<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/NCT04419389</url>
  </required_header>
  <id_info>
    <org_study_id>A20-11197</org_study_id>
    <nct_id>NCT04419389</nct_id>
  </id_info>
  <brief_title>APR-246 in Combination With Acalabrutinib or Venetoclax Based Therapy in Subjects With R/R Non Hodgkin Lymphomas (NHL)</brief_title>
  <acronym>R/R</acronym>
  <official_title>Phase 1 and Dose Expansion Study of APR-246 in Combination With Acalabrutinib or Venetoclax-based Therapy in Subjects With R/R NHL Including Chronic Lymphocytic Leukemia (CLL) and Mantle Cell Lymphoma (MCL)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aprea Therapeutics</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Aprea Therapeutics</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of&#xD;
      APR-246 in combination with either acalabrutinib or venetoclax + rituximab therapy in&#xD;
      subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase 1, open-label, dose-finding and cohort expansion study to determine the preliminary&#xD;
      safety, tolerability, and pharmacokinetic (PK) profile of APR-246 (eprenetapopt) in&#xD;
      combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL,&#xD;
      including relapsed and/or refractory (R/R) CLL and R/R MCL.&#xD;
&#xD;
      The study includes a safety lead-in portion followed by an expansion portion in subjects with&#xD;
      R/R CLL, Richter Transformation (RT), and R/R MCL.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Terminated</overall_status>
  <why_stopped>
    Sponsor decision&#xD;
  </why_stopped>
  <start_date type="Actual">March 2, 2021</start_date>
  <completion_date type="Actual">August 24, 2021</completion_date>
  <primary_completion_date type="Actual">August 23, 2021</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Single (Participant)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>To determine the DLT of APR-246 in combination with acalabrutinib or in combination with venetoclax + rituximab therapy in subjects with NHL, including subjects with R/R CLL, RT and R/R MCL.</measure>
    <time_frame>Through study completion, approximately 1 year</time_frame>
    <description>The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events .</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To assess the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy.</measure>
    <time_frame>Through study completion, approximately 1 year</time_frame>
    <description>The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy</description>
  </primary_outcome>
  <primary_outcome>
    <measure>To determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) in subjects with TP53 mutant NHL, including subjects with R/R CLL, RT and R/R MCL.</measure>
    <time_frame>Through study completion, approximately 1 year</time_frame>
    <description>The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT).</description>
  </primary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Non Hodgkin Lymphoma</condition>
  <condition>Chronic Lymphocytic Leukemia</condition>
  <condition>Mantle Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Safety Lead-In Cohort 1</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>APR-246 + Acalabrutinib in Subjects with R/R CLL.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Lead-In Cohort 2</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>APR-246 + Venetoclax + Rituximab in Subjects with R/R CLL.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Expansion Cohorts</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>APR-246 + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Safety Lead-In Cohort 3</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>APR-246 + Venetoclax + Rituximab in Subjects with RT</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APR-246 (eprenetapopt) + Acalabrutinib in CLL</intervention_name>
    <description>APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule</description>
    <arm_group_label>Safety Lead-In Cohort 1</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL</intervention_name>
    <description>APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule</description>
    <arm_group_label>Safety Lead-In Cohort 2</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APR-246 (eprenetapopt) + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT</intervention_name>
    <description>APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule Venetoclax and Rituxiab will be given at a standard dose and schedule</description>
    <arm_group_label>Expansion Cohorts</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT</intervention_name>
    <description>APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule</description>
    <arm_group_label>Safety Lead-In Cohort 3</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Is able to understand and is willing and able to comply with the study requirements&#xD;
             and to provide written informed consent.&#xD;
&#xD;
          2. Documented histologic diagnosis of R/R CLL, RT, or R/R MCL&#xD;
&#xD;
          3. Safety Lead-In Cohort 1: Patients whose most recent regimen did not include BTK&#xD;
             inhibitor therapy.&#xD;
&#xD;
          4. Safety Lead-In Cohort 2: Patients whose most recent regimen did not include Bcl-2&#xD;
             inhibitor therapy.&#xD;
&#xD;
          5. Safety Lead-In Cohort 3: APR-246 + venetoclax + rituximab in patients with RT&#xD;
&#xD;
          6. Prothrombin time (or international normalized ratio) and partial thromboplastin time&#xD;
             not to exceed 1.2 × the institution's normal range.&#xD;
&#xD;
          7. Adequate BM function independent of growth factor or transfusion support, per local&#xD;
             laboratory reference range at screening as follows:&#xD;
&#xD;
               1. platelet count ≥ 75 000/mm3;&#xD;
&#xD;
               2. absolute neutrophil count (ANC) ≥ 1000/mm3 unless cytopenia is clearly due to&#xD;
                  marrow involvement from CLL or MCL&#xD;
&#xD;
               3. total hemoglobin ≥ 9 g/dL (without transfusion support within 2 weeks of&#xD;
                  screening);&#xD;
&#xD;
          8. Adequate organ function as defined by the following laboratory values:&#xD;
&#xD;
               1. Creatinine clearance ≥ 30 mL/min.&#xD;
&#xD;
               2. Total serum bilirubin ≤ 1.5 × upper limit of normal (ULN) unless due to Gilbert's&#xD;
                  syndrome, NHL organ involvement, controlled immune hemolysis or considered an&#xD;
                  effect of regular blood transfusions.&#xD;
&#xD;
               3. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN,&#xD;
                  unless due to NHL organ involvement.&#xD;
&#xD;
          9. Age ≥18 years at the time of signing the informed consent form.&#xD;
&#xD;
         10. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2.&#xD;
&#xD;
         11. Projected life expectancy of ≥ 12 weeks.&#xD;
&#xD;
         12. Women of childbearing potential and men with female partners of childbearing potential&#xD;
             must be willing to use an effective form of contraception.&#xD;
&#xD;
             Exclusion Criteria:&#xD;
&#xD;
         13. Patient with known allergies to xanthine oxidase inhibitors and/or rasburicase.&#xD;
&#xD;
         14. For patients to receive rituximab on this protocol, prior allergy to rituximab is&#xD;
             prohibited.&#xD;
&#xD;
         15. No concomitant anticancer therapies, immunotherapies, cellular, or radiotherapy. No&#xD;
             major surgery within 3 weeks prior to first dose of study treatment.&#xD;
&#xD;
         16. Uncontrolled autoimmune hemolytic anemia (AIHA) or immune thrombocytopenia.&#xD;
&#xD;
         17. Consumption of grapefruit, grapefruit products, Seville oranges, or star fruit within&#xD;
             7 days of starting study treatment.&#xD;
&#xD;
         18. Concomitant steroids for disease related pain control are allowed at any dose but must&#xD;
             be discontinued prior to any study treatment initiation. Chronic use of&#xD;
             corticosteroids is allowed up to ≤ 20 mg prednisone daily for non-cancer related&#xD;
             conditions at the time of study start.&#xD;
&#xD;
         19. History of allogeneic or autologous stem cell transplant (SCT) or CAR-T therapy within&#xD;
             the last 30 days or with any of the following:&#xD;
&#xD;
         20. Active graft versus host disease (GVHD)&#xD;
&#xD;
         21. Cytopenias from incomplete blood cell count recovery post-transplant;&#xD;
&#xD;
         22. Need for anti-cytokine therapy for residual symptoms of neurotoxicity &gt; grade 1 from&#xD;
             CAR-T therapy;&#xD;
&#xD;
         23. Ongoing immunosuppressive therapy.&#xD;
&#xD;
         24. Known history of human immunodeficiency virus (HIV) serum positivity.&#xD;
&#xD;
         25. Active hepatitis B/C.&#xD;
&#xD;
         26. Known central nervous system (CNS) involvement by lymphoma. Patients with previous&#xD;
             treatment for CNS involvement who are neurologically stable and without evidence of&#xD;
             disease may be eligible if a compelling clinical rationale is provided to sponsor.&#xD;
&#xD;
         27. Known neurologic disorder or residual neurologic toxicities that may put patients at&#xD;
             increased risk of neurologic toxicity in the opinion of the investigator.&#xD;
&#xD;
         28. Cardiac abnormalities.&#xD;
&#xD;
         29. Concomitant malignancies or previous malignancies with less than a 1 year disease-&#xD;
             free interval at the time of signing consent.&#xD;
&#xD;
         30. A female patient who is pregnant or breast-feeding.&#xD;
&#xD;
         31. Active uncontrolled systemic infection.&#xD;
&#xD;
         32. Received an investigational agent within 30 days or within 5 T1/2, whichever is&#xD;
             shorter prior to the first dose of study treatment.&#xD;
&#xD;
         33. Clinically significant active malabsorption syndrome or other condition likely to&#xD;
             affect gastrointestinal (GI) absorption of ibrutinib or venetoclax.&#xD;
&#xD;
         34. Current treatment with certain strong cytochrome P450 3A4 (CYP3A4) inhibitors or&#xD;
             inducers and/or strong P-gp inhibitors..&#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>Joachim Gullbo, MD</last_name>
    <role>Study Director</role>
    <affiliation>Theradex Oncology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02114</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Dana Farber Cancer Institute</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Cancer Center</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10065</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>MD Anderson Cancer Center</name>
      <address>
        <city>Houston</city>
        <state>Texas</state>
        <zip>77030</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>June 1, 2020</study_first_submitted>
  <study_first_submitted_qc>June 3, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 5, 2020</study_first_posted>
  <last_update_submitted>August 4, 2023</last_update_submitted>
  <last_update_submitted_qc>August 4, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 7, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>APR-246</keyword>
  <keyword>eprenetapopt</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>Lymphoma, Non-Hodgkin</mesh_term>
    <mesh_term>Leukemia, Lymphoid</mesh_term>
    <mesh_term>Leukemia, Lymphocytic, Chronic, B-Cell</mesh_term>
    <mesh_term>Lymphoma, Mantle-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>
    <mesh_term>Acalabrutinib</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/NCT04419389
org study id: A20-11197
nct id: NCT04419389
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Study to determine the preliminary safety, tolerability, and pharmacokinetic (PK) profile of
      APR-246 in combination with either acalabrutinib or venetoclax + rituximab therapy in
      subjects with NHL, including relapsed and/or refractory (R/R) CLL and R/R MCL.
Phase 1, open-label, dose-finding and cohort expansion study to determine the preliminary
      safety, tolerability, and pharmacokinetic (PK) profile of APR-246 (eprenetapopt) in
      combination with either acalabrutinib or venetoclax + rituximab therapy in subjects with NHL,
      including relapsed and/or refractory (R/R) CLL and R/R MCL.

      The study includes a safety lead-in portion followed by an expansion portion in subjects with
      R/R CLL, Richter Transformation (RT), and R/R MCL.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Single (Participant)
measure: To determine the DLT of APR-246 in combination with acalabrutinib or in combination with venetoclax + rituximab therapy in subjects with NHL, including subjects with R/R CLL, RT and R/R MCL.
time frame: Through study completion, approximately 1 year
description: The occurrence of DLTs, classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events .
measure: To assess the frequency of treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy.
time frame: Through study completion, approximately 1 year
description: The frequency of TEAEs and SAEs related to APR-246 in combination with acalabrutinib and with venetoclax + rituximab therapy
measure: To determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) in subjects with TP53 mutant NHL, including subjects with R/R CLL, RT and R/R MCL.
time frame: Through study completion, approximately 1 year
description: The highest dose of APR-246 with acceptable toxicity (RP2D of APR-246) (the dose producing ≤ 20% of DLT).
arm group label: Safety Lead-In Cohort 1
arm group type: Experimental
description: APR-246 + Acalabrutinib in Subjects with R/R CLL.
arm group label: Safety Lead-In Cohort 2
arm group type: Experimental
description: APR-246 + Venetoclax + Rituximab in Subjects with R/R CLL.
arm group label: Expansion Cohorts
arm group type: Experimental
description: APR-246 + (Acalabrutinib, OR, (Ven+R)) in Subjects with R/R TP53-mutant CLL, and/or MCL, and/or RT
arm group label: Safety Lead-In Cohort 3
arm group type: Experimental
description: APR-246 + Venetoclax + Rituximab in Subjects with RT
intervention type: Drug
intervention name: APR-246 (eprenetapopt) + Acalabrutinib in CLL
description: APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule
arm group label: Safety Lead-In Cohort 1
intervention type: Drug
intervention name: APR-246 (eprenetapopt) + Venetoclax + Rituximab in CLL
description: APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule
arm group label: Safety Lead-In Cohort 2
intervention type: Drug
intervention name: APR-246 (eprenetapopt) + (Acalabrutinib, OR, (Venetoclax +Rituximab)), in CLL and/or MCL and/or RT
description: APR-246 D1, 8 and 15 of each cycle Acalabrutinib will be given at a standard dose and schedule Venetoclax and Rituxiab will be given at a standard dose and schedule
arm group label: Expansion Cohorts
intervention type: Drug
intervention name: APR-246 (eprenetapopt) + Venetoclax + Rituximab in RT
description: APR-246 D1, 8 and 15 of each cycle Venetoclax + Rituximab will be given at a standard dose and schedule
arm group label: Safety Lead-In Cohort 3
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Joachim Gullbo, MD
role: Study Director
affiliation: Theradex Oncology
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Leukemia
mesh term: Lymphoma, Non-Hodgkin
mesh term: Leukemia, Lymphoid
mesh term: Leukemia, Lymphocytic, Chronic, B-Cell
mesh term: Lymphoma, Mantle-Cell
mesh term: Rituximab
mesh term: Venetoclax
mesh term: Acalabrutinib
sharing ipd: No