<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/NCT01701375</url>
  </required_header>
  <id_info>
    <org_study_id>J1275</org_study_id>
    <secondary_id>NA_00076003</secondary_id>
    <nct_id>NCT01701375</nct_id>
  </id_info>
  <brief_title>A Phase 1 Trial of TST of PD 0332991 Followed by Cytarabine and Mitoxantrone for Adults With Relapsed and Refractory Acute Leukemias and High-Risk Myelodysplasia</brief_title>
  <official_title>A Phase I and Pharmacodynamic Trial of Timed Sequential Administration of the Cyclin Dependent Kinase 4/6 Inhibitor PD 0332991 Followed by Cytarabine Plus Mitoxantrone for Adults With Relapsed and Refractory Acute Leukemias and High-Risk Myelodysplasias</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>The Leukemia and Lymphoma Society</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Pfizer</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      1.1 Primary Objectives&#xD;
&#xD;
        -  To determine the feasibility, tolerability, and toxicities of administering the&#xD;
           selective CDK 4/6 inhibitor PD 0332991 prior to the combination of ara-C and&#xD;
           Mitoxantrone for adults with relapsed and refractory acute leukemias and high risk&#xD;
           myelodysplasias (MDS), including primary refractory disease&#xD;
&#xD;
        -  To determine the direct cytotoxic effects of single agent PD 0332991 on malignant blasts&#xD;
&#xD;
        -  To determine the maximal tolerated dose (MTD) of PD 0332991 in timed sequential&#xD;
           combination with ara-C and Mitoxantrone&#xD;
&#xD;
        -  To determine if the timed sequential combination of PD 0332991 with ara-C and&#xD;
           mitoxantrone can induce clinical responses in adults with relapsed or refractory acute&#xD;
           leukemias and high-risk MDS&#xD;
&#xD;
      1.2 Secondary Objectives:&#xD;
&#xD;
        -  To determine the ability of PD 0332991 to directly induce apoptosis in malignant cell&#xD;
           populations in vivo&#xD;
&#xD;
        -  To obtain pharmacodynamic (PD) data regarding the ability of PD 0332991 to arrest&#xD;
           malignant cells in the G 1 phase of cell cycle, followed by synchronized release of&#xD;
           those cells into S phase upon discontinuation of PD 0332991 and resultant enhanced ara-C&#xD;
           cytotoxicity&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Material sponsor withdrew support&#xD;
  </why_stopped>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">April 2013</completion_date>
  <primary_completion_date type="Actual">April 2013</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>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.</measure>
    <time_frame>42 days</time_frame>
    <description>The number of participants experiencing toxicities of administration of PD 0332991 in combination with cytarabine and mitoxantrone will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone</measure>
    <time_frame>42 days</time_frame>
    <description>Dose escalation decisions will be based on nonhematologic toxicities in Cycle 1 (28 days) and hematologic toxicities, in the case of an aplastic marrow through Day 56, For cytopenias including ANC &lt; 500/mm3 or platelets &lt; 50, 000/mm3 a bone marrow will be performed between days 42 and 49.. Dose limiting toxicity (DLT) will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">2</enrollment>
  <condition>Relapsed Acute Leukemia</condition>
  <condition>Refractory Acute Leukemia</condition>
  <condition>High-Risk Myelodysplasia</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>PD 0332991 will be given orally days 1,2,3&#xD;
Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6&#xD;
Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>PD 0332991</intervention_name>
    <description>• PD 0332991 will be given orally days 1,2,3</description>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Adults age ≥ 18 years&#xD;
&#xD;
               -  Multilineage bone marrow failure&#xD;
&#xD;
               -  Serum creatinine ≤ 2.0 mg/dl&#xD;
&#xD;
               -  Hepatic enzymes (AST, ALT) ≤ 3x upper limit of normal (ULN)&#xD;
&#xD;
               -  Bilirubin ≤ 2.0 mg/dl, unless due to Gilbert's disease, hemolysis or leukemic&#xD;
                  infiltration&#xD;
&#xD;
               -  Left ventricular ejection fraction ≥ 45%&#xD;
&#xD;
               -  QTc ≤ 470 msec&#xD;
&#xD;
               -  RB expression is required for the action of PD 0332991. Because rb deletions and&#xD;
                  mutations are rare in acute leukemias and MDS, screening for RB expression will&#xD;
                  not be required before enrollment. Pretreatment biopsies will be stored and&#xD;
                  analyzed for RB expression if needed subsequently.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  • No more than 5 cytotoxic regimens&#xD;
&#xD;
               -  Previous allogeneic or autologous stem cell transplantation permitted&#xD;
&#xD;
               -  ≥ 3 weeks delay from prior cytotoxic chemotherapy or radiation therapy&#xD;
&#xD;
               -  ≥ 2 week delay from prior biologic therapies including hematopoietic growth&#xD;
                  factors and vidaza or decitabine&#xD;
&#xD;
               -  If using Hydroxyurea, steroids, tyrosine kinase/src kinase inhibitors, arsenic,&#xD;
                  interferon for count control, must be off therapy for ≥ 48 hours prior to&#xD;
                  beginning PD 0332991&#xD;
&#xD;
               -  No concomitant use of potent CYP450 3A4 inhibitors (e.g. triazole antifungal&#xD;
                  agents) or inducers (e.g. omperazole, dilantin, dexamethasone) within 7 days&#xD;
                  prior to beginning PD 0332991&#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>Judith Karp, MD</last_name>
    <role>Study Chair</role>
    <affiliation>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21287</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Weill Cornell Medical Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2013</verification_date>
  <study_first_submitted>September 11, 2012</study_first_submitted>
  <study_first_submitted_qc>October 3, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 5, 2012</study_first_posted>
  <results_first_submitted>June 14, 2013</results_first_submitted>
  <results_first_submitted_qc>August 30, 2013</results_first_submitted_qc>
  <results_first_posted type="Estimate">September 9, 2013</results_first_posted>
  <last_update_submitted>August 30, 2013</last_update_submitted>
  <last_update_submitted_qc>August 30, 2013</last_update_submitted_qc>
  <last_update_posted type="Estimate">September 9, 2013</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>Preleukemia</mesh_term>
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Acute Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Palbociclib</mesh_term>
  </intervention_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>2 subjects were accrued</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Arm 1</title>
          <description>PD 0332991 125 was given orally days 1,2,3&#xD;
Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6&#xD;
Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose</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_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="2"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Arm 1</title>
          <description>PD 0332991 will be given orally days 1,2,3&#xD;
Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6&#xD;
Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="2"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="45.5" spread="27"/>
                  </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="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.</title>
        <description>The number of participants experiencing toxicities of administration of PD 0332991 in combination with cytarabine and mitoxantrone will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
        <time_frame>42 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Arm 1</title>
            <description>PD 0332991 will be given orally days 1,2,3&#xD;
Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6&#xD;
Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose</description>
          </group>
        </group_list>
        <measure>
          <title>The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.</title>
          <description>The number of participants experiencing toxicities of administration of PD 0332991 in combination with cytarabine and mitoxantrone will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
          <units>participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="2"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone</title>
        <description>Dose escalation decisions will be based on nonhematologic toxicities in Cycle 1 (28 days) and hematologic toxicities, in the case of an aplastic marrow through Day 56, For cytopenias including ANC &lt; 500/mm3 or platelets &lt; 50, 000/mm3 a bone marrow will be performed between days 42 and 49.. Dose limiting toxicity (DLT) will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0</description>
        <time_frame>42 days</time_frame>
      </outcome>
    </outcome_list>

    <reported_events>
      <group_list>
        <group group_id="E1">
          <title>Arm 1</title>
          <description>PD 0332991 will be given orally days 1,2,3&#xD;
Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6&#xD;
Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>10005364</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title vocab="10048580">Bone marrow aplasia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperbilirubinemia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>5</frequency_threshold>
        <default_vocab>10034835</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"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>mucositis</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="2"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Ivana Gojo, MD</name_or_title>
      <organization>Johns Hopkins University</organization>
      <phone>410-502-7726</phone>
      <email>Igojo1@jhmi.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/NCT01701375
org study id: J1275
secondary id: NA_00076003
nct id: NCT01701375
lead sponsor: 
collaborator: 
collaborator: 
has dmc: Yes
1.1 Primary Objectives

        -  To determine the feasibility, tolerability, and toxicities of administering the
           selective CDK 4/6 inhibitor PD 0332991 prior to the combination of ara-C and
           Mitoxantrone for adults with relapsed and refractory acute leukemias and high risk
           myelodysplasias (MDS), including primary refractory disease

        -  To determine the direct cytotoxic effects of single agent PD 0332991 on malignant blasts

        -  To determine the maximal tolerated dose (MTD) of PD 0332991 in timed sequential
           combination with ara-C and Mitoxantrone

        -  To determine if the timed sequential combination of PD 0332991 with ara-C and
           mitoxantrone can induce clinical responses in adults with relapsed or refractory acute
           leukemias and high-risk MDS

      1.2 Secondary Objectives:

        -  To determine the ability of PD 0332991 to directly induce apoptosis in malignant cell
           populations in vivo

        -  To obtain pharmacodynamic (PD) data regarding the ability of PD 0332991 to arrest
           malignant cells in the G 1 phase of cell cycle, followed by synchronized release of
           those cells into S phase upon discontinuation of PD 0332991 and resultant enhanced ara-C
           cytotoxicity
allocation: Non-Randomized
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The Toxicities of Administration of PD 0332991 in Combination With Cytarabine and Mitoxantrone.
time frame: 42 days
description: The number of participants experiencing toxicities of administration of PD 0332991 in combination with cytarabine and mitoxantrone will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
measure: To Determine the Maximal Tolerated Dose (MTD) of PD 0332991 in Timed Sequential Combination With Ara-C and Mitoxantrone
time frame: 42 days
description: Dose escalation decisions will be based on nonhematologic toxicities in Cycle 1 (28 days) and hematologic toxicities, in the case of an aplastic marrow through Day 56, For cytopenias including ANC < 500/mm3 or platelets < 50, 000/mm3 a bone marrow will be performed between days 42 and 49.. Dose limiting toxicity (DLT) will be measured according to NCI-Common Terminology Criteria for Adverse Events (CTCAE) version 4.0
arm group label: Arm 1
arm group type: Experimental
description: PD 0332991 will be given orally days 1,2,3
Cytarabine (ara-C) will be given by continuous 72 hour intravenous infusion beginning on day 6
Mitoxantrone will be given over 2 hour infusion day 9, 12 hours after the completion of the ara-C infusion. The mitoxantrone dose may be reduced by 25-50% for patients who have received previous anthracyclines as determined by total previous anthracycline dose
intervention type: Drug
intervention name: PD 0332991
description: • PD 0332991 will be given orally days 1,2,3
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Judith Karp, MD
role: Study Chair
affiliation: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Preleukemia
mesh term: Myelodysplastic Syndromes
mesh term: Acute Disease
mesh term: Palbociclib
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 