<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/NCT02995655</url>
  </required_header>
  <id_info>
    <org_study_id>201608032</org_study_id>
    <secondary_id>CNTX-CX-01-2016-MDS-1</secondary_id>
    <nct_id>NCT02995655</nct_id>
  </id_info>
  <brief_title>CX-01 Combined With Azacitidine in the Treatment of Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia</brief_title>
  <official_title>A Pilot Study of CX-01 Combined With Azacitidine in the Treatment of Relapsed or Refractory Myelodysplastic Syndrome and Acute Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Washington University School of Medicine</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cantex Pharmaceuticals</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators hypothesize that CX-01 will disrupt the bone marrow microenvironment and&#xD;
      increase the cytotoxic effects of azacitidine on myelodysplastic syndrome (MDS) and acute&#xD;
      myeloid leukemia (AML) hematopoietic stem cells by disrupting the High-mobility group box&#xD;
      protein 1 (HMGB1) interaction with toll-like receptor 4 (TLR4) and receptors for advanced&#xD;
      glycation end products (RAGE), the CXC chemokine CXCL12/chemokine receptor 4 (CXCR4) axis,&#xD;
      and by disrupting other leukocyte and vascular adhesion molecules. In addition, CX-01 may&#xD;
      also help promote count recovery after treatment given its affinity for platelet factor-4&#xD;
      (PF4).&#xD;
&#xD;
      The selection of CX-01 dose for study in relapsed or refractory MDS and AML has been based&#xD;
      upon the dual requirements to have sufficient drug administered to have potential activity&#xD;
      but without clinically significant anticoagulation. The study dose chosen (4 mg/kg bolus&#xD;
      followed by 0.25 mg/kg/hour) fulfills both of these criteria. In addition, this dose is&#xD;
      expected to result in serum levels of CX-01 which are significantly higher than the IC90&#xD;
      identified in preclinical studies for inhibition of HMGB1-RAGE, toll-like receptor 2 (TLR2)&#xD;
      and TLR4 interaction. Therefore, the chosen dose represents a rational balance between&#xD;
      effective dosing and safety in thrombocytopenic patients with MDS and AML. This dose was&#xD;
      previously established to be safe and tolerable when combined with cytarabine and idarubicin&#xD;
      in patients with AML.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">April 7, 2017</start_date>
  <completion_date type="Actual">April 29, 2019</completion_date>
  <primary_completion_date type="Actual">September 13, 2018</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall response rate (partial response or higher)</measure>
    <time_frame>30 days following completion of treatment (estimated to be 28 weeks)</time_frame>
    <description>Overall response rate = the percentage of patients obtaining partial response or higher&#xD;
Patients will be assessed for response according to modified International Working Group (IWG) criteria</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival (PFS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The interval from the date of first dose of study drug to disease progression or death.&#xD;
Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Disease-free survival (DFS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The interval from the date of first documentation of a CR to date of recurrence or death. This is determined only for patients achieving a CR&#xD;
Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>Up to 5 years</time_frame>
    <description>The date of first dose of study drug to the date of death from any cause.&#xD;
Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Safety and tolerability of regimen as measured by adverse events tabulated by patient</measure>
    <time_frame>30 days following completion of therapy (estimated to be 28 weeks)</time_frame>
    <description>-The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">20</enrollment>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Acute Myeloid Leukemia</condition>
  <condition>AML</condition>
  <condition>MDS</condition>
  <arm_group>
    <arm_group_label>CX-01 + Azacitidine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>CX-01 will be administered as a 5-minute bolus infusion at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle. The dose of CX-01 should be calculated based on actual body weight (kg) as measured on Day 1 of each cycle.&#xD;
Azacitidine will be administered as a 15-minute intravenous infusion at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle. Azacitidine dose should be calculated based on actual body weight and height to determine BSA. CX-01 may be administered before or after azacitidine, at the discretion of the treating physician.&#xD;
Up to 6 cycles of treatment allowed</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>CX-01</intervention_name>
    <description>CX-01 at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle.</description>
    <arm_group_label>CX-01 + Azacitidine</arm_group_label>
    <other_name>2-O, 3-O desulfated heparin</other_name>
    <other_name>ODSH</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine</intervention_name>
    <description>Azacitidine at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle.</description>
    <arm_group_label>CX-01 + Azacitidine</arm_group_label>
    <other_name>Vidaza®</other_name>
    <other_name>Ladakamycin</other_name>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Bone marrow biopsy</intervention_name>
    <description>-Baseline, day 28 of even-numbered cycle through Cycle 6, and end of study</description>
    <arm_group_label>CX-01 + Azacitidine</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Peripheral blood draw</intervention_name>
    <description>-Day 1 of each cycle, day 3 of each cycle, day 7 of each cycle, day 28 of every even-numbered cycle through Cycle 6, and end of study</description>
    <arm_group_label>CX-01 + Azacitidine</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  One of the following diagnoses:&#xD;
&#xD;
               -  MDS with International Prostate Symptom Score (IPSS) score of INT-1 or higher and&#xD;
                  one of the following:&#xD;
&#xD;
                    -  Symptomatic anemia with either hemoglobin &lt; 10.0 g/dL or requiring red blood&#xD;
                       cell (RBC) transfusion&#xD;
&#xD;
                    -  Thrombocytopenia with a history of two or more platelet counts &lt; 50,000/µL&#xD;
                       or a significant hemorrhage requiring platelet transfusions&#xD;
&#xD;
                    -  Neutropenia with two or more absolute neutrophil count (ANC) &lt; 1,000/µL&#xD;
&#xD;
               -  Non-M3 AML&#xD;
&#xD;
          -  Prior treatment with ≥ 4 cycles of a hypomethylating agent (decitabine or azacitidine)&#xD;
             without response OR documented disease progression on or after hypomethylating agent&#xD;
             therapy&#xD;
&#xD;
          -  Age ≥ 18 years old&#xD;
&#xD;
          -  Adequate renal and hepatic function defined as all of the following:&#xD;
&#xD;
               -  total bilirubin ≤ 1.5 x upper limit of normal (ULN), except in cases of Gilbert's&#xD;
                  disease&#xD;
&#xD;
               -  aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN&#xD;
&#xD;
               -  serum creatinine &lt; 2.0 x ULN&#xD;
&#xD;
          -  Peripheral blood blast count &lt; 10,000/ µL.&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2&#xD;
&#xD;
          -  Females must be surgically or biologically sterile or postmenopausal or, if of&#xD;
             childbearing potential, must agree to use an adequate method of contraception during&#xD;
             the study until 30 days after the last treatment. Males must be surgically or&#xD;
             biologically sterile or agree to use an adequate method of contraception during the&#xD;
             study until 30 days after the last treatment.&#xD;
&#xD;
          -  Ability to understand and willingness to sign an IRB approved written informed consent&#xD;
             document (or that of legally authorized representative, if applicable).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior allogeneic stem cell transplant&#xD;
&#xD;
          -  Central nervous system (CNS) leukemia&#xD;
&#xD;
          -  Diagnosed with AML and eligible for standard induction chemotherapy or stem cell&#xD;
             transplantation.&#xD;
&#xD;
          -  At an increased risk of hemorrhage.&#xD;
&#xD;
          -  Known allergies, hypersensitivity, or intolerance to any form of heparin or&#xD;
             azacitidine&#xD;
&#xD;
          -  Presence of significant active bleeding or condition requiring maintenance of a&#xD;
             platelet count &gt; 50,000/µL&#xD;
&#xD;
          -  Presence of any condition requiring any form of anticoagulant therapy (heparin flushes&#xD;
             for IV catheter are permitted)&#xD;
&#xD;
          -  Receiving concomitant chemotherapy, radiation therapy, or immunotherapy during the&#xD;
             duration of treatment on protocol, or within 21 days prior to enrollment&#xD;
&#xD;
          -  Known seropositivity for or active viral infection with human immunodeficiency virus&#xD;
             (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV). Patients who are&#xD;
             seropositive because of hepatitis B virus vaccine are eligible.&#xD;
&#xD;
          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active&#xD;
             infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac&#xD;
             arrhythmia&#xD;
&#xD;
          -  Pregnant and/or breastfeeding. Women of childbearing potential must have a negative&#xD;
             pregnancy test within 28 days of study entry.&#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>Peter Westervelt, 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>December 2019</verification_date>
  <study_first_submitted>December 13, 2016</study_first_submitted>
  <study_first_submitted_qc>December 13, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 16, 2016</study_first_posted>
  <last_update_submitted>December 4, 2019</last_update_submitted>
  <last_update_submitted_qc>December 4, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">December 5, 2019</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>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</mesh_term>
    <mesh_term>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Syndrome</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Heparin</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/NCT02995655
org study id: 201608032
secondary id: CNTX-CX-01-2016-MDS-1
nct id: NCT02995655
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The investigators hypothesize that CX-01 will disrupt the bone marrow microenvironment and
      increase the cytotoxic effects of azacitidine on myelodysplastic syndrome (MDS) and acute
      myeloid leukemia (AML) hematopoietic stem cells by disrupting the High-mobility group box
      protein 1 (HMGB1) interaction with toll-like receptor 4 (TLR4) and receptors for advanced
      glycation end products (RAGE), the CXC chemokine CXCL12/chemokine receptor 4 (CXCR4) axis,
      and by disrupting other leukocyte and vascular adhesion molecules. In addition, CX-01 may
      also help promote count recovery after treatment given its affinity for platelet factor-4
      (PF4).

      The selection of CX-01 dose for study in relapsed or refractory MDS and AML has been based
      upon the dual requirements to have sufficient drug administered to have potential activity
      but without clinically significant anticoagulation. The study dose chosen (4 mg/kg bolus
      followed by 0.25 mg/kg/hour) fulfills both of these criteria. In addition, this dose is
      expected to result in serum levels of CX-01 which are significantly higher than the IC90
      identified in preclinical studies for inhibition of HMGB1-RAGE, toll-like receptor 2 (TLR2)
      and TLR4 interaction. Therefore, the chosen dose represents a rational balance between
      effective dosing and safety in thrombocytopenic patients with MDS and AML. This dose was
      previously established to be safe and tolerable when combined with cytarabine and idarubicin
      in patients with AML.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall response rate (partial response or higher)
time frame: 30 days following completion of treatment (estimated to be 28 weeks)
description: Overall response rate = the percentage of patients obtaining partial response or higher
Patients will be assessed for response according to modified International Working Group (IWG) criteria
measure: Progression-free survival (PFS)
time frame: Up to 5 years
description: The interval from the date of first dose of study drug to disease progression or death.
Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
measure: Disease-free survival (DFS)
time frame: Up to 5 years
description: The interval from the date of first documentation of a CR to date of recurrence or death. This is determined only for patients achieving a CR
Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
measure: Overall survival (OS)
time frame: Up to 5 years
description: The date of first dose of study drug to the date of death from any cause.
Described by median time-to-event and a 95% confidence interval, if estimable, using Kaplan-Meier models
measure: Safety and tolerability of regimen as measured by adverse events tabulated by patient
time frame: 30 days following completion of therapy (estimated to be 28 weeks)
description: -The descriptions and grading scales found in the revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 will be utilized for all toxicity reporting.
arm group label: CX-01 + Azacitidine
arm group type: Experimental
description: CX-01 will be administered as a 5-minute bolus infusion at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle. The dose of CX-01 should be calculated based on actual body weight (kg) as measured on Day 1 of each cycle.
Azacitidine will be administered as a 15-minute intravenous infusion at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle. Azacitidine dose should be calculated based on actual body weight and height to determine BSA. CX-01 may be administered before or after azacitidine, at the discretion of the treating physician.
Up to 6 cycles of treatment allowed
intervention type: Drug
intervention name: CX-01
description: CX-01 at a dose of 4mg/kg on Day 1 of each 28-day cycle, followed by a continuous intravenous infusion at a dose of 0.25 mg/kg/hour for Days 1 through 7 of each cycle.
arm group label: CX-01 + Azacitidine
other name: 2-O, 3-O desulfated heparin
other name: ODSH
intervention type: Drug
intervention name: Azacitidine
description: Azacitidine at a dose of 75mg/m^2 on Days 1-7 of each 28-day cycle.
arm group label: CX-01 + Azacitidine
other name: Vidaza®
other name: Ladakamycin
intervention type: Procedure
intervention name: Bone marrow biopsy
description: -Baseline, day 28 of even-numbered cycle through Cycle 6, and end of study
arm group label: CX-01 + Azacitidine
intervention type: Procedure
intervention name: Peripheral blood draw
description: -Day 1 of each cycle, day 3 of each cycle, day 7 of each cycle, day 28 of every even-numbered cycle through Cycle 6, and end of study
arm group label: CX-01 + Azacitidine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Peter Westervelt, 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: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Syndrome
mesh term: Azacitidine
mesh term: Heparin
sharing ipd: No