<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/NCT02194829</url>
  </required_header>
  <id_info>
    <org_study_id>NCI-2014-01425</org_study_id>
    <secondary_id>NCI-2014-01425</secondary_id>
    <secondary_id>EA2131</secondary_id>
    <secondary_id>U10CA180820</secondary_id>
    <secondary_id>U10CA021115</secondary_id>
    <nct_id>NCT02194829</nct_id>
  </id_info>
  <brief_title>Paclitaxel Albumin-Stabilized Nanoparticle Formulation and Gemcitabine Hydrochloride With or Without WEE1 Inhibitor AZD1775 in Treating Patients With Previously Untreated Pancreatic Cancer That Is Metastatic or Cannot Be Removed by Surgery</brief_title>
  <official_title>A Phase I and Randomized Phase II Study of Nab-Paclitaxel/Gemcitabine With or Without AZD1775 for Treatment of Metastatic Adenocarcinoma of the Pancreas</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Cancer Institute (NCI)</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This partially randomized phase I/II trial studies the side effects and best dose of WEE1&#xD;
      inhibitor AZD1775 when given together with paclitaxel albumin-stabilized nanoparticle&#xD;
      formulation and gemcitabine hydrochloride and how well they work in treating patients with&#xD;
      previously untreated pancreatic cancer that has spread to another place in the body or cannot&#xD;
      be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized&#xD;
      nanoparticle formulation and gemcitabine hydrochloride, work in different ways to stop the&#xD;
      growth of tumor cells, either by killing the cells, by stopping them from dividing, or by&#xD;
      stopping them from spreading. WEE1 inhibitor AZD1775 may stop the growth of tumor cells by&#xD;
      blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel&#xD;
      albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride are more effective&#xD;
      with or without WEE1 inhibitor AZD1775 in treating patients with pancreatic cancer.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel&#xD;
      albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and&#xD;
      AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma&#xD;
      of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically&#xD;
      resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with&#xD;
      nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I)&#xD;
      III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and&#xD;
      gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with&#xD;
      nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with&#xD;
      metastatic adenocarcinoma of the pancreas. (Phase II)&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or&#xD;
      nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the&#xD;
      pancreas. (Phase II) II. To evaluate response rate (complete response [CR] + partial response&#xD;
      [PR]) associated with nab-paclitaxel/gemcitabine/placebo or&#xD;
      nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the&#xD;
      pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease [SD])&#xD;
      associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in&#xD;
      patients with metastatic adenocarcinoma of the pancreas. (Phase II)&#xD;
&#xD;
      TERTIARY OBJECTIVES:&#xD;
&#xD;
      I. To evaluate the ability of AZD1775 to inhibit Wee1 and increase deoxyribonucleic acid&#xD;
      (DNA) damage and tumor cell death when combined with nab-paclitaxel/gemcitabine compared to&#xD;
      nab-paclitaxel/gemcitabine/placebo. (Phase II) II. To evaluate if biomarker changes in tumor&#xD;
      tissue associated with Wee1 inhibition may also be present in hair follicles. (Phase II) III.&#xD;
      To evaluate the change in tumor fludeoxyglucose (FDG) uptake (maximum standardized uptake&#xD;
      value [SUVmax]) between baseline FDG-positron emission tomography (PET) and week 4 FDG-PET as&#xD;
      a predictor of response using Response Evaluation Criteria in Solid Tumors (RECIST) as the&#xD;
      reference standard for response. (Phase II) IV. To evaluate the change in tumor FDG uptake&#xD;
      (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free&#xD;
      survival. (Phase II) V. To compare the change in tumor FDG uptake (SUVmax) between baseline&#xD;
      FDG-PET and week 4 FDG-PET between the patients from treatment arms C and D. (Phase II) VI.&#xD;
      To evaluate if an early increase in tumor fluorothymidine (FLT) uptake (FLT-flare) is&#xD;
      observed within 24 hours after initiation of treatment with&#xD;
      nab-paclitaxel/gemcitabine/placebo. (Phase II) VII. To evaluate if an early (within 24 hours&#xD;
      [h]) increase in tumor FLT uptake (FLT-flare) is abrogated after initiation of treatment with&#xD;
      nab-paclitaxel/gemcitabine/AZD1775. (Phase II) VIII. To compare the change in tumor FLT&#xD;
      uptake (SUVmax) from baseline to 24 hours after initiation of treatment between the patients&#xD;
      from treatment arms C and D. (Phase II)&#xD;
&#xD;
      OUTLINE: This is a phase I, dose escalation study of WEE1 inhibitor AZD1775 followed by a&#xD;
      randomized phase II study. Patients in phase I are assigned to arm A or B and patients in&#xD;
      phase II are randomized to arm C or D.&#xD;
&#xD;
      ARM A (PHASE I, DOSE LEVEL 1): Patients receive paclitaxel albumin-stabilized nanoparticle&#xD;
      formulation intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30&#xD;
      minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 orally (PO) daily&#xD;
      on days 1, 2, 8, 9, 15, and 16.&#xD;
&#xD;
      ARM B (PHASE I, DOSE LEVEL -2): Patients receive paclitaxel albumin-stabilized nanoparticle&#xD;
      formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.&#xD;
&#xD;
      ARMS C - G (PHASE I, DOSE LEVEL -1 to DOSE LEVEL 4): Patients receive paclitaxel&#xD;
      albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor&#xD;
      AZD1775 as in Arm A at various dose levels. These arms did not enroll any patients.&#xD;
&#xD;
      ARM H (PHASE II, Control): Patients receive paclitaxel albumin-stabilized nanoparticle&#xD;
      formulation and gemcitabine hydrochloride as in Arm A. The study did not move forward to the&#xD;
      phase II part.&#xD;
&#xD;
      ARM I (PHASE II, WEE1 INHIBITOR AZD1775): Patients receive paclitaxel albumin-stabilized&#xD;
      nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.&#xD;
      The study did not move forward to the phase II part.&#xD;
&#xD;
      In all arms, courses repeat every 28 days in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up every 3 months for 2 years.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 19, 2014</start_date>
  <completion_date type="Actual">December 21, 2022</completion_date>
  <primary_completion_date type="Actual">June 3, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of Participants With Dose Limiting Toxicities (DLT)</measure>
    <time_frame>Assessed at 28 days</time_frame>
    <description>A dose-limiting toxicity (DLT) was defined by the occurrence of any of the toxicities listed in section 5.1.5 of the protocol that are possibly, probably, or definitely related to study drug(s) within the first cycle (4 weeks = 28 days).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To Determine the Pharmacokinetics of AZD1775 in Combination With Nab-paclitaxel and Gemcitabine</measure>
    <time_frame>Assessed at Day 1 and Day 16</time_frame>
    <description>Plasma was to be collected on Cycle 1 Day 1 and Cycle 1 Day 16 for the pharmacokinetics analysis.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Progression-free Survival</measure>
    <time_frame>Assessed every 3 months for 2 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival</measure>
    <time_frame>Assessed every 3 months for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response Rate</measure>
    <time_frame>Assessed every 3 months for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease Control Rate</measure>
    <time_frame>Assessed every 3 months for 2 years</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">8</enrollment>
  <condition>Metastatic Pancreatic Adenocarcinoma</condition>
  <condition>Stage III Pancreatic Cancer AJCC v6 and v7</condition>
  <condition>Stage IV Pancreatic Cancer AJCC v6 and v7</condition>
  <condition>Unresectable Pancreatic Carcinoma</condition>
  <arm_group>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Arm B</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>AZD1775</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
    <other_name>Adavosertib</other_name>
    <other_name>MK-1775</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Gemcitabine</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
    <other_name>2'-Deoxy-2'</other_name>
    <other_name>2'-difluorocytidine monohydrochloride</other_name>
    <other_name>Gemzar</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nab-paclitaxel</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Arm A</arm_group_label>
    <arm_group_label>Arm B</arm_group_label>
    <other_name>ABI-007</other_name>
    <other_name>paclitaxel protein-bound particles for injectable suspension</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria (Phase I):&#xD;
&#xD;
          -  Patients must have histologically or cytologically confirmed metastatic or&#xD;
             unresectable locally advanced adenocarcinoma of the pancreas. Prior therapy with a&#xD;
             non-gemcitabine based regimen is permitted.&#xD;
&#xD;
          -  Previous neo-adjuvant or adjuvant treatment is allowed provided that it was given &gt;= 6&#xD;
             months prior to registration&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1&#xD;
&#xD;
          -  Patients must have a life expectancy of &gt;= 12 weeks&#xD;
&#xD;
          -  Patients may have had prior radiotherapy for metastatic disease as long as it was &gt; 4&#xD;
             weeks prior to registration and the patient has recovered from adverse events&#xD;
             associated with the radiotherapy&#xD;
&#xD;
          -  Patients must be able to swallow capsules whole&#xD;
&#xD;
          -  Patients must be able to tolerate computed tomography (CT), magnetic resonance imaging&#xD;
             (MRI) or PET imaging including contrast agents&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal and barrier method of birth control; two barrier methods of birth control;&#xD;
             abstinence) for the duration of study treatment and for 3 months after the last dose&#xD;
             of study treatment; should a woman become pregnant or suspect she is pregnant while&#xD;
             participating in this study, she should inform her treating physician immediately;&#xD;
             should a man impregnate or suspect that he has impregnated a woman while participating&#xD;
             in this study, he should inform his treating physician immediately&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase&#xD;
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])&#xD;
             =&lt; 3 X institutional upper limit of normal (ULN) or =&lt; 5 X ULN if the patient has&#xD;
             liver metastases&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 mg/dL or creatinine clearance (Cockcroft-Gault) &gt;= 60 mL/min for&#xD;
             patients with creatinine levels above institutional upper limit of normal (ULN)&#xD;
&#xD;
        Exclusion Criteria (Phase I):&#xD;
&#xD;
          -  Receiving any other investigational agents concurrently&#xD;
&#xD;
          -  Have received any other investigational agents =&lt; 4 weeks prior to registration&#xD;
&#xD;
          -  Pre-existing &gt; grade 1 motor or sensory neuropathy&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to nab-paclitaxel, gemcitabine or AZD1775&#xD;
&#xD;
          -  Major surgical procedures &lt;=28 days of beginning study treatment or minor surgical&#xD;
             procedures &lt;=7 days&#xD;
&#xD;
          -  Taking current medications or substances that are inhibitors of CYP3A4, inhibitors or&#xD;
             substrates of P-glycoprotein or inhibitors of breast cancer resistance protein (BCRP)&#xD;
&#xD;
          -  Uncontrolled serious medical illness including, but not limited to, ongoing or active&#xD;
             infection, cardiac arrhythmia, or psychiatric illness that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Patients with known human immunodeficiency virus (HIV) and cluster of differentiation&#xD;
             (CD)4 count is =&lt; 200 cell/mm^3 or receiving antiretroviral therapy due to potential&#xD;
             unfavorable interaction of the agents with the study treatment&#xD;
&#xD;
          -  Previous or concurrent malignancy; exceptions are made for patients who meet any of&#xD;
             the following conditions:&#xD;
&#xD;
               -  Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or&#xD;
                  superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)&#xD;
&#xD;
               -  Prior malignancy completely excised or removed and patient has been continuously&#xD;
                  disease free for &gt; 5 years&#xD;
&#xD;
          -  Pregnant or breast-feeding&#xD;
&#xD;
               -  Females of childbearing potential must have a blood test or urine study within 5&#xD;
                  days prior to registration to rule out pregnancy; a female of childbearing&#xD;
                  potential is any woman, regardless of sexual orientation or whether they have&#xD;
                  undergone tubal ligation, who meets the following criteria: 1) has not undergone&#xD;
                  a hysterectomy or bilateral oophorectomy; or 2) has not been naturally&#xD;
                  postmenopausal for at least 24 consecutive months (i.e., has had menses at any&#xD;
                  time in the preceding 24 consecutive months)&#xD;
&#xD;
          -  At least18 years of age&#xD;
&#xD;
        Inclusion Criteria (Phase II):&#xD;
&#xD;
          -  Histologically or cytologically confirmed metastatic adenocarcinoma of the pancreas&#xD;
&#xD;
          -  Patients must have measurable disease outside of the primary tumor (pancreas) by&#xD;
             RECIST 1.1 criteria; baseline measurements and evaluations of all sites of disease&#xD;
             must be obtained =&lt; 4 weeks prior to randomization&#xD;
&#xD;
          -  Previous neo-adjuvant or adjuvant treatment is allowed provided that there was no&#xD;
             evidence of recurrent disease for at least 6 months after completion of&#xD;
             neo-adjuvant/adjuvant treatment&#xD;
&#xD;
          -  Patients may have had prior radiotherapy for metastatic disease as long as it was &gt; 4&#xD;
             weeks prior to randomization and the patient has recovered from adverse events&#xD;
             associated with the radiotherapy&#xD;
&#xD;
          -  ECOG performance status of 0 or 1&#xD;
&#xD;
          -  Life expectancy of &gt;= 12 weeks&#xD;
&#xD;
          -  Patients must be able to swallow capsules whole&#xD;
&#xD;
          -  Patients with biliary stents are allowed&#xD;
&#xD;
          -  Patients must be able to tolerate CT, MRI or PET imaging including contrast agents&#xD;
&#xD;
          -  Women of child-bearing potential and men must agree to use adequate contraception&#xD;
             (hormonal and barrier method of birth control; two barrier methods of birth control;&#xD;
             abstinence) for the duration of study treatment and for 3 months after the last dose&#xD;
             of study treatment; should a woman become pregnant or suspect she is pregnant while&#xD;
             participating in this study, she should inform her treating physician immediately;&#xD;
             should a man impregnate or suspect that he has impregnated a woman while participating&#xD;
             in this study, he should inform his treating physician immediately&#xD;
&#xD;
          -  Leukocytes &gt;= 3,000/mcL&#xD;
&#xD;
          -  Absolute neutrophil count &gt;= 1,500/mcL&#xD;
&#xD;
          -  Hemoglobin &gt;= 9 g/dL&#xD;
&#xD;
          -  Platelets &gt;= 100,000/mcL&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  AST (SGOT)/ALT (SGPT) =&lt; 3 X institutional upper limit of normal (ULN) or =&lt; 5 X ULN&#xD;
             if the patient has liver metastases&#xD;
&#xD;
          -  Creatinine =&lt; 1.5 mg/dL or creatinine clearance (Cockcroft-Gault) &gt;= 60 mL/min for&#xD;
             patients with creatinine levels above institutional upper limit of normal (ULN)&#xD;
&#xD;
          -  For participation in the imaging research studies, patients must meet the additional&#xD;
             following criteria:&#xD;
&#xD;
               -  The patient is participating in the trial at an institutional which has agreed to&#xD;
                  perform the imaging research studies, completed the American College of Radiation&#xD;
                  Imaging Network (ACRIN) defined scanner qualification procedures and received&#xD;
                  ACRIN approval&#xD;
&#xD;
               -  The patient has consented in writing to participate in one of the imaging&#xD;
                  research studies&#xD;
&#xD;
               -  The patient meets the criteria required for the imaging study in which the site&#xD;
                  is participating:&#xD;
&#xD;
                    -  NOTE: Eligibility for participating in either imaging sub-study will depend&#xD;
                       on the availability of the imaging sub-study at a particular institution&#xD;
&#xD;
               -  For participation in the FDG-PET sub-study:&#xD;
&#xD;
                    -  Patients must have an evaluable lesion of &gt; 20 mm in size on standard&#xD;
                       practice imaging study as assessed by site (either primary pancreas mass or&#xD;
                       metastasis)&#xD;
&#xD;
               -  For participation in the FLT-PET sub-study:&#xD;
&#xD;
                    -  Patients must be able to lie still for a 1.5 hour PET scan.&#xD;
&#xD;
                    -  Patients must have an evaluable lesion in the pancreas &gt; 20 mm in size on&#xD;
                       standard practice imaging study as assessed by site (lesion must be likely&#xD;
                       primary adenocarcinoma of the pancreas that is not primarily fibrotic or&#xD;
                       mucinous in nature)&#xD;
&#xD;
        Phase II Exclusion Criteria:&#xD;
&#xD;
          -  Prior systemic therapy for metastatic disease&#xD;
&#xD;
          -  Locally advanced disease&#xD;
&#xD;
          -  Major surgical procedures &lt;=28 days of beginning study treatment or minor surgical&#xD;
             procedures &lt;=7 days&#xD;
&#xD;
          -  Any of the following cardiac diseases at registration or within the last 6 months as&#xD;
             defined by New York Heart Association (NYHA) ≥ Class 2:&#xD;
&#xD;
               -  Unstable angina pectoris&#xD;
&#xD;
               -  Congestive heart failure&#xD;
&#xD;
               -  Acute myocardial infarction&#xD;
&#xD;
               -  Conduction abnormality not controlled with pacemaker or medication&#xD;
&#xD;
               -  Significant ventricular or supraventricular arrhythmias (patients with chronic&#xD;
                  rate-controlled atrial fibrillation in the absence of other cardiac abnormalities&#xD;
                  are eligible.)&#xD;
&#xD;
          -  Taking current medications or substances that are inhibitors of CYP3A4, inhibitors or&#xD;
             substrates of P-glycoprotein or inhibitors of breast cancer resistance protein (BCRP)&#xD;
&#xD;
          -  Prior Wee1 inhibitors or AZD1775&#xD;
&#xD;
          -  Prior gemcitabine or nab-paclitaxel in a metastatic setting&#xD;
&#xD;
          -  Corrected QT interval QTc &gt; 470 msec (as calculated per institutional standards) at&#xD;
             study entry or congenital long QT syndrome).&#xD;
&#xD;
          -  Receiving any other investigational agents concurrently or have received any other&#xD;
             investigational agents =&lt; 4 weeks prior to randomization&#xD;
&#xD;
          -  Pre-existing &gt; grade 1 motor or sensory neuropathy&#xD;
&#xD;
          -  History of allergic reactions attributed to compounds of similar chemical or biologic&#xD;
             composition to nab-paclitaxel, gemcitabine or AZD1775&#xD;
&#xD;
          -  Uncontrolled serious medical illness including, but not limited to, ongoing or active&#xD;
             infection, cardiac arrhythmia, or psychiatric illness that would limit compliance with&#xD;
             study requirements&#xD;
&#xD;
          -  Previous or concurrent malignancy; exceptions are made for patients who meet any of&#xD;
             the following conditions:&#xD;
&#xD;
               -  Non-melanoma skin cancer, in situ cervical cancer, breast cancer in situ, or&#xD;
                  superficial bladder cancer (noninvasive papillary carcinoma or carcinoma in situ)&#xD;
&#xD;
               -  Prior malignancy completely excised or removed and patient has been continuously&#xD;
                  disease free for &gt; 5 years&#xD;
&#xD;
          -  Pregnant or breast-feeding&#xD;
&#xD;
               -  Females of childbearing potential must have a blood test or urine study within 5&#xD;
                  days prior to randomization to rule out pregnancy; a female of childbearing&#xD;
                  potential is any woman, regardless of sexual orientation or whether they have&#xD;
                  undergone tubal ligation, who meets the following criteria: 1) has not undergone&#xD;
                  a hysterectomy or bilateral oophorectomy; or 2) has not been naturally&#xD;
                  postmenopausal for at least 24 consecutive months (i.e., has had menses at any&#xD;
                  time in the preceding 24 consecutive months)&#xD;
&#xD;
          -  For participation in the FDG-PET sub-study:&#xD;
&#xD;
               -  Poorly controlled diabetes (defined as fasting glucose level &gt;= 200 mg/dL)&#xD;
                  despite efforts to improve glucose control by fasting duration and adjustment of&#xD;
                  medications&#xD;
&#xD;
               -  Weigh more than the maximum weight limit for the PET table&#xD;
&#xD;
          -  For participation in the FLT-PET sub-study:&#xD;
&#xD;
               -  History of allergic reaction attributable to compounds of similar chemical or&#xD;
                  biologic composition to 18F-fluorothymidine&#xD;
&#xD;
               -  Weigh more than the maximum weight limit for the PET table&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jennifer R Eads</last_name>
    <role>Principal Investigator</role>
    <affiliation>ECOG-ACRIN Cancer Research Group</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northwestern University</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Case Western Reserve University</name>
      <address>
        <city>Cleveland</city>
        <state>Ohio</state>
        <zip>44106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Pennsylvania/Abramson Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19104</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Fox Chase Cancer Center</name>
      <address>
        <city>Philadelphia</city>
        <state>Pennsylvania</state>
        <zip>19111</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Vanderbilt University/Ingram Cancer Center</name>
      <address>
        <city>Nashville</city>
        <state>Tennessee</state>
        <zip>37232</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 16, 2014</study_first_submitted>
  <study_first_submitted_qc>July 16, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">July 18, 2014</study_first_posted>
  <results_first_submitted>March 3, 2023</results_first_submitted>
  <results_first_submitted_qc>April 5, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">April 25, 2023</results_first_posted>
  <last_update_submitted>April 5, 2023</last_update_submitted>
  <last_update_submitted_qc>April 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 25, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Metastatic Pancreatic Adenocarcinoma</keyword>
  <keyword>Nab-paclitaxel</keyword>
  <keyword>Gemcitabine</keyword>
  <keyword>AZD1775</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Adenocarcinoma</mesh_term>
    <mesh_term>Pancreatic Neoplasms</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Paclitaxel</mesh_term>
    <mesh_term>Albumin-Bound Paclitaxel</mesh_term>
    <mesh_term>Gemcitabine</mesh_term>
    <mesh_term>Adavosertib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.</ipd_description>
  </patient_data>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>October 18, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/29/NCT02194829/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>A total of 8 patients were enrolled between August 19, 2014 and November 1, 2016.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Arm A (Phase I - Initial Dose Level)</title>
          <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.</description>
        </group>
        <group group_id="P2">
          <title>Arm B ((Phase I - Dose Level -2)</title>
          <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.</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="6"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Received Protocol Therapy</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="5"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="6"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Death</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Disease progression</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Never started protocol therapy</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Only patients who started protocol therapy were included in this analysis.</population>
      <group_list>
        <group group_id="B1">
          <title>Arm A (Phase I - Initial Dose Level)</title>
          <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.</description>
        </group>
        <group group_id="B2">
          <title>Arm B ((Phase I - Dose Level -2)</title>
          <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.</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="5"/>
            <count group_id="B3" value="7"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <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="70.5" lower_limit="68" upper_limit="73"/>
                    <measurement group_id="B2" value="73" lower_limit="39" upper_limit="76"/>
                    <measurement group_id="B3" value="73" lower_limit="39" upper_limit="76"/>
                  </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="3"/>
                    <measurement group_id="B3" value="5"/>
                  </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="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="5"/>
                    <measurement group_id="B3" value="7"/>
                  </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="1"/>
                    <measurement group_id="B3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_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_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Number of Participants With Dose Limiting Toxicities (DLT)</title>
        <description>A dose-limiting toxicity (DLT) was defined by the occurrence of any of the toxicities listed in section 5.1.5 of the protocol that are possibly, probably, or definitely related to study drug(s) within the first cycle (4 weeks = 28 days).</description>
        <time_frame>Assessed at 28 days</time_frame>
        <population>Only patients who received protocol therapy were included in this analysis.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phase I - Initial Dose Level)</title>
            <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Phase I - Dose Level -2)</title>
            <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.</description>
          </group>
        </group_list>
        <measure>
          <title>Number of Participants With Dose Limiting Toxicities (DLT)</title>
          <description>A dose-limiting toxicity (DLT) was defined by the occurrence of any of the toxicities listed in section 5.1.5 of the protocol that are possibly, probably, or definitely related to study drug(s) within the first cycle (4 weeks = 28 days).</description>
          <population>Only patients who received protocol therapy were included in this analysis.</population>
          <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="5"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>To Determine the Pharmacokinetics of AZD1775 in Combination With Nab-paclitaxel and Gemcitabine</title>
        <description>Plasma was to be collected on Cycle 1 Day 1 and Cycle 1 Day 16 for the pharmacokinetics analysis.</description>
        <time_frame>Assessed at Day 1 and Day 16</time_frame>
        <population>Insufficient plasma samples were collected on this study so no pharmacokinetics analysis of AZD1775 in combination with nab-paclitaxel and gemcitabine was performed. Data were not collected. Consequently, no pharmacokinetics results of AZD1775 would be reported here.</population>
        <group_list>
          <group group_id="O1">
            <title>Arm A (Phase I - Initial Dose Level)</title>
            <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.</description>
          </group>
          <group group_id="O2">
            <title>Arm B (Phase I - Dose Level -2)</title>
            <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.</description>
          </group>
        </group_list>
        <measure>
          <title>To Determine the Pharmacokinetics of AZD1775 in Combination With Nab-paclitaxel and Gemcitabine</title>
          <description>Plasma was to be collected on Cycle 1 Day 1 and Cycle 1 Day 16 for the pharmacokinetics analysis.</description>
          <population>Insufficient plasma samples were collected on this study so no pharmacokinetics analysis of AZD1775 in combination with nab-paclitaxel and gemcitabine was performed. Data were not collected. Consequently, no pharmacokinetics results of AZD1775 would be reported here.</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>Primary</type>
        <title>Progression-free Survival</title>
        <time_frame>Assessed every 3 months for 2 years</time_frame>
        <population>This study stopped at phase I and did not move forward to the phase II part.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>This study stopped at phase I and did not move forward to the phase II part.</description>
          </group>
        </group_list>
        <measure>
          <title>Progression-free Survival</title>
          <population>This study stopped at phase I and did not move forward to the phase II part.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Overall Survival</title>
        <time_frame>Assessed every 3 months for 2 years</time_frame>
        <population>This study stopped at phase I and did not move forward to the phase II part.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>This study stopped at phase I and did not move forward to the phase II part.</description>
          </group>
        </group_list>
        <measure>
          <title>Overall Survival</title>
          <population>This study stopped at phase I and did not move forward to the phase II part.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Response Rate</title>
        <time_frame>Assessed every 3 months for 2 years</time_frame>
        <population>This study stopped at phase I and did not move forward to the phase II part.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>This study stopped at phase I and did not move forward to the phase II part.</description>
          </group>
        </group_list>
        <measure>
          <title>Response Rate</title>
          <population>This study stopped at phase I and did not move forward to the phase II part.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Disease Control Rate</title>
        <time_frame>Assessed every 3 months for 2 years</time_frame>
        <population>This study stopped at phase I and did not move forward to the phase II part.</population>
        <group_list>
          <group group_id="O1">
            <title>Phase II</title>
            <description>This study stopped at phase I and did not move forward to the phase II part.</description>
          </group>
        </group_list>
        <measure>
          <title>Disease Control Rate</title>
          <population>This study stopped at phase I and did not move forward to the phase II part.</population>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="0"/>
              </count_list>
            </analyzed>
          </analyzed_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Assessed every 4 weeks while on treatment and for 30 days after the end of treatment</time_frame>
      <desc>All patients are included in the analyses of all-cause mortality and adverse events.</desc>
      <group_list>
        <group group_id="E1">
          <title>Arm A (Phase I - Initial Dose Level)</title>
          <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor MK-1775 PO daily on days 1, 2, 8, 9, 15, and 16.</description>
        </group>
        <group group_id="E2">
          <title>Arm B (Phase I - Dose Level -2)</title>
          <description>Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor MK-1775 as in Arm A.</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="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>CTCAE 4.0</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Atrial fibrillation</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sinus bradycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Sinus tachycardia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Periodontal disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Gastroesophageal reflux disease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="5" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Papulopustular rash</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary tract infection</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Injury, poisoning and procedural complications</title>
            <event_list>
              <event>
                <sub_title>Fall</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Vascular access complication</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alanine aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="4" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Blood bilirubin increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Creatinine increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>INR increased</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Weight loss</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Investigations - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Weight gain</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypoalbuminemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypocalcemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypophosphatemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypokalemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypomagnesemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dehydration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Metabolism and nutrition disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Myalgia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pain in extremity</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Cognitive disturbance</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Peripheral sensory neuropathy</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Anxiety</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Depression</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Renal and urinary disorders</title>
            <event_list>
              <event>
                <sub_title>Proteinuria</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urinary incontinence</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Urine discoloration</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Epistaxis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Productive cough</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Respiratory, thoracic and mediastinal disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Palmar-plantar erythrodysesthesia syndrome</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Rash maculo-papular</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other, specify</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Flushing</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Thromboembolic event</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="5"/>
              </event>
              <event>
                <sub_title>Hypertension</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="2"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="5"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Study Statistician</name_or_title>
      <organization>ECOG-ACRIN Biostatistics Center</organization>
      <phone>617-632-3012</phone>
      <email>eatrials@jimmy.harvard.edu</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/NCT02194829
org study id: NCI-2014-01425
secondary id: NCI-2014-01425
secondary id: EA2131
secondary id: U10CA180820
secondary id: U10CA021115
nct id: NCT02194829
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This partially randomized phase I/II trial studies the side effects and best dose of WEE1
      inhibitor AZD1775 when given together with paclitaxel albumin-stabilized nanoparticle
      formulation and gemcitabine hydrochloride and how well they work in treating patients with
      previously untreated pancreatic cancer that has spread to another place in the body or cannot
      be removed by surgery. Drugs used in chemotherapy, such as paclitaxel albumin-stabilized
      nanoparticle formulation and gemcitabine hydrochloride, work in different ways to stop the
      growth of tumor cells, either by killing the cells, by stopping them from dividing, or by
      stopping them from spreading. WEE1 inhibitor AZD1775 may stop the growth of tumor cells by
      blocking some of the enzymes needed for cell growth. It is not yet known whether paclitaxel
      albumin-stabilized nanoparticle formulation and gemcitabine hydrochloride are more effective
      with or without WEE1 inhibitor AZD1775 in treating patients with pancreatic cancer.
PRIMARY OBJECTIVES:

      I. To evaluate the toxicity of combination therapy with nab-paclitaxel (paclitaxel
      albumin-stabilized nanoparticle formulation), gemcitabine (gemcitabine hydrochloride) and
      AZD1775 (WEE1 inhibitor MK-1775) in patients with treatment-naive metastatic adenocarcinoma
      of the pancreas or locally-advanced adenocarcinoma of the pancreas which is not surgically
      resectable. (Phase I) II. To determine the dose of AZD1775 to be used in combination with
      nab-paclitaxel and gemcitabine chemotherapy in the phase II portion of the trial. (Phase I)
      III. To determine the pharmacokinetics of AZD1775 in combination with nab-paclitaxel and
      gemcitabine. (Phase I) IV. To evaluate progression-free survival (PFS) associated with
      nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in patients with
      metastatic adenocarcinoma of the pancreas. (Phase II)

      SECONDARY OBJECTIVES:

      I. To evaluate overall survival (OS) associated with nab-paclitaxel/gemcitabine/placebo or
      nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the
      pancreas. (Phase II) II. To evaluate response rate (complete response [CR] + partial response
      [PR]) associated with nab-paclitaxel/gemcitabine/placebo or
      nab-paclitaxel/gemcitabine/AZD1775 in patients with metastatic adenocarcinoma of the
      pancreas. (Phase II) III. To evaluate disease control rate (CR + PR + stable disease [SD])
      associated with nab-paclitaxel/gemcitabine/placebo or nab-paclitaxel/gemcitabine/AZD1775 in
      patients with metastatic adenocarcinoma of the pancreas. (Phase II)

      TERTIARY OBJECTIVES:

      I. To evaluate the ability of AZD1775 to inhibit Wee1 and increase deoxyribonucleic acid
      (DNA) damage and tumor cell death when combined with nab-paclitaxel/gemcitabine compared to
      nab-paclitaxel/gemcitabine/placebo. (Phase II) II. To evaluate if biomarker changes in tumor
      tissue associated with Wee1 inhibition may also be present in hair follicles. (Phase II) III.
      To evaluate the change in tumor fludeoxyglucose (FDG) uptake (maximum standardized uptake
      value [SUVmax]) between baseline FDG-positron emission tomography (PET) and week 4 FDG-PET as
      a predictor of response using Response Evaluation Criteria in Solid Tumors (RECIST) as the
      reference standard for response. (Phase II) IV. To evaluate the change in tumor FDG uptake
      (SUVmax) between baseline FDG-PET and week 4 FDG-PET as a predictor of progression-free
      survival. (Phase II) V. To compare the change in tumor FDG uptake (SUVmax) between baseline
      FDG-PET and week 4 FDG-PET between the patients from treatment arms C and D. (Phase II) VI.
      To evaluate if an early increase in tumor fluorothymidine (FLT) uptake (FLT-flare) is
      observed within 24 hours after initiation of treatment with
      nab-paclitaxel/gemcitabine/placebo. (Phase II) VII. To evaluate if an early (within 24 hours
      [h]) increase in tumor FLT uptake (FLT-flare) is abrogated after initiation of treatment with
      nab-paclitaxel/gemcitabine/AZD1775. (Phase II) VIII. To compare the change in tumor FLT
      uptake (SUVmax) from baseline to 24 hours after initiation of treatment between the patients
      from treatment arms C and D. (Phase II)

      OUTLINE: This is a phase I, dose escalation study of WEE1 inhibitor AZD1775 followed by a
      randomized phase II study. Patients in phase I are assigned to arm A or B and patients in
      phase II are randomized to arm C or D.

      ARM A (PHASE I, DOSE LEVEL 1): Patients receive paclitaxel albumin-stabilized nanoparticle
      formulation intravenously (IV) over 30 minutes and gemcitabine hydrochloride IV over 30
      minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 orally (PO) daily
      on days 1, 2, 8, 9, 15, and 16.

      ARM B (PHASE I, DOSE LEVEL -2): Patients receive paclitaxel albumin-stabilized nanoparticle
      formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.

      ARMS C - G (PHASE I, DOSE LEVEL -1 to DOSE LEVEL 4): Patients receive paclitaxel
      albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor
      AZD1775 as in Arm A at various dose levels. These arms did not enroll any patients.

      ARM H (PHASE II, Control): Patients receive paclitaxel albumin-stabilized nanoparticle
      formulation and gemcitabine hydrochloride as in Arm A. The study did not move forward to the
      phase II part.

      ARM I (PHASE II, WEE1 INHIBITOR AZD1775): Patients receive paclitaxel albumin-stabilized
      nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.
      The study did not move forward to the phase II part.

      In all arms, courses repeat every 28 days in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 2 years.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of Participants With Dose Limiting Toxicities (DLT)
time frame: Assessed at 28 days
description: A dose-limiting toxicity (DLT) was defined by the occurrence of any of the toxicities listed in section 5.1.5 of the protocol that are possibly, probably, or definitely related to study drug(s) within the first cycle (4 weeks = 28 days).
measure: To Determine the Pharmacokinetics of AZD1775 in Combination With Nab-paclitaxel and Gemcitabine
time frame: Assessed at Day 1 and Day 16
description: Plasma was to be collected on Cycle 1 Day 1 and Cycle 1 Day 16 for the pharmacokinetics analysis.
measure: Progression-free Survival
time frame: Assessed every 3 months for 2 years
measure: Overall Survival
time frame: Assessed every 3 months for 2 years
measure: Response Rate
time frame: Assessed every 3 months for 2 years
measure: Disease Control Rate
time frame: Assessed every 3 months for 2 years
arm group label: Arm A
arm group type: Experimental
description: Patients receive paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes and gemcitabine hydrochloride IV over 30 minutes on days 1, 8, and 15. Patients also receive WEE1 inhibitor AZD1775 PO daily on days 1, 2, 8, 9, 15, and 16.
arm group label: Arm B
arm group type: Experimental
description: Patients receive paclitaxel albumin-stabilized nanoparticle formulation, gemcitabine hydrochloride, and WEE1 inhibitor AZD1775 as in Arm A.
intervention type: Drug
intervention name: AZD1775
description: Given PO
arm group label: Arm A
arm group label: Arm B
other name: Adavosertib
other name: MK-1775
intervention type: Drug
intervention name: Gemcitabine
description: Given IV
arm group label: Arm A
arm group label: Arm B
other name: 2'-Deoxy-2'
other name: 2'-difluorocytidine monohydrochloride
other name: Gemzar
intervention type: Drug
intervention name: Nab-paclitaxel
description: Given IV
arm group label: Arm A
arm group label: Arm B
other name: ABI-007
other name: paclitaxel protein-bound particles for injectable suspension
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jennifer R Eads
role: Principal Investigator
affiliation: ECOG-ACRIN Cancer Research Group
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Adenocarcinoma
mesh term: Pancreatic Neoplasms
mesh term: Paclitaxel
mesh term: Albumin-Bound Paclitaxel
mesh term: Gemcitabine
mesh term: Adavosertib
sharing ipd: Yes
ipd description: Individual participant data may be made available upon request as per the ECOG-ACRIN Data Sharing Policy.
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 