<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/NCT01677559</url>
  </required_header>
  <id_info>
    <org_study_id>201210123</org_study_id>
    <nct_id>NCT01677559</nct_id>
  </id_info>
  <brief_title>Combining MLN8237 With Nab-Paclitaxel in Patients With Advanced Solid Malignancies</brief_title>
  <official_title>Phase I Study Combining MLN8237 With Nab-Paclitaxel in Patients With Advanced Solid Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Washington University School of Medicine</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This phase I trial studies the side effects and the best dose of MLN8237 (alisertib) when&#xD;
      given together with paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel)&#xD;
      in treating patients with solid malignancies that are metastatic or cannot be removed by&#xD;
      surgery. Alisertib may stop the growth of tumor cells by blocking some of the enzymes needed&#xD;
      for cell growth. Drugs used in chemotherapy, such as nab-paclitaxel work by killing the cells&#xD;
      or by stopping them from dividing. Giving alisertib together with nab-paclitaxel may provide&#xD;
      a more effective anticancer treatment with fewer side effects.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">May 7, 2013</start_date>
  <completion_date type="Actual">August 11, 2017</completion_date>
  <primary_completion_date type="Actual">September 30, 2014</primary_completion_date>
  <phase>Phase 1</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>Maximum tolerated dose (MTD)</measure>
    <time_frame>Completion of cycle 1</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Dose-limiting toxicities (DLTs)</measure>
    <time_frame>Completion of cycle 1</time_frame>
    <description>Hematologic DLT is defined as any of the following that occurs during the first cycle that is attributed as possibly, probably or definitely related to the study treatment:&#xD;
Grade 4 neutropenia &gt; 7 days duration&#xD;
Febrile neutropenia of any duration with temperature ≥ 38.5 °C&#xD;
Grade 4 thrombocytopenia &gt; 7 days duration&#xD;
Non-hematologic DLT is defined as any possibly, probably, or definitely related grade 3 or grade 4 non-hematologic toxicity that occurs during the first cycle with the following specific exceptions:&#xD;
Grade 3 fatigue&#xD;
Grade 3 or 4 nausea, vomiting, or anorexia that returns to Grade 1 prior to the start of Cycle 2&#xD;
Grade 3 non-hematological laboratory abnormalities that resolve to grade 1 or baseline prior to the start of Cycle 2&#xD;
Any delay in treatment &gt;14 days that is possibly, probably, or definitely related to study treatment will be considered a DLT.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Antitumor activity of MLN8237 and nab-paclitaxel combination therapy</measure>
    <time_frame>60 days</time_frame>
    <description>Overall response rate (ORR = CR + PR) as a preliminary measure</description>
  </secondary_outcome>
  <number_of_arms>5</number_of_arms>
  <enrollment type="Actual">34</enrollment>
  <condition>Adenocarcinoma</condition>
  <condition>Pancreatic Neoplasms</condition>
  <arm_group>
    <arm_group_label>Dose Level 0</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MLN8237 20 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.&#xD;
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Level 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MLN8237 30 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.&#xD;
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Level 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MLN8237 40 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.&#xD;
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Dose Level 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MLN8237 50 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.&#xD;
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>MTD Expansion Phase</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>MLN8237 as determined during the dose escalation phase on Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.&#xD;
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>MLN8237</intervention_name>
    <arm_group_label>Dose Level 0</arm_group_label>
    <arm_group_label>Dose Level 1</arm_group_label>
    <arm_group_label>Dose Level 2</arm_group_label>
    <arm_group_label>Dose Level 3</arm_group_label>
    <arm_group_label>MTD Expansion Phase</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>nab-Paclitaxel</intervention_name>
    <arm_group_label>Dose Level 0</arm_group_label>
    <arm_group_label>Dose Level 1</arm_group_label>
    <arm_group_label>Dose Level 2</arm_group_label>
    <arm_group_label>Dose Level 3</arm_group_label>
    <arm_group_label>MTD Expansion Phase</arm_group_label>
    <other_name>Abraxane</other_name>
    <other_name>Coroxane</other_name>
    <other_name>Capxol</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient must have a histologically confirmed malignancy that is metastatic or&#xD;
             unresectable and for which standard curative or palliative measures to not exist or&#xD;
             are no longer effective (dose-escalation cohorts only).&#xD;
&#xD;
          -  Patient must have a histologically or cytologically confirmed diagnosis of pancreatic&#xD;
             cancer or poorly differentiated neuroendocrine tumor and must have been treated with a&#xD;
             regimen with known benefit for pancreatic cancer or poorly differentiated&#xD;
             neuroendocrine tumor (MTD expansion cohort only).&#xD;
&#xD;
          -  Patient must have measurable disease defined as lesions that can be accurately&#xD;
             measured in at least one dimension (longest diameter to be recorded) as ≥ 10 mm with&#xD;
             CT scan, ≥ 20 mm by chest x-ray, or ≥ 10 mm with calipers by clinical exam.&#xD;
&#xD;
          -  Patient must have disease that is easily accessible for a core biopsy as determined by&#xD;
             the treating physician or study PI. Patient must agree to the mandatory biopsies at&#xD;
             baseline and end of Cycle 2 (MTD expansion cohort only, and at the discretion of the&#xD;
             PI/PI optional).&#xD;
&#xD;
          -  Patient must be ≥ 18 years of age.&#xD;
&#xD;
          -  Patient must have an ECOG performance status of 0 or 1&#xD;
&#xD;
          -  Patient must have normal bone marrow and organ function as defined below:&#xD;
&#xD;
               -  Leukocytes ≥ 3,000/mcL&#xD;
&#xD;
               -  Absolute neutrophil count ≥ 1,500/mcL&#xD;
&#xD;
               -  Platelets ≥ 100,000/mcL&#xD;
&#xD;
               -  Hemoglobin &gt; 9.0 g/dL&#xD;
&#xD;
               -  Total bilirubin ≤ institutional ULN&#xD;
&#xD;
               -  AST and ALT &lt; 1.5 x ULN (or &lt; 5 x ULN if known liver metastases)&#xD;
&#xD;
               -  Calculated creatinine clearance must be &gt; 40 mL/min (by Cockcroft-Gault)&#xD;
&#xD;
          -  If a female of childbearing potential (defined as a female who is non-menopausal or&#xD;
             surgically sterilized), patient must be willing to use an acceptable method of birth&#xD;
             control (i.e., hormonal contraceptive, intra-uterine device, diaphragm with&#xD;
             spermicide, condom with spermicide, or abstinence) for the duration of the study. If a&#xD;
             male with a partner who is a female of childbearing potential, patient must agree to&#xD;
             use an acceptable method of contraception during the entire study treatment period&#xD;
             through 4 months after the last dose of MLN8237. Should a woman become pregnant or&#xD;
             suspect she is pregnant while participating in this study, she must inform her&#xD;
             treating physician immediately.&#xD;
&#xD;
          -  Patient must be able to take oral medication and to maintain a fast as required for 2&#xD;
             hours before and 1 hour after MLN8237 administration.&#xD;
&#xD;
          -  Patient (or legally authorized representative if applicable) must be able to&#xD;
             understand and willing to sign an IRB approved written informed consent document.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Patient must not have received chemotherapy or radiotherapy ≤ 4 weeks or 5 half-lives&#xD;
             prior to study entry.&#xD;
&#xD;
          -  Patient must not have had radiation therapy to more than 25% of the bone marrow. Whole&#xD;
             pelvic radiation is considered to be over 25%.&#xD;
&#xD;
          -  Patient must not have a history of other malignancy ≤ 2 years previous with the&#xD;
             exception of basal cell or squamous cell carcinoma of the skin which was treated with&#xD;
             local resection only, an in situ malignancy, or low-risk prostate cancer after&#xD;
             curative therapy.&#xD;
&#xD;
          -  Patient must not have had a prior allogeneic bone marrow or organ transplantation.&#xD;
&#xD;
          -  Patient must not have previously received nab-paclitaxel.&#xD;
&#xD;
          -  Patient must not have received any other investigational agents within 14 days prior&#xD;
             to study enrollment.&#xD;
&#xD;
          -  Patient must not have known brain metastases. Patients with known brain metastases&#xD;
             must be excluded from this clinical trial because of their poor prognosis and because&#xD;
             they often develop progressive neurologic dysfunction that would confound the&#xD;
             evaluation of neurologic and other adverse events.&#xD;
&#xD;
          -  Patient must not have a history of allergic reactions attributed to compounds of&#xD;
             similar chemical or biologic composition to either MLN8237 or nab-paclitaxel, or other&#xD;
             agents used in the study.&#xD;
&#xD;
          -  Patient must not have been treated with clinically significant enzyme inducers, such&#xD;
             as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine, or Phenobarbital,&#xD;
             or rifampin, rifabutin, rifapentine, or St. John's wort within 14 days prior to the&#xD;
             first dose of MLN8237.&#xD;
&#xD;
          -  Patient must not have received any previous treatment with any Aurora-kinase&#xD;
             inhibitors (MTD expansion cohort only).&#xD;
&#xD;
          -  Patient must not have a history of gastric resection (MTD expansion cohort only).&#xD;
&#xD;
          -  Patient must not have an uncontrolled intercurrent illness including, but not limited&#xD;
             to, ongoing or active infection, uncontrolled diabetes, malabsorption, resection of&#xD;
             the pancreas or upper small bowel, symptomatic congestive heart failure, or&#xD;
             psychiatric illness/social situations that would limit compliance with study&#xD;
             requirements.&#xD;
&#xD;
          -  Patient must not have ≥ grade 2 peripheral neuropathy within 14 days before&#xD;
             enrollment.&#xD;
&#xD;
          -  Patient must not have a known history of uncontrolled sleep apnea syndrome and other&#xD;
             conditions that could result in excessive daytime sleepiness, such as severe chronic&#xD;
             obstructive pulmonary disease.&#xD;
&#xD;
          -  Patient must not have a requirement for supplemental oxygen.&#xD;
&#xD;
          -  Patient must not require constant administration of a proton pump inhibitor, H2&#xD;
             antagonist, or pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are&#xD;
             allowed.&#xD;
&#xD;
          -  Patient must not have QTc &gt; 500ms within 14 days before enrollment.&#xD;
&#xD;
          -  Patient must not have had a myocardial infarction within 6 months prior to enrollment&#xD;
             or have New York Heart Association (NYHA) Class III or IV heart failure, uncontrolled&#xD;
             angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence&#xD;
             of acute ischemia or active conduction system abnormalities.&#xD;
&#xD;
          -  Patient must not be pregnant and/or breastfeeding.&#xD;
&#xD;
          -  Patient must not be known to be HIV-positive on combination antiretroviral because of&#xD;
             the potential for pharmacokinetic interactions with MLN8237 or Abraxane. In addition,&#xD;
             these patients are at increased risk of lethal infections when treated with&#xD;
             marrow-suppressive therapy. Appropriate studies will be undertaken in patients&#xD;
             receiving combination antiretroviral therapy when indicated.&#xD;
&#xD;
        Inclusion of Women and Minorities&#xD;
&#xD;
        Both men and women and members of all races and ethnic groups are eligible for this trial.&#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>Andrea Wang-Gillam, M.D., Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Washington University School of Medicine</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Washington University School of Medicine</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.siteman.wustl.edu</url>
    <description>Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine</description>
  </link>
  <verification_date>January 2018</verification_date>
  <study_first_submitted>August 27, 2012</study_first_submitted>
  <study_first_submitted_qc>August 31, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 3, 2012</study_first_posted>
  <last_update_submitted>January 9, 2018</last_update_submitted>
  <last_update_submitted_qc>January 9, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">January 11, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <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>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01677559
org study id: 201210123
nct id: NCT01677559
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
This phase I trial studies the side effects and the best dose of MLN8237 (alisertib) when
      given together with paclitaxel albumin-stabilized nanoparticle formulation (nab-paclitaxel)
      in treating patients with solid malignancies that are metastatic or cannot be removed by
      surgery. Alisertib may stop the growth of tumor cells by blocking some of the enzymes needed
      for cell growth. Drugs used in chemotherapy, such as nab-paclitaxel work by killing the cells
      or by stopping them from dividing. Giving alisertib together with nab-paclitaxel may provide
      a more effective anticancer treatment with fewer side effects.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose (MTD)
time frame: Completion of cycle 1
measure: Dose-limiting toxicities (DLTs)
time frame: Completion of cycle 1
description: Hematologic DLT is defined as any of the following that occurs during the first cycle that is attributed as possibly, probably or definitely related to the study treatment:
Grade 4 neutropenia > 7 days duration
Febrile neutropenia of any duration with temperature ≥ 38.5 °C
Grade 4 thrombocytopenia > 7 days duration
Non-hematologic DLT is defined as any possibly, probably, or definitely related grade 3 or grade 4 non-hematologic toxicity that occurs during the first cycle with the following specific exceptions:
Grade 3 fatigue
Grade 3 or 4 nausea, vomiting, or anorexia that returns to Grade 1 prior to the start of Cycle 2
Grade 3 non-hematological laboratory abnormalities that resolve to grade 1 or baseline prior to the start of Cycle 2
Any delay in treatment >14 days that is possibly, probably, or definitely related to study treatment will be considered a DLT.
measure: Antitumor activity of MLN8237 and nab-paclitaxel combination therapy
time frame: 60 days
description: Overall response rate (ORR = CR + PR) as a preliminary measure
arm group label: Dose Level 0
arm group type: Experimental
description: MLN8237 20 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.
arm group label: Dose Level 1
arm group type: Experimental
description: MLN8237 30 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.
arm group label: Dose Level 2
arm group type: Experimental
description: MLN8237 40 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.
arm group label: Dose Level 3
arm group type: Experimental
description: MLN8237 50 mg BID Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.
arm group label: MTD Expansion Phase
arm group type: Experimental
description: MLN8237 as determined during the dose escalation phase on Days 1, 2 and 3 of each week for 3 weeks out of a 4 week cycle.
nab-Paclitaxel 100 mg/m2 IV Day 1 of each week for 3 weeks out of a 4 week cycle.
intervention type: Drug
intervention name: MLN8237
arm group label: Dose Level 0
arm group label: Dose Level 1
arm group label: Dose Level 2
arm group label: Dose Level 3
arm group label: MTD Expansion Phase
intervention type: Drug
intervention name: nab-Paclitaxel
arm group label: Dose Level 0
arm group label: Dose Level 1
arm group label: Dose Level 2
arm group label: Dose Level 3
arm group label: MTD Expansion Phase
other name: Abraxane
other name: Coroxane
other name: Capxol
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Andrea Wang-Gillam, M.D., Ph.D.
role: Principal Investigator
affiliation: Washington University School of Medicine
facility: 
country: United States
url: http://www.siteman.wustl.edu
description: Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
responsible party type: Sponsor
mesh term: Pancreatic Neoplasms
mesh term: Paclitaxel
sharing ipd: No