<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/NCT04505254</url>
  </required_header>
  <id_info>
    <org_study_id>2019-1141</org_study_id>
    <secondary_id>NCI-2020-05262</secondary_id>
    <secondary_id>2019-1141</secondary_id>
    <nct_id>NCT04505254</nct_id>
  </id_info>
  <brief_title>Acalabrutinib and Obinutuzumab for the Treatment of Chronic Lymphocytic Leukemia</brief_title>
  <official_title>Intermittent Therapy With the BTK Inhibitor Acalabrutinib (Calquence) in Combination With Obinutuzumab in Treatment Naive (Tn) Patients With Chronic Lymphocytic Leukemia (CLL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>M.D. Anderson Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Cancer Institute (NCI)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>M.D. Anderson Cancer Center</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 phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating&#xD;
      patients with chronic lymphocytic leukemia (CLL). Acalabrutinib may stop the growth of tumor&#xD;
      cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab&#xD;
      may induce changes in body's immune system and may interfere with the ability of tumor cells&#xD;
      to grow and spread. Giving acalabrutinib and obinutuzumab may help to control disease&#xD;
      progression in CLL patients who have not received treatment for CLL.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      PRIMARY OBJECTIVE:&#xD;
&#xD;
      I. To determine the proportion of patients who have treatment-free remission 6 months after&#xD;
      discontinuation of acalabrutinib in patients who complete 24 cycles of frontline therapy.&#xD;
&#xD;
      SECONDARY OBJECTIVES:&#xD;
&#xD;
      I. To determine clinical factors associated with a treatment-free remission of more than 6&#xD;
      months after discontinuation of acalabrutinib.&#xD;
&#xD;
      II. To determine the treatment-free remission length. III. To evaluate the efficacy of&#xD;
      re-treatment with acalabrutinib plus obinutuzumab in patients who relapse.&#xD;
&#xD;
      EXPLORATORY OBJECTIVES:&#xD;
&#xD;
      I. To characterize the effects of limited-duration acalabrutinib plus obinutuzumab therapy on&#xD;
      the clonal architecture as determined by genome-wide genotyping and analysis (GWAs) and whole&#xD;
      exome sequencing (WES).&#xD;
&#xD;
      II. To determine the frequency of BTK and PLCG2 mutation in patients relapsing after&#xD;
      limited-duration acalabrutinib plus obinutuzumab therapy.&#xD;
&#xD;
      OUTLINE:&#xD;
&#xD;
      Patients receive acalabrutinib orally (PO) twice a day (BID) every 12 hours starting on day 1&#xD;
      of cycle 1, and obinutuzumab intravenously (IV) over 4-6 hours on days 1 and 2 of cycle 3,&#xD;
      and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after&#xD;
      cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at&#xD;
      the discretion of their treating physician. Patients who are in partial response or who have&#xD;
      stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV.&#xD;
      Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or&#xD;
      unacceptable toxicity.&#xD;
&#xD;
      After completion of study treatment, patients are followed up at 30 days then every 3 months.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">August 25, 2020</start_date>
  <completion_date type="Anticipated">June 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2024</primary_completion_date>
  <phase>Phase 2</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>Treatment-free remission</measure>
    <time_frame>At 6 months after discontinuation of acalabrutinib, up to 4 years</time_frame>
    <description>Defined as the time from discontinuation of acalabrutinib to the date of CLL relapse with active disease.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall response rate</measure>
    <time_frame>After 6 cycles (each cycle 28 days) of treatment,up to 4 years</time_frame>
    <description>Defined as complete response</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Overall response rate</measure>
    <time_frame>After 6 cycles (each cycle 28 days) of treatment,up to 4 years</time_frame>
    <description>Defined as partial response</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Clinical factors associated with a treatment-free remission</measure>
    <time_frame>Up to 6 months after completion of treatment</time_frame>
    <description>Will use Cox's proportional hazards analysis of predictors that have a p value &lt; 0.2 in the univariate analysis. Explanatory variables that were highly correlated will be independently entered into the Cox's regression model. Factors significant in at least one model tested will be taken to be possible independent predictors of relapse risk. Demographic and clinical characteristics will be summarized using descriptive statistics, including means with standard deviations, or medians with ranges, histograms and box-plot. Fisher's exact test and Wilcoxon rank test will be used in the data analyses of categorical and continuous variables, respectively.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Treatment-free remission length</measure>
    <time_frame>Up to 6 months after completion of treatment</time_frame>
    <description>The median length of treatment-free remission will be estimated using the Kaplan-Meier method.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Success rate of re-treatment in patients who relapse</measure>
    <time_frame>Up to 6 months after completion of treatment</time_frame>
    <description>The success rate of re-treatment, along with the 95% confidence interval will be computed, and median length of treatment-free remission will be estimated.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">60</enrollment>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <condition>Small Lymphocytic Lymphoma</condition>
  <arm_group>
    <arm_group_label>Treatment (acalabrutinib, obinutuzumab)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients receive acalabrutinib PO BID every 12 hours starting on day 1 of cycle 1, and obinutuzumab IV over 4-6 hours on days 1 and 2 of cycle 3, and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at the discretion of their treating physician. Patients who are in partial response or who have stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acalabrutinib</intervention_name>
    <description>Given PO</description>
    <arm_group_label>Treatment (acalabrutinib, obinutuzumab)</arm_group_label>
    <other_name>ACP-196</other_name>
    <other_name>Bruton Tyrosine Kinase Inhibitor ACP-196</other_name>
    <other_name>Calquence</other_name>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Obinutuzumab</intervention_name>
    <description>Given IV</description>
    <arm_group_label>Treatment (acalabrutinib, obinutuzumab)</arm_group_label>
    <other_name>Anti-CD20 Monoclonal Antibody R7159</other_name>
    <other_name>GA-101</other_name>
    <other_name>GA101</other_name>
    <other_name>Gazyva</other_name>
    <other_name>huMAB(CD20)</other_name>
    <other_name>R7159</other_name>
    <other_name>RO 5072759</other_name>
    <other_name>RO-5072759</other_name>
    <other_name>RO5072759</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Diagnosis CLL/small lymphocytic lymphoma (SLL) and be untreated&#xD;
&#xD;
          -  Patients must have an indication for treatment by 2018 International Workshop on&#xD;
             Chronic Lymphocytic Leukemia (IWCLL) Criteria&#xD;
&#xD;
          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2&#xD;
&#xD;
          -  Patients of childbearing potential must be willing to practice highly effective birth&#xD;
             control during treatment and for 2 days after the last dose of acalabrutinib or 18&#xD;
             months after the last dose of obinutuzumab, whichever is later&#xD;
&#xD;
          -  A negative urine pregnancy test (within 7 days of day 1) is required for women with&#xD;
             childbearing potential&#xD;
&#xD;
          -  Total bilirubin =&lt; 1.5 x institutional upper limit of normal (ULN) except for patients&#xD;
             with bilirubin elevation due to Gilbert's disease who will be allowed to participate&#xD;
&#xD;
          -  An alanine transferase (ALT) =&lt; 2.5 x ULN&#xD;
&#xD;
          -  An estimated creatinine clearance (CrCl) of &gt; 30 mL/min, as calculated by the&#xD;
             Cockcroft-Gault equation unless disease related&#xD;
&#xD;
          -  Free of prior malignancies for 2 years with exception of patients diagnosed with basal&#xD;
             cell or squamous cell carcinoma of the skin, or carcinoma &quot;in situ&quot; of the cervix or&#xD;
             breast who are eligible even if they are currently treated or have been treated and/or&#xD;
             diagnosed in the past 2 years prior to study enrollment. If patients had another&#xD;
             malignancy of indolent behavior in the past 2 years prior to study enrollment that is&#xD;
             expected to be cured with treatment they received such patients can be enrolled, after&#xD;
             consultation with the principal investigator&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Pregnant or breast-feeding females&#xD;
&#xD;
          -  Prior CLL/SLL treatment&#xD;
&#xD;
          -  Known history of infection with human immunodeficiency virus (HIV) or any uncontrolled&#xD;
             active significant infection (eg, bacterial, viral or fungal)&#xD;
&#xD;
          -  Signs of active hepatitis B or C. Subjects who are hepatitis B core antibody&#xD;
             (anti-HBc) positive and who are surface antigen negative will need to have a negative&#xD;
             polymerase chain reaction (PCR). Those who are hepatitis B surface antigen (HBsAg)&#xD;
             positive or hepatitis B PCR positive will be excluded. Subjects who are hepatitis C&#xD;
             antibody positive will need to have a negative PCR result. Those who are hepatitis C&#xD;
             PCR positive will be excluded&#xD;
&#xD;
          -  Patients with uncontrolled autoimmune hemolytic anemia (AIHA) or autoimmune&#xD;
             thrombocytopenia (ITP)&#xD;
&#xD;
          -  An absolute neutrophil count of less than 500/uL, unless disease-related at time of&#xD;
             screening for this protocol&#xD;
&#xD;
          -  A platelet count of less than 30,000/uL at time of screening for this protocol&#xD;
&#xD;
          -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic&#xD;
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of&#xD;
             heart failure, or any class 3 or 4 cardiac disease as defined by the New York Heart&#xD;
             Association Functional Classification. Subjects with controlled, asymptomatic atrial&#xD;
             fibrillation can enroll. Patients with a history of paroxysmal atrial fibrillation&#xD;
             (PAF) or deep vein thrombosis or pulmonary embolism (DVT/PE) can be included if they&#xD;
             had no signs of PAF or DVT/PE in the last 6 months before enrolment. Patients with&#xD;
             ongoing atrial fibrillation (AFib) or ongoing PAF or DVT/PE should be excluded&#xD;
&#xD;
          -  History of stroke or cerebral hemorrhage within 6 months&#xD;
&#xD;
          -  Known history or evidence of bleeding diathesis or coagulopathy within 3 months&#xD;
&#xD;
          -  Major surgical procedure, open biopsy, or significant traumatic injury within 28 days&#xD;
&#xD;
          -  Minor surgical procedures, fine needle aspirations or core biopsies within 7 days&#xD;
             prior to day 1. Bone marrow aspiration and/or biopsy are allowed&#xD;
&#xD;
          -  Serious, non-healing wound, ulcer, or bone fracture&#xD;
&#xD;
          -  Treatment with warfarin (Coumadin) or any other vitamin K antagonist. Patients who&#xD;
             recently received warfarin must be off warfarin for at least 7 days prior to start of&#xD;
             the study. Patients receiving novel oral anticoagulant (NOAC), also termed direct oral&#xD;
             anticoagulant (DOAC) are permitted to enroll. Patients who are currently on a vitamin&#xD;
             K antagonist must be switched to a non-vitamin K antagonist, such as a NOAC/DOAC&#xD;
&#xD;
          -  Has difficulty with or is unable to swallow oral medication, or has significant&#xD;
             gastrointestinal disease that would limit absorption of oral medication&#xD;
&#xD;
          -  Known history of drug-specific hypersensitivity or anaphylaxis to study drug&#xD;
             (including active product or excipient components)&#xD;
&#xD;
          -  Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer&#xD;
&#xD;
          -  Prothrombin time (PT)/international normalized ratio (INR) or activated partial&#xD;
             thromboplastin time (aPTT) (in the absence of lupus anticoagulant) &gt; 2 x ULN&#xD;
&#xD;
          -  Requires treatment with proton pump inhibitors&#xD;
&#xD;
          -  Concurrent participation in another therapeutic clinical 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>Jan A Burger</last_name>
    <role>Principal Investigator</role>
    <affiliation>M.D. Anderson Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>M D Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jan A. Burger</last_name>
      <phone>713-563-1487</phone>
      <email>jaburger@mdanderson.org</email>
    </contact>
    <investigator>
      <last_name>Jan A. Burger</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mdanderson.org</url>
    <description>M D Anderson Cancer Center</description>
  </link>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>July 21, 2020</study_first_submitted>
  <study_first_submitted_qc>August 5, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">August 10, 2020</study_first_posted>
  <last_update_submitted>March 13, 2023</last_update_submitted>
  <last_update_submitted_qc>March 13, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">March 14, 2023</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, 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>Obinutuzumab</mesh_term>
    <mesh_term>Acalabrutinib</mesh_term>
    <mesh_term>Tyrosine Protein Kinase Inhibitors</mesh_term>
  </intervention_browse>
  <!-- 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/NCT04505254
org study id: 2019-1141
secondary id: NCI-2020-05262
secondary id: 2019-1141
nct id: NCT04505254
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
This phase II trial investigates the how well acalabrutinib and obinutuzumab work in treating
      patients with chronic lymphocytic leukemia (CLL). Acalabrutinib may stop the growth of tumor
      cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab
      may induce changes in body's immune system and may interfere with the ability of tumor cells
      to grow and spread. Giving acalabrutinib and obinutuzumab may help to control disease
      progression in CLL patients who have not received treatment for CLL.
PRIMARY OBJECTIVE:

      I. To determine the proportion of patients who have treatment-free remission 6 months after
      discontinuation of acalabrutinib in patients who complete 24 cycles of frontline therapy.

      SECONDARY OBJECTIVES:

      I. To determine clinical factors associated with a treatment-free remission of more than 6
      months after discontinuation of acalabrutinib.

      II. To determine the treatment-free remission length. III. To evaluate the efficacy of
      re-treatment with acalabrutinib plus obinutuzumab in patients who relapse.

      EXPLORATORY OBJECTIVES:

      I. To characterize the effects of limited-duration acalabrutinib plus obinutuzumab therapy on
      the clonal architecture as determined by genome-wide genotyping and analysis (GWAs) and whole
      exome sequencing (WES).

      II. To determine the frequency of BTK and PLCG2 mutation in patients relapsing after
      limited-duration acalabrutinib plus obinutuzumab therapy.

      OUTLINE:

      Patients receive acalabrutinib orally (PO) twice a day (BID) every 12 hours starting on day 1
      of cycle 1, and obinutuzumab intravenously (IV) over 4-6 hours on days 1 and 2 of cycle 3,
      and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after
      cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at
      the discretion of their treating physician. Patients who are in partial response or who have
      stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV.
      Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days then every 3 months.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Treatment-free remission
time frame: At 6 months after discontinuation of acalabrutinib, up to 4 years
description: Defined as the time from discontinuation of acalabrutinib to the date of CLL relapse with active disease.
measure: Overall response rate
time frame: After 6 cycles (each cycle 28 days) of treatment,up to 4 years
description: Defined as complete response
measure: Overall response rate
time frame: After 6 cycles (each cycle 28 days) of treatment,up to 4 years
description: Defined as partial response
measure: Clinical factors associated with a treatment-free remission
time frame: Up to 6 months after completion of treatment
description: Will use Cox's proportional hazards analysis of predictors that have a p value < 0.2 in the univariate analysis. Explanatory variables that were highly correlated will be independently entered into the Cox's regression model. Factors significant in at least one model tested will be taken to be possible independent predictors of relapse risk. Demographic and clinical characteristics will be summarized using descriptive statistics, including means with standard deviations, or medians with ranges, histograms and box-plot. Fisher's exact test and Wilcoxon rank test will be used in the data analyses of categorical and continuous variables, respectively.
measure: Treatment-free remission length
time frame: Up to 6 months after completion of treatment
description: The median length of treatment-free remission will be estimated using the Kaplan-Meier method.
measure: Success rate of re-treatment in patients who relapse
time frame: Up to 6 months after completion of treatment
description: The success rate of re-treatment, along with the 95% confidence interval will be computed, and median length of treatment-free remission will be estimated.
arm group label: Treatment (acalabrutinib, obinutuzumab)
arm group type: Experimental
description: Patients receive acalabrutinib PO BID every 12 hours starting on day 1 of cycle 1, and obinutuzumab IV over 4-6 hours on days 1 and 2 of cycle 3, and day 1 of cycles 4-8. Patients who do not achieve a complete response or remission after cycle 8 may receive single-agent acalabrutinib therapy PO BID for an additional 6 cycles at the discretion of their treating physician. Patients who are in partial response or who have stable disease receive an additional 6 cycles of acalabrutinib PO BID and obinutuzumab IV. Treatment repeats every 28 days for up to 24 cycles in the absence of disease progression or unacceptable toxicity.
intervention type: Drug
intervention name: Acalabrutinib
description: Given PO
arm group label: Treatment (acalabrutinib, obinutuzumab)
other name: ACP-196
other name: Bruton Tyrosine Kinase Inhibitor ACP-196
other name: Calquence
intervention type: Biological
intervention name: Obinutuzumab
description: Given IV
arm group label: Treatment (acalabrutinib, obinutuzumab)
other name: Anti-CD20 Monoclonal Antibody R7159
other name: GA-101
other name: GA101
other name: Gazyva
other name: huMAB(CD20)
other name: R7159
other name: RO 5072759
other name: RO-5072759
other name: RO5072759
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Jan A Burger
role: Principal Investigator
affiliation: M.D. Anderson Cancer Center
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
url: http://www.mdanderson.org
description: M D Anderson Cancer Center
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Obinutuzumab
mesh term: Acalabrutinib
mesh term: Tyrosine Protein Kinase Inhibitors