<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/NCT01661881</url>
  </required_header>
  <id_info>
    <org_study_id>12-168</org_study_id>
    <nct_id>NCT01661881</nct_id>
  </id_info>
  <brief_title>Rituximab/Bendamustine + Rituximab/Cytarabine for Mantle Cell Lymphoma</brief_title>
  <official_title>A Phase II Study of Rituximab/Bendamustine Followed by Rituximab/Cytarabine for Untreated Mantle Cell Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Dana-Farber Cancer Institute</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Massachusetts General Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Dana-Farber Cancer Institute</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Mantle cell lymphoma (MCL) is not curable with conventional therapy. This study sought to&#xD;
      improve upon standard of care in newly diagnosed, untreated MCL patients who were&#xD;
      transplant-eligible using drugs already established as active in MCL. The combination of&#xD;
      Rituximab-Bendamustine followed by Rituximab-Cytarabine (RB/RC) was expected to maximize&#xD;
      pre-ASCT complete response (CR) rate compared to historical rates approximating 55% with&#xD;
      tolerable toxicity.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This was a PII single-arm design to determine whether the regimen looked promising for&#xD;
      further study.&#xD;
&#xD;
      Primary Objective&#xD;
&#xD;
      • To evaluate the efficacy of an alternating regimen of Rituximab-Bendamustine and&#xD;
      Rituximab-Cytarabine (RB/RC) using the CR/Cru rate.&#xD;
&#xD;
      Secondary Objectives&#xD;
&#xD;
        -  To assess safety.&#xD;
&#xD;
        -  To estimate the rate of complete remission (CR), unconfirmed CR (CRu), partial remission&#xD;
           (PR), stable disease (SD) and progressive disease (PD).&#xD;
&#xD;
        -  To estimate the rate of successful stem cell mobilization after RB/RC in responding&#xD;
           patients.&#xD;
&#xD;
        -  To estimate the proportion of patients who can successfully complete the regimen and&#xD;
           proceed to autologous stem cell transplantation (ASCT).&#xD;
&#xD;
        -  To estimate the rate of neutrophil and platelet engraftment after ASCT.&#xD;
&#xD;
        -  To estimate the CR/CRu and PR rate for patients with blastoid variant MCL.&#xD;
&#xD;
        -  To estimate the rate of minimal residual disease (MRD)-negativity at treatment&#xD;
           completion.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Active, not recruiting</overall_status>
  <start_date type="Actual">August 16, 2012</start_date>
  <completion_date type="Anticipated">March 2025</completion_date>
  <primary_completion_date type="Actual">February 2015</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>Complete Remission (CR) Rate After 6 Cycles</measure>
    <time_frame>Disease was assessed after three- and six-cycles of therapy, up to approximately 25 weeks. All patients completed 6 cycles of therapy with a cycle duration of 28 days.</time_frame>
    <description>The CR rate is defined as the proportion of patients who after 6 cycles of therapy achieve complete remission based on the International Working Group (IWG) Criteria (Cheson et al, 1999), using CT scans. CR or CRu (CR unconfirmed) by CT scans was defined by standard IWG criteria, ie resolution of all abnormal adenopathy and organomegaly, and clearance of marrow disease when present at baseline.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>1 Year Progression-Free Survival</measure>
    <time_frame>Disease was assessed after three- and six-cycles of therapy and in long-term follow-up per standard practice every 6 months until the earliest of relapse, death or 5 years. Median follow-up in this study cohort was 13 months.</time_frame>
    <description>1-year progression-free survival is the probability of patients remaining alive and progression-free at 1 year from study entry estimated using Kaplan-Meier methods. Disease progression was based on the International Working Group (IWG) Criteria (Cheson et al, 1999).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Autologous Stem Cell Transplant (ASCT) Rate</measure>
    <time_frame>All patients were followed for continuation to ASCT upon completion of induction therapy. Patients usually proceed to ASCT within 3 months of completing induction.</time_frame>
    <description>ASCT rate is the proportion of patients who completed therapy and proceeded to autologous stem cell transplant (ASCT)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">23</enrollment>
  <condition>Mantle Cell Lymphoma</condition>
  <arm_group>
    <arm_group_label>RB/RC</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity.&#xD;
Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Rituximab</intervention_name>
    <arm_group_label>RB/RC</arm_group_label>
    <other_name>Rituxan</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Bendamustine</intervention_name>
    <arm_group_label>RB/RC</arm_group_label>
    <other_name>Treanda</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <arm_group_label>RB/RC</arm_group_label>
    <other_name>Depocyt</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Mandatory pathologic review of the diagnostic specimen(s) at Brigham and Women's&#xD;
             Hospital or Massachusetts General Hospital&#xD;
&#xD;
          -  Measurable disease&#xD;
&#xD;
          -  Candidate for ASCT&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Prior anti-lymphoma therapy&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Hypersensitivity to rituximab&#xD;
&#xD;
          -  Uncontrolled intercurrent illness&#xD;
&#xD;
          -  Receiving other study agents&#xD;
&#xD;
          -  HIV positive on combination antiretroviral therapy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>69 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Philippe Armand, MD, PhD</last_name>
    <role>Study Chair</role>
    <affiliation>Dana-Farber Cancer Institute</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Massachusetts General Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02113</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Brigham and Women's Hospital</name>
      <address>
        <city>Boston</city>
        <state>Massachusetts</state>
        <zip>02215</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_countries>
    <country>United States</country>
  </location_countries>
  <results_reference>
    <citation>Armand P, Redd R, Bsat J, Mayuram S, Giardino A, Fisher DC, LaCasce AS, Jacobson C, Davids MS, Brown JR, Weng L, Wilkins J, Faham M, Freedman AS, Joyce R, Jacobsen ED. A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016 Apr;173(1):89-95. doi: 10.1111/bjh.13929. Epub 2016 Jan 5.</citation>
    <PMID>26729345</PMID>
  </results_reference>
  <results_reference>
    <citation>Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. doi: 10.1182/bloodadvances.2019001355.</citation>
    <PMID>32126141</PMID>
  </results_reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>July 15, 2012</study_first_submitted>
  <study_first_submitted_qc>August 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 10, 2012</study_first_posted>
  <results_first_submitted>September 15, 2016</results_first_submitted>
  <results_first_submitted_qc>November 15, 2016</results_first_submitted_qc>
  <results_first_posted type="Estimate">January 12, 2017</results_first_posted>
  <last_update_submitted>June 6, 2023</last_update_submitted>
  <last_update_submitted_qc>June 6, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Dana-Farber Cancer Institute</investigator_affiliation>
    <investigator_full_name>Philippe Armand, MD, PhD</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Newly diagnosed</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>Cytarabine</mesh_term>
    <mesh_term>Rituximab</mesh_term>
    <mesh_term>Bendamustine Hydrochloride</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Patients enrolled from August 2012 through March 2014.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>RB/RC</title>
          <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="23"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="22"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Disease Progression</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>RB/RC</title>
          <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="23"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="57" lower_limit="42" upper_limit="69"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="8"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>MIPI at Diagnosis</title>
          <description>The MIPI (Mantle Cell Lymphoma international prognostic index) (Hoster et al, 2008) is a risk index based on clinical characteristics (eg, LDH, white blood count, etc). Patients with higher MIPI scores tend to have a worse prognosis with frontline therapy.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <title>Low</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Intermediate</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>High</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Complete Remission (CR) Rate After 6 Cycles</title>
        <description>The CR rate is defined as the proportion of patients who after 6 cycles of therapy achieve complete remission based on the International Working Group (IWG) Criteria (Cheson et al, 1999), using CT scans. CR or CRu (CR unconfirmed) by CT scans was defined by standard IWG criteria, ie resolution of all abnormal adenopathy and organomegaly, and clearance of marrow disease when present at baseline.</description>
        <time_frame>Disease was assessed after three- and six-cycles of therapy, up to approximately 25 weeks. All patients completed 6 cycles of therapy with a cycle duration of 28 days.</time_frame>
        <population>The analysis dataset is comprised of all enrolled patients.</population>
        <group_list>
          <group group_id="O1">
            <title>RB/RC</title>
            <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study.</description>
          </group>
        </group_list>
        <measure>
          <title>Complete Remission (CR) Rate After 6 Cycles</title>
          <description>The CR rate is defined as the proportion of patients who after 6 cycles of therapy achieve complete remission based on the International Working Group (IWG) Criteria (Cheson et al, 1999), using CT scans. CR or CRu (CR unconfirmed) by CT scans was defined by standard IWG criteria, ie resolution of all abnormal adenopathy and organomegaly, and clearance of marrow disease when present at baseline.</description>
          <population>The analysis dataset is comprised of all enrolled patients.</population>
          <units>proportion of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".96" lower_limit=".81" upper_limit="1.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>1 Year Progression-Free Survival</title>
        <description>1-year progression-free survival is the probability of patients remaining alive and progression-free at 1 year from study entry estimated using Kaplan-Meier methods. Disease progression was based on the International Working Group (IWG) Criteria (Cheson et al, 1999).</description>
        <time_frame>Disease was assessed after three- and six-cycles of therapy and in long-term follow-up per standard practice every 6 months until the earliest of relapse, death or 5 years. Median follow-up in this study cohort was 13 months.</time_frame>
        <population>The analysis dataset is comprised of all enrolled patients.</population>
        <group_list>
          <group group_id="O1">
            <title>RB/RC</title>
            <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study.</description>
          </group>
        </group_list>
        <measure>
          <title>1 Year Progression-Free Survival</title>
          <description>1-year progression-free survival is the probability of patients remaining alive and progression-free at 1 year from study entry estimated using Kaplan-Meier methods. Disease progression was based on the International Working Group (IWG) Criteria (Cheson et al, 1999).</description>
          <population>The analysis dataset is comprised of all enrolled patients.</population>
          <units>probability</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".96" lower_limit=".73" upper_limit=".99"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Autologous Stem Cell Transplant (ASCT) Rate</title>
        <description>ASCT rate is the proportion of patients who completed therapy and proceeded to autologous stem cell transplant (ASCT)</description>
        <time_frame>All patients were followed for continuation to ASCT upon completion of induction therapy. Patients usually proceed to ASCT within 3 months of completing induction.</time_frame>
        <group_list>
          <group group_id="O1">
            <title>RB/RC</title>
            <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity. Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study.</description>
          </group>
        </group_list>
        <measure>
          <title>Autologous Stem Cell Transplant (ASCT) Rate</title>
          <description>ASCT rate is the proportion of patients who completed therapy and proceeded to autologous stem cell transplant (ASCT)</description>
          <units>proportion of participants</units>
          <param>Number</param>
          <dispersion>90% Confidence Interval</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="23"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value=".91" lower_limit=".75" upper_limit=".98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Assessed throughout the treatment period, from time of first dose and up to day 30 post-treatment, ie approximately 26 weeks. All patients received 6 cycles of therapy with protocol cycle duration of 28 days.</time_frame>
      <desc>Maximum grade toxicity by type was first calculated including only events with treatment-attribution of possible, probable or definite. Serious AEs and Other AEs were defined as treatment-related grade 3-5 events and grade 1-2 events, respectively, per CTCAEv4. No further data is available to specify classification of other beyond the general term.</desc>
      <group_list>
        <group group_id="E1">
          <title>RB/RC</title>
          <description>Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:&#xD;
2 g/m2 for age &gt;60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;&#xD;
1.5 g/m2 for age &gt;60 years old AND creatinine 114.9-176.8 lmol/l, or for age &gt;60 years old AND pre-existing neurotoxicity;&#xD;
1 g/m2 for age &gt; 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity.&#xD;
Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study.</description>
        </group>
      </group_list>
      <serious_events>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="15" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Thrombotic thrombocytopenic purpura</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Sepsis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Lymphocyte count decreased</sub_title>
                <counts group_id="E1" subjects_affected="11" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="8" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (4.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="23" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Blood and lymphatic system disorders</title>
            <event_list>
              <event>
                <sub_title>Anemia</sub_title>
                <counts group_id="E1" subjects_affected="12" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Febrile neutropenia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Eye disorders</title>
            <event_list>
              <event>
                <sub_title>Eye disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Constipation</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Diarrhea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Esophageal pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Mucositis oral</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="7" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Vomiting</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Gastrointestinal disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Edema limbs</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Fever</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Infusion related reaction</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Irritability</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Pain</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>General disorders and administration site conditions - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Immune system disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Infections and infestations</title>
            <event_list>
              <event>
                <sub_title>Mucosal infection</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Infections and infestations - Other</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Alkaline phosphatase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Aspartate aminotransferase increased</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Neutrophil count decreased</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Platelet count decreased</sub_title>
                <counts group_id="E1" subjects_affected="10" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>White blood cell decreased</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Investigations - Other</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Anorexia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Hyperglycemia</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Hyponatremia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Bone pain</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Psychiatric disorders</title>
            <event_list>
              <event>
                <sub_title>Insomnia</sub_title>
                <counts group_id="E1" subjects_affected="3" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Respiratory, thoracic and mediastinal disorders</title>
            <event_list>
              <event>
                <sub_title>Cough</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Dyspnea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Alopecia</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Pruritus</sub_title>
                <counts group_id="E1" subjects_affected="5" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Skin and subcutaneous tissue disorders - Other</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Hypotension</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
              <event>
                <sub_title>Phlebitis</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="23"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Philippe Armand MD, PhD</name_or_title>
      <organization>Dana-Farber Cancer Institute</organization>
      <phone>617.632.2305</phone>
      <email>Philippe_Armand@dfci.harvard.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01661881
org study id: 12-168
nct id: NCT01661881
lead sponsor: 
collaborator: 
has dmc: Yes
Mantle cell lymphoma (MCL) is not curable with conventional therapy. This study sought to
      improve upon standard of care in newly diagnosed, untreated MCL patients who were
      transplant-eligible using drugs already established as active in MCL. The combination of
      Rituximab-Bendamustine followed by Rituximab-Cytarabine (RB/RC) was expected to maximize
      pre-ASCT complete response (CR) rate compared to historical rates approximating 55% with
      tolerable toxicity.
This was a PII single-arm design to determine whether the regimen looked promising for
      further study.

      Primary Objective

      • To evaluate the efficacy of an alternating regimen of Rituximab-Bendamustine and
      Rituximab-Cytarabine (RB/RC) using the CR/Cru rate.

      Secondary Objectives

        -  To assess safety.

        -  To estimate the rate of complete remission (CR), unconfirmed CR (CRu), partial remission
           (PR), stable disease (SD) and progressive disease (PD).

        -  To estimate the rate of successful stem cell mobilization after RB/RC in responding
           patients.

        -  To estimate the proportion of patients who can successfully complete the regimen and
           proceed to autologous stem cell transplantation (ASCT).

        -  To estimate the rate of neutrophil and platelet engraftment after ASCT.

        -  To estimate the CR/CRu and PR rate for patients with blastoid variant MCL.

        -  To estimate the rate of minimal residual disease (MRD)-negativity at treatment
           completion.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Complete Remission (CR) Rate After 6 Cycles
time frame: Disease was assessed after three- and six-cycles of therapy, up to approximately 25 weeks. All patients completed 6 cycles of therapy with a cycle duration of 28 days.
description: The CR rate is defined as the proportion of patients who after 6 cycles of therapy achieve complete remission based on the International Working Group (IWG) Criteria (Cheson et al, 1999), using CT scans. CR or CRu (CR unconfirmed) by CT scans was defined by standard IWG criteria, ie resolution of all abnormal adenopathy and organomegaly, and clearance of marrow disease when present at baseline.
measure: 1 Year Progression-Free Survival
time frame: Disease was assessed after three- and six-cycles of therapy and in long-term follow-up per standard practice every 6 months until the earliest of relapse, death or 5 years. Median follow-up in this study cohort was 13 months.
description: 1-year progression-free survival is the probability of patients remaining alive and progression-free at 1 year from study entry estimated using Kaplan-Meier methods. Disease progression was based on the International Working Group (IWG) Criteria (Cheson et al, 1999).
measure: Autologous Stem Cell Transplant (ASCT) Rate
time frame: All patients were followed for continuation to ASCT upon completion of induction therapy. Patients usually proceed to ASCT within 3 months of completing induction.
description: ASCT rate is the proportion of patients who completed therapy and proceeded to autologous stem cell transplant (ASCT)
arm group label: RB/RC
arm group type: Experimental
description: Patients received 3 cycles of outpatient RB (rituximab 375 mg/m2 day 1, bendamustine 90 mg/m2 days 1 and 2 of a 4-week cycle), followed by interim CT restaging. Patients with progressive disease (PD) went off study. Those with stable disease (SD) or better went on to receive three cycles of inpatient RC (rituximab 375 mg/m2 day 1, cytarabine 3 g/m2 every 12 h for 4 doses). The cytarabine was dose reduced to:
2 g/m2 for age >60 years old, creatinine 114.9-176.8 lmol/l (for patients ≤60 years old), and pre-existing neurotoxicity;
1.5 g/m2 for age >60 years old AND creatinine 114.9-176.8 lmol/l, or for age >60 years old AND pre-existing neurotoxicity;
1 g/m2 for age > 60 years old AND creatinine 114.9-176.8 lmol/l AND pre-existing neurotoxicity.
Stem cell mobilization and collection, ASCT and post-transplantation supportive care were performed per institutional standard and not as part of this study.
intervention type: Drug
intervention name: Rituximab
arm group label: RB/RC
other name: Rituxan
intervention type: Drug
intervention name: Bendamustine
arm group label: RB/RC
other name: Treanda
intervention type: Drug
intervention name: Cytarabine
arm group label: RB/RC
other name: Depocyt
criteria: 
gender: All
minimum age: 18 Years
maximum age: 69 Years
healthy volunteers: No
last name: Philippe Armand, MD, PhD
role: Study Chair
affiliation: Dana-Farber Cancer Institute
facility: 
facility: 
facility: 
country: United States
citation: Armand P, Redd R, Bsat J, Mayuram S, Giardino A, Fisher DC, LaCasce AS, Jacobson C, Davids MS, Brown JR, Weng L, Wilkins J, Faham M, Freedman AS, Joyce R, Jacobsen ED. A phase 2 study of Rituximab-Bendamustine and Rituximab-Cytarabine for transplant-eligible patients with mantle cell lymphoma. Br J Haematol. 2016 Apr;173(1):89-95. doi: 10.1111/bjh.13929. Epub 2016 Jan 5.
PMID: 26729345
citation: Merryman RW, Edwin N, Redd R, Bsat J, Chase M, LaCasce A, Freedman A, Jacobson C, Fisher D, Ng S, Crombie J, Kim A, Odejide O, Davids MS, Brown JR, Jacene H, Cashen A, Bartlett NL, Mehta-Shah N, Ghobadi A, Kahl B, Joyce R, Armand P, Jacobsen E. Rituximab/bendamustine and rituximab/cytarabine induction therapy for transplant-eligible mantle cell lymphoma. Blood Adv. 2020 Mar 10;4(5):858-867. doi: 10.1182/bloodadvances.2019001355.
PMID: 32126141
responsible party type: Principal Investigator
investigator affiliation: Dana-Farber Cancer Institute
investigator full name: Philippe Armand, MD, PhD
investigator title: Principal Investigator
mesh term: Lymphoma
mesh term: Lymphoma, Mantle-Cell
mesh term: Cytarabine
mesh term: Rituximab
mesh term: Bendamustine Hydrochloride
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 