary Objectives

        -  To characterize the population pharmacokinetics of MEK162 administered in combination
           with carboplatin and pemetrexed (Phase I).

        -  To explore relationships between KRAS mutation (and sub-types) and additional genomic
           mutations and objective clinical response.

      1.3 Trial End-points Primary Phase I • Development of dose-limiting toxicity (DLT), (defined
      in section 4.3) as measured with NCI CTC AE v4.

      Phase Ib

      • Objective response rate (ORR) as per RECIST v1.1.

      Secondary Phase I • Adverse events, serious adverse events, changes in hematology and
      chemistry values, vital signs, ECGs.

      Phase Ib

        -  Evaluation of response rate (RR), progression-free survival (PFS) and disease control
           rate (DCR) for patients with and without KRAS mutation in tumor tissue.

        -  Exploratory analysis of KRAS mutation sub-type.

      Exploratory end-points

      • A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance
      of MEK162 is not influenced by the concurrent administration of pemetrexed-based
      chemotherapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Development of dose-limiting toxicity (DLT) in milligrams per day.
time frame: 18 weeks of treatment
description: To determine the recommended dose in milligrams per day of the combination of MEK162 with standard therapy pemetrexed and carboplatin as determined by toxicity.
measure: Objective response rate (ORR) as per RECIST v1.1.
time frame: 18 weeks of treatment & 30 days followup
description: The size of tumours in centimetres before and after treatment. The measurements will be compared against the RECIST v1.1 criteria to ascertain response as defined in the protocol.
measure: Clearance (millilitres per minute)of MEK162
time frame: 18 weeks of treatment
description: Exploratory end-points
• A limited sampling strategy pharmacokinetic model will be used to ensure that the clearance of MEK162 is not influenced by the concurrent administration of pemetrexed-based chemotherapy.
measure: Progression Free Survival measured in weeks.
time frame: 18 weeks of treatment and 30 days of Follow up
description: • Evaluation progression-free survival (PFS) for patients with and without KRAS mutation in tumor tissue.
Number of weeks survived before progression or death.
arm group label: Binimetinib efficacy/safety
arm group type: Other
description: This is a Phase I/Ib, open-label, dose-escalation, multi-center, non-randomized study designed to evaluate the safety and tolerability of oral Binimetinib in combination with carboplatin and pemetrexed.
Phase I part A standard 3+3 dose-escalation will be used to determine the maximum administered dose (MAD) and the RP2D for the combination in subjects with advanced non-squamous lung carcinoma.
Phase Ib part Once RP2D has been identified, an expansion cohort will be accrued; these patients will be stratified by KRAS genotype.
The RP2D will be expanded by enrolling additional patients, stratified by KRAS genotype, to a total of 30 patients eligible for the safety set (including those treated at the same dose combination in the dose-escalation phase of the study who are eligible for the safety set) to be evaluated for safety, tolerability, pharmacokinetics and biologic activity of MEK162.
intervention type: Drug
intervention name: Binimetinib
description: Continuous MEK162 with dose escalation until the Recommended Phase 2 dose (RP2D) one dose level below the Maximum administered dose (MAD) or progression of disease.
MEK162 tablets 15 mg strength will be taken orally on a BID dose schedule.
arm group label: Binimetinib efficacy/safety
other name: MEK162
intervention type: Drug
intervention name: Pemetrexed
description: 4-6 cycles given intravenously in combination with carboplatin as per standard therapy.
arm group label: Binimetinib efficacy/safety
other name: Alimta
intervention type: Drug
intervention name: Carboplatin
description: 4-6 cycles of intravenous Carboplatin in combination with Pemetrexed as per standard therapy.
arm group label: Binimetinib efficacy/safety
other name: Paraplatin AG
criteria: 
gender: All
minimum age: 18 Years
maximum age: 90 Years
healthy volunteers: No
last name: Natasha Leighl, MD
role: Principal Investigator
affiliation: UHN - Princess Margaret Cancer Centre
last name: Amit Oza, MD
role: Study Director
affiliation: Princess Margaret Cancer Centre Drug Development Program
facility: 
facility: 
facility: 
facility: 
country: Canada
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PMID: 23775961
responsible party type: Sponsor
mesh term: Carcinoma
mesh term: Lung Neoplasms
mesh term: Carboplatin
mesh term: Pemetrexed