<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/NCT02192541</url>
  </required_header>
  <id_info>
    <org_study_id>140150</org_study_id>
    <secondary_id>14-C-0150</secondary_id>
    <nct_id>NCT02192541</nct_id>
  </id_info>
  <brief_title>Ganetespib and Ziv-Aflibercept in Refractory Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas</brief_title>
  <official_title>Phase I Study of Ganetespib and Ziv-Aflibercept in Patients With Advanced Gastrointestinal Carcinomas, Non-Squamous Non-Small Cell Lung Carcinomas, Urothelial Carcinomas, and Sarcomas</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>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Some people have cancers that don't respond to standard treatments. In these cases, doctors&#xD;
      may try to use drugs to slow the growth of the cancer.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To test the safety and efficacy of the drug combination of ganetespib and ziv-aflibercept.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      - Adults age 18 and over with advanced cancer of the colon, lung, urinary tract, and&#xD;
      sarcomas.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with medical history, blood tests, and scans to measure&#xD;
           their tumors.&#xD;
&#xD;
        -  Participants will have one or two eye exams, with dilating eye drops.&#xD;
&#xD;
        -  Participants will get the study drugs at the clinic as an infusion in a vein. Ganetespib&#xD;
           will be given once a week on the same day for 3 weeks in a row, followed by a 1-week&#xD;
           rest period. Ziv-aflibercept will be given once every other week. The drugs will be&#xD;
           given in 28-day cycles.&#xD;
&#xD;
        -  Participants may have a small piece of their tumor collected once or twice. This is done&#xD;
           using a small needle during computed tomography (CT), magnetic resonance imaging (MRI),&#xD;
           or ultrasound scan.&#xD;
&#xD;
        -  Participants will have their blood pressure checked at each visit. They will check it at&#xD;
           home every day of the study.&#xD;
&#xD;
        -  Participants may have one or more whole-body positron emission tomography (PET) scans&#xD;
           with 89Zr-panitumumab. A small amount of a radioactive chemical will be injected through&#xD;
           a tube in an arm. Participants will lie on a bed that slides in and out of the&#xD;
           donut-shaped PET scanner. They will have small amounts of blood drawn.&#xD;
&#xD;
        -  Participants may stay in the study as long as they are tolerating the drugs and their&#xD;
           tumor is not getting worse.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      BACKGROUND:&#xD;
&#xD;
        -  Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 that has demonstrated&#xD;
           activity against multiple cancer cell lines and tumor xenografts in preclinical models.&#xD;
           Inhibiting the Hsp90 chaperone complex results in the recruitment of ubiquitin ligases,&#xD;
           polyubiquination, and proteosomal degradation of Hsp90 client proteins, including&#xD;
           transcription factors and proteins involved in angiogenesis vascular endothelial growth&#xD;
           factor (VEGF), vascular endothelial growth factor receptor (VEGFR), hypoxia-inducible&#xD;
           factor 1 (HIF-1), signal transducers and activators of transcription protein 3 (STAT-3);&#xD;
           growth factor independence rapidly accelerated fibrosarcoma (RAF), epidermal growth&#xD;
           factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), insulin-like&#xD;
           growth factor 1 receptor (IGFR); resistance to anti-growth signals cyclin-dependent&#xD;
           kinase 4 (CDK4); tissue invasion and metastases mesenchymal-epithelial transition factor&#xD;
           (MET), matrix metalloproteinase-2 (MMP2); and avoidance of apoptosis protein kinase B&#xD;
           (AKT), rat insulin promoter (RIP), Survivin, B cell lymphoma (Bcl-2).&#xD;
&#xD;
        -  HIF-1-alpha activation has been implicated in mediating resistance to anti-angiogenic&#xD;
           therapy; recent evidence implicates a greater role for Hsp90 in direct modulation of&#xD;
           VEGF signaling.&#xD;
&#xD;
        -  Combining Hsp90 inhibition with ganetespib and anti-angiogenic therapy with&#xD;
           Ziv-Aflibercept, a soluble fusion protein with high binding affinity for vascular&#xD;
           endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and&#xD;
           placenta growth factor (PIGF), presents a rational novel strategy for improving upon and&#xD;
           overcoming resistance to anti-angiogenic therapy&#xD;
&#xD;
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      - To establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination&#xD;
      of ganetespib and Ziv-Aflibercept in patients with refractory gastrointestinal carcinomas,&#xD;
      non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas&#xD;
&#xD;
      SECONDARY OBJECTIVE:&#xD;
&#xD;
        -  To assess modulation of HIF-1-alpha as a pharmacodynamic marker of therapy with the&#xD;
           combination of ganetespib and Ziv-Aflibercept&#xD;
&#xD;
        -  To assess modulation of epidermal growth factor receptor (EGFR) expression using&#xD;
           89Zr-labeled, EGFR-targeting antibody panitumumab positron emission tomography&#xD;
           (PET)/computed tomography (CT) imaging of tumor lesions prior to and following treatment&#xD;
           with study drugs&#xD;
&#xD;
      ELIGIBILITY:&#xD;
&#xD;
        -  Adult patients with histologically confirmed metastatic gastrointestinal carcinomas,&#xD;
           non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas with&#xD;
           disease progression after at least one line of standard therapy&#xD;
&#xD;
        -  Participants in the expansion phase must demonstrate EGFR expression on archival tumor&#xD;
           samples and have disease amenable to biopsy with willingness to undergo pre- and&#xD;
           post-treatment biopsies&#xD;
&#xD;
        -  No major surgery within 4 weeks prior to study enrollment, no radiation or chemotherapy&#xD;
           within 3 weeks prior to enrollment; patients must have recovered from toxicities of&#xD;
           prior therapies to at least eligibility levels prior to enrollment.&#xD;
&#xD;
      STUDY DESIGN:&#xD;
&#xD;
        -  Ganetespib will be administered intravenously weekly on days 1, 8, and 15 of a 28-day&#xD;
           cycle. Ziv-Aflibercept will be administered intravenously every 2 weeks, on days 1 and&#xD;
           15, during a 28-day cycle.&#xD;
&#xD;
        -  The escalation portion of the trial will follow a standard 3+3 design, whereby patients&#xD;
           are dose-escalated in cohorts of 3 until dose-limiting toxicity is observed.&#xD;
&#xD;
        -  Once the MTD is established, 10 additional patients will be enrolled to the expansion&#xD;
           phase, at the MTD, and tumor biopsies will be obtained to assess pharmacodynamic&#xD;
           endpoints. During cycle 1 of the expansion phase, ganetespib will be administered&#xD;
           intravenously weekly, on days 8 and 15 with omission of day 1 treatment to accommodate a&#xD;
           baseline biopsy pre-ganetespib but after administration of Ziv-Aflibercept. For all&#xD;
           subsequent cycles, ganetespib will be administered days 1, 8, and 15. Ziv-Aflibercept&#xD;
           will still be administered intravenously every 2 weeks, on days 1 and 15, of a 28-day&#xD;
           cycle.&#xD;
&#xD;
        -  PET/CT imaging with 89Zr-labeled panitumumab will be performed to evaluate tumor&#xD;
           distribution prior to and following treatment with study agents.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Drug supplier suspended further clinical development of Ganetespib&#xD;
  </why_stopped>
  <start_date type="Actual">December 2, 2014</start_date>
  <completion_date type="Actual">February 25, 2016</completion_date>
  <primary_completion_date type="Actual">February 25, 2016</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0</measure>
    <time_frame>Date treatment consent signed to date off study, approximately 12 months and 44 days</time_frame>
    <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs</measure>
    <time_frame>Date treatment consent signed to date off study, approximately 12 months and 44 days</time_frame>
    <description>Adverse Events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the Adverse Event. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE). AEs were considered possibly attributable to both study drugs, except where otherwise noted. Star (*) symbol indicates that the AE is possibly related to Ziv-aflibercept and unlikely to be related to Ganetespib.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept</measure>
    <time_frame>Cycle one (28 days)</time_frame>
    <description>MTD is defined as the dose level at which no more than 1 of 6 patients experience a dose limiting toxicity (DLT) during the first cycle of the treatment, and the dose level below that at which at least 2 (of &lt;6) patients have a DLT as a result of the drug. Determination of DLT is based on the first cycle of treatment.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha</measure>
    <time_frame>Cycle 2, Day 7</time_frame>
    <description>To determine whether the combination of ganetespib and ziv-aflibercept modulated intratumoral Hypoxia-inducible factor 1 (HIF-1)-alpha expression, tumor biopsies were to be analyzed for change in HIF-1-alpha expression by immunofluorescence assay (IFA). Paired pre-and post-combination treatment samples were to be compared for qualitative changes in levels of HIF-1- alpha expression. Cores were to be normalized against the percentage of tumor within the sample.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Modulation of Epidermal Growth Factor Receptor (EGFR) Expression</measure>
    <time_frame>Cycle 1 Day 16</time_frame>
    <description>To evaluate for tumor distribution of EGFR, patients were to undergo 89Zr-immuno-positron emission tomography (PET) imaging with 89Zr-labeled EGFR-targeting panitumumab antibody evaluate modulation of EGFR client protein prior to and after treatment with the combination of ganetespib and ziv-aflibercept. Panitumumab is a fully human monoclonal antibody that targets EGFR and competes with endogenous ligands to block stimulation of EGFR. 89z-immuno-PET imaging with panitumumab as a targeting ligand allows for quantification of EGFR within tumors.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)</measure>
    <time_frame>Baseline and every 2 months up to 5 months</time_frame>
    <description>Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles to evaluate tumor response based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria for target lesions: Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of Cycles on Treatment</measure>
    <time_frame>up to 5 months</time_frame>
    <description>The number of 28-day treatment cycles (ganetespib on days 1, 8, and 15; ziv-aflibercept on days 1 and 15) administered to each evaluable patient. Number represents treatment cycles that were started; not all cycles were completed.</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number of Participants Who Had a Dose Limiting Toxicity (DLT)</measure>
    <time_frame>Cycle one (28 days)</time_frame>
    <description>A DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of study drugs during cycle one and is a Grade ≥ 3 non-hematological toxicity. Grade ≥3 non-hematological toxicity felt to be related to study medications are: Grade 3 diarrhea if it is refractory to treatment; Grade 3 nausea and vomiting if it is refractory to anti-emetic therapy and unable to be corrected; rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with intravenous (IV) fluids; Any Grade 4 corrected QT interval (QTc) prolongation; Grade 4 neutropenia ≥5 days or febrile neutropenia,...).</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Neoplasms</condition>
  <arm_group>
    <arm_group_label>Ganetespib and Ziv-Aflibercept</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 + ziv-aflibercept at 3 mg/kg or 4 mg/kg.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ziv-Aflibercept</intervention_name>
    <description>Ziv-aflibercept is a soluble fusion protein with high binding affinity for vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (PIGF) and thus confers anti-angiogenic activity</description>
    <arm_group_label>Ganetespib and Ziv-Aflibercept</arm_group_label>
    <other_name>ZALTRAP</other_name>
    <other_name>VEGF-TRAP</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ganetespib</intervention_name>
    <description>Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 with activity against multiple cancer cell lines and tumor xenografts in preclinical models.</description>
    <arm_group_label>Ganetespib and Ziv-Aflibercept</arm_group_label>
    <other_name>STA-9090</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Patients must have histologically confirmed recurrent or metastatic gastrointestinal&#xD;
        carcinomas, non-squamous non-small cell lung carcinomas, urothelial carcinomas, and&#xD;
        sarcomas with disease progression after at least one line of standard therapy. Disease&#xD;
        should have progressed following all treatments known to prolong survival, unless a given&#xD;
        treatment is contraindicated.&#xD;
&#xD;
          -  Patients with colorectal carcinoma must have progressed through at least two lines of&#xD;
             standard chemotherapy in the metastatic setting.&#xD;
&#xD;
          -  Patients with non-small cell lung cancer with known sensitizing epidermal growth&#xD;
             factor receptor (EGFR) mutation and/or anaplastic lymphoma receptor tyrosine kinase&#xD;
             (ALK) rearrangement should have received prior erlotinib and/or crizotinib,&#xD;
             respectively.&#xD;
&#xD;
          -  Patients with urothelial carcinoma will have progressed on prior platinum-based&#xD;
             therapy or for which platinum-based therapy is contraindicated.&#xD;
&#xD;
          -  Patients enrolled on the expansion phase of the protocol must demonstrate EGFR&#xD;
             expression by immunohistochemistry on archival tumor samples prior to undergoing (89)&#xD;
             Zr-panitumumab positron emission tomography (PET)/computed tomography (CT) scans.&#xD;
&#xD;
        Age greater than or equal to 18 years of age.&#xD;
&#xD;
        Eastern Cooperative Oncology Group (ECOG) performance status &lt; 2.&#xD;
&#xD;
        Life expectancy &gt; 3 months.&#xD;
&#xD;
        Patients must have normal organ and marrow function as defined below:&#xD;
&#xD;
          -  absolute neutrophil count greater than or equal to 1,500/mcL&#xD;
&#xD;
          -  platelets greater than or equal to 100,000/mcL&#xD;
&#xD;
          -  total bilirubin less than or equal to 1.5 times institutional upper limit of normal&#xD;
&#xD;
          -  Aspartate aminotransferase (AST)(serum glutamic oxaloacetic transaminase SGOT)/alanine&#xD;
             aminotransferase (ALT)(serum glutamic pyruvic transaminase SGPT) less than or equal to&#xD;
             3 times institutional upper limit of normal&#xD;
&#xD;
          -  creatinine less than or equal to 1.2 times institutional upper limit of normal&#xD;
&#xD;
        OR&#xD;
&#xD;
          -  creatinine clearance greater than or equal to 60 mL/min/1.73 m^2 for patients with&#xD;
             creatinine levels above institutional normal&#xD;
&#xD;
          -  urine protein/creatinine &lt; 1 mg/mg&#xD;
&#xD;
          -  International Normalized Ratio (INR) &lt; 1.5&#xD;
&#xD;
        Cardiac function within institutional normal limits on echocardiogram.&#xD;
&#xD;
        Patients must have blood pressure no greater than 140 mmHg (systolic blood pressure) and 90&#xD;
        mmHg (diastolic blood pressure) for eligibility. Initiation or adjustment of&#xD;
        antihypertensive medications is permitted prior to study entry provided that the average of&#xD;
        three blood pressure measurements at enrollment visit is less than 140/90 mmHg.&#xD;
&#xD;
        The effects of ganetespib on the developing human fetus are unknown. For this reason and&#xD;
        because anti-angiogenic agents similar to ziv-aflibercept are known to be teratogenic,&#xD;
        women of child-bearing potential and men must agree to use two forms of contraception&#xD;
        (hormonal or barrier method of birth control; abstinence; sterilization) prior to study&#xD;
        entry, for the duration of study participation, and for 3 months after completing study&#xD;
        treatment. Should a woman become pregnant or suspect she is pregnant while she or her&#xD;
        partner is participating in this study, she should inform her treating physician&#xD;
        immediately. Men treated or enrolled on this protocol must also agree to use two forms of&#xD;
        contraception prior to the study, for the duration of study participation, and for 3 months&#xD;
        after completion of administration of both ganetespib and ziv-aflibercept.&#xD;
&#xD;
        Ability to understand and the willingness to sign a written informed consent document.&#xD;
&#xD;
        During the escalation phase of the protocol, patients may have evaluable or measurable&#xD;
        disease. During the expansion phase of the protocol, patients must have 1) measurable&#xD;
        disease, 2) disease amenable to biopsy and 3) willingness to undergo pre- and&#xD;
        post-treatment biopsies.&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
        Patients who have had chemotherapy or radiotherapy within 3 weeks (6 weeks for nitrosoureas&#xD;
        or mitomycin C) prior to entering the study or those who have not recovered from adverse&#xD;
        events due to agents administered more than 3 weeks earlier.&#xD;
&#xD;
        Patients who are receiving any other investigational agents.&#xD;
&#xD;
        Patients with known active brain metastases or carcinomatous meningitis are excluded from&#xD;
        this clinical trial. Patients whose brain metastatic disease status has remained stable for&#xD;
        greater than or equal to 4 weeks following treatment of brain metastases are eligible to&#xD;
        participate at the discretion of the principal investigator.&#xD;
&#xD;
        Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
        untreated infection, or psychiatric illness/social situations that would limit compliance&#xD;
        with study requirements.&#xD;
&#xD;
        Patients with known serious cardiac illness or medical conditions, including but not&#xD;
&#xD;
        limited to:&#xD;
&#xD;
          -  Clinically unstable cardiac disease, including unstable atrial fibrillation,&#xD;
             symptomatic bradycardia, unstable congestive heart failure, unstable angina or history&#xD;
             of myocardial infarct within 6 months prior to enrollment, or indwelling temporary&#xD;
             pacemaker&#xD;
&#xD;
          -  Ventricular tachycardia or a supraventricular tachycardia that requires treatment with&#xD;
             antiarrhythmic agents&#xD;
&#xD;
          -  Second- or third-degree atrioventricular block unless treated with a permanent&#xD;
             pacemaker&#xD;
&#xD;
          -  Complete left bundle branch block&#xD;
&#xD;
          -  History of long Q wave, T wave (QT) syndrome or a family member with this condition&#xD;
&#xD;
        No major surgery within 4 weeks prior to enrollment or history of gastrointestinal bleeding&#xD;
        within 3 months prior to enrollment. No signs or symptoms of active bleeding or nonhealing&#xD;
        ulcer will be permitted at study entry. Patients with central pulmonary tumors with&#xD;
        evidence of bronchial invasion, or presenting with hemoptysis will be excluded.&#xD;
&#xD;
        Corrected QT interval (QTc) &gt; 470 msec on electrocardiogram (by Bazett's; average of&#xD;
        triplicate recordings at the discretion of the principal investigator (PI) will exclude&#xD;
        patients from entry on study. Medications that are known to cause QTc interval prolongation&#xD;
        are prohibited for patients entering on trial. Patients for whom a given medication that&#xD;
        may cause QTc interval prolongation cannot be discontinued, may be eligible at the&#xD;
        discretion of the study PI, provided QTc interval criteria is met at enrollment. A&#xD;
        comprehensive list of agents with the potential to cause QTc prolongation can be found in&#xD;
        Appendix C and at http://crediblemeds.org.&#xD;
&#xD;
        Pregnant women and women who are breastfeeding are excluded from this study because the&#xD;
        effects of the study drugs on the developing fetus are unknown.&#xD;
&#xD;
        Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy&#xD;
        are ineligible because of the potential for pharmacokinetic interactions with ganetespib&#xD;
        and zivaflibercept. In addition, these patients are at increased risk of lethal infections&#xD;
        when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in&#xD;
        patients receiving combination antiretroviral therapy when indicated.&#xD;
&#xD;
        Substrates of cytochrome P450 3A4 (CYP3A4) or cytochrome P450 2C19 (CYP2C19):&#xD;
&#xD;
          -  Preliminary results of a clinical drug-drug interaction study, examining the effect of&#xD;
             ganetespib on the pharmacokinetics of the CYP2C19-sensitive probe omeprazole, show a&#xD;
             modest (20%) increase in omeprazole exposure when coadministered with ganetespib.&#xD;
&#xD;
          -  In vitro data implies expectation of greater interaction with CYP2C19 substrates than&#xD;
             with CYP3A4 substrates.&#xD;
&#xD;
          -  Caution is advised when sensitive narrow therapeutic range CYP3A4 or CYP2C19&#xD;
             substrates are concomitantly administered.&#xD;
&#xD;
        Inhibitors of P-Glycoprotein Efflux Transporters: Concomitant medications that are strong&#xD;
        inhibitors of P-glycoprotein efflux transporters should be used with caution during the&#xD;
        study; examples of these medications include:&#xD;
&#xD;
          -  ritonavir,&#xD;
&#xD;
          -  cyclosporine,&#xD;
&#xD;
          -  verapamil,&#xD;
&#xD;
          -  erythromycin,&#xD;
&#xD;
          -  ketoconazole,&#xD;
&#xD;
          -  itraconazole,&#xD;
&#xD;
          -  quinidine, and&#xD;
&#xD;
          -  elacridar.&#xD;
&#xD;
        Concurrent anticoagulation will be permitted providing the patient is receiving a stable&#xD;
        dose of anticoagulants before study entry. Patients receiving anticoagulants will be&#xD;
        eligible for this trial. Evidence of clinically significant bleeding diathesis or&#xD;
        underlying coagulopathy (e.g., INR &gt; 1.5 without vitamin K antagonist therapy) will not be&#xD;
        permitted.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>120 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Alice P Chen, 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>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-C-0150.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <reference>
    <citation>Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.</citation>
    <PMID>21376230</PMID>
  </reference>
  <reference>
    <citation>Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012 Nov 10;30(32):4026-34. doi: 10.1200/JCO.2012.41.9242. Epub 2012 Sep 24. Erratum In: J Clin Oncol. 2013 Feb 20;31(6):824.</citation>
    <PMID>23008289</PMID>
  </reference>
  <reference>
    <citation>Stravopodis DJ, Margaritis LH, Voutsinas GE. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr Med Chem. 2007;14(29):3122-38. doi: 10.2174/092986707782793925.</citation>
    <PMID>18220746</PMID>
  </reference>
  <verification_date>March 2018</verification_date>
  <study_first_submitted>July 15, 2014</study_first_submitted>
  <study_first_submitted_qc>July 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 17, 2014</study_first_posted>
  <results_first_submitted>October 30, 2017</results_first_submitted>
  <results_first_submitted_qc>January 2, 2018</results_first_submitted_qc>
  <results_first_posted type="Actual">January 30, 2018</results_first_posted>
  <last_update_submitted>March 2, 2018</last_update_submitted>
  <last_update_submitted_qc>March 2, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">March 29, 2018</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>Alice Chen, M.D.</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Urothelial Carcinomas</keyword>
  <keyword>Non-Squamous Non-Small Cell Lung Carcinomas</keyword>
  <keyword>Refractory Gastrointestinal Carcinomas</keyword>
  <keyword>Hsp90 Inhibitor</keyword>
  <keyword>Sarcomas</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Carcinoma</mesh_term>
    <mesh_term>Sarcoma</mesh_term>
    <mesh_term>Carcinoma, Transitional Cell</mesh_term>
    <mesh_term>Lung Neoplasms</mesh_term>
    <mesh_term>Carcinoma, Non-Small-Cell Lung</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Aflibercept</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Informed Consent Form</document_type>
      <document_has_protocol>No</document_has_protocol>
      <document_has_icf>Yes</document_has_icf>
      <document_has_sap>No</document_has_sap>
      <document_date>February 3, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/41/NCT02192541/ICF_000.pdf</document_url>
    </provided_document>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>March 20, 2017</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/41/NCT02192541/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <pre_assignment_details>The escalation of dose was not performed as planned for this study due to toxicity and early termination of the trial.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
          <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
        </group>
        <group group_id="P2">
          <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
          <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Treated</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Evaluable for Response</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="3"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
          <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
        </group>
        <group group_id="B2">
          <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
          <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
        </group>
        <group group_id="B3">
          <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="2"/>
            <count group_id="B2" value="3"/>
            <count group_id="B3" value="5"/>
          </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_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="4"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </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="59" lower_limit="51" upper_limit="67"/>
                    <measurement group_id="B2" value="60" lower_limit="50" upper_limit="63"/>
                    <measurement group_id="B3" value="60" lower_limit="50" upper_limit="67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="2"/>
                  </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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="4"/>
                  </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_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_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="0"/>
                  </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_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </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_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </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="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Diagnosis</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Colon adenocarcinomas</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Small bowel adenocarcinomas</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Rectal adenocarcinomas</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Eastern Cooperative Oncology Group (ECOG) Performance Status</title>
          <description>The Eastern Cooperative Oncology Group (ECOG) Scale of Performance Status is graded on a scale of 0 to 5, with higher scores indicating lower levels of functioning in terms of ability to care for oneself, daily activities, and physical abilities (walking, working, etc.).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>0: Fully active</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>1: Restricted in physically strenuous activity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="3"/>
                    <measurement group_id="B3" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>2: Unable to carry out any work activities</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>3: Capable of only limited self-care</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>4: Completely disabled</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>5: Dead</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Number of Prior Therapies</title>
          <units>prior therapies</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6.5" lower_limit="5" upper_limit="8"/>
                    <measurement group_id="B2" value="8" lower_limit="6" upper_limit="15"/>
                    <measurement group_id="B3" value="8" lower_limit="5" upper_limit="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0</title>
        <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
        <time_frame>Date treatment consent signed to date off study, approximately 12 months and 44 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0</title>
          <description>Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs</title>
        <description>Adverse Events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the Adverse Event. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE). AEs were considered possibly attributable to both study drugs, except where otherwise noted. Star (*) symbol indicates that the AE is possibly related to Ziv-aflibercept and unlikely to be related to Ganetespib.</description>
        <time_frame>Date treatment consent signed to date off study, approximately 12 months and 44 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs</title>
          <description>Adverse Events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the Adverse Event. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE). AEs were considered possibly attributable to both study drugs, except where otherwise noted. Star (*) symbol indicates that the AE is possibly related to Ziv-aflibercept and unlikely to be related to Ganetespib.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Grade 2 Alanine Aminotransferase Increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Anorexia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Diarrhea</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 EKG QT Corrected Interval Prolonged</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Fatigue</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Hypertension*</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Hypocalcemia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Infusion Related Reaction</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 2 Lymphocycte Count Decreased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 Abdominal Pain</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 Alkaline Phosphtase Increased</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 3 Gastritis*</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 5 Small Intestinal Perforation*</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Grade 5 Sudden Death Not Otherwise Specified*</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept</title>
        <description>MTD is defined as the dose level at which no more than 1 of 6 patients experience a dose limiting toxicity (DLT) during the first cycle of the treatment, and the dose level below that at which at least 2 (of &lt;6) patients have a DLT as a result of the drug. Determination of DLT is based on the first cycle of treatment.</description>
        <time_frame>Cycle one (28 days)</time_frame>
        <population>An MTD was not established because no MTD data were collected. The trial was terminated before the MTD was reached due to the decision of the drug supplier to suspend further clinical development of ganetespib.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept</title>
          <description>MTD is defined as the dose level at which no more than 1 of 6 patients experience a dose limiting toxicity (DLT) during the first cycle of the treatment, and the dose level below that at which at least 2 (of &lt;6) patients have a DLT as a result of the drug. Determination of DLT is based on the first cycle of treatment.</description>
          <population>An MTD was not established because no MTD data were collected. The trial was terminated before the MTD was reached due to the decision of the drug supplier to suspend further clinical development of ganetespib.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha</title>
        <description>To determine whether the combination of ganetespib and ziv-aflibercept modulated intratumoral Hypoxia-inducible factor 1 (HIF-1)-alpha expression, tumor biopsies were to be analyzed for change in HIF-1-alpha expression by immunofluorescence assay (IFA). Paired pre-and post-combination treatment samples were to be compared for qualitative changes in levels of HIF-1- alpha expression. Cores were to be normalized against the percentage of tumor within the sample.</description>
        <time_frame>Cycle 2, Day 7</time_frame>
        <population>Data were not collected from any participant. Biopsies were to be collected from an expansion cohort treated at the maximum tolerated dose, after the conclusion of the dose escalation phase. Trial was closed before the MTD was established, patients were not enrolled to an expansion phase, and samples for pharmacodynamics analysis were not obtained.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha</title>
          <description>To determine whether the combination of ganetespib and ziv-aflibercept modulated intratumoral Hypoxia-inducible factor 1 (HIF-1)-alpha expression, tumor biopsies were to be analyzed for change in HIF-1-alpha expression by immunofluorescence assay (IFA). Paired pre-and post-combination treatment samples were to be compared for qualitative changes in levels of HIF-1- alpha expression. Cores were to be normalized against the percentage of tumor within the sample.</description>
          <population>Data were not collected from any participant. Biopsies were to be collected from an expansion cohort treated at the maximum tolerated dose, after the conclusion of the dose escalation phase. Trial was closed before the MTD was established, patients were not enrolled to an expansion phase, and samples for pharmacodynamics analysis were not obtained.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Modulation of Epidermal Growth Factor Receptor (EGFR) Expression</title>
        <description>To evaluate for tumor distribution of EGFR, patients were to undergo 89Zr-immuno-positron emission tomography (PET) imaging with 89Zr-labeled EGFR-targeting panitumumab antibody evaluate modulation of EGFR client protein prior to and after treatment with the combination of ganetespib and ziv-aflibercept. Panitumumab is a fully human monoclonal antibody that targets EGFR and competes with endogenous ligands to block stimulation of EGFR. 89z-immuno-PET imaging with panitumumab as a targeting ligand allows for quantification of EGFR within tumors.</description>
        <time_frame>Cycle 1 Day 16</time_frame>
        <population>Data were not collected from any participant for this Outcome Measure. As the trial was closed before the maximum tolerated dose (MTD) was established, patients were not enrolled to an expansion phase, and samples for pharmacodynamics analysis were not obtained.</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Modulation of Epidermal Growth Factor Receptor (EGFR) Expression</title>
          <description>To evaluate for tumor distribution of EGFR, patients were to undergo 89Zr-immuno-positron emission tomography (PET) imaging with 89Zr-labeled EGFR-targeting panitumumab antibody evaluate modulation of EGFR client protein prior to and after treatment with the combination of ganetespib and ziv-aflibercept. Panitumumab is a fully human monoclonal antibody that targets EGFR and competes with endogenous ligands to block stimulation of EGFR. 89z-immuno-PET imaging with panitumumab as a targeting ligand allows for quantification of EGFR within tumors.</description>
          <population>Data were not collected from any participant for this Outcome Measure. As the trial was closed before the maximum tolerated dose (MTD) was established, patients were not enrolled to an expansion phase, and samples for pharmacodynamics analysis were not obtained.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
                <count group_id="O2" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)</title>
        <description>Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles to evaluate tumor response based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria for target lesions: Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.</description>
        <time_frame>Baseline and every 2 months up to 5 months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)</title>
          <description>Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles to evaluate tumor response based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria for target lesions: Partial Response (PR), &gt;=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Complete Response</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</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</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Progressive Disease</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Number of Cycles on Treatment</title>
        <description>The number of 28-day treatment cycles (ganetespib on days 1, 8, and 15; ziv-aflibercept on days 1 and 15) administered to each evaluable patient. Number represents treatment cycles that were started; not all cycles were completed.</description>
        <time_frame>up to 5 months</time_frame>
        <population>The number of participants who were evaluable for response</population>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Cycles on Treatment</title>
          <description>The number of 28-day treatment cycles (ganetespib on days 1, 8, and 15; ziv-aflibercept on days 1 and 15) administered to each evaluable patient. Number represents treatment cycles that were started; not all cycles were completed.</description>
          <population>The number of participants who were evaluable for response</population>
          <units>cycles</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="1" lower_limit="1" upper_limit="1"/>
                    <measurement group_id="O2" value="4" lower_limit="4" upper_limit="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Number of Participants Who Had a Dose Limiting Toxicity (DLT)</title>
        <description>A DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of study drugs during cycle one and is a Grade ≥ 3 non-hematological toxicity. Grade ≥3 non-hematological toxicity felt to be related to study medications are: Grade 3 diarrhea if it is refractory to treatment; Grade 3 nausea and vomiting if it is refractory to anti-emetic therapy and unable to be corrected; rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with intravenous (IV) fluids; Any Grade 4 corrected QT interval (QTc) prolongation; Grade 4 neutropenia ≥5 days or febrile neutropenia,...).</description>
        <time_frame>Cycle one (28 days)</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
          </group>
          <group group_id="O2">
            <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
            <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants Who Had a Dose Limiting Toxicity (DLT)</title>
          <description>A DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of study drugs during cycle one and is a Grade ≥ 3 non-hematological toxicity. Grade ≥3 non-hematological toxicity felt to be related to study medications are: Grade 3 diarrhea if it is refractory to treatment; Grade 3 nausea and vomiting if it is refractory to anti-emetic therapy and unable to be corrected; rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with intravenous (IV) fluids; Any Grade 4 corrected QT interval (QTc) prolongation; Grade 4 neutropenia ≥5 days or febrile neutropenia,...).</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
                <count group_id="O2" value="3"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Date treatment consent signed to date off study, approximately 12 months and 44 days</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Dose Level 1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 4 mg/kg</title>
          <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 and ziv-aflibercept at 4 mg/kg.</description>
        </group>
        <group group_id="E2">
          <title>Dose Level -1: Ganetespib 100 mg/m^2 + Ziv-Aflibercept 3 mg/kg</title>
          <description>Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was administered at a level of 100 mg/m^2 and ziv-aflibercept at 3 mg/kg.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Rectal perforation</sub_title>
                <description>Grade 5, Stent placement; surgical complications (unlikely related to study drugs)</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Small intestinal perforation</sub_title>
                <description>Grade 5, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Sudden death Not Otherwise Specified</sub_title>
                <description>Grade 5, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </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="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Electrocardiogram QT corrected interval prolonged</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Electrocardiogram QT corrected interval prolonged</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Blurred vision</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <description>Grade 3, possibly related to study drugs</description>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <description>Grade 1, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="8" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gastritis</sub_title>
                <description>Grade 3, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Gastrointestinal pain</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hemorrhoidal hemorrhage</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Oral pain</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Rectal hemorrhage</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fatigue</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Eye infection</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Bruising</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Activated partial thromboplastin time prolonged</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <description>Grade 3, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="3" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <description>Grade 1, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Serum amylase increased</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Anorexia</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypercalcemia</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyperkalemia</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyperuricemia</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="3" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <description>Grade 2, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Back pain</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="2" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Shoulder pain</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Dizziness</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Hematuria</sub_title>
                <description>Grade 1, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Proteinuria</sub_title>
                <description>Grade 1, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypertension</sub_title>
                <description>Grade 2, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <description>Grade 1, unlikely related to study drugs</description>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <description>Grade 1, possibly related to study drugs</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <description>Grade 1, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="2" subjects_affected="1" subjects_at_risk="3"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <description>Grade 2, possibly related to Ziv-Aflibercept</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="3"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE 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>Alice P. Chen, M.D.</name_or_title>
      <organization>National Cancer Institute</organization>
      <phone>(240) 781-3320</phone>
      <email>chenali@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/NCT02192541
org study id: 140150
secondary id: 14-C-0150
nct id: NCT02192541
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
Background:

      - Some people have cancers that don't respond to standard treatments. In these cases, doctors
      may try to use drugs to slow the growth of the cancer.

      Objectives:

      - To test the safety and efficacy of the drug combination of ganetespib and ziv-aflibercept.

      Eligibility:

      - Adults age 18 and over with advanced cancer of the colon, lung, urinary tract, and
      sarcomas.

      Design:

        -  Participants will be screened with medical history, blood tests, and scans to measure
           their tumors.

        -  Participants will have one or two eye exams, with dilating eye drops.

        -  Participants will get the study drugs at the clinic as an infusion in a vein. Ganetespib
           will be given once a week on the same day for 3 weeks in a row, followed by a 1-week
           rest period. Ziv-aflibercept will be given once every other week. The drugs will be
           given in 28-day cycles.

        -  Participants may have a small piece of their tumor collected once or twice. This is done
           using a small needle during computed tomography (CT), magnetic resonance imaging (MRI),
           or ultrasound scan.

        -  Participants will have their blood pressure checked at each visit. They will check it at
           home every day of the study.

        -  Participants may have one or more whole-body positron emission tomography (PET) scans
           with 89Zr-panitumumab. A small amount of a radioactive chemical will be injected through
           a tube in an arm. Participants will lie on a bed that slides in and out of the
           donut-shaped PET scanner. They will have small amounts of blood drawn.

        -  Participants may stay in the study as long as they are tolerating the drugs and their
           tumor is not getting worse.
BACKGROUND:

        -  Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 that has demonstrated
           activity against multiple cancer cell lines and tumor xenografts in preclinical models.
           Inhibiting the Hsp90 chaperone complex results in the recruitment of ubiquitin ligases,
           polyubiquination, and proteosomal degradation of Hsp90 client proteins, including
           transcription factors and proteins involved in angiogenesis vascular endothelial growth
           factor (VEGF), vascular endothelial growth factor receptor (VEGFR), hypoxia-inducible
           factor 1 (HIF-1), signal transducers and activators of transcription protein 3 (STAT-3);
           growth factor independence rapidly accelerated fibrosarcoma (RAF), epidermal growth
           factor receptor (EGFR), human epidermal growth factor receptor 2 (Her2), insulin-like
           growth factor 1 receptor (IGFR); resistance to anti-growth signals cyclin-dependent
           kinase 4 (CDK4); tissue invasion and metastases mesenchymal-epithelial transition factor
           (MET), matrix metalloproteinase-2 (MMP2); and avoidance of apoptosis protein kinase B
           (AKT), rat insulin promoter (RIP), Survivin, B cell lymphoma (Bcl-2).

        -  HIF-1-alpha activation has been implicated in mediating resistance to anti-angiogenic
           therapy; recent evidence implicates a greater role for Hsp90 in direct modulation of
           VEGF signaling.

        -  Combining Hsp90 inhibition with ganetespib and anti-angiogenic therapy with
           Ziv-Aflibercept, a soluble fusion protein with high binding affinity for vascular
           endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and
           placenta growth factor (PIGF), presents a rational novel strategy for improving upon and
           overcoming resistance to anti-angiogenic therapy

      PRIMARY OBJECTIVE:

      - To establish the safety, tolerability, and maximum tolerated dose (MTD) of the combination
      of ganetespib and Ziv-Aflibercept in patients with refractory gastrointestinal carcinomas,
      non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas

      SECONDARY OBJECTIVE:

        -  To assess modulation of HIF-1-alpha as a pharmacodynamic marker of therapy with the
           combination of ganetespib and Ziv-Aflibercept

        -  To assess modulation of epidermal growth factor receptor (EGFR) expression using
           89Zr-labeled, EGFR-targeting antibody panitumumab positron emission tomography
           (PET)/computed tomography (CT) imaging of tumor lesions prior to and following treatment
           with study drugs

      ELIGIBILITY:

        -  Adult patients with histologically confirmed metastatic gastrointestinal carcinomas,
           non-squamous non-small cell lung carcinomas, urothelial carcinomas, and sarcomas with
           disease progression after at least one line of standard therapy

        -  Participants in the expansion phase must demonstrate EGFR expression on archival tumor
           samples and have disease amenable to biopsy with willingness to undergo pre- and
           post-treatment biopsies

        -  No major surgery within 4 weeks prior to study enrollment, no radiation or chemotherapy
           within 3 weeks prior to enrollment; patients must have recovered from toxicities of
           prior therapies to at least eligibility levels prior to enrollment.

      STUDY DESIGN:

        -  Ganetespib will be administered intravenously weekly on days 1, 8, and 15 of a 28-day
           cycle. Ziv-Aflibercept will be administered intravenously every 2 weeks, on days 1 and
           15, during a 28-day cycle.

        -  The escalation portion of the trial will follow a standard 3+3 design, whereby patients
           are dose-escalated in cohorts of 3 until dose-limiting toxicity is observed.

        -  Once the MTD is established, 10 additional patients will be enrolled to the expansion
           phase, at the MTD, and tumor biopsies will be obtained to assess pharmacodynamic
           endpoints. During cycle 1 of the expansion phase, ganetespib will be administered
           intravenously weekly, on days 8 and 15 with omission of day 1 treatment to accommodate a
           baseline biopsy pre-ganetespib but after administration of Ziv-Aflibercept. For all
           subsequent cycles, ganetespib will be administered days 1, 8, and 15. Ziv-Aflibercept
           will still be administered intravenously every 2 weeks, on days 1 and 15, of a 28-day
           cycle.

        -  PET/CT imaging with 89Zr-labeled panitumumab will be performed to evaluate tumor
           distribution prior to and following treatment with study agents.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Serious and Non-serious Adverse Events Regardless of Attribution Assessed by the Common Terminology Criteria in Adverse Events (CTCAE) v4.0
time frame: Date treatment consent signed to date off study, approximately 12 months and 44 days
description: Here is the count of participants with serious and non-serious adverse events assessed by the Common Terminology Criteria in Adverse Events (CTCAE v4.0). A non-serious adverse event is any untoward medical occurrence. A serious adverse event is an adverse event or suspected adverse reaction that results in death, a life threatening adverse drug experience, hospitalization, disruption of the ability to conduct normal life functions, congenital anomaly/birth defect or important medical events that jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the previous outcomes mentioned.
measure: Number of Participants With Grade 2 or Greater Adverse Events Possibly, Probably, or Definitely Related to Administration of the Study Drugs
time frame: Date treatment consent signed to date off study, approximately 12 months and 44 days
description: Adverse Events were graded according to Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0. Grade refers to the severity of the Adverse Event. Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated. Grade 2 Moderate; minimal, local or noninvasive intervention indicated. Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling. Grade 4 Life-threatening consequences; urgent intervention indicated. Grade 5 Death related to adverse event (AE). AEs were considered possibly attributable to both study drugs, except where otherwise noted. Star (*) symbol indicates that the AE is possibly related to Ziv-aflibercept and unlikely to be related to Ganetespib.
measure: Maximum Tolerated Dose (MTD) of the Combination of Ganetespib and Ziv-aflibercept
time frame: Cycle one (28 days)
description: MTD is defined as the dose level at which no more than 1 of 6 patients experience a dose limiting toxicity (DLT) during the first cycle of the treatment, and the dose level below that at which at least 2 (of <6) patients have a DLT as a result of the drug. Determination of DLT is based on the first cycle of treatment.
measure: Modulation of Hypoxia-Inducible Factor 1 (HIF-1) Alpha
time frame: Cycle 2, Day 7
description: To determine whether the combination of ganetespib and ziv-aflibercept modulated intratumoral Hypoxia-inducible factor 1 (HIF-1)-alpha expression, tumor biopsies were to be analyzed for change in HIF-1-alpha expression by immunofluorescence assay (IFA). Paired pre-and post-combination treatment samples were to be compared for qualitative changes in levels of HIF-1- alpha expression. Cores were to be normalized against the percentage of tumor within the sample.
measure: Modulation of Epidermal Growth Factor Receptor (EGFR) Expression
time frame: Cycle 1 Day 16
description: To evaluate for tumor distribution of EGFR, patients were to undergo 89Zr-immuno-positron emission tomography (PET) imaging with 89Zr-labeled EGFR-targeting panitumumab antibody evaluate modulation of EGFR client protein prior to and after treatment with the combination of ganetespib and ziv-aflibercept. Panitumumab is a fully human monoclonal antibody that targets EGFR and competes with endogenous ligands to block stimulation of EGFR. 89z-immuno-PET imaging with panitumumab as a targeting ligand allows for quantification of EGFR within tumors.
measure: Number of Participants According to Best Response Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1)
time frame: Baseline and every 2 months up to 5 months
description: Radiologic response assessments by computed tomography (CT) scans were performed at baseline and every two cycles to evaluate tumor response based on the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. Per Response Evaluation Criteria In Solid Tumors Criteria for target lesions: Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for a Partial Response nor sufficient increase to qualify for Progressive Disease (PD); PD, 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Complete Response (CR), Disappearance of all target lesions.
measure: Number of Cycles on Treatment
time frame: up to 5 months
description: The number of 28-day treatment cycles (ganetespib on days 1, 8, and 15; ziv-aflibercept on days 1 and 15) administered to each evaluable patient. Number represents treatment cycles that were started; not all cycles were completed.
measure: Number of Participants Who Had a Dose Limiting Toxicity (DLT)
time frame: Cycle one (28 days)
description: A DLT is defined as an adverse event that is related (possibly, probably, or definitely) to administration of study drugs during cycle one and is a Grade ≥ 3 non-hematological toxicity. Grade ≥3 non-hematological toxicity felt to be related to study medications are: Grade 3 diarrhea if it is refractory to treatment; Grade 3 nausea and vomiting if it is refractory to anti-emetic therapy and unable to be corrected; rise in creatinine to Grade 3, not corrected to Grade 1 or less within 48 hours with intravenous (IV) fluids; Any Grade 4 corrected QT interval (QTc) prolongation; Grade 4 neutropenia ≥5 days or febrile neutropenia,...).
arm group label: Ganetespib and Ziv-Aflibercept
arm group type: Experimental
description: Ganetespib was administered intravenously, over 1 hour, weekly, on days 1, 8, and 15 of each 28-day cycle. Ziv-aflibercept was administered intravenously, over 1 hour, every 2 weeks, on days 1 and 15 of each 28-day cycle. Ganetespib was started at a dose level of 100 mg/m^2 + ziv-aflibercept at 3 mg/kg or 4 mg/kg.
intervention type: Drug
intervention name: Ziv-Aflibercept
description: Ziv-aflibercept is a soluble fusion protein with high binding affinity for vascular endothelial growth factor A (VEGF-A), vascular endothelial growth factor B (VEGF-B), and placenta growth factor (PIGF) and thus confers anti-angiogenic activity
arm group label: Ganetespib and Ziv-Aflibercept
other name: ZALTRAP
other name: VEGF-TRAP
intervention type: Drug
intervention name: Ganetespib
description: Ganetespib is a non-geldamycin synthetic inhibitor of Hsp90 with activity against multiple cancer cell lines and tumor xenografts in preclinical models.
arm group label: Ganetespib and Ziv-Aflibercept
other name: STA-9090
criteria: 
gender: All
minimum age: 18 Years
maximum age: 120 Years
healthy volunteers: No
last name: Alice P Chen, M.D.
role: Principal Investigator
affiliation: National Cancer Institute (NCI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2014-C-0150.html
description: NIH Clinical Center Detailed Web Page
citation: Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
PMID: 21376230
citation: Bottsford-Miller JN, Coleman RL, Sood AK. Resistance and escape from antiangiogenesis therapy: clinical implications and future strategies. J Clin Oncol. 2012 Nov 10;30(32):4026-34. doi: 10.1200/JCO.2012.41.9242. Epub 2012 Sep 24. Erratum In: J Clin Oncol. 2013 Feb 20;31(6):824.
PMID: 23008289
citation: Stravopodis DJ, Margaritis LH, Voutsinas GE. Drug-mediated targeted disruption of multiple protein activities through functional inhibition of the Hsp90 chaperone complex. Curr Med Chem. 2007;14(29):3122-38. doi: 10.2174/092986707782793925.
PMID: 18220746
responsible party type: Principal Investigator
investigator affiliation: National Institutes of Health Clinical Center (CC)
investigator full name: Alice Chen, M.D.
investigator title: Principal Investigator
mesh term: Carcinoma
mesh term: Sarcoma
mesh term: Carcinoma, Transitional Cell
mesh term: Lung Neoplasms
mesh term: Carcinoma, Non-Small-Cell Lung
mesh term: Aflibercept
sharing ipd: No
provided document: 
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 