<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/NCT01675128</url>
  </required_header>
  <id_info>
    <org_study_id>120187</org_study_id>
    <secondary_id>12-C-0187</secondary_id>
    <nct_id>NCT01675128</nct_id>
  </id_info>
  <brief_title>ISIS 183750 With Irinotecan for Advanced Solid Tumors or Colorectal Cancer</brief_title>
  <official_title>A Phase I/II Study of ISIS 183750 in Combination With Irinotecan in Irinotecan-refractory Colorectal Cancer</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the&#xD;
      deoxyribonucleic acid (DNA) of growing cancer cells. It is most often used with other&#xD;
      chemotherapy drugs. Researchers want to test it with an experimental drug, ISIS 183750. They&#xD;
      want to see if the drugs are a safe and effective treatment for advanced solid tumors or&#xD;
      colorectal cancer that has not responded to other treatments.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To test the safety and effectiveness of ISIS 183750 with irinotecan for advanced solid&#xD;
      tumors or colorectal cancer.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Individuals at least 18 years of age who have solid tumors or colorectal cancer that has&#xD;
      not responded to other treatments.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with a physical exam and medical history. Blood and urine&#xD;
           samples will also be collected. Tumor tissue samples may be collected as well before and&#xD;
           after treatment. Imaging studies will also be performed.&#xD;
&#xD;
        -  Participants will take ISIS 183750 once a week for 28-day cycles of treatment. On the&#xD;
           first cycle, they will also have ISIS 183750 on days 3 and 5.&#xD;
&#xD;
        -  Participants will take irinotecan every second week, beginning on day 15 of the first&#xD;
           cycle.&#xD;
&#xD;
        -  Treatment will be monitored with frequent blood tests and imaging studies.&#xD;
&#xD;
        -  Treatment will continue as long as the cancer does not grow and the side effects are not&#xD;
           severe.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      The eukaryotic translation initiation factor - eIF4E - is a potent oncogene that is found to&#xD;
      be dysregulated in approximately 30% of human cancers. Upregulation of eIF4E is an early&#xD;
      event in colorectal cancer (CRC) and correlates with CRC progression. ISIS 183750 is a&#xD;
      second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the&#xD;
      human eukaryotic translation initiation factor 4E (eIF4E) protein.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      Primary:&#xD;
&#xD;
      To establish Maximum Tolerated Dose (MTD) and establish safety for the combination of ISIS&#xD;
      183750 and irinotecan in advanced solid tumors.&#xD;
&#xD;
      Secondary:&#xD;
&#xD;
        -  To evaluate Response Rate, Progression Free Survival (PFS), Overall Survival (OS) for&#xD;
           the combination of ISIS 183750 and irinotecan in advanced irinotecan-refractory&#xD;
           colorectal cancer.&#xD;
&#xD;
        -  To perform correlative studies to evaluate the effect of eIF4E inhibition on relevant&#xD;
           regulated proteins and immune cells.&#xD;
&#xD;
        -  To characterize the plasma pharmacokinetic (PK) parameters for ISIS 183750 in the&#xD;
           absence and presence of irinotecan&#xD;
&#xD;
        -  To characterize the plasma PK parameters for irinotecan in the presence of ISIS 183750&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      -Adult patients with irinotecan-resistant colorectal cancer (or advanced solid tumor in phase&#xD;
      I part).&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  This is a single-arm phase I/II study whereby all patients will receive the combination&#xD;
           of ISIS 183750 and irinotecan. All cycles are 28 days.&#xD;
&#xD;
        -  Cycle 1 only: ISIS 183750 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8,&#xD;
           15 and 22.&#xD;
&#xD;
        -  Cycle 2 and beyond: ISIS 183750 will be administered as an intravenous infusion every&#xD;
           week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be&#xD;
           re-staged every 8 weeks.&#xD;
&#xD;
        -  Irinotecan will be administered at a dose of 160mg/m^2 as an intravenous infusion every&#xD;
           second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be&#xD;
           to establish maximum tolerated dose (MTD) for the combination of ISIS 183750 and&#xD;
           irinotecan in advanced solid tumors. The phase II portion of the study will be confined&#xD;
           to irinotecan-refractory colorectal cancer. Irinotecan-refractory will be defined as&#xD;
           patients who have radiological evidence of disease progression whilst receiving&#xD;
           irinotecan or within 3 months after completing it.&#xD;
&#xD;
        -  Correlative studies will comprise: Mandatory pre- and post- dose biopsies for eIF4e&#xD;
           messenger ribonucleic acid (mRNA) and protein (IHC) analysis will be performed in the&#xD;
           phase II portion of the study; Immune subsets; positron emission tomography (PET)&#xD;
           responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of&#xD;
           irinotecan and ISIS183750 in 10-12 patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">December 2015</completion_date>
  <primary_completion_date type="Actual">December 2014</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors</measure>
    <time_frame>2 years</time_frame>
    <description>MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of &lt;/=6) patients have DLT as a result of the drug.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors</measure>
    <time_frame>2 years</time_frame>
    <description>MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of &lt;/=6) patients have DLT as a result of the drug.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies</measure>
    <time_frame>2 weeks</time_frame>
    <description>A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies</measure>
    <time_frame>2 weeks</time_frame>
    <description>A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Adverse Events</measure>
    <time_frame>21 months</time_frame>
    <description>Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Objective Response</measure>
    <time_frame>up to 2 cycles</time_frame>
    <description>Objective response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to &lt;10mm. Partial response (PR) is at least a 30% reduction in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of athe 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 lesions is also considered progression).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Progression Free Survival</measure>
    <time_frame>≤ 6 months</time_frame>
    <description>Progression free survival is defined as the time beginning on the on study date and continuing until date of progression or date removed from study for an adverse event.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>≥ 12 months</time_frame>
    <description>Overall survival is defined as the time from the on study date until the date of death or date last known alive.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)</measure>
    <time_frame>up to 24 hours post end of infusion</time_frame>
    <description>AUC(ALL) (Area under the plasma concentration vs. time curve for all time points) was assessed for CPT-11 (irinotecan), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G to derive the total AUC(ALL).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue</measure>
    <time_frame>2 weeks</time_frame>
    <description>Intracellular and stromal presence of ISIS in tumor tissue was assessed by immunohistochemistry (IHC) and Crystal Violet staining to determine effectiveness of drug. Tissue that retains stain indicates intracellular and stromal presence of ISIS and determines if the drug is working. Relative staining intensity (intensity criteria unavailable) was evaluated by a pathologist.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins</measure>
    <time_frame>2 weeks</time_frame>
    <description>Protein levels in the biopsy sample was assessed by immunohistochemistry using anti-oligonucleotide antibody to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a reduced effect (criteria unavailable) of elF4E inhibition on relevant regulated proteins determines if the drug is working.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood</measure>
    <time_frame>2 weeks</time_frame>
    <description>Peripheral blood analysis of elF4E mRNA expression was performed using real time quantitative polymerase chain reaction (q-PCR) to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a decrease (criteria unavailable) in elF4E determines if the drug is working. Cell proliferation or reduction was evaluated by a pathologist.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Colorectal Neoplasms</condition>
  <condition>Colorectal Carcinoma</condition>
  <condition>Colorectal Tumors</condition>
  <arm_group>
    <arm_group_label>Phase I Dose Level I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase I Dose Level II</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Phase II Dose Level I</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ISIS 183750</intervention_name>
    <arm_group_label>Phase I Dose Level I</arm_group_label>
    <arm_group_label>Phase I Dose Level II</arm_group_label>
    <arm_group_label>Phase II Dose Level I</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Irinotecan</intervention_name>
    <arm_group_label>Phase I Dose Level I</arm_group_label>
    <arm_group_label>Phase I Dose Level II</arm_group_label>
    <arm_group_label>Phase II Dose Level I</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  Phase I: Patients must have histopathological confirmation of carcinoma by the&#xD;
             Laboratory of Pathology of the National Cancer Institute (NCI) prior to entering this&#xD;
             study.&#xD;
&#xD;
          -  Phase II: Patients must have histopathological confirmation of Colorectal Carcinoma&#xD;
             (CRC) by the Laboratory of Pathology of the NCI prior to entering this study. For this&#xD;
             portion of the study patients must also have irinotecan-refractory colorectal cancer&#xD;
             and have also received prior treatment for advanced/metastatic disease with an&#xD;
             oxaliplatin-, bevacizumab-, or epidermal growth factor receptor (EGFR)&#xD;
             inhibitor-containing (only for subjects with wild type Kras) regimen.&#xD;
             Irinotecan-refractory will be defined as patients who have radiological evidence of&#xD;
             disease progression whilst receiving irinotecan or within 3 months after completing&#xD;
             it.&#xD;
&#xD;
          -  Patients must have disease that is not amenable to potentially curative resection or&#xD;
             ablative techniques and have received at least one prior standard chemotherapeutic&#xD;
             regimen for metastatic disease.&#xD;
&#xD;
          -  All patients enrolled will be required to have measurable disease. For the phase II&#xD;
             portion of the study patients must have disease that is amenable to biopsy and be&#xD;
             willing to undergo this.&#xD;
&#xD;
          -  Age greater than18 years&#xD;
&#xD;
          -  Life expectancy of greater than 3 months&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status 0-2&#xD;
&#xD;
          -  Patients must have acceptable organ and marrow function as defined below:&#xD;
&#xD;
               -  leukocytes &gt; 3,000/mcL&#xD;
&#xD;
               -  absolute neutrophil count &gt; 1,500/mcL&#xD;
&#xD;
               -  platelets &gt; 100,000/mcL&#xD;
&#xD;
               -  total bilirubin Within normal institutional limits&#xD;
&#xD;
               -  Serum albumin greater than or equal to 2.5 g/dL&#xD;
&#xD;
               -  Patients are eligible with alanine aminotransferase (ALT) or aspartate&#xD;
                  aminotransferase (AST) measuring 3 x upper limit of normal (ULN) if no liver&#xD;
                  metastasis or up to 5 x ULN with liver metastasis.&#xD;
&#xD;
               -  creatinine &lt; 1.5X institution upper limit of normal&#xD;
&#xD;
               -  OR&#xD;
&#xD;
               -  creatinine clearance &gt; 45 mL/min/1.73 m^2, as calculated below, for patients with&#xD;
                  creatinine levels above institutional normal&#xD;
&#xD;
               -  Estimated creatinine clearance (mL/min)&#xD;
&#xD;
                    -  Females see calculations&#xD;
&#xD;
                    -  Males see calculations - May use a 24 hr. urine collection to determine&#xD;
                       creatinine clearance.&#xD;
&#xD;
               -  Measured creatinine clearance (mL/min)&#xD;
&#xD;
          -  Patients must have recovered from any acute toxicity related to prior therapy,&#xD;
             including surgery. Toxicity should be &lt; grade 1 or returned to baseline.&#xD;
&#xD;
          -  Patients must not have other invasive malignancies within the past 3 years (with the&#xD;
             exception of non-melanoma skin cancers, carcinoma in situ of the cervix and&#xD;
             noninvasive bladder cancer that has had successful curative treatment).&#xD;
&#xD;
          -  The effects of ISIS 183750 on the developing human fetus are unknown. For this reason&#xD;
             women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal or barrier method of birth control; abstinence) prior to study entry, for&#xD;
             the duration of study participation, and for 3 months after dosing with study&#xD;
             medication ceases. However, adequate contraception for male patients should be used&#xD;
             for 16 weeks post- last dose due to sperm life cycle. Should a woman become pregnant&#xD;
             or suspect she is pregnant while she or her partner is participating in this study,&#xD;
             she should inform her treating physician immediately. Women of child-bearing potential&#xD;
             must have a negative pregnancy test prior to entry.&#xD;
&#xD;
          -  Patient must be able to understand and willing to sign a written informed consent&#xD;
             document.&#xD;
&#xD;
          -  Men and women of all races and ethnic groups are eligible for this trial.&#xD;
&#xD;
          -  Ejection fraction &gt; 55% on echocardiogram.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Patients who have had chemotherapy (or so-called targeted systemic therapy), large&#xD;
             field radiotherapy, or major surgery must wait 4 weeks after completing treatment&#xD;
             prior to entering the study.&#xD;
&#xD;
          -  Patients may not be receiving any antineoplastics or other drugs intended to treat&#xD;
             cancer within 4 weeks prior to starting ISIS 183750.&#xD;
&#xD;
          -  Patients with known brain metastases will be excluded from this clinical trial because&#xD;
             of their poor prognosis and because they often develop progressive neurologic&#xD;
             dysfunction that would confound the evaluation of neurologic and other adverse events.&#xD;
             Patients with clinically significant ascites, pleural effusion, and/or peripheral&#xD;
             edema, unless the ascites or pleural effusion occurred as a result of malignancy.&#xD;
&#xD;
          -  Patients with known hypersensitivity to irinotecan.&#xD;
&#xD;
          -  Patients with known homozygous mutations in the UTG1A1 UUDP-glucuronosyltransferase&#xD;
             1-1) allele, or with unknown UTG1A1 status but who could not tolerate irinotecan even&#xD;
             after dose reduction.&#xD;
&#xD;
          -  Patients with bleeding diathesis and subjects who are receiving anticoagulation&#xD;
             treatment with International Normalized Ratio (INR) &gt; 2.5 are excluded.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, hypertension&#xD;
             (systolic blood pressure (BP) &gt; 160, diastolic BP &gt; 100), ongoing or active systemic&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac&#xD;
             arrhythmia or psychiatric illness/social situations that would limit compliance with&#xD;
             study requirements.&#xD;
&#xD;
          -  Human immunodeficiency virus (HIV)-positive patients receiving anti-retroviral therapy&#xD;
             are excluded from this study due to the possibility of pharmacokinetic interactions&#xD;
             between antiretroviral medications and the investigational agent.&#xD;
&#xD;
          -  Known hepatitis B or hepatitis C infection.&#xD;
&#xD;
          -  Pregnancy and breast feeding are exclusion factors. Enrolled patients must agree to&#xD;
             use adequate contraception (hormonal or barrier method of birth control; abstinence)&#xD;
             prior to study entry, the duration of study participation and 3 months after the end&#xD;
             of the treatment.&#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>Tim F Greten, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Cancer Institute (NCI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-C-0187.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <results_reference>
    <citation>Duffy AG, Makarova-Rusher OV, Ulahannan SV, Rahma OE, Fioravanti S, Walker M, Abdullah S, Raffeld M, Anderson V, Abi-Jaoudeh N, Levy E, Wood BJ, Lee S, Tomita Y, Trepel JB, Steinberg SM, Revenko AS, MacLeod AR, Peer CJ, Figg WD, Greten TF. Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer. Int J Cancer. 2016 Oct 1;139(7):1648-57. doi: 10.1002/ijc.30199. Epub 2016 Jun 27.</citation>
    <PMID>27194579</PMID>
  </results_reference>
  <verification_date>March 2016</verification_date>
  <study_first_submitted>August 25, 2012</study_first_submitted>
  <study_first_submitted_qc>August 25, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 29, 2012</study_first_posted>
  <results_first_submitted>November 30, 2015</results_first_submitted>
  <results_first_submitted_qc>March 22, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">April 25, 2016</results_first_posted>
  <last_update_submitted>March 22, 2016</last_update_submitted>
  <last_update_submitted_qc>March 22, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">April 25, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>National Institutes of Health Clinical Center (CC)</investigator_affiliation>
    <investigator_full_name>Tim Greten, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Human Eukaryotic Translation Initiation Factor 4E (eIF4E) protein</keyword>
  <keyword>Refractory</keyword>
  <keyword>Oncogene</keyword>
  <keyword>Maximum Tolerated Dose</keyword>
  <keyword>Safety</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Colorectal Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Irinotecan</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Phase I Dose Level I</title>
          <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
        </group>
        <group group_id="P2">
          <title>Phase I Dose Level II</title>
          <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
        </group>
        <group group_id="P3">
          <title>Phase II Dose Level I</title>
          <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="4"/>
                <participants group_id="P2" count="10"/>
                <participants group_id="P3" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="8"/>
                <participants group_id="P3" count="9"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Disease progression on study</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Refused further treatment</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Pulmonary complication; off study</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Phase I Dose Level I</title>
          <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
        </group>
        <group group_id="B2">
          <title>Phase I Dose Level II</title>
          <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
        </group>
        <group group_id="B3">
          <title>Phase II Dose Level I</title>
          <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
        </group>
        <group group_id="B4">
          <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="4"/>
            <count group_id="B2" value="10"/>
            <count group_id="B3" value="10"/>
            <count group_id="B4" value="24"/>
          </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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="15"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="61.6" lower_limit="54.7" upper_limit="73.15"/>
                    <measurement group_id="B2" value="65.7" lower_limit="43.37" upper_limit="79.64"/>
                    <measurement group_id="B3" value="60.6" lower_limit="50.4" upper_limit="72.7"/>
                    <measurement group_id="B4" value="62.7" lower_limit="43.4" upper_limit="79.6"/>
                  </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="4"/>
                    <measurement group_id="B3" value="4"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="6"/>
                    <measurement group_id="B3" value="6"/>
                    <measurement group_id="B4" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</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_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="4"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="24"/>
                  </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_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_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                    <measurement group_id="B4" value="1"/>
                  </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_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="7"/>
                    <measurement group_id="B3" value="7"/>
                    <measurement group_id="B4" value="17"/>
                  </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_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_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="4"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="10"/>
                    <measurement group_id="B4" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors</title>
        <description>MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of &lt;/=6) patients have DLT as a result of the drug.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>All Phase I Participants</title>
            <description>ISIS 183750 started 800mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors</title>
          <description>MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of &lt;/=6) patients have DLT as a result of the drug.</description>
          <units>mg</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1000"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors</title>
        <description>MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of &lt;/=6) patients have DLT as a result of the drug.</description>
        <time_frame>2 years</time_frame>
        <group_list>
          <group group_id="O1">
            <title>All Phase I Participants</title>
            <description>Irinotecan 160 (and 180) mg/m^2 every other week.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors</title>
          <description>MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of &lt;/=6) patients have DLT as a result of the drug.</description>
          <units>mg/m^2</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="14"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="160"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies</title>
        <description>A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).</description>
        <time_frame>2 weeks</time_frame>
        <population>Mandatory pre- and post-dose biopsies for elF4e messenger ribonucleic acid (mRNA) analysis was performed in the phase II portion of the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies</title>
          <description>A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).</description>
          <population>Mandatory pre- and post-dose biopsies for elF4e messenger ribonucleic acid (mRNA) analysis was performed in the phase II portion of the study.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies</title>
        <description>A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.</description>
        <time_frame>2 weeks</time_frame>
        <population>Mandatory pre- and post-dose biopsies for elF4e messenger ribonucleic acid (mRNA) analysis was performed in the phase II portion of the study.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies</title>
          <description>A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.</description>
          <population>Mandatory pre- and post-dose biopsies for elF4e messenger ribonucleic acid (mRNA) analysis was performed in the phase II portion of the study.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Adverse Events</title>
        <description>Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.</description>
        <time_frame>21 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Phase I Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Phase I Dose Level II</title>
            <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
          <group group_id="O3">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Adverse Events</title>
          <description>Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="4"/>
                <count group_id="O2" value="10"/>
                <count group_id="O3" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4"/>
                    <measurement group_id="O2" value="10"/>
                    <measurement group_id="O3" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Objective Response</title>
        <description>Objective response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to &lt;10mm. Partial response (PR) is at least a 30% reduction in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of athe 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 lesions is also considered progression).</description>
        <time_frame>up to 2 cycles</time_frame>
        <population>Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable for response. Per protocol, no responses were to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus there are no objective responses for Phase I Dose Level I.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I Dose Level 2</title>
            <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Objective Response</title>
          <description>Objective response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to &lt;10mm. Partial response (PR) is at least a 30% reduction in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of athe 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 lesions is also considered progression).</description>
          <population>Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable for response. Per protocol, no responses were to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus there are no objective responses for Phase I Dose Level I.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response (CR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Partial Response (PR)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Stable Disease (SD)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive (PD)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Progression Free Survival</title>
        <description>Progression free survival is defined as the time beginning on the on study date and continuing until date of progression or date removed from study for an adverse event.</description>
        <time_frame>≤ 6 months</time_frame>
        <population>Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable. Per protocol, progression free survival was not to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus there is no progression free survival data for Phase I Dose Level I.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I Dose Level II</title>
            <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Progression Free Survival</title>
          <description>Progression free survival is defined as the time beginning on the on study date and continuing until date of progression or date removed from study for an adverse event.</description>
          <population>Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable. Per protocol, progression free survival was not to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus there is no progression free survival data for Phase I Dose Level I.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <description>Overall survival is defined as the time from the on study date until the date of death or date last known alive.</description>
        <time_frame>≥ 12 months</time_frame>
        <population>Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable. Per protocol, overall survival was not to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus overall survival data for Phase I Dose Level I.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I Dose Level II</title>
            <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
          <group group_id="O2">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <description>Overall survival is defined as the time from the on study date until the date of death or date last known alive.</description>
          <population>Only 6/10 participants in Phase I, Dose Level II and 9/10 participants in Phase II were evaluable. Per protocol, overall survival was not to be reported for the Phase I Dose Level I Arm because the participants have different histologies, thus overall survival data for Phase I Dose Level I.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="6"/>
                <count group_id="O2" value="9"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)</title>
        <description>AUC(ALL) (Area under the plasma concentration vs. time curve for all time points) was assessed for CPT-11 (irinotecan), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G to derive the total AUC(ALL).</description>
        <time_frame>up to 24 hours post end of infusion</time_frame>
        <population>Phase I Dose Level I and Phase I Dose Level II were grouped together for this outcome measure. Complete pharmacokinetic data for only ten of the fourteen participants enrolled on the phase I portion of the study were available for analysis. Data is unavailable to report each individual time point.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase I Dose Level I &amp; Phase I Dose Level II</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.&#xD;
Phase I Dose Level II Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)</title>
          <description>AUC(ALL) (Area under the plasma concentration vs. time curve for all time points) was assessed for CPT-11 (irinotecan), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G to derive the total AUC(ALL).</description>
          <population>Phase I Dose Level I and Phase I Dose Level II were grouped together for this outcome measure. Complete pharmacokinetic data for only ten of the fourteen participants enrolled on the phase I portion of the study were available for analysis. Data is unavailable to report each individual time point.</population>
          <units>hr*ng/mL</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>CPT-11 (irinotecan)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="9016" spread="1793"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SN38</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="119" spread="42.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>SN38-G</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1340" spread="751"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue</title>
        <description>Intracellular and stromal presence of ISIS in tumor tissue was assessed by immunohistochemistry (IHC) and Crystal Violet staining to determine effectiveness of drug. Tissue that retains stain indicates intracellular and stromal presence of ISIS and determines if the drug is working. Relative staining intensity (intensity criteria unavailable) was evaluated by a pathologist.</description>
        <time_frame>2 weeks</time_frame>
        <population>Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue</title>
          <description>Intracellular and stromal presence of ISIS in tumor tissue was assessed by immunohistochemistry (IHC) and Crystal Violet staining to determine effectiveness of drug. Tissue that retains stain indicates intracellular and stromal presence of ISIS and determines if the drug is working. Relative staining intensity (intensity criteria unavailable) was evaluated by a pathologist.</description>
          <population>Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins</title>
        <description>Protein levels in the biopsy sample was assessed by immunohistochemistry using anti-oligonucleotide antibody to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a reduced effect (criteria unavailable) of elF4E inhibition on relevant regulated proteins determines if the drug is working.</description>
        <time_frame>2 weeks</time_frame>
        <population>Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins</title>
          <description>Protein levels in the biopsy sample was assessed by immunohistochemistry using anti-oligonucleotide antibody to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a reduced effect (criteria unavailable) of elF4E inhibition on relevant regulated proteins determines if the drug is working.</description>
          <population>Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood</title>
        <description>Peripheral blood analysis of elF4E mRNA expression was performed using real time quantitative polymerase chain reaction (q-PCR) to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a decrease (criteria unavailable) in elF4E determines if the drug is working. Cell proliferation or reduction was evaluated by a pathologist.</description>
        <time_frame>2 weeks</time_frame>
        <population>Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II Dose Level I</title>
            <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood</title>
          <description>Peripheral blood analysis of elF4E mRNA expression was performed using real time quantitative polymerase chain reaction (q-PCR) to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a decrease (criteria unavailable) in elF4E determines if the drug is working. Cell proliferation or reduction was evaluated by a pathologist.</description>
          <population>Per protocol, this outcome measure was assessed in the phase II portion only because all participants were getting the same dose.</population>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Phase I Dose Level I</title>
          <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
        </group>
        <group group_id="E2">
          <title>Phase I Dose Level II</title>
          <description>Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.</description>
        </group>
        <group group_id="E3">
          <title>Phase II Dose Level I</title>
          <description>Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg/every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.</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, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="4" subjects_at_risk="10"/>
              </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="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Endocrine disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperthyroidism</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pancreatitis</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death Not otherwise specified (NOS)</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Lung infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lipase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dysarthria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Acute kidney injury</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hematoma</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</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="4" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="10" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" events="13" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E2" events="28" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E3" events="26" subjects_affected="9" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Ear and labyrinth disorders</title>
            <event_list>
              <event>
                <sub_title>Tinnitus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Eye pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal distension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="6" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" events="6" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="14" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="17" subjects_affected="9" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspepsia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Gastrointestinal pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="11" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="10" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Obstruction gastric</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" events="4" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Bloating</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry mouth</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rectal pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Stomach pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="3" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Edema trunk</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="7" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="10" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="8" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="12" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Flu like symptoms</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Malaise</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="10" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Edema face</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Hepatobiliary disorders</title>
            <event_list>
              <event>
                <sub_title>Portal vein thrombosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic reaction</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sinusitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Upper respiratory infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Wound complication</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <counts group_id="E1" events="7" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E2" events="23" subjects_affected="7" subjects_at_risk="10"/>
                <counts group_id="E3" events="14" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="19" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="31" subjects_affected="8" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="14" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="24" subjects_affected="9" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="10" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="18" subjects_affected="7" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="4" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="21" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="9" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" events="22" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E2" events="27" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" events="9" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="35" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="7" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" events="5" subjects_affected="3" subjects_at_risk="4"/>
                <counts group_id="E2" events="25" subjects_affected="7" subjects_at_risk="10"/>
                <counts group_id="E3" events="11" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" events="18" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E2" events="51" subjects_affected="8" subjects_at_risk="10"/>
                <counts group_id="E3" events="17" subjects_affected="7" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="8" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="7" subjects_affected="5" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="6" subjects_affected="4" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="8" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypermagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypernatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" events="10" subjects_affected="4" subjects_at_risk="4"/>
                <counts group_id="E2" events="36" subjects_affected="9" subjects_at_risk="10"/>
                <counts group_id="E3" events="35" subjects_affected="9" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypoglycemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" events="8" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="11" subjects_affected="5" subjects_at_risk="10"/>
                <counts group_id="E3" events="5" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="4" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" events="4" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="5" subjects_affected="4" subjects_at_risk="10"/>
                <counts group_id="E3" events="20" subjects_affected="9" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" events="3" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="11" subjects_affected="6" subjects_at_risk="10"/>
                <counts group_id="E3" events="14" subjects_affected="6" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Non-cardiac chest pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dysgeusia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="6" subjects_affected="6" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypersomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Presyncope</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Paresthesia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nervous system disorders- Other, specify (alteration in smell)</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Agitation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Confusion</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </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="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hematuria</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Reproductive system and breast disorders</title>
            <event_list>
              <event>
                <sub_title>Vaginal discharge</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Allergic rhinitis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pneumothorax</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Dry skin</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Nail ridging</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="3" subjects_affected="3" subjects_at_risk="10"/>
                <counts group_id="E3" events="3" subjects_affected="3" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Skin ulceration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="10"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="4"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="10"/>
                <counts group_id="E3" events="2" subjects_affected="2" subjects_at_risk="10"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="4"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="10"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="10"/>
              </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>
    <point_of_contact>
      <name_or_title>Dr.Tim Greten</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>301-451-4723</phone>
      <email>gretentf@mail.nih.gov</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/NCT01675128
org study id: 120187
secondary id: 12-C-0187
nct id: NCT01675128
lead sponsor: 
has dmc: Yes
Background:

      - Irinotecan is a drug that is used to treat colon or rectal cancer. It affects the
      deoxyribonucleic acid (DNA) of growing cancer cells. It is most often used with other
      chemotherapy drugs. Researchers want to test it with an experimental drug, ISIS 183750. They
      want to see if the drugs are a safe and effective treatment for advanced solid tumors or
      colorectal cancer that has not responded to other treatments.

      Objectives:

      - To test the safety and effectiveness of ISIS 183750 with irinotecan for advanced solid
      tumors or colorectal cancer.

      Eligibility:

      - Individuals at least 18 years of age who have solid tumors or colorectal cancer that has
      not responded to other treatments.

      Design:

        -  Participants will be screened with a physical exam and medical history. Blood and urine
           samples will also be collected. Tumor tissue samples may be collected as well before and
           after treatment. Imaging studies will also be performed.

        -  Participants will take ISIS 183750 once a week for 28-day cycles of treatment. On the
           first cycle, they will also have ISIS 183750 on days 3 and 5.

        -  Participants will take irinotecan every second week, beginning on day 15 of the first
           cycle.

        -  Treatment will be monitored with frequent blood tests and imaging studies.

        -  Treatment will continue as long as the cancer does not grow and the side effects are not
           severe.
Background:

      The eukaryotic translation initiation factor - eIF4E - is a potent oncogene that is found to
      be dysregulated in approximately 30% of human cancers. Upregulation of eIF4E is an early
      event in colorectal cancer (CRC) and correlates with CRC progression. ISIS 183750 is a
      second-generation antisense oligonucleotide (ASO) designed to inhibit the production of the
      human eukaryotic translation initiation factor 4E (eIF4E) protein.

      Objectives:

      Primary:

      To establish Maximum Tolerated Dose (MTD) and establish safety for the combination of ISIS
      183750 and irinotecan in advanced solid tumors.

      Secondary:

        -  To evaluate Response Rate, Progression Free Survival (PFS), Overall Survival (OS) for
           the combination of ISIS 183750 and irinotecan in advanced irinotecan-refractory
           colorectal cancer.

        -  To perform correlative studies to evaluate the effect of eIF4E inhibition on relevant
           regulated proteins and immune cells.

        -  To characterize the plasma pharmacokinetic (PK) parameters for ISIS 183750 in the
           absence and presence of irinotecan

        -  To characterize the plasma PK parameters for irinotecan in the presence of ISIS 183750

      Eligibility:

      -Adult patients with irinotecan-resistant colorectal cancer (or advanced solid tumor in phase
      I part).

      Design:

        -  This is a single-arm phase I/II study whereby all patients will receive the combination
           of ISIS 183750 and irinotecan. All cycles are 28 days.

        -  Cycle 1 only: ISIS 183750 will be administered intravenously on Cycle 1 Days 1, 3, 5, 8,
           15 and 22.

        -  Cycle 2 and beyond: ISIS 183750 will be administered as an intravenous infusion every
           week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be
           re-staged every 8 weeks.

        -  Irinotecan will be administered at a dose of 160mg/m^2 as an intravenous infusion every
           second week commencing on Day 15 of Cycle 1. The primary endpoint of the study will be
           to establish maximum tolerated dose (MTD) for the combination of ISIS 183750 and
           irinotecan in advanced solid tumors. The phase II portion of the study will be confined
           to irinotecan-refractory colorectal cancer. Irinotecan-refractory will be defined as
           patients who have radiological evidence of disease progression whilst receiving
           irinotecan or within 3 months after completing it.

        -  Correlative studies will comprise: Mandatory pre- and post- dose biopsies for eIF4e
           messenger ribonucleic acid (mRNA) and protein (IHC) analysis will be performed in the
           phase II portion of the study; Immune subsets; positron emission tomography (PET)
           responses (only in expansion cohort); Pharmacokinetic data regarding the interaction of
           irinotecan and ISIS183750 in 10-12 patients.
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum Tolerated Dose (MTD) of ISIS 183750 in Advanced Solid Tumors
time frame: 2 years
description: MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of </=6) patients have DLT as a result of the drug.
measure: Maximum Tolerated Dose of Irinotecan in Advanced Solid Tumors
time frame: 2 years
description: MTD is the dose level at which no more than 1 of up to 6 patients experience dose-limiting toxicity (DLT) during the first 6 weeks of treatment, and no dose below that which at least 2 (of </=6) patients have DLT as a result of the drug.
measure: Number of Participants With a Change in the Level of a Particular Gene Called elF4E [Eukaryotic Initiation Factors (elF)4e Messenger Ribonucleic Acid (mRNA) Levels] in Matched Pre and Post Tumor Biopsies
time frame: 2 weeks
description: A change in elF4e levels is defined as an increase or decrease compared to baseline and is measured between two time points before rand after 2 weeks of treatment by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR).
measure: Number of Participants With a Change in elF4e Protein Levels in Matched Pre and Post Tumor Biopsies
time frame: 2 weeks
description: A change in protein is defined as an increase or decrease compared to baseline and is measured between two time points by immunohistochemistry (IHC) analysis.
measure: Number of Participants With Adverse Events
time frame: 21 months
description: Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse event module.
measure: Objective Response
time frame: up to 2 cycles
description: Objective response was evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete Response (CR) is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non target) must have reduction in short axis to <10mm. Partial response (PR) is at least a 30% reduction in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Progressive disease (PD) is at least a 20% increase in the sum of athe 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 lesions is also considered progression).
measure: Number of Participants With Progression Free Survival
time frame: ≤ 6 months
description: Progression free survival is defined as the time beginning on the on study date and continuing until date of progression or date removed from study for an adverse event.
measure: Overall Survival
time frame: ≥ 12 months
description: Overall survival is defined as the time from the on study date until the date of death or date last known alive.
measure: AUC(ALL) (Area Under the Plasma Concentration vs. Time Curve for All Time Points)
time frame: up to 24 hours post end of infusion
description: AUC(ALL) (Area under the plasma concentration vs. time curve for all time points) was assessed for CPT-11 (irinotecan), its active metabolite SN38, and the glucuronic acid metabolite of SN38, SN38-G to derive the total AUC(ALL).
measure: Number of Participants With Intracellular and Stromal Presence of ISIS in Tumor Tissue
time frame: 2 weeks
description: Intracellular and stromal presence of ISIS in tumor tissue was assessed by immunohistochemistry (IHC) and Crystal Violet staining to determine effectiveness of drug. Tissue that retains stain indicates intracellular and stromal presence of ISIS and determines if the drug is working. Relative staining intensity (intensity criteria unavailable) was evaluated by a pathologist.
measure: Number of Participants With a Reduced Effect of elF4E Inhibition on Relevant Regulated Proteins
time frame: 2 weeks
description: Protein levels in the biopsy sample was assessed by immunohistochemistry using anti-oligonucleotide antibody to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a reduced effect (criteria unavailable) of elF4E inhibition on relevant regulated proteins determines if the drug is working.
measure: Number of Participants With a Decrease in elF4E mRNA Expression in Peripheral Blood
time frame: 2 weeks
description: Peripheral blood analysis of elF4E mRNA expression was performed using real time quantitative polymerase chain reaction (q-PCR) to assess the downstream effect and determine if proteins are being manufactured. The number of participants with a decrease (criteria unavailable) in elF4E determines if the drug is working. Cell proliferation or reduction was evaluated by a pathologist.
arm group label: Phase I Dose Level I
arm group type: Experimental
description: Irinotecan 160 mg/m^2 every other week; ISIS 183750 started 800 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.
arm group label: Phase I Dose Level II
arm group type: Experimental
description: Irinotecan 180 mg/m^2 every other week; ISIS 183750 1000 mg/every week will be administered intravenously on Cycle 1 Days 1, 3, 5, 8, 15 and 22 of a 28 day cycle, restaged every 8 weeks.
arm group label: Phase II Dose Level I
arm group type: Experimental
description: Irinotecan 160 mg/m^2 every other week; ISIS 183750 1000mg every week will be administered as an intravenous infusion every week without break, i.e. Days 1, 8, 15 and 22 of a 28-day cycle. Patients will be re-staged every 8 weeks.
intervention type: Drug
intervention name: ISIS 183750
arm group label: Phase I Dose Level I
arm group label: Phase I Dose Level II
arm group label: Phase II Dose Level I
intervention type: Drug
intervention name: Irinotecan
arm group label: Phase I Dose Level I
arm group label: Phase I Dose Level II
arm group label: Phase II Dose Level I
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Tim F Greten, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: http://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2012-C-0187.html
description: NIH Clinical Center Detailed Web Page
citation: Duffy AG, Makarova-Rusher OV, Ulahannan SV, Rahma OE, Fioravanti S, Walker M, Abdullah S, Raffeld M, Anderson V, Abi-Jaoudeh N, Levy E, Wood BJ, Lee S, Tomita Y, Trepel JB, Steinberg SM, Revenko AS, MacLeod AR, Peer CJ, Figg WD, Greten TF. Modulation of tumor eIF4E by antisense inhibition: A phase I/II translational clinical trial of ISIS 183750-an antisense oligonucleotide against eIF4E-in combination with irinotecan in solid tumors and irinotecan-refractory colorectal cancer. Int J Cancer. 2016 Oct 1;139(7):1648-57. doi: 10.1002/ijc.30199. Epub 2016 Jun 27.
PMID: 27194579
responsible party type: Principal Investigator
investigator affiliation: National Institutes of Health Clinical Center (CC)
investigator full name: Tim Greten, M.D.
investigator title: Principal Investigator
mesh term: Colorectal Neoplasms
mesh term: Irinotecan
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 