<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/NCT03834688</url>
  </required_header>
  <id_info>
    <org_study_id>PrE0405</org_study_id>
    <secondary_id>ML40551</secondary_id>
    <nct_id>NCT03834688</nct_id>
  </id_info>
  <brief_title>Phase II Study of Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma Over 60 Years of Age</brief_title>
  <acronym>PrE0405</acronym>
  <official_title>Phase II Study of Bendamustine and Rituximab Plus Venetoclax in Untreated Mantle Cell Lymphoma Over 60 Years of Age</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>PrECOG, LLC.</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Genentech, Inc.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>PrECOG, LLC.</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>
      Eligible untreated patients will receive single arm venetoclax, bendamustine and rituximab as&#xD;
      induction therapy. After 6 cycles, maintenance rituximab may be administered per physician&#xD;
      discretion.&#xD;
&#xD;
      Venetoclax is an oral Bcl-2 family protein inhibitor. It targets the B-cell lymphoma 2&#xD;
      (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with&#xD;
      mantle cell lymphoma. Venetoclax may make the cancer cells sensitive to chemotherapy. This&#xD;
      may help to slow down the growth of cancer or may cause cancer cells to die.&#xD;
&#xD;
      The purpose of this study is to see if venetoclax in combination with bendamustine and&#xD;
      rituximab chemotherapy is effective in treating people who have mantle cell lymphoma and to&#xD;
      examine the side effects, good and bad, associated with this combination.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin Lymphoma (NHL) which is considered&#xD;
      incurable with conventional therapy. With an incidence of approximately 70,000 cases&#xD;
      diagnosed in the United States (US) per year, the disease is rare.&#xD;
&#xD;
      This is an open-label phase II study of venetoclax in combination with bendamustine and&#xD;
      rituximab. Patients will receive induction therapy with venetoclax, bendamustine and&#xD;
      rituximab for six cycles (1 cycle = 28 days). There will be an interim analysis after 19&#xD;
      patients are enrolled to evaluate for tumor lysis syndrome (TLS). TLS is caused by the fast&#xD;
      breakdown of cancer cells which can lead to electrolyte and kidney problems.&#xD;
&#xD;
      Tumor assessments will be performed after Cycle 3-4 and at end of induction therapy.&#xD;
&#xD;
      Mandatory pre-treatment tumor tissue sample (i.e., obtained in the course of standard biopsy&#xD;
      or surgery) will be required for research (if sufficient tissue is available).&#xD;
&#xD;
      Mandatory bone marrow aspirate (obtained in the course of standard biopsy) and peripheral&#xD;
      blood sample will be collected at the end of treatment for Minimal Residual Disease (MRD).&#xD;
      MRD measures the disease remaining after treatment. Optional peripheral blood samples will&#xD;
      also be collected for future research.&#xD;
&#xD;
      10/11/2021: Due to slower than anticipated enrollment, the study was redesigned to reflect&#xD;
      the current historical complete response rate and with a lowered sample size for prompt&#xD;
      primary endpoint readout.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">January 13, 2020</start_date>
  <completion_date type="Anticipated">November 2024</completion_date>
  <primary_completion_date type="Actual">October 20, 2022</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>
    <intervention_model_description>Open-Label, Single-Arm Study, Cycle 1 Dose Escalation</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Complete Response (CR) rate at end of induction</measure>
    <time_frame>8 months</time_frame>
    <description>CR assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with treatment-related adverse events as assessed by CTCAE v5.0</measure>
    <time_frame>8 months</time_frame>
    <description>Number of participants with abnormal laboratory values and/or adverse events with particular attention to TLS related to treatment</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Response Rate (ORR)</measure>
    <time_frame>8 months</time_frame>
    <description>ORR assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-Free Survival (PFS)</measure>
    <time_frame>57 months</time_frame>
    <description>PFS assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>57 months</time_frame>
    <description>OS assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">33</enrollment>
  <condition>Mantle Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>Induction</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Venetoclax, bendamustine and rituximab as induction therapy for 6 cycles of 28 days.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Venetoclax</intervention_name>
    <description>Cycle 1: Venetoclax by mouth daily. The dose will gradually increase during Cycle 1. (Day 1-7: 20 mg; Day 8-14: 50 mg; Day 15-21: 100 mg; Day 22-28: 200 mg.)&#xD;
Cycles 2-6: Venetoclax 400 mg by mouth daily on Days 1-10 (1 cycle = 28 days).</description>
    <arm_group_label>Induction</arm_group_label>
    <other_name>GDC-0199</other_name>
    <other_name>ABT-199</other_name>
    <other_name>RO5537382</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bendamustine</intervention_name>
    <description>Cycle 1-6: Bendamustine 90 mg/m² intravenous (IV) on Days 1 and 2 of each cycle. Bendamustine may be started at 70 mg/m² in patients over the age of 75 years with comorbid conditions or patients over the age of 80 years without comorbid conditions.</description>
    <arm_group_label>Induction</arm_group_label>
    <other_name>Bendamustine hydrochloride</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <description>Cycle 1-6: Rituximab 375 mg/m² IV on Day 1 of each cycle. After 2 consecutive cycles of Rituximab IV are well tolerated, Rituximab may be given subcutaneously.</description>
    <arm_group_label>Induction</arm_group_label>
    <other_name>Chimeric anti-CD20 monoclonal antibody</other_name>
    <other_name>Rituxan</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients must have histologically confirmed (biopsy-proven) diagnosis of mantle cell&#xD;
             lymphoma (MCL), with documented cyclin D1 (BCL1) expression by immunohistochemical&#xD;
             stains and/or t(11;14) by cytogenetics or FISH.&#xD;
&#xD;
          -  Patients must have measurable or evaluable disease as defined as a lymph node&#xD;
             measuring &gt;1.5 cm in any dimension or splenomegaly with spleen &gt;15 cm in craniocaudal&#xD;
             dimension.&#xD;
&#xD;
          -  Age ≥ 60 years.&#xD;
&#xD;
          -  No intention to undergo consolidation with high dose chemotherapy and autologous stem&#xD;
             cell rescue (Autologous Stem Cell Transplant) in first remission.&#xD;
&#xD;
          -  ECOG performance status of 0-2.&#xD;
&#xD;
          -  Ability to understand and willingness to sign Institutional Review Board&#xD;
             (IRB)-approved informed consent.&#xD;
&#xD;
          -  Willing to provide mandatory tissue samples (if sufficient tissue available), bone&#xD;
             marrow and blood samples for research purposes.&#xD;
&#xD;
          -  Adequate organ function as measured by the following criteria, obtained ≤ 2 weeks&#xD;
             prior to registration:&#xD;
&#xD;
               -  Absolute Neutrophil Count (ANC) ≥ 1000/mm³&#xD;
&#xD;
               -  Hemoglobin ≥ 8 g/dL&#xD;
&#xD;
               -  Platelets ˃75,000/mm³&#xD;
&#xD;
               -  Creatinine clearance ≥ 40 mL/min, calculated with the use of 24-hour creatinine&#xD;
                  clearance or by Cockcroft-Gault formula&#xD;
&#xD;
               -  Total Bilirubin ≤ 1.5x Upper Limit of Normal (ULN) or ≤ 3x ULN for patients with&#xD;
                  documented Gilbert's syndrome&#xD;
&#xD;
               -  Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) ≤ 2.5x ULN&#xD;
&#xD;
          -  All females of childbearing potential (not surgically sterilized and between menarche&#xD;
             and 1 year post menopause) must have a blood test to rule out pregnancy within 2 weeks&#xD;
             prior to registration.&#xD;
&#xD;
          -  Women must not be pregnant or breastfeeding. Females of childbearing potential who are&#xD;
             sexually active with a non-sterilized male partner and sexually active men must agree&#xD;
             to use 2 methods of adequate contraception (hormonal plus barrier or 2 barrier forms)&#xD;
             prior to study entry, for the duration of study participation, and for 12 months after&#xD;
             last dose of therapy. Method of contraception must be documented.&#xD;
&#xD;
          -  Patients should not have prior chemotherapy, radiotherapy or immunotherapy for&#xD;
             lymphoma.&#xD;
&#xD;
          -  Patients must have no recent (&lt;1 year) history of malignancy except for the following:&#xD;
&#xD;
               -  adequately treated non-melanoma skin cancer&#xD;
&#xD;
               -  adequately treated Stage I melanoma of the skin&#xD;
&#xD;
               -  in situ cervical cancer&#xD;
&#xD;
               -  low grade prostate adenocarcinoma (Gleason grade ≤ 6) managed with observation&#xD;
                  and stable for 6 months.&#xD;
&#xD;
          -  Patients should not have known evidence of central nervous system (CNS) lymphoma.&#xD;
&#xD;
          -  Patients must not have received a prior allogeneic stem cell transplant or solid organ&#xD;
             transplant (except for cornea) for any indication.&#xD;
&#xD;
          -  Patients must have no active, uncontrolled infections.&#xD;
&#xD;
          -  Patients must not have active hepatitis B or be chronic carriers of hepatitis B. This&#xD;
             is defined as patients with hepatitis B surface antigen (HBsAg) positive. Patients&#xD;
             with prior exposure to hepatitis B (hepatitis B core antibody (anti-HBc) positive AND&#xD;
             HBsAg negative) are allowed with a protective level hepatitis B surface antibody AND a&#xD;
             negative hepatitis B viral load by polymerase-chain reaction (PCR).&#xD;
&#xD;
          -  Patients must not have active hepatitis C (HCV) as defined by a hepatitis C viral load&#xD;
             detectable by PCR. Patients with a negative HCV antibody are assumed to have a&#xD;
             negative HCV viral load. Patients with a positive HCV antibody must have a negative&#xD;
             hepatitis C viral load by PCR. Prior treatment for an active HCV infection will be&#xD;
             allowed as long as the hepatitis C viral load by PCR is negative.&#xD;
&#xD;
          -  Patients must not have known active Human Immunodeficiency Virus (HIV). Testing not&#xD;
             required in absence of clinical suspicion.&#xD;
&#xD;
          -  Patients must not have evidence of significant, uncontrolled concomitant diseases,&#xD;
             including psychiatric diseases, that could affect compliance with the protocol or&#xD;
             interpretation of results or that could increase risk to the patient.&#xD;
&#xD;
          -  Patients must not have conditions that preclude oral administration or absorption of&#xD;
             medications through the GI tract, including but not limited to the inability to&#xD;
             swallow pills or malabsorption syndromes.&#xD;
&#xD;
          -  Patients must not have known allergies to both xanthine oxidase inhibitors and&#xD;
             rasburicase.&#xD;
&#xD;
          -  Patients must not require the use of warfarin. Blood thinners of other classes are&#xD;
             permitted.&#xD;
&#xD;
          -  Patient may not receive the following agents within 7 days prior to the first dose of&#xD;
             venetoclax:&#xD;
&#xD;
               -  Strong and moderate CYP3A inhibitors&#xD;
&#xD;
               -  Strong and moderate CYP3A inducers&#xD;
&#xD;
               -  Strong and moderate P-gp inhibitors&#xD;
&#xD;
          -  Patients must not have consumed grapefruit, grapefruit products, Seville oranges&#xD;
             (including marmalade containing Seville oranges), or star fruit within 3 days prior to&#xD;
             the first dose of venetoclax.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>60 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Craig Portell, MD</last_name>
    <role>Study Chair</role>
    <affiliation>University of Virginia</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Carle Cancer Center</name>
      <address>
        <city>Urbana</city>
        <state>Illinois</state>
        <zip>61801</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Indiana University Simon Cancer Center</name>
      <address>
        <city>Indianapolis</city>
        <state>Indiana</state>
        <zip>46202</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>St. Joseph Mercy Hospital Cancer Care Center</name>
      <address>
        <city>Ann Arbor</city>
        <state>Michigan</state>
        <zip>48106</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Mayo Clinic</name>
      <address>
        <city>Rochester</city>
        <state>Minnesota</state>
        <zip>55905</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Washington University School of Medicine Siteman Cancer Center</name>
      <address>
        <city>Saint Louis</city>
        <state>Missouri</state>
        <zip>63110</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rutgers Cancer Institute of New Jersey</name>
      <address>
        <city>New Brunswick</city>
        <state>New Jersey</state>
        <zip>08903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Penn State Cancer Institute</name>
      <address>
        <city>Hershey</city>
        <state>Pennsylvania</state>
        <zip>17033</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Reading Hospital/McGlinn Cancer Institute</name>
      <address>
        <city>West Reading</city>
        <state>Pennsylvania</state>
        <zip>19611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of Virginia Health System</name>
      <address>
        <city>Charlottesville</city>
        <state>Virginia</state>
        <zip>22903</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Gundersen Health System</name>
      <address>
        <city>La Crosse</city>
        <state>Wisconsin</state>
        <zip>54601</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>November 2022</verification_date>
  <study_first_submitted>February 6, 2019</study_first_submitted>
  <study_first_submitted_qc>February 6, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 8, 2019</study_first_posted>
  <last_update_submitted>November 10, 2022</last_update_submitted>
  <last_update_submitted_qc>November 10, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">November 14, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Venetoclax</keyword>
  <keyword>Bendamustine</keyword>
  <keyword>Rituximab</keyword>
  <keyword>Bcl-2 Family Protein Inhibitor</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</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>Bendamustine Hydrochloride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
    <ipd_description>Data is proprietary</ipd_description>
  </patient_data>
  <pending_results>
    <submitted>September 8, 2023</submitted>
  </pending_results>
  <!-- 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/NCT03834688
org study id: PrE0405
secondary id: ML40551
nct id: NCT03834688
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
Eligible untreated patients will receive single arm venetoclax, bendamustine and rituximab as
      induction therapy. After 6 cycles, maintenance rituximab may be administered per physician
      discretion.

      Venetoclax is an oral Bcl-2 family protein inhibitor. It targets the B-cell lymphoma 2
      (BCL-2) protein, which supports cancer cell growth and is overexpressed in many patients with
      mantle cell lymphoma. Venetoclax may make the cancer cells sensitive to chemotherapy. This
      may help to slow down the growth of cancer or may cause cancer cells to die.

      The purpose of this study is to see if venetoclax in combination with bendamustine and
      rituximab chemotherapy is effective in treating people who have mantle cell lymphoma and to
      examine the side effects, good and bad, associated with this combination.
Mantle cell lymphoma (MCL) is a subtype of Non-Hodgkin Lymphoma (NHL) which is considered
      incurable with conventional therapy. With an incidence of approximately 70,000 cases
      diagnosed in the United States (US) per year, the disease is rare.

      This is an open-label phase II study of venetoclax in combination with bendamustine and
      rituximab. Patients will receive induction therapy with venetoclax, bendamustine and
      rituximab for six cycles (1 cycle = 28 days). There will be an interim analysis after 19
      patients are enrolled to evaluate for tumor lysis syndrome (TLS). TLS is caused by the fast
      breakdown of cancer cells which can lead to electrolyte and kidney problems.

      Tumor assessments will be performed after Cycle 3-4 and at end of induction therapy.

      Mandatory pre-treatment tumor tissue sample (i.e., obtained in the course of standard biopsy
      or surgery) will be required for research (if sufficient tissue is available).

      Mandatory bone marrow aspirate (obtained in the course of standard biopsy) and peripheral
      blood sample will be collected at the end of treatment for Minimal Residual Disease (MRD).
      MRD measures the disease remaining after treatment. Optional peripheral blood samples will
      also be collected for future research.

      10/11/2021: Due to slower than anticipated enrollment, the study was redesigned to reflect
      the current historical complete response rate and with a lowered sample size for prompt
      primary endpoint readout.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Open-Label, Single-Arm Study, Cycle 1 Dose Escalation
primary purpose: Treatment
masking: None (Open Label)
measure: Complete Response (CR) rate at end of induction
time frame: 8 months
description: CR assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
measure: Number of participants with treatment-related adverse events as assessed by CTCAE v5.0
time frame: 8 months
description: Number of participants with abnormal laboratory values and/or adverse events with particular attention to TLS related to treatment
measure: Overall Response Rate (ORR)
time frame: 8 months
description: ORR assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
measure: Progression-Free Survival (PFS)
time frame: 57 months
description: PFS assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
measure: Overall Survival (OS)
time frame: 57 months
description: OS assessed in accordance with Lymphoma Response Criteria (Cheson Criteria)
arm group label: Induction
arm group type: Experimental
description: Venetoclax, bendamustine and rituximab as induction therapy for 6 cycles of 28 days.
intervention type: Drug
intervention name: Venetoclax
description: Cycle 1: Venetoclax by mouth daily. The dose will gradually increase during Cycle 1. (Day 1-7: 20 mg; Day 8-14: 50 mg; Day 15-21: 100 mg; Day 22-28: 200 mg.)
Cycles 2-6: Venetoclax 400 mg by mouth daily on Days 1-10 (1 cycle = 28 days).
arm group label: Induction
other name: GDC-0199
other name: ABT-199
other name: RO5537382
intervention type: Drug
intervention name: Bendamustine
description: Cycle 1-6: Bendamustine 90 mg/m² intravenous (IV) on Days 1 and 2 of each cycle. Bendamustine may be started at 70 mg/m² in patients over the age of 75 years with comorbid conditions or patients over the age of 80 years without comorbid conditions.
arm group label: Induction
other name: Bendamustine hydrochloride
intervention type: Drug
intervention name: Rituximab
description: Cycle 1-6: Rituximab 375 mg/m² IV on Day 1 of each cycle. After 2 consecutive cycles of Rituximab IV are well tolerated, Rituximab may be given subcutaneously.
arm group label: Induction
other name: Chimeric anti-CD20 monoclonal antibody
other name: Rituxan
criteria: 
gender: All
minimum age: 60 Years
maximum age: N/A
healthy volunteers: No
last name: Craig Portell, MD
role: Study Chair
affiliation: University of Virginia
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Mantle-Cell
mesh term: Rituximab
mesh term: Venetoclax
mesh term: Bendamustine Hydrochloride
sharing ipd: No
ipd description: Data is proprietary
submitted: September 8, 2023