<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/NCT03295240</url>
  </required_header>
  <id_info>
    <org_study_id>17-216</org_study_id>
    <nct_id>NCT03295240</nct_id>
  </id_info>
  <brief_title>The Study of Bendamustine, Rituximab, Ibrutinib, and Venetoclax in Relapsed, Refractory Mantle Cell Lymphoma</brief_title>
  <official_title>Phase I Study of Bendamustine, Rituximab, Ibrutinib, and Venetoclax in Relapsed, Refractory Mantle Cell Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Memorial Sloan Kettering Cancer Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Memorial Sloan Kettering Cancer Center</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to test the safety of Venetoclax in combination with FDA&#xD;
      approved treatments Bendamustine, Rituximab and Ibrutinib (BR-I). This study will examine the&#xD;
      effects Venetoclax has on participants when it is given in combination with BR-I.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">September 20, 2017</start_date>
  <completion_date type="Anticipated">September 20, 2024</completion_date>
  <primary_completion_date type="Anticipated">September 20, 2024</primary_completion_date>
  <phase>Early Phase 1</phase>
  <study_type>Interventional</study_type>
  <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>Maximum tolerated dose</measure>
    <time_frame>1 year</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Treatment related toxicity evaluated using CTCAE v4.0</measure>
    <time_frame>1 years</time_frame>
    <description>Participants symptoms will be evaluated using CTCAE v4.0</description>
  </primary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Mantle Cell Lymphoma</condition>
  <condition>Lymphoma</condition>
  <arm_group>
    <arm_group_label>BR-I in combination with VEN</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The BR-I (bendamustine, rituximab, ibrutinib) regimen will be administered in combination with VEN (Venetoclax).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>BR-I (bendamustine, rituximab, ibrutinib)</intervention_name>
    <description>The BR-I (bendamustine, rituximab, ibrutinib) regimen will be administered for six 28-day cycles: bendamustine (90 mg/m2; (or 70mg/m2 for dose level -1); day 1 and 2 ), rituximab (375 mg/m2; day 1), and ibrutinib one pill or four 140mg capsules (560 mg oral daily; day 1-28).</description>
    <arm_group_label>BR-I in combination with VEN</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>VEN (Venetoclax)</intervention_name>
    <description>The initial cycle 1 VEN (Venetoclax) dose ramp-up will be: 20 mg daily for 1 week, 50 mg daily for week 2, 100 mg daily for week 3, and 200 mg daily for week 4. Thereafter, VEN will be administered at a fixed dose level of 400 mg daily for varying durations of each 28-day cycle. Now also include a -2 dose level which has the reduced 3-day duration of Ventoclax 400 mg daily.</description>
    <arm_group_label>BR-I in combination with VEN</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age greater than or equal to 18 years&#xD;
&#xD;
          -  Histologically confirmed MCL&#xD;
&#xD;
          -  Relapse, refractory or progressive disease following at least 1 line of systemic&#xD;
             therapy for mantle cell lymphoma&#xD;
&#xD;
          -  ECOG Performance Status &lt;/= 2&#xD;
&#xD;
          -  Patients must have completed anticancer treatment with chemotherapy, small molecule&#xD;
             inhibitors, immune modulator drugs, biologics, and/or treatment with other anticancer&#xD;
             agents at least 3 weeks prior treatment, or 2 weeks if progressing, and recovered from&#xD;
             clinically significant toxicity associated with treatment&#xD;
&#xD;
             ° Palliative radiotherapy must have been discontinued at least 1 week prior to&#xD;
             treatment in this study&#xD;
&#xD;
          -  Short-course corticosteroids are allowed (≤ 10 days) and must be discontinued prior to&#xD;
             study treatment start (Cycle 1, Day 1)&#xD;
&#xD;
             ° Ongoing administration of a stable dose of corticosteroid therapy (equivalent to ≤&#xD;
             30 mg prednisone daily and previously received for ≥ 30 days) is permissible provided&#xD;
             there is evidence of measurable disease and there will be no increase in steroid dose&#xD;
             during the clinical trial&#xD;
&#xD;
          -  Patients who have been previously treated with BR or Bendamustine alone are eligible,&#xD;
             provided they did not progress during treatment or within 6 months of completing BR or&#xD;
             B treatment&#xD;
&#xD;
          -  Patients who have been previously treated with ibrutinib or acalabrutinib (or any&#xD;
             alternate BTK-inhibitor) are eligible, provided they had evidence of response (at&#xD;
             least Stable Disease, Partial Response, or Complete Response) and did not progress&#xD;
             within 6 months of treatment initiation&#xD;
&#xD;
          -  Female subject of childbearing potential should have a negative urine or serum&#xD;
             pregnancy within 2 weeks prior to receiving the first dose of study medication. If the&#xD;
             urine test is positive or cannot be confirmed as negative, a serum pregnancy test will&#xD;
             be required.&#xD;
&#xD;
          -  A positive serum pregnancy test due to fertility preservation will not be an exclusion&#xD;
             after physician review&#xD;
&#xD;
          -  Adequate organ function and laboratory values within the following ranges:&#xD;
&#xD;
          -  Absolute neutrophil count &gt; 1,000 cells/mm3 (1.0 x 109L), if neutropenia is due to&#xD;
             bone marrow involvement absolute neutrophil count must be &gt;/= 500 cells.mm3 (0.5 x&#xD;
             10^9/L)&#xD;
&#xD;
          -  Platelet count &gt; 75,000 cells/mm3 (75 x 109/L), unless thrombocytopenia is due to bone&#xD;
             marrow involvement platelet count must be greater than 25,000 cells/mm3&#xD;
&#xD;
          -  Hemoglobin &gt; 8.0 g/dL&#xD;
&#xD;
          -  Serum aspartate transaminase (AST) and alanine transaminase (ALT) &lt;/= 2.5 x upper&#xD;
             limit of normal (ULN)&#xD;
&#xD;
          -  Estimate creatinine clearance (Cockcroft-Gault) &gt;/= 40 mL/min. If creatinine clearance&#xD;
             is &lt; 40 mL/min, but the serum creatinine is within institutional normal limits, the&#xD;
             patient will be eligible&#xD;
&#xD;
          -  Bilirubin &lt;1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of&#xD;
             non-hepatic origin)&#xD;
&#xD;
          -  For women of childbearing potential:&#xD;
&#xD;
               -  Agreement to remain abstinent (refrain from heterosexual intercourse) or use a&#xD;
                  contraceptive method with a failure rate of &lt; 1% per year during the treatment&#xD;
                  period and for at least 30 days afte rthe last dose of venetoclax or 18 months&#xD;
                  after the last dose of rituximab, whichever is longer&#xD;
&#xD;
               -  Examples of contraceptive methods with a failure rate of &lt; 1% per years include&#xD;
                  bilateral tubal ligation, male sterilization, hormonal contraceptives that&#xD;
                  inhibit ovulation, hormone-releasing intrauterine devices, and copper&#xD;
                  intrauterine devices&#xD;
&#xD;
               -  A woman is considered to be of childbearing potential if she is postmenarcheal,&#xD;
                  has not reached a postmenopausal state (&gt;/= 12 continuous months of amenorrhea&#xD;
                  with no identified cause other than menopause), and has not undergone surgical&#xD;
                  sterilization (removal of ovaries and/or uterus)&#xD;
&#xD;
          -  For men:&#xD;
&#xD;
               -  Agreement to remain abstinent (refrain from heterosexual intercourse) or use&#xD;
                  contraceptive measures, and agreement to refrain from donating sperm, as defined&#xD;
                  below&#xD;
&#xD;
               -  With female partners of childbearing potential, men must remain abstinent or use&#xD;
                  a condom plus an additional contraceptive method that together result in a&#xD;
                  failure rate of &lt;1% per year during the treatment period and for at least 6&#xD;
                  months after the last dose of rituximab. Men must refrain from donating sperm&#xD;
                  during this same period.&#xD;
&#xD;
               -  With pregnant female partners, men must remain abstinent or use a condom during&#xD;
                  the treatment period and for at least 6 months after the last dose of rituximab&#xD;
                  to avoid exposing the embryo&#xD;
&#xD;
               -  The reliability of sexual abstinence should be evaluated in relation to the&#xD;
                  duration of the clinical trial and the preferred and usual lifestyle of the&#xD;
                  patient. Periodic abstinence (e.g. calendar, ovulation, symptothermal, or&#xD;
                  postovulation methods) and withdrawal are not acceptable methods of contraception&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior therapy with venetoclax or alternate BCL-2 inhibitor&#xD;
&#xD;
          -  Any life-threatening illness, medical condition, or organ system dysfunction that, in&#xD;
             the opinion of the investigator, could compromise the subject's safety or put the&#xD;
             study outcomes at undue risk.&#xD;
&#xD;
          -  Unable to swallow capsules or tablets, malabsorption syndrome, disease significantly&#xD;
             affecting gastrointestinal function, resection of the stomach or small bowel,&#xD;
             symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete&#xD;
             bowel obstruction or other condition that precludes enteral route of administration&#xD;
&#xD;
          -  Cerebral/meningeal disease related to the underlying malignancy. Patients with a&#xD;
             history of cerebral/meningeal disease related to the underlying malignancy are allowed&#xD;
             if prior central nervous system disease has been definitively treated with no evidence&#xD;
             of disease or requirement for steroids&#xD;
&#xD;
          -  Active HIV or hepatitis B or C with positive viral load, requiring anti-viral therapy&#xD;
&#xD;
          -  Bleeding diathesis or use of warfarin or other vitamin K antagonist&#xD;
&#xD;
          -  Prior history of infusion reactions or hypersensitivity to any of the study drugs&#xD;
&#xD;
          -  Active concurrent malignancy requiring active therapy&#xD;
&#xD;
          -  Pregnant or lactating females&#xD;
&#xD;
          -  Prior autologous stem cell transplant within 90 days of study start&#xD;
&#xD;
          -  Prior allogenic stem cell transplant within 12 months of study start&#xD;
&#xD;
               -  Patients with active graft-versus-host-disease are not eligible&#xD;
&#xD;
               -  Patients receiving immunosuppressive therapy for prevention of&#xD;
                  graft-versus-host-disease are not eligible&#xD;
&#xD;
          -  Patients who requires treatment with a potent cytochrome P450 (CYP) 3A inhibitor or&#xD;
             inducer&#xD;
&#xD;
          -  Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection&#xD;
             (excluding fungal infections of nail beds) at study enrollment, or any major episode&#xD;
             of infection requiring treatment with IV antibiotics or hospitalization (relating to&#xD;
             the completion of the course of antibiotics) within 2 weeks prior to Cycle 1, Day 1&#xD;
&#xD;
          -  Clinically significant history of liver disease, including viral or other hepatitis,&#xD;
             current alcohol abuse, or cirrhosis&#xD;
&#xD;
          -  Receipt of live-virus vaccines within 28 days prior to the initiation of study&#xD;
             treatment or need for live-virus vaccines at any time during study treatment&#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>Anita Kumar</last_name>
    <role>Principal Investigator</role>
    <affiliation>Memorial Sloan Kettering Cancer Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Basking Ridge</name>
      <address>
        <city>Basking Ridge</city>
        <state>New Jersey</state>
        <zip>07920</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Monmouth</name>
      <address>
        <city>Middletown</city>
        <state>New Jersey</state>
        <zip>07748</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Bergen</name>
      <address>
        <city>Montvale</city>
        <state>New Jersey</state>
        <zip>07645</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Commack</name>
      <address>
        <city>Commack</city>
        <state>New York</state>
        <zip>11725</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Memorial Sloan Kettering Westchester</name>
      <address>
        <city>Harrison</city>
        <state>New York</state>
        <zip>10604</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>Memorial Sloan Kettering Nassau</name>
      <address>
        <city>Uniondale</city>
        <state>New York</state>
        <zip>11553</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>http://www.mskcc.org</url>
    <description>Memorial Sloan Kettering Cancer Center</description>
  </link>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>September 25, 2017</study_first_submitted>
  <study_first_submitted_qc>September 26, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 27, 2017</study_first_posted>
  <last_update_submitted>June 29, 2023</last_update_submitted>
  <last_update_submitted_qc>June 29, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 3, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Mantle Cell Lymphoma</keyword>
  <keyword>MCL</keyword>
  <keyword>Lymphoma</keyword>
  <keyword>Venetoclax</keyword>
  <keyword>17-216</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>
  <!-- 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/NCT03295240
org study id: 17-216
nct id: NCT03295240
lead sponsor: 
is fda regulated drug: Yes
is fda regulated device: No
The purpose of this study is to test the safety of Venetoclax in combination with FDA
      approved treatments Bendamustine, Rituximab and Ibrutinib (BR-I). This study will examine the
      effects Venetoclax has on participants when it is given in combination with BR-I.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Maximum tolerated dose
time frame: 1 year
measure: Treatment related toxicity evaluated using CTCAE v4.0
time frame: 1 years
description: Participants symptoms will be evaluated using CTCAE v4.0
arm group label: BR-I in combination with VEN
arm group type: Experimental
description: The BR-I (bendamustine, rituximab, ibrutinib) regimen will be administered in combination with VEN (Venetoclax).
intervention type: Drug
intervention name: BR-I (bendamustine, rituximab, ibrutinib)
description: The BR-I (bendamustine, rituximab, ibrutinib) regimen will be administered for six 28-day cycles: bendamustine (90 mg/m2; (or 70mg/m2 for dose level -1); day 1 and 2 ), rituximab (375 mg/m2; day 1), and ibrutinib one pill or four 140mg capsules (560 mg oral daily; day 1-28).
arm group label: BR-I in combination with VEN
intervention type: Drug
intervention name: VEN (Venetoclax)
description: The initial cycle 1 VEN (Venetoclax) dose ramp-up will be: 20 mg daily for 1 week, 50 mg daily for week 2, 100 mg daily for week 3, and 200 mg daily for week 4. Thereafter, VEN will be administered at a fixed dose level of 400 mg daily for varying durations of each 28-day cycle. Now also include a -2 dose level which has the reduced 3-day duration of Ventoclax 400 mg daily.
arm group label: BR-I in combination with VEN
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Anita Kumar
role: Principal Investigator
affiliation: Memorial Sloan Kettering Cancer Center
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
url: http://www.mskcc.org
description: Memorial Sloan Kettering Cancer Center
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Lymphoma, Mantle-Cell
mesh term: Rituximab
mesh term: Venetoclax
mesh term: Bendamustine Hydrochloride