<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/NCT03256136</url>
  </required_header>
  <id_info>
    <org_study_id>17-011</org_study_id>
    <nct_id>NCT03256136</nct_id>
  </id_info>
  <brief_title>Nivolumab in Combination With Chemotherapy, or Nivolumab in Combination With Ipilimumab, in Advanced EGFR-Mutant or ALK-Rearranged NSCLC</brief_title>
  <official_title>A Phase II Study of Nivolumab in Combination With Carboplatin and Pemetrexed, or Nivolumab in Combination With Ipilimumab, in Patients With Advanced, EGFR-mutant or ALK-rearranged, Non-Small Cell Lung Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Bristol-Myers Squibb</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Massachusetts General Hospital</source>
  <oversight_info>
    <has_dmc>No</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 research study is studying a drug intervention as a possible treatment for lung cancer.&#xD;
&#xD;
      The drugs involved in this study are:&#xD;
&#xD;
        -  Nivolumab&#xD;
&#xD;
        -  Carboplatin&#xD;
&#xD;
        -  Pemetrexed&#xD;
&#xD;
        -  Ipilimumab&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This research study is a Phase II clinical trial. Phase II clinical trials test the safety&#xD;
      and effectiveness of an investigational intervention to learn whether the intervention works&#xD;
      in treating a specific disease.&#xD;
&#xD;
      The FDA (the U.S. Food and Drug Administration) has approved Nivolumab as a treatment for&#xD;
      other types of cancers including lung cancer. However, the combination of Nivolumab with&#xD;
      other drugs (such as those being tested in this study) has not been approved by the FDA as a&#xD;
      treatment for this type of lung cancer.&#xD;
&#xD;
      The purpose of this study is to test the effectiveness (how well the drug works), safety, and&#xD;
      tolerability of the drug Nivolumab in combination with standard of care chemotherapies, or in&#xD;
      combination with Ipilimumab. Nivolumab and Ipilimumab are antibodies (a type of human&#xD;
      protein) that are being tested to see if they will allow the body's immune system to work&#xD;
      against tumor cells. This study is being done to see if Nivolumab and Ipilimumab, or&#xD;
      Nivolumab and chemotherapy drugs (Carboplatin and Pemetrexed), are more effective against&#xD;
      cancer when administered together.&#xD;
&#xD;
      These drugs are given as infusions. They are designed to &quot;boost&quot; the immune system's ability&#xD;
      to suppress or kill cancer cells that are foreign to the human body.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">November 22, 2017</start_date>
  <completion_date type="Actual">August 19, 2019</completion_date>
  <primary_completion_date type="Actual">August 19, 2019</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Objective Response Rate (ORR), Presented in Numbers of Participants</measure>
    <time_frame>Up to approximately 2 years</time_frame>
    <description>Complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate (DCR), Presented in Numbers of Participants</measure>
    <time_frame>Up to approximately 2 years</time_frame>
    <description>The number of patients that achieved either complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression Free Survival (PFS)</measure>
    <time_frame>From the start of treatment until disease progression or death due to any cause, up to approximately 2 years</time_frame>
    <description>Time from initiation of the study drugs to progression or death, whichever occurs first. Disease progression was assessed via RECIST 1.1&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).&#xD;
Confidence Intervals (CIs) were calculated using the Kaplan Meier (KM) method</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>From the start of treatment until death due to any cause, up to approximately 2 years</time_frame>
    <description>Time from initiation of the study drugs to date of death due to any cause. CIs are the KM estimate CIs.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration Of Response</measure>
    <time_frame>From the first documented response until disease progression or death, up to approximately 2 years</time_frame>
    <description>Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">9</enrollment>
  <condition>Lung Cancer</condition>
  <arm_group>
    <arm_group_label>Nivolumab Plus Ipilimumab EGFR</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivolumab Plus Ipilimumab ALK</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carboplatin</intervention_name>
    <description>Chemotherapy</description>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive</arm_group_label>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive</arm_group_label>
    <other_name>Paraplatin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nivolumab</intervention_name>
    <description>will allow the body's immune system to work against tumor cells</description>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive</arm_group_label>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive</arm_group_label>
    <arm_group_label>Nivolumab Plus Ipilimumab ALK</arm_group_label>
    <arm_group_label>Nivolumab Plus Ipilimumab EGFR</arm_group_label>
    <other_name>Opdivo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>pemetrexed</intervention_name>
    <description>Chemo therapy</description>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive</arm_group_label>
    <arm_group_label>Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive</arm_group_label>
    <other_name>Alimta</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ipilimumab</intervention_name>
    <description>will allow the body's immune system to work against tumor cells</description>
    <arm_group_label>Nivolumab Plus Ipilimumab ALK</arm_group_label>
    <arm_group_label>Nivolumab Plus Ipilimumab EGFR</arm_group_label>
    <other_name>Yervoy</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Histologically or cytologically confirmed advanced (stage IIIB or IV) non-small-cell&#xD;
             lung cancer (NSCLC).&#xD;
&#xD;
               -  ALK-rearranged NSCLC: ALK rearrangement as assessed by ALK FISH, IHC, or&#xD;
                  next-generation sequencing (NGS). For ALK FISH, rearrangements must be detected&#xD;
                  in &gt;15% of tumor cells.&#xD;
&#xD;
               -  EGFR-mutant NSCLC: EGFR activating gene mutation (e.g., L858R, exon 19 deletion)&#xD;
                  as well as a T790M mutation per local testing.&#xD;
&#xD;
          -  Presence of at least one measurable lesion as defined by RECIST v1.1. A previously&#xD;
             irradiated site lesion may only be counted as a target lesion if there is clear sign&#xD;
             of progression since the completion of irradiation.&#xD;
&#xD;
          -  Prior treatment with appropriate tyrosine kinase inhibitors (TKIs) as follows:&#xD;
&#xD;
               -  ALK-positive NSCLC (cohorts B and D): Participants must have progressed on or&#xD;
                  after 1 or more next-generation ALK-TKI(s).&#xD;
&#xD;
               -  EGFR-mutant NSCLC (cohorts A and C): Participants must have progressed on or&#xD;
                  after 1 or more third-generation, T790M mutant-selective EGFR-TKI(s).&#xD;
&#xD;
          -  Prior systemic chemotherapy requirements are as follows:&#xD;
&#xD;
               -  Nivolumab plus carboplatin and pemetrexed arms (cohorts A and B): NO prior&#xD;
                  systemic chemotherapy is allowed. NOTE: Prior adjuvant or neoadjuvant&#xD;
                  chemotherapy is allowed if received more than 12 months prior to the study.&#xD;
&#xD;
               -  Nivolumab plus ipilimumab arms (cohorts C and D): Participants must have received&#xD;
                  a platinum-based combination chemotherapy for their advanced lung cancer and&#xD;
                  either progressed on/after this chemotherapy or are intolerant. Only ONE line of&#xD;
                  chemotherapy is allowed. NOTE: Prior adjuvant or neoadjuvant chemotherapy does&#xD;
                  not count as an additional line of chemotherapy if received more than 12 months&#xD;
                  prior to the study.&#xD;
&#xD;
          -  Tumor tissue sample is required following the participant's last line of systemic&#xD;
             therapy (TKI or chemotherapy). Tissue sample may be fresh (core needle, excisional, or&#xD;
             incisional biopsy), or archival if obtained within 6 months prior to enrollment. There&#xD;
             can have been no systemic therapy administered after the sample was obtained. If a&#xD;
             tissue sample is available but it has been &gt; 6 months and there has been no&#xD;
             intervening therapy, the Principal Investigator may approve the sample after&#xD;
             discussion. PD-L1 IHC testing will be performed on the tumor tissue, but positivity on&#xD;
             the PD-L1 IHC testing is not required to enroll in the study.&#xD;
&#xD;
          -  Clinically asymptomatic and stable central nervous system (CNS) metastases are allowed&#xD;
             (including untreated CNS metastases) if they have not required increasing doses of&#xD;
             steroids or stable doses equivalent to prednisone &gt; 10 mg daily within 2 weeks prior&#xD;
             to study entry for CNS symptoms.&#xD;
&#xD;
          -  Prior palliative radiotherapy must have been completed at least 2 weeks prior to study&#xD;
             entry.&#xD;
&#xD;
          -  Subjects must have been off any prior systemic anti-cancer treatment (including TKIs)&#xD;
             for at least 5 half-lives of that drug.&#xD;
&#xD;
          -  Age ≥ 18 years old.&#xD;
&#xD;
          -  ECOG performance status of 0 or 1.&#xD;
&#xD;
          -  Life expectancy ≥ 12 weeks.&#xD;
&#xD;
          -  Screening laboratory values must meet the following criteria:&#xD;
&#xD;
               -  WBC ≥ 2.0 x 109/L&#xD;
&#xD;
               -  Neutrophils ≥ 1.5 x 109/L&#xD;
&#xD;
               -  Platelet ≥ 100 x 109/L&#xD;
&#xD;
               -  Hemoglobin ≥ 9/dL&#xD;
&#xD;
               -  Serum creatinine ≤ 1.5 x ULN or calculated creatinine clearance using&#xD;
                  Cockcroft-Gault formula ≥ 50 mL/min&#xD;
&#xD;
                    -  Female CrCl = (140-age in years) x weight in kg x 0.85 72 x serum creatinine&#xD;
                       in mg/dL&#xD;
&#xD;
                    -  Male CrCl = (140 - age in years) x weight in kg x 1.00 72 x serum creatinine&#xD;
                       in mg/dL&#xD;
&#xD;
               -  Total bilirubin ≤ 1.5 x ULN (except in patients with Gilbert's syndrome who may&#xD;
                  have total bilirubin &lt; 3.0 mg/dL)&#xD;
&#xD;
               -  AST and ALT ≤ 3.0 x ULN (or ≤ 5.0 x ULN if liver metastases are present)&#xD;
&#xD;
          -  Females of child-bearing potential (defined as a sexually mature woman who has not&#xD;
             undergone a hysterectomy or bilateral oophorectomy or has not been naturally&#xD;
             post-menopausal for at least 24 consecutive months) must:&#xD;
&#xD;
               -  Have a negative serum or urine pregnancy test obtained within 24 hours prior to&#xD;
                  starting the investigational drug.&#xD;
&#xD;
               -  Not be breastfeeding.&#xD;
&#xD;
               -  Agree to use, and be able to comply with, highly effective contraception (failure&#xD;
                  rate less than 1% per year) without interruption while on study treatment plus 5&#xD;
                  half-lives of nivolumab (half-life up to 25 days) plus 30 days (duration of&#xD;
                  ovulatory cycle) for a total of 23 weeks post treatment completion. Complete&#xD;
                  abstinence is acceptable if it is in line with the preferred and usual lifestyle&#xD;
                  of the patient. Period abstinence (e.g., calendar, ovulation, symptothermal, or&#xD;
                  postovulation methods) and withdrawal are not acceptable methods of&#xD;
                  contraception. Examples of non-hormonal contraceptive methods with a failure rate&#xD;
                  of &lt; 1% per year include bilateral tubal ligation, male sterilization, hormonal&#xD;
                  implants, established and proper use of combined oral or injected hormonal&#xD;
                  contraceptives, and certain intrauterine devices. Alternatively, two methods&#xD;
                  (e.g., two barrier methods from the options of diaphragm, cervical cap, vaginal&#xD;
                  sponge, and condom, or progesterone-only oral hormonal contraception where&#xD;
                  inhibition of ovulation is not the primary mode of action) may be combined to&#xD;
                  achieve a failure rate of &lt; 1% per year. Barrier methods must always be&#xD;
                  supplemented with the use of a spermicide.&#xD;
&#xD;
          -  Male subjects agree to remain abstinent or use a condom plus an additional&#xD;
             contraceptive method that result in a failure rate of &lt;1% per year during sexual&#xD;
             contact with a female of childbearing potential while participating in the study,&#xD;
             during dose interruptions, and for 31 weeks following the last dose of the study&#xD;
             treatment, even if he has undergone a successful vasectomy. Abstinence is only&#xD;
             acceptable if it is in line with the preferred and usual lifestyle of the patient.&#xD;
             Periodic abstinence and withdrawal are not acceptable.&#xD;
&#xD;
          -  Subject has the ability to understand and provide signed informed consent.&#xD;
&#xD;
          -  Subject has the willingness and ability to comply with scheduled visits, treatment&#xD;
             plans, laboratory tests, and other study procedures&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Subjects previously treated with T cell immune-modulating antibodies, including&#xD;
             anti-CTLA-4, anti-PD-1 and/or anti-PD-L1 agents.&#xD;
&#xD;
          -  Subjects with symptomatic brain metastases, carcinomatous meningitis, spinal cord&#xD;
             compression, or intractable back pain due to compression of destructive mass.&#xD;
&#xD;
          -  Subjects with active, known, or suspected autoimmune disease. Subjects with type I&#xD;
             diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders&#xD;
             (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or&#xD;
             conditions not expected to recur in the absence of an external trigger are permitted&#xD;
             to enroll.&#xD;
&#xD;
          -  Subjects with a condition requiring systemic treatment with either corticosteroids (&gt;&#xD;
             10 mg daily prednisone equivalent) or other immunosuppressive medications within 14&#xD;
             days of randomization (unless used to treat investigational drug-related adverse&#xD;
             events). Inhaled or topical steroids, and adrenal replacement steroid doses &gt; 10 mg&#xD;
             daily prednisone equivalent, are permitted in the absence of active autoimmune&#xD;
             disease.&#xD;
&#xD;
          -  Subjects with interstitial lung disease or interstitial pneumonitis that is&#xD;
             symptomatic or may interfere with the detection or management of suspected&#xD;
             drug-related pulmonary toxicity.&#xD;
&#xD;
          -  Subjects must have recovered from the effects of major surgery or significant&#xD;
             traumatic injury at least 14 days prior to screening. No major surgery, other than&#xD;
             diagnostic surgery, is allowed within 4 weeks prior to treatment in the study.&#xD;
&#xD;
          -  Co-administration of anti-cancer therapies other than those administered in the study.&#xD;
&#xD;
          -  Subjects with other active malignancy requiring concurrent intervention.&#xD;
&#xD;
          -  Known history of testing positive for human immunodeficiency virus (HIV) or known&#xD;
             acquired immunodeficiency syndrome (AIDS). HIV-positive participants are ineligible&#xD;
             because these participants are at increased risk of lethal infections when treated&#xD;
             with marrow-suppressive therapy, and because there is the potential for&#xD;
             pharmacokinetic interactions with combination antiretroviral therapy and study drugs.&#xD;
&#xD;
          -  Any positive test for hepatitis B virus or hepatitis C virus indicating acute or&#xD;
             chronic infection.&#xD;
&#xD;
          -  Subjects with ≥ grade 2 peripheral neuropathy at enrollment per the National Cancer&#xD;
             Institute Common Terminology Criteria for Adverse Events (NCI CTCAE).&#xD;
&#xD;
          -  Pregnant or lactating women. Pregnant women are excluded from this study because the&#xD;
             study drugs (i.e., nivolumab, ipilimumab, carboplatin, and pemetrexed) have the&#xD;
             potential for teratogenic or abortifacient effects. Because there is an unknown but&#xD;
             potential risk for adverse events in nursing infants secondary to treatment of the&#xD;
             mother with these agents, breastfeeding should be discontinued.&#xD;
&#xD;
          -  Subjects currently enrolled in any other clinical protocol or investigational trial&#xD;
             that involves administration of experimental therapy and/or therapeutic devices, or&#xD;
             investigational drug.&#xD;
&#xD;
          -  History of allergy or hypersensitivity to any study drugs or their excipients.&#xD;
&#xD;
          -  Any known clinically significant concomitant medical condition, laboratory&#xD;
             abnormality, or psychiatric illness that, in the investigator's opinion, would prevent&#xD;
             the subject from participating in the study, pose an unacceptable risk to the patient&#xD;
             in this study, or interfere with the interpretation of safety results.&#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>Alice Shaw, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Massachusetts General Hospital</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Beth Israel Deaconess Medical Center</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02115</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Massachusetts general Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02214</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>August 17, 2017</study_first_submitted>
  <study_first_submitted_qc>August 17, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 21, 2017</study_first_posted>
  <results_first_submitted>September 22, 2020</results_first_submitted>
  <results_first_submitted_qc>September 22, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">October 19, 2020</results_first_posted>
  <last_update_submitted>October 14, 2020</last_update_submitted>
  <last_update_submitted_qc>October 14, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 4, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Massachusetts General Hospital</investigator_affiliation>
    <investigator_full_name>Alice Shaw</investigator_full_name>
    <investigator_title>Director, Center for Thoracic Cancers</investigator_title>
  </responsible_party>
  <keyword>Lung Cancer</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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>Nivolumab</mesh_term>
    <mesh_term>Pemetrexed</mesh_term>
    <mesh_term>Ipilimumab</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 20, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/36/NCT03256136/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Nivolumab Plus Ipilimumab EGFR</title>
          <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
        </group>
        <group group_id="P2">
          <title>Nivolumab Plus Ipilimumab ALK</title>
          <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
        </group>
        <group group_id="P3">
          <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
          <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
        </group>
        <group group_id="P4">
          <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
          <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="3"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="4"/>
                <participants group_id="P4" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
                <participants group_id="P4" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nivolumab Plus Ipilimumab EGFR</title>
          <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
        </group>
        <group group_id="B2">
          <title>Nivolumab Plus Ipilimumab ALK</title>
          <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
        </group>
        <group group_id="B3">
          <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
          <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
        </group>
        <group group_id="B4">
          <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
          <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
        </group>
        <group group_id="B5">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="3"/>
            <count group_id="B2" value="1"/>
            <count group_id="B3" value="4"/>
            <count group_id="B4" value="1"/>
            <count group_id="B5" value="9"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                    <measurement group_id="B5" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Treatment Regimen Received</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="1"/>
                    <measurement group_id="B5" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Objective Response Rate (ORR), Presented in Numbers of Participants</title>
        <description>Complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.</description>
        <time_frame>Up to approximately 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab Plus Ipilimumab EGFR</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O2">
            <title>Nivolumab Plus Ipilimumab ALK</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O3">
            <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
          <group group_id="O4">
            <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response Rate (ORR), Presented in Numbers of Participants</title>
          <description>Complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Disease Control Rate (DCR), Presented in Numbers of Participants</title>
        <description>The number of patients that achieved either complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.</description>
        <time_frame>Up to approximately 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab Plus Ipilimumab EGFR</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O2">
            <title>Nivolumab Plus Ipilimumab ALK</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O3">
            <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
          <group group_id="O4">
            <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Control Rate (DCR), Presented in Numbers of Participants</title>
          <description>The number of patients that achieved either complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="3"/>
                    <measurement group_id="O4" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Progression Free Survival (PFS)</title>
        <description>Time from initiation of the study drugs to progression or death, whichever occurs first. Disease progression was assessed via RECIST 1.1&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).&#xD;
Confidence Intervals (CIs) were calculated using the Kaplan Meier (KM) method</description>
        <time_frame>From the start of treatment until disease progression or death due to any cause, up to approximately 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab Plus Ipilimumab EGFR</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O2">
            <title>Nivolumab Plus Ipilimumab ALK</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O3">
            <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
          <group group_id="O4">
            <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Progression Free Survival (PFS)</title>
          <description>Time from initiation of the study drugs to progression or death, whichever occurs first. Disease progression was assessed via RECIST 1.1&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).&#xD;
Confidence Intervals (CIs) were calculated using the Kaplan Meier (KM) method</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1.3" lower_limit="0.6" upper_limit="1.4"/>
                    <measurement group_id="O2" value="0.7" lower_limit="NA" upper_limit="NA">confidence interval is not defined due to an insufficient number of events</measurement>
                    <measurement group_id="O3" value="4.65" lower_limit="1.2" upper_limit="8.4"/>
                    <measurement group_id="O4" value="2.8" lower_limit="NA" upper_limit="NA">confidence interval is not defined due to an insufficient number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival (OS)</title>
        <description>Time from initiation of the study drugs to date of death due to any cause. CIs are the KM estimate CIs.</description>
        <time_frame>From the start of treatment until death due to any cause, up to approximately 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab Plus Ipilimumab EGFR</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O2">
            <title>Nivolumab Plus Ipilimumab ALK</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O3">
            <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
          <group group_id="O4">
            <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival (OS)</title>
          <description>Time from initiation of the study drugs to date of death due to any cause. CIs are the KM estimate CIs.</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.3" lower_limit="2.6" upper_limit="23.7"/>
                    <measurement group_id="O2" value="7.6" lower_limit="NA" upper_limit="NA">confidence interval is not defined due to an insufficient number of events</measurement>
                    <measurement group_id="O3" value="7.75" lower_limit="2.1" upper_limit="16.2"/>
                    <measurement group_id="O4" value="15.9" lower_limit="NA" upper_limit="NA">confidence interval is not defined due to an insufficient number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Duration Of Response</title>
        <description>Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).</description>
        <time_frame>From the first documented response until disease progression or death, up to approximately 2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Nivolumab Plus Ipilimumab EGFR</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O2">
            <title>Nivolumab Plus Ipilimumab ALK</title>
            <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
          </group>
          <group group_id="O3">
            <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
          <group group_id="O4">
            <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
            <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
          </group>
        </group_list>
        <measure>
          <title>Duration Of Response</title>
          <description>Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first&#xD;
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to &lt;10 mm.&#xD;
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.&#xD;
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).</description>
          <units>months</units>
          <param>Median</param>
          <dispersion>95% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="3"/>
                <count group_id="O2" value="1"/>
                <count group_id="O3" value="4"/>
                <count group_id="O4" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="NA" lower_limit="NA" upper_limit="NA">no objective responses in this cohort</measurement>
                    <measurement group_id="O2" value="NA" lower_limit="NA" upper_limit="NA">no objective responses in this cohort</measurement>
                    <measurement group_id="O3" value="0.9" lower_limit="NA" upper_limit="NA">confidence interval is not defined due to an insufficient number of events</measurement>
                    <measurement group_id="O4" value="1.4" lower_limit="NA" upper_limit="NA">confidence interval is not defined due to an insufficient number of events</measurement>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>From the start of treatment until 30 days after the end of treatment, up to approximately 2 years</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Nivolumab Plus Ipilimumab EGFR</title>
          <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
        </group>
        <group group_id="E2">
          <title>Nivolumab Plus Ipilimumab ALK</title>
          <description>Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
Ipilimumab: will allow the body's immune system to work against tumor cells</description>
        </group>
        <group group_id="E3">
          <title>Nivolumab + Carboplatin + Pemetrexed With EGFR Chemo Naive</title>
          <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
        </group>
        <group group_id="E4">
          <title>Nivolumab + Carboplatin + Pemetrexed ALK Chemo Naive</title>
          <description>Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks&#xD;
Carboplatin: Chemotherapy&#xD;
Nivolumab: will allow the body's immune system to work against tumor cells&#xD;
pemetrexed: Chemo therapy</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Neutrophil count decrease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Skin infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood bilirubin increase</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Seizure</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Aspiration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Chest pain - cardiac</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Vertigo</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Floaters</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Eye disorders - other: red vision</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Anal hemorrhage</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>General disorders, other - Tick bite</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Gait disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Rash pustular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Gum infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nail infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Lymphocyte decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthralgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nervous system disorders, other - numbness to chin and extremities</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Nasal congestion</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hoarseness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Sneezing</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Wheezing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Hiccups</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Rash maculopapular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Skin induration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="3"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="1"/>
                <counts group_id="E3" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E4" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>Early termination leading to small numbers of subjects analyzed.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Dr. Jessica Lin</name_or_title>
      <organization>Massachusetts General Hospital</organization>
      <phone>617-724-1134</phone>
      <email>jjlin1@partners.org</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03256136
org study id: 17-011
nct id: NCT03256136
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This research study is studying a drug intervention as a possible treatment for lung cancer.

      The drugs involved in this study are:

        -  Nivolumab

        -  Carboplatin

        -  Pemetrexed

        -  Ipilimumab
This research study is a Phase II clinical trial. Phase II clinical trials test the safety
      and effectiveness of an investigational intervention to learn whether the intervention works
      in treating a specific disease.

      The FDA (the U.S. Food and Drug Administration) has approved Nivolumab as a treatment for
      other types of cancers including lung cancer. However, the combination of Nivolumab with
      other drugs (such as those being tested in this study) has not been approved by the FDA as a
      treatment for this type of lung cancer.

      The purpose of this study is to test the effectiveness (how well the drug works), safety, and
      tolerability of the drug Nivolumab in combination with standard of care chemotherapies, or in
      combination with Ipilimumab. Nivolumab and Ipilimumab are antibodies (a type of human
      protein) that are being tested to see if they will allow the body's immune system to work
      against tumor cells. This study is being done to see if Nivolumab and Ipilimumab, or
      Nivolumab and chemotherapy drugs (Carboplatin and Pemetrexed), are more effective against
      cancer when administered together.

      These drugs are given as infusions. They are designed to "boost" the immune system's ability
      to suppress or kill cancer cells that are foreign to the human body.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Objective Response Rate (ORR), Presented in Numbers of Participants
time frame: Up to approximately 2 years
description: Complete response (CR) or partial response (PR) per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
measure: Disease Control Rate (DCR), Presented in Numbers of Participants
time frame: Up to approximately 2 years
description: The number of patients that achieved either complete response (CR), partial response (PR), or stable disease (SD) per RECIST version 1.1
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference the smallest sum diameters while on study.
measure: Progression Free Survival (PFS)
time frame: From the start of treatment until disease progression or death due to any cause, up to approximately 2 years
description: Time from initiation of the study drugs to progression or death, whichever occurs first. Disease progression was assessed via RECIST 1.1
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).
Confidence Intervals (CIs) were calculated using the Kaplan Meier (KM) method
measure: Overall Survival (OS)
time frame: From the start of treatment until death due to any cause, up to approximately 2 years
description: Time from initiation of the study drugs to date of death due to any cause. CIs are the KM estimate CIs.
measure: Duration Of Response
time frame: From the first documented response until disease progression or death, up to approximately 2 years
description: Time from the first documentation of objective tumor response (CR or PR) to the first documentation of objective tumor progression or death due to any cause, whichever occurs first
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters.
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study(this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:the appearance of one or more new lesions is also considered progression).
arm group label: Nivolumab Plus Ipilimumab EGFR
arm group type: Experimental
description: Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks
arm group label: Nivolumab Plus Ipilimumab ALK
arm group type: Experimental
description: Nivolumab administered intravenously every 2 weeks Ipilimumab administered intravenously every 6 weeks
arm group label: Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive
arm group type: Experimental
description: Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks
arm group label: Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive
arm group type: Experimental
description: Nivolumab administered intravenously every 3 weeks Carboplatin administered intravenously every 3 weeks Pemetrexed administered intravenously every 3 weeks
intervention type: Drug
intervention name: Carboplatin
description: Chemotherapy
arm group label: Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive
arm group label: Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive
other name: Paraplatin
intervention type: Drug
intervention name: Nivolumab
description: will allow the body's immune system to work against tumor cells
arm group label: Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive
arm group label: Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive
arm group label: Nivolumab Plus Ipilimumab ALK
arm group label: Nivolumab Plus Ipilimumab EGFR
other name: Opdivo
intervention type: Drug
intervention name: pemetrexed
description: Chemo therapy
arm group label: Nivolumab + Carboplatin + Pemetrexed ALK Chemo naive
arm group label: Nivolumab + Carboplatin + Pemetrexed with EGFR Chemo naive
other name: Alimta
intervention type: Drug
intervention name: Ipilimumab
description: will allow the body's immune system to work against tumor cells
arm group label: Nivolumab Plus Ipilimumab ALK
arm group label: Nivolumab Plus Ipilimumab EGFR
other name: Yervoy
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Alice Shaw, MD, PhD
role: Principal Investigator
affiliation: Massachusetts General Hospital
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Massachusetts General Hospital
investigator full name: Alice Shaw
investigator title: Director, Center for Thoracic Cancers
mesh term: Lung Neoplasms
mesh term: Carboplatin
mesh term: Nivolumab
mesh term: Pemetrexed
mesh term: Ipilimumab
sharing ipd: No
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: Early termination leading to small numbers of subjects analyzed.
point of contact: 