<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/NCT03788291</url>
  </required_header>
  <id_info>
    <org_study_id>ULYM18086</org_study_id>
    <nct_id>NCT03788291</nct_id>
  </id_info>
  <brief_title>Acalabrutinib and High Frequency Low Dose Subcutaneous Rituximab in Patients With Previously Untreated Chronic Lymphocytic Leukemia / Small Lymphocytic Lymphoma</brief_title>
  <official_title>Phase II Study of Acalabrutinib and High Frequency Low Dose Subcutaneous Rituximab in Patients With Previously Untreated CLL/SLL</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Rochester</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Rochester</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 main purpose of this research study is to find out if the combination of acalabrutinib&#xD;
      and high frequency low dose subcutaneous rituximab is safe and effective in patients who have&#xD;
      previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Despite an array of available therapies, CLL remains an incurable disease. Furthermore, the&#xD;
      presence of certain cytogenetic abnormalities and high-risk mutational features predicts for&#xD;
      a reduced response to treatment, and as a result, a shorter period of progression-free&#xD;
      survival. The development of a well-tolerated more effective, easily administered and limited&#xD;
      duration therapy would be a major contribution to the management of CLL and other B cell&#xD;
      malignancies.&#xD;
&#xD;
      Acalabrutinib is an imidazopyrazine analogue and a potent inhibitor of BTK in vitro and in&#xD;
      vivo. Acalabrutinib shows improved selectivity for BTK compared with ibrutinib. Functional&#xD;
      inhibition of non-target cells (eg, T cells, NK cells, platelets) was not observed for&#xD;
      acalabrutinib at clinically relevant concentrations. Rituximab is a chimeric monoclonal&#xD;
      antibody targeting CD20 FDA approved for the treatment of CLL/SLL using intravenous or&#xD;
      subcutaneous formulations.&#xD;
&#xD;
      Antibody dependent cellular phagocytosis may be optimized using high frequency subcutaneous&#xD;
      administration of anti-CD20 monoclonal antibodies. Unlike ibrutinib, acalabrutinib does not&#xD;
      cause significant in vitro inhibition of rituximab induced antibody dependent cellular&#xD;
      phagocytosis in vitro. The investigator thus proposes that acalabrutinib would be an ideal&#xD;
      partner drug with high frequency low dose SQ rituximab in the treatment of CLL and that the&#xD;
      combination will increase the efficacy of therapy for CLL patients by decreasing the time to&#xD;
      achievement of complete response and allowing for shorter and less toxic therapy.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">March 25, 2019</start_date>
  <completion_date type="Anticipated">February 1, 2024</completion_date>
  <primary_completion_date type="Anticipated">February 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>Proportion of subjects with a complete response rate (CR) at 1 year of therapy</measure>
    <time_frame>1 year</time_frame>
    <description>To satisfy criteria for a CR, all of the following criteria must be met:&#xD;
No evidence of new disease&#xD;
ALC in peripheral blood of &lt;4 x 109/L&#xD;
Regression of all target nodal masses to normal size ≤1.5 cm in the LD&#xD;
Normal spleen and liver size&#xD;
Regression to normal of all nodal non-target disease and disappearance of all detectable non-nodal, non-target disease&#xD;
Morphologically negative bone marrow defined as &lt;30% of nucleated cells being lymphoid cells and no lymphoid nodules in a bone marrow sample (the presence of benign reactive nodules is still compatible with a CR)&#xD;
Absence of constitutional symptoms&#xD;
Peripheral blood counts meeting all of the following criteria:&#xD;
ANC &gt;1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF)&#xD;
Platelet count ≥100 x 109/L without need for exogenous growth factors&#xD;
Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for exogenous growth factors (e.g., erythropoietin)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Proportion of subjects with minimal residual disease in peripheral blood and bone</measure>
    <time_frame>1 year</time_frame>
    <description>6-color flow cytometry</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">39</enrollment>
  <condition>Chronic Lymphocytic Leukemia (CLL)</condition>
  <condition>Small Lymphocytic Lymphoma (SLL)</condition>
  <arm_group>
    <arm_group_label>Acalabrutinib and Rituximab treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Rituximab: administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, Then 50 mg SQ thereafter.&#xD;
Acalabrutinib: 100 mg po BID starting on day 8 of cycle 1.&#xD;
Patients who have attained a complete response who are also MRD negative at cycle 12 will undergo a BM biopsy to confirm CR and MRD negatively. If confirmed, the patient will stop therapy and be followed until disease progression.&#xD;
Patients not in a MRD negative CR, will continue acalabrutinib.&#xD;
Repeat response assessments (CTs, MRD testing in blood) will be performed at 24 cycles of therapy for those continuing on acalabrutinib. If both negative the patient will undergo a BM biopsy to confirm CR and MRD negativity. If confirmed, the patient will stop therapy and be followed until disease progression. In the absence of a CR or if MRD +, acalabrutinib may be continued until disease progression, unacceptable toxicity or physician/patient discretion.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Acalabrutinib</intervention_name>
    <description>100 mg by mouth twice a day starting on day 8 of cycle 1</description>
    <arm_group_label>Acalabrutinib and Rituximab treatment</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, then 50 mg SQ thereafter.</description>
    <arm_group_label>Acalabrutinib and Rituximab treatment</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Diagnosis of B-cell CLL or SLL, with diagnosis established according to IWCLL criteria&#xD;
             and documented within medical records. Patients must not have received previous&#xD;
             therapy for CLL/SLL&#xD;
&#xD;
          2. CLL/SLL that warrants treatment consistent with accepted IWCLL criteria for initiation&#xD;
             of therapy. Any one of the following conditions constitutes CLL/SLL that warrants&#xD;
             treatment:&#xD;
&#xD;
               1. Evidence of progressive marrow failure as manifested by the onset or worsening of&#xD;
                  anemia and/or thrombocytopenia, or&#xD;
&#xD;
               2. Massive (i.e., lower edge of spleen ≥6 cm below the left costal margin),&#xD;
                  progressive, or symptomatic splenomegaly, or&#xD;
&#xD;
               3. Massive (i.e., ≥10 cm in the longest diameter), progressive, or symptomatic&#xD;
                  lymphadenopathy, or&#xD;
&#xD;
               4. Progressive lymphocytosis in the absence of infection, with an increase in blood&#xD;
                  absolute lymphocyte count (ALC) ≥50% over a 2-month period or lymphocyte doubling&#xD;
                  time of &lt;6 months (as long as initial ALC was ≥30,000/L), or&#xD;
&#xD;
               5. Autoimmune anemia and/or thrombocytopenia that is poorly responsive to&#xD;
                  corticosteroids or other standard therapy, or&#xD;
&#xD;
               6. Constitutional symptoms, defined as any one or more of the following&#xD;
                  disease-related symptoms or signs occurring in the absence of evidence of&#xD;
                  infection:&#xD;
&#xD;
             i. Unintentional weight loss of ≥10% within the previous 6 months, or&#xD;
&#xD;
             ii. Significant fatigue (≥Grade 2), or&#xD;
&#xD;
             iii. Fevers &gt;100.5°F or 38.0°C for ≥2 weeks, or&#xD;
&#xD;
             iv. Drenching night sweats for &gt;1 month.&#xD;
&#xD;
          3. Adequate organ system function, defined as follows:&#xD;
&#xD;
               1. Absolute neutrophil count (ANC) ≥ 0.5x109/L and platelet count ≥ 30x109/L&#xD;
&#xD;
               2. Total bilirubin ≤2.5 times the upper limit of normal (ULN) unless due to&#xD;
                  Gilbert's disease&#xD;
&#xD;
               3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN if&#xD;
                  no liver involvement or ≤5 x the ULN if known liver involvement&#xD;
&#xD;
               4. Calculated creatinine clearance &gt;30 mL/min (as calculated by the Cockcroft-Gault&#xD;
                  formula)&#xD;
&#xD;
               5. Patients with PT/INR or aPTT ≤2xULN.&#xD;
&#xD;
          4. ECOG performance status ≤ 2 unless related to CLL.&#xD;
&#xD;
          5. Male or female ≥ 18 years of age.&#xD;
&#xD;
          6. Ability to swallow and retain oral medication.&#xD;
&#xD;
          7. Woman of childbearing potential (WOCBP) who are sexually active must use highly&#xD;
             effective methods of contraception during treatment and for 2 days after the last dose&#xD;
             of acalabrutinib and for 12 months following last dose of rituximab. (see Appendix 3&#xD;
             for examples)&#xD;
&#xD;
          8. Willingness and ability to comply with study and follow-up procedures, and give&#xD;
             written informed consent.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy,&#xD;
             immunotherapy, biologic therapy, hormonal therapy, surgery).&#xD;
&#xD;
             a. Systemic corticosteroid therapy started prior to study entry is allowed as&#xD;
             clinically warranted. Topical or inhaled corticosteroids are permitted.&#xD;
&#xD;
          2. Serologic status reflecting active hepatitis B or C infection. Patients who are&#xD;
             hepatitis B core antibody (anti-HBc) positive and who are surface antigen negative&#xD;
             will need to have a negative polymerase chain reaction (PCR). Those who are hepatitis&#xD;
             B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded.&#xD;
             Subjects who are hepatitis C antibody positive will need to have a negative PCR&#xD;
             result. Those who are hepatitis C PCR positive will be excluded.&#xD;
&#xD;
          3. Known history of HIV.&#xD;
&#xD;
          4. Known histological transformation from CLL to an aggressive lymphoma.&#xD;
&#xD;
          5. Evidence of ongoing systemic bacterial, fungal or viral infection, except localized&#xD;
             fungal infections of skin or nails. NOTE: Patients may be receiving prophylactic&#xD;
             antiviral or antibacterial therapies at investigator discretion.&#xD;
&#xD;
          6. Live virus vaccines within 4 weeks prior to C1D1 or during rituximab therapy.&#xD;
&#xD;
          7. History of anaphylaxis (excluding infusion related reactions) in association with&#xD;
             previous anti-CD20 administration or acalabrutinib.&#xD;
&#xD;
          8. Any severe and/or uncontrolled medical conditions or other conditions that could&#xD;
             affect their participation in the study such as:&#xD;
&#xD;
               1. Symptomatic, or history of documented congestive heart failure (NY Heart&#xD;
                  Association functional classification III-IV)&#xD;
&#xD;
               2. Uncontrolled cardiac arrhythmia (Patients with controlled atrial&#xD;
                  fibrillation/flutter are eligible)&#xD;
&#xD;
               3. Myocardial infarction within 3 months of enrollment&#xD;
&#xD;
               4. Angina not well-controlled by medication&#xD;
&#xD;
               5. Poorly controlled or clinically significant atherosclerotic vascular disease&#xD;
                  including cerebrovascular accident (CVA), transient ischemic attack (TIA),&#xD;
                  angioplasty, cardiac/vascular stenting within 3 months of enrollment.&#xD;
&#xD;
               6. Active bleeding or history of bleeding diathesis (eg, hemophilia or von&#xD;
                  Willebrand disease).&#xD;
&#xD;
               7. Any history of intracranial bleed or stroke within 6 months of first dose of&#xD;
                  study drug&#xD;
&#xD;
               8. Patients with suspected or confirmed PML&#xD;
&#xD;
               9. Patients with malabsorption syndrome or gastrointestinal disease that limits&#xD;
                  absorption of oral medication&#xD;
&#xD;
          9. Malignancy within 2 years of study enrollment except for adequately treated basal,&#xD;
             squamous cell carcinoma or non-melanomatous skin cancer, carcinoma in situ of the&#xD;
             cervix, superficial bladder cancer not treated with intravesical chemotherapy or BCG&#xD;
             within 6 months, localized prostate cancer and PSA &lt;1.0 mg/dL on 2 consecutive&#xD;
             measurements at least 3 months apart with the most recent one being within 4 weeks of&#xD;
             study entry.&#xD;
&#xD;
         10. Patients with active uncontrolled autoimmune hemolytic anemia or ITP.&#xD;
&#xD;
         11. Inability to discontinue use of strong CYP3A inhibitors. Patients taking moderate&#xD;
             CYP3A inhibitors or strong CYP3A inducers are eligible.&#xD;
&#xD;
         12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K&#xD;
             antagonists (eg, phenprocoumon) within 7 days of first dose of study drug.&#xD;
&#xD;
         13. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole,&#xD;
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole) at study entry. Subjects&#xD;
             receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are&#xD;
             eligible for enrollment to this study.&#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>Paul Barr</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Rochester</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Rochester</name>
      <address>
        <city>Rochester</city>
        <state>New York</state>
        <zip>14642</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>December 24, 2018</study_first_submitted>
  <study_first_submitted_qc>December 24, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 27, 2018</study_first_posted>
  <last_update_submitted>February 8, 2023</last_update_submitted>
  <last_update_submitted_qc>February 8, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 9, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Rochester</investigator_affiliation>
    <investigator_full_name>Paul Barr</investigator_full_name>
    <investigator_title>Director of the Clinical Trials Office for Wilmot Cancer Institute</investigator_title>
  </responsible_party>
  <keyword>Chronic Lymphocytic Leukemia (CLL)</keyword>
  <keyword>Small Lymphocytic Lymphoma (SLL)</keyword>
  <keyword>Phase II</keyword>
  <keyword>Acalabrutinib</keyword>
  <keyword>Rituximab</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>Acalabrutinib</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/NCT03788291
org study id: ULYM18086
nct id: NCT03788291
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
The main purpose of this research study is to find out if the combination of acalabrutinib
      and high frequency low dose subcutaneous rituximab is safe and effective in patients who have
      previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
Despite an array of available therapies, CLL remains an incurable disease. Furthermore, the
      presence of certain cytogenetic abnormalities and high-risk mutational features predicts for
      a reduced response to treatment, and as a result, a shorter period of progression-free
      survival. The development of a well-tolerated more effective, easily administered and limited
      duration therapy would be a major contribution to the management of CLL and other B cell
      malignancies.

      Acalabrutinib is an imidazopyrazine analogue and a potent inhibitor of BTK in vitro and in
      vivo. Acalabrutinib shows improved selectivity for BTK compared with ibrutinib. Functional
      inhibition of non-target cells (eg, T cells, NK cells, platelets) was not observed for
      acalabrutinib at clinically relevant concentrations. Rituximab is a chimeric monoclonal
      antibody targeting CD20 FDA approved for the treatment of CLL/SLL using intravenous or
      subcutaneous formulations.

      Antibody dependent cellular phagocytosis may be optimized using high frequency subcutaneous
      administration of anti-CD20 monoclonal antibodies. Unlike ibrutinib, acalabrutinib does not
      cause significant in vitro inhibition of rituximab induced antibody dependent cellular
      phagocytosis in vitro. The investigator thus proposes that acalabrutinib would be an ideal
      partner drug with high frequency low dose SQ rituximab in the treatment of CLL and that the
      combination will increase the efficacy of therapy for CLL patients by decreasing the time to
      achievement of complete response and allowing for shorter and less toxic therapy.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Proportion of subjects with a complete response rate (CR) at 1 year of therapy
time frame: 1 year
description: To satisfy criteria for a CR, all of the following criteria must be met:
No evidence of new disease
ALC in peripheral blood of <4 x 109/L
Regression of all target nodal masses to normal size ≤1.5 cm in the LD
Normal spleen and liver size
Regression to normal of all nodal non-target disease and disappearance of all detectable non-nodal, non-target disease
Morphologically negative bone marrow defined as <30% of nucleated cells being lymphoid cells and no lymphoid nodules in a bone marrow sample (the presence of benign reactive nodules is still compatible with a CR)
Absence of constitutional symptoms
Peripheral blood counts meeting all of the following criteria:
ANC >1.5 x 109/L without need for exogenous growth factors (e.g., G-CSF)
Platelet count ≥100 x 109/L without need for exogenous growth factors
Hemoglobin ≥110 g/L (11.0 g/dL) without red blood cell transfusions or need for exogenous growth factors (e.g., erythropoietin)
measure: Proportion of subjects with minimal residual disease in peripheral blood and bone
time frame: 1 year
description: 6-color flow cytometry
arm group label: Acalabrutinib and Rituximab treatment
arm group type: Experimental
description: Rituximab: administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, Then 50 mg SQ thereafter.
Acalabrutinib: 100 mg po BID starting on day 8 of cycle 1.
Patients who have attained a complete response who are also MRD negative at cycle 12 will undergo a BM biopsy to confirm CR and MRD negatively. If confirmed, the patient will stop therapy and be followed until disease progression.
Patients not in a MRD negative CR, will continue acalabrutinib.
Repeat response assessments (CTs, MRD testing in blood) will be performed at 24 cycles of therapy for those continuing on acalabrutinib. If both negative the patient will undergo a BM biopsy to confirm CR and MRD negativity. If confirmed, the patient will stop therapy and be followed until disease progression. In the absence of a CR or if MRD +, acalabrutinib may be continued until disease progression, unacceptable toxicity or physician/patient discretion.
intervention type: Drug
intervention name: Acalabrutinib
description: 100 mg by mouth twice a day starting on day 8 of cycle 1
arm group label: Acalabrutinib and Rituximab treatment
intervention type: Drug
intervention name: Rituximab
description: Administered 2 times weekly for 6 cycles. Initial dose day 1: 50 mg IV, then 50 mg SQ thereafter.
arm group label: Acalabrutinib and Rituximab treatment
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Paul Barr
role: Principal Investigator
affiliation: University of Rochester
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Rochester
investigator full name: Paul Barr
investigator title: Director of the Clinical Trials Office for Wilmot Cancer Institute
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Rituximab
mesh term: Acalabrutinib