<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/NCT01682616</url>
  </required_header>
  <id_info>
    <org_study_id>M13-365</org_study_id>
    <nct_id>NCT01682616</nct_id>
  </id_info>
  <brief_title>A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma</brief_title>
  <official_title>A Phase 1b Study Evaluating the Safety and Tolerability of ABT-199 in Combination With Rituximab in Subjects With Relapsed Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>AbbVie</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>AbbVie</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>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a Phase 1b, open-label, multicenter study evaluating the safety and tolerability of&#xD;
      ABT-199 in combination with rituximab in up to 50 subjects with Relapsed Chronic Lymphocytic&#xD;
      Leukemia and Small Lymphocytic Lymphoma. The primary objectives of this study are to assess&#xD;
      the safety profile, to determine the maximum tolerated dose and establish the Recommended&#xD;
      Phase Two Dose of ABT-199 when administered in combination with rituximab. The dose&#xD;
      escalation portion of the study will include approximately 30 subjects. Once the recommended&#xD;
      phase two dose and schedule have been determined, up to 20 additional subjects will be&#xD;
      enrolled in an expanded safety portion of the study. Subjects who meet criteria for CR, CRi,&#xD;
      or MRD-negative PR during the study may discontinue ABT 199. If disease progression occurs,&#xD;
      as defined by iwCLL NCI/WG criteria for tumor response, or MRD progression, subjects may&#xD;
      re-initiate ABT-199.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 25, 2012</start_date>
  <completion_date type="Actual">June 23, 2022</completion_date>
  <primary_completion_date type="Actual">June 23, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>Yes</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>Assess the safety profile, to determine the maximum tolerated dose and Recommended Phase Two Dose of ABT-199 when administered in combination with rituximab (R) in subjects with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma.</measure>
    <time_frame>Continuous dosing at designated dose level up to Month 6. At end of combination treatment, ABT-199 monotherapy may continue up to 8 years following the date of the last subject enrolled. If disease progression occurs, subjects may re-initiate ABT-199.</time_frame>
    <description>Protocol-defined events, which are attributed as having a reasonable possibility of being related to the administration of ABT-199 and/or rituximab, or can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, underlying disease or concomitant medication, will be considered a dose limiting toxicity.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determination of peak concentration (Cmax) of ABT-199 and/or Rituximab.</measure>
    <time_frame>PK samples collected up to Month 6 for ABT-199 and Rituximab</time_frame>
    <description>Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the exploratory efficacy of the combination ABT-199 and rituximab.</measure>
    <time_frame>Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.</time_frame>
    <description>Tumor response or clinical disease progression (Objective Response Rate)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of trough concentration (Ctrough) of ABT-199 and/or Rituximab</measure>
    <time_frame>PK samples collected up to Month 6 for ABT-199 and Rituximab</time_frame>
    <description>Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Determination of area under the concentration versus time curve (AUC) of ABT-199 and/or Rituximab</measure>
    <time_frame>PK samples collected up to Month 6 for ABT-199 and Rituximab</time_frame>
    <description>Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the exploratory efficacy of the combination ABT-199 and rituximab</measure>
    <time_frame>Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.</time_frame>
    <description>Tumor response or clinical disease progression for (Overall Survival)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the exploratory efficacy of the combination ABT-199 and rituximab</measure>
    <time_frame>Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.</time_frame>
    <description>Tumor response or clinical disease progression for (Progression Free Survival)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the exploratory efficacy of the combination ABT-199 and rituximab</measure>
    <time_frame>Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.</time_frame>
    <description>Tumor response or clinical disease progression for (Time to Tumor Progression)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the exploratory efficacy of the combination ABT-199 and rituximab</measure>
    <time_frame>Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.</time_frame>
    <description>Tumor response or clinical disease progression for (Duration Of Response)</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Assess the exploratory pharmacodynamics and pharmacogenetics of the combination of ABT-199 and rituximab.</measure>
    <time_frame>MRD Assessments will be performed at following timepoints: At least 2 months after CR/CRi criteria for tumor response first met, every 12 weeks thereafter until MRD negativity is achieved, and as needed.</time_frame>
    <description>Minimal residual disease (MRD) will be assessed in the peripheral blood and bone marrow (BM) either by flow cytometry or real-time PCR.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">49</enrollment>
  <condition>Small Lymphocytic Lymphoma</condition>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <arm_group>
    <arm_group_label>Arm 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>ABT-199</intervention_name>
    <description>ABT-199 is taken continuously once daily. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study.</description>
    <arm_group_label>Arm 1</arm_group_label>
    <other_name>venetoclax</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Rituximab will be given by intravenous infusion on day 1 of Months 1, 2, 3, 4, 5, and 6. May be reinitiated for an additional 6 months.</description>
    <arm_group_label>Arm 1</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject must be greater then or equal to 18 years of age.&#xD;
&#xD;
          -  Subject must have relapsed Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma.&#xD;
&#xD;
          -  Subject has an Eastern Cooperative Oncology Group performance score of less than or&#xD;
             equal to 1.&#xD;
&#xD;
          -  Subject must have adequate bone marrow independent of growth factor support per local&#xD;
             laboratory reference range at Screening.&#xD;
&#xD;
          -  Subject must have adequate coagulation, renal, and hepatic function, per laboratory&#xD;
             reference range at Screening.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chronic lymphocytic leukemia or Small Lymphocytic Lymphoma subject has undergone an&#xD;
             allogeneic or autologous stem cell transplant.&#xD;
&#xD;
          -  Subject has uncontrolled autoimmune hemolytic anemia or thrombocytopenia.&#xD;
&#xD;
          -  Subject has tested positive for human immunodeficiency virus.&#xD;
&#xD;
          -  Seropositivity for hepatitis B surface antigen or hepatitis C virus antibody or&#xD;
             ribonucleic acid.&#xD;
&#xD;
          -  History of severe allergic or anaphylactic reactions to rituximab.&#xD;
&#xD;
          -  Subject has received a live viral vaccine within 6 months prior to the first dose of&#xD;
             study drug.&#xD;
&#xD;
          -  Subject has received a monoclonal antibody for anti-neoplastic intent within 8 weeks&#xD;
             prior to the first dose of study drug.&#xD;
&#xD;
          -  Subject has received any of the following within 14 days prior to the first dose of&#xD;
             study drug, or has not recovered to less than grade 2 clinically significant adverse&#xD;
             effect(s)/toxicity(s) of the previous therapy:&#xD;
&#xD;
               -  Any anti-cancer therapy including chemotherapy, immunotherapy, or radiotherapy;&#xD;
&#xD;
               -  Investigational therapy, including targeted small molecule agents.&#xD;
&#xD;
          -  Subject has a cardiovascular disability status of New York Heart Association Class&#xD;
             greater then or equal to 2. Class 2 is defined as cardiac disease in which subjects&#xD;
             are comfortable at rest but ordinary physical activity results in fatigue,&#xD;
             palpitations, dyspnea or anginal pain.&#xD;
&#xD;
          -  Subject has a significant history of renal, neurologic, psychiatric, pulmonary,&#xD;
             endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the&#xD;
             opinion of the investigator would adversely affect his/her participating in this&#xD;
             study.&#xD;
&#xD;
          -  Subject has a history of other active malignancies other than CLL/SLL within the past&#xD;
             2 years prior to study entry, with the exception of:&#xD;
&#xD;
               -  Adequately treated in situ carcinoma of the cervix uteri;&#xD;
&#xD;
               -  Basal cell carcinoma of the skin or localized squamous cell carcinoma of the&#xD;
                  skin;&#xD;
&#xD;
               -  Previous malignancy confined and surgically resected (or treated with other&#xD;
                  modalities) with curative intent.&#xD;
&#xD;
          -  Subject has malabsorption syndrome or other condition that precludes enteral route of&#xD;
             administration.&#xD;
&#xD;
          -  Subject exhibits evidence of other clinically significant ongoing or recent&#xD;
             condition(s) including, but not limited to:&#xD;
&#xD;
               -  Ongoing systemic infection (viral, bacterial, or fungal);&#xD;
&#xD;
               -  Diagnosis of fever and neutropenia within 1 week prior to study drug&#xD;
                  administration&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>99 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>ABBVIE INC.</last_name>
    <role>Study Director</role>
    <affiliation>AbbVie</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Moores Cancer Center at UC San Diego /ID# 70398</name>
      <address>
        <city>La Jolla</city>
        <state>California</state>
        <zip>92093</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Northwestern University Feinberg School of Medicine /ID# 71593</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611-2927</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>North Shore University Hospital /ID# 71813</name>
      <address>
        <city>New Hyde Park</city>
        <state>New York</state>
        <zip>11040</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Duke Cancer Center /ID# 71393</name>
      <address>
        <city>Durham</city>
        <state>North Carolina</state>
        <zip>27710-3000</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Peter MacCallum Cancer Ctr /ID# 70394</name>
      <address>
        <city>Melbourne</city>
        <state>Victoria</state>
        <zip>3000</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Royal Melbourne Hospital /ID# 70393</name>
      <address>
        <city>Parkville</city>
        <state>Victoria</state>
        <zip>3050</zip>
        <country>Australia</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Australia</country>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://www.abbvieclinicaltrials.com/study/?id=M13-365#additional-resources-section</url>
    <description>clinical study report synopsis</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>June 26, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2012</study_first_posted>
  <last_update_submitted>June 5, 2023</last_update_submitted>
  <last_update_submitted_qc>June 5, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Safety</keyword>
  <keyword>Small Lymphocytic Lymphoma</keyword>
  <keyword>Chronic Lymphocytic Leukemia</keyword>
  <keyword>Rituximab</keyword>
  <keyword>Tolerability</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>ABT-199</keyword>
  <keyword>Cancer</keyword>
  <keyword>Preliminary</keyword>
  <keyword>Efficacy</keyword>
  <keyword>Maximum Tolerated Dose</keyword>
  <keyword>Venetoclax</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Venetoclax</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/NCT01682616
org study id: M13-365
nct id: NCT01682616
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This is a Phase 1b, open-label, multicenter study evaluating the safety and tolerability of
      ABT-199 in combination with rituximab in up to 50 subjects with Relapsed Chronic Lymphocytic
      Leukemia and Small Lymphocytic Lymphoma. The primary objectives of this study are to assess
      the safety profile, to determine the maximum tolerated dose and establish the Recommended
      Phase Two Dose of ABT-199 when administered in combination with rituximab. The dose
      escalation portion of the study will include approximately 30 subjects. Once the recommended
      phase two dose and schedule have been determined, up to 20 additional subjects will be
      enrolled in an expanded safety portion of the study. Subjects who meet criteria for CR, CRi,
      or MRD-negative PR during the study may discontinue ABT 199. If disease progression occurs,
      as defined by iwCLL NCI/WG criteria for tumor response, or MRD progression, subjects may
      re-initiate ABT-199.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Assess the safety profile, to determine the maximum tolerated dose and Recommended Phase Two Dose of ABT-199 when administered in combination with rituximab (R) in subjects with relapsed chronic lymphocytic leukemia and small lymphocytic lymphoma.
time frame: Continuous dosing at designated dose level up to Month 6. At end of combination treatment, ABT-199 monotherapy may continue up to 8 years following the date of the last subject enrolled. If disease progression occurs, subjects may re-initiate ABT-199.
description: Protocol-defined events, which are attributed as having a reasonable possibility of being related to the administration of ABT-199 and/or rituximab, or can not be attributed by the investigator to a clearly identifiable cause such as tumor progression, concurrent illness, underlying disease or concomitant medication, will be considered a dose limiting toxicity.
measure: Determination of peak concentration (Cmax) of ABT-199 and/or Rituximab.
time frame: PK samples collected up to Month 6 for ABT-199 and Rituximab
description: Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.
measure: Assess the exploratory efficacy of the combination ABT-199 and rituximab.
time frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.
description: Tumor response or clinical disease progression (Objective Response Rate)
measure: Determination of trough concentration (Ctrough) of ABT-199 and/or Rituximab
time frame: PK samples collected up to Month 6 for ABT-199 and Rituximab
description: Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.
measure: Determination of area under the concentration versus time curve (AUC) of ABT-199 and/or Rituximab
time frame: PK samples collected up to Month 6 for ABT-199 and Rituximab
description: Blood samples for analysis of ABT-199 and rituximab will be collected at designated time points.
measure: Assess the exploratory efficacy of the combination ABT-199 and rituximab
time frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.
description: Tumor response or clinical disease progression for (Overall Survival)
measure: Assess the exploratory efficacy of the combination ABT-199 and rituximab
time frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.
description: Tumor response or clinical disease progression for (Progression Free Survival)
measure: Assess the exploratory efficacy of the combination ABT-199 and rituximab
time frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.
description: Tumor response or clinical disease progression for (Time to Tumor Progression)
measure: Assess the exploratory efficacy of the combination ABT-199 and rituximab
time frame: Tumor Assessments will be performed at: Screening, Day 1 on Months 1, 3, 7, and then every 3 months thereafter up to 8 years following the date of the last subject first dose.
description: Tumor response or clinical disease progression for (Duration Of Response)
measure: Assess the exploratory pharmacodynamics and pharmacogenetics of the combination of ABT-199 and rituximab.
time frame: MRD Assessments will be performed at following timepoints: At least 2 months after CR/CRi criteria for tumor response first met, every 12 weeks thereafter until MRD negativity is achieved, and as needed.
description: Minimal residual disease (MRD) will be assessed in the peripheral blood and bone marrow (BM) either by flow cytometry or real-time PCR.
arm group label: Arm 1
arm group type: Experimental
description: Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL)
intervention type: Drug
intervention name: ABT-199
description: ABT-199 is taken continuously once daily. This is a dose escalation study, therefore the dose of ABT-199 will change throughout the study.
arm group label: Arm 1
other name: venetoclax
intervention type: Drug
intervention name: Rituximab
description: Rituximab will be given by intravenous infusion on day 1 of Months 1, 2, 3, 4, 5, and 6. May be reinitiated for an additional 6 months.
arm group label: Arm 1
criteria: 
gender: All
minimum age: 18 Years
maximum age: 99 Years
healthy volunteers: No
last name: ABBVIE INC.
role: Study Director
affiliation: AbbVie
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Australia
country: United States
url: https://www.abbvieclinicaltrials.com/study/?id=M13-365#additional-resources-section
description: clinical study report synopsis
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Rituximab
mesh term: Venetoclax
sharing ipd: No