<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/NCT04463953</url>
  </required_header>
  <id_info>
    <org_study_id>BDH-WM2020/04</org_study_id>
    <nct_id>NCT04463953</nct_id>
  </id_info>
  <brief_title>Zanubrutinib, Ixazomib and Dexamethasone in Patients With Treatment Naive Waldenstrom's Macroglobulinemia</brief_title>
  <official_title>A Phase 2 Clinical Trial to Evaluate the Efficacy of Zanubrutinib Plus Ixazomib and Dexamethasone in Newly Diagnosed Symptomatic Waldenström Macroglobulinemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Institute of Hematology &amp; Blood Diseases Hospital, China</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Institute of Hematology &amp; Blood Diseases Hospital, China</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study aims to evaluate the efficacy of BTK inhibitor Zanubrutinib combined with Ixazomib&#xD;
      and Dexamethasone (ZID) for the newly diagnosed Waldenstrom Macroglobulinemia. This ZID&#xD;
      regimen will be given up to 24 months and stopped for observation. We propose this&#xD;
      combination will improve the deep remission (≥VGPR) compared to single Zanubrutinib or IRD&#xD;
      regimen and can be a time-limited regimen which will reduce the life-time therapy and benefit&#xD;
      the patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      As Waldenstrom Macroglobulinemia cells always have two or three components tumor cells,&#xD;
      including lymphocyte, Lymphoplasmacytic cells and plasma cells. We designed a oral regimen to&#xD;
      target both lymphoma cells (Zanubrutinib) and plasma cells (Ixazomib plus Dexamethasone) to&#xD;
      eliminate the tumor cells of WM. We propose this combination will improve the deep remission&#xD;
      of WM (≥VGPR) . Zanubrutinib will be given 160mg Bid per day, up to 24 months, Ixazomib 4mg&#xD;
      per week and Dexamethasone 20mg per week for three weeks, every 4 weeks one course. ID will&#xD;
      be given 6 course as introduction and then one course every 12 weeks for up to 24 months. At&#xD;
      the last ID course, Zanubrutinib will be stopped. The last ID course is to prevent the bounce&#xD;
      of IgM because of Zanubrutinib discontinue.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 20, 2020</start_date>
  <completion_date type="Anticipated">May 20, 2025</completion_date>
  <primary_completion_date type="Anticipated">May 20, 2023</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>Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15.</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Deep remission response rate</measure>
    <time_frame>up to 5 years</time_frame>
    <description>≥VGPR after 6 cycles introduction</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Complete response (CR)</measure>
    <time_frame>up to 12 months</time_frame>
    <description>Disappearance of monoclonal protein on immunofixation (both serum and urine); No histologic evidence of bone marrow involvement; Resolution of adenopathy and/or organomegaly on CT; Resolution of clinical signs or symptoms attributed to WM/LPL.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progress-free survival (PFS)</measure>
    <time_frame>up to 5 years</time_frame>
    <description>the time from treatment initiation until disease progression or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of response (DoR)</measure>
    <time_frame>up to 5 years</time_frame>
    <description>the time from best response (R) to progression/death (P/D)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>up to 36 months</time_frame>
    <description>The percentage of patients in treatment group who are still alive for a certain period of time after they were diagnosed with Waldenstrom's Macroglobulinemia.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to next treatment (TTNT)</measure>
    <time_frame>up to 5 years</time_frame>
    <description>time from end of primary treatment to institution of next therapy</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall response</measure>
    <time_frame>up to 5 year</time_frame>
    <description>minimor response+partial response+VGPR+CR</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">55</enrollment>
  <condition>Waldenström Macroglobulinemia</condition>
  <arm_group>
    <arm_group_label>ZID regimen</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Zanubrutinib,Ixazomib and Dexamethasone</intervention_name>
    <description>Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15；Ixazomib and dexamethasone every 4 weeks of a cycle, with induction of 6 cycles, and then maintain every 12 weeks, up to 6 cycles (96 cycles in total). Zanubrutinib is taken orally twice a day for up to 96 cycles, with a reduction in the last ID cycle. ZID regimen will continue 6 cycles after reaching the maximum response after introduction section.</description>
    <arm_group_label>ZID regimen</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. The gender of the patient is not limited, and the age is ≥18 years old;&#xD;
&#xD;
          2. Must meet WM's diagnostic standards;&#xD;
&#xD;
          3. The patient is an untreated or patient who has not undergone standard treatment. The&#xD;
             specific conditions are as follows:&#xD;
&#xD;
               1. No combined chemotherapy with BR, RCD, VRD, CHOP and COP&#xD;
&#xD;
               2. No treatment regimen containing fludarabine&#xD;
&#xD;
               3. Chlorambucil or cyclophosphamide for less than 4 weeks (alone or in combination&#xD;
                  with adrenal glucocorticoids)&#xD;
&#xD;
               4. The above treatment did not reach the treatment response (MR)&#xD;
&#xD;
               5. If the above treatment has been applied, the treatment needs to be stopped for 2&#xD;
                  weeks before entering the group to start treatment&#xD;
&#xD;
          4. The indications for the treatment of indolent lymphoma mainly include (at least one of&#xD;
             the following conditions):&#xD;
&#xD;
               1. Symptomatic hyperviscosity;&#xD;
&#xD;
               2. symptomatic peripheral neuropathy;&#xD;
&#xD;
               3. Amyloidosis;&#xD;
&#xD;
               4. Cold agglutinin disease; cryoglobulinemia;&#xD;
&#xD;
               5. Disease-related cytopenia (Hb&lt;100 g/L, PLT&lt;100×10^9/L);&#xD;
&#xD;
               6. giant lymph nodes;&#xD;
&#xD;
               7. Those with systemic systemic symptoms: for two weeks/recurrent fever (above 38℃)&#xD;
                  and not caused by infection, or Night sweats and/or weight loss &gt;10% within 6&#xD;
                  months;&#xD;
&#xD;
               8. The disease progresses rapidly, for example, the lymph nodes increase by more&#xD;
                  than 50% within 2 months, and/or peripheral blood lymphocytes absolute value&#xD;
                  doubling time &lt;6 months, and/or rapid hemoglobin or platelet non-autoimmune&#xD;
                  causes slow down&#xD;
&#xD;
               9. When there is evidence that the disease has transformed.&#xD;
&#xD;
          5. ECOG score ≤ 2 points&#xD;
&#xD;
          6. Laboratory examination: neutrophils ≥ 0.75×10^9/L; platelets ≥ 50×10^9/L; total&#xD;
             bilirubin ≤ 2.5 times upper limit; alanine aminotransferase/aspartate aminotransferase&#xD;
             ≤3 times upper limit. Creatinine clearance rate ≥ 30ml/min.&#xD;
&#xD;
          7. The patient's expected survival time is ≥ 3 months.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Malignant tumors (including active central nervous system lymphoma) other than B-NHL&#xD;
             have been diagnosed or treated within the past year;&#xD;
&#xD;
          2. There is clinical evidence that large cell lymphoma transformation has occurred;&#xD;
&#xD;
          3. Non-lymphoma-related liver and kidney damage: alanine aminotransferase (ALT)&gt; 3 times&#xD;
             the upper limit of normal value, aspartate aminotransferase (AST)&gt; 3 times the upper&#xD;
             limit of normal value, total bilirubin (TBIL)&gt; upper limit of normal value 2 Times,&#xD;
             serum creatinine clearance rate &lt;30ml/min;&#xD;
&#xD;
          4. Other serious medical conditions will affect the study (such as uncontrolled diabetes,&#xD;
             gastric ulcers, other serious cardiopulmonary diseases, etc.). The decision-making&#xD;
             power belongs to the researcher;&#xD;
&#xD;
          5. Known history of infection with human immunodeficiency virus (HIV) or active hepatitis&#xD;
             B virus (HBV) infection, or any uncontrolled active systemic infection requiring&#xD;
             intravenous antibiotics.&#xD;
&#xD;
          6. Central nervous system dysfunction with clinical manifestations or central invasion&#xD;
             (Bing-Neel syndrome);&#xD;
&#xD;
          7. Patients who have undergone major surgery (not including lymph node biopsy) within the&#xD;
             past 14 days or expected major surgery during treatment;&#xD;
&#xD;
          8. Inability to swallow capsules or suffer from malabsorption syndrome, diseases that&#xD;
             significantly affect gastrointestinal function, have undergone gastric or small bowel&#xD;
             resection, symptomatic inflammatory bowel disease or ulcerative colitis, partial or&#xD;
             complete intestinal obstruction.&#xD;
&#xD;
          9. Need to receive strong cytochrome P450 (CYP) 3A inhibitor treatment.&#xD;
&#xD;
         10. Women who are pregnant or breastfeeding, women of childbearing age who have not taken&#xD;
             contraception;&#xD;
&#xD;
         11. Allergy to the drugs used.&#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>Shuhua Yi</last_name>
    <role>Principal Investigator</role>
    <affiliation>Chinese Academy of Medical Sciences and Peking Union Medical College</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Shuhua Yi, Dr</last_name>
    <phone>86-22-23909106</phone>
    <email>yishuhua@ihcams.ac.cn</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Lugui Qiu, Dr</last_name>
    <phone>86-22-23909172</phone>
    <email>qiulg@ihcams.ac.cn</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Institute of Hematology &amp; Blood Diseases Hospital</name>
      <address>
        <city>Tianjin</city>
        <state>Tianjin</state>
        <zip>300020</zip>
        <country>China</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Shuhua Yi, Dr.</last_name>
      <phone>86-022-23909106</phone>
      <email>yishuhua@ihcams.ac.cn</email>
    </contact>
    <contact_backup>
      <last_name>Lugui Qiu, Dr.</last_name>
      <phone>86-022-23909286</phone>
      <email>qiulg@ihcams.ac.cn</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <reference>
    <citation>Treon SP, Xu L, Guerrera ML, Jimenez C, Hunter ZR, Liu X, Demos M, Gustine J, Chan G, Munshi M, Tsakmaklis N, Chen JG, Kofides A, Sklavenitis-Pistofidis R, Bustoros M, Keezer A, Meid K, Patterson CJ, Sacco A, Roccaro A, Branagan AR, Yang G, Ghobrial IM, Castillo JJ. Genomic Landscape of Waldenstrom Macroglobulinemia and Its Impact on Treatment Strategies. J Clin Oncol. 2020 Apr 10;38(11):1198-1208. doi: 10.1200/JCO.19.02314. Epub 2020 Feb 21.</citation>
    <PMID>32083995</PMID>
  </reference>
  <reference>
    <citation>Treon SP, Xu L, Hunter Z. MYD88 Mutations and Response to Ibrutinib in Waldenstrom's Macroglobulinemia. N Engl J Med. 2015 Aug 6;373(6):584-6. doi: 10.1056/NEJMc1506192. No abstract available.</citation>
    <PMID>26244327</PMID>
  </reference>
  <reference>
    <citation>Castillo JJ, Meid K, Gustine JN, Dubeau T, Severns P, Hunter ZR, Yang G, Xu L, Treon SP. Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenstrom Macroglobulinemia. Clin Cancer Res. 2018 Jul 15;24(14):3247-3252. doi: 10.1158/1078-0432.CCR-18-0152. Epub 2018 Apr 16.</citation>
    <PMID>29661775</PMID>
  </reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>July 4, 2020</study_first_submitted>
  <study_first_submitted_qc>July 4, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 9, 2020</study_first_posted>
  <last_update_submitted>July 8, 2020</last_update_submitted>
  <last_update_submitted_qc>July 8, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">July 10, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Institute of Hematology &amp; Blood Diseases Hospital, China</investigator_affiliation>
    <investigator_full_name>Yi Shuhua</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>Waldenström Macroglobulinemia</keyword>
  <keyword>Zanubrutinib</keyword>
  <keyword>Ixazomib</keyword>
  <keyword>Dexamethasone</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Waldenstrom Macroglobulinemia</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Ixazomib</mesh_term>
    <mesh_term>Zanubrutinib</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04463953
org study id: BDH-WM2020/04
nct id: NCT04463953
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
This study aims to evaluate the efficacy of BTK inhibitor Zanubrutinib combined with Ixazomib
      and Dexamethasone (ZID) for the newly diagnosed Waldenstrom Macroglobulinemia. This ZID
      regimen will be given up to 24 months and stopped for observation. We propose this
      combination will improve the deep remission (≥VGPR) compared to single Zanubrutinib or IRD
      regimen and can be a time-limited regimen which will reduce the life-time therapy and benefit
      the patients.
As Waldenstrom Macroglobulinemia cells always have two or three components tumor cells,
      including lymphocyte, Lymphoplasmacytic cells and plasma cells. We designed a oral regimen to
      target both lymphoma cells (Zanubrutinib) and plasma cells (Ixazomib plus Dexamethasone) to
      eliminate the tumor cells of WM. We propose this combination will improve the deep remission
      of WM (≥VGPR) . Zanubrutinib will be given 160mg Bid per day, up to 24 months, Ixazomib 4mg
      per week and Dexamethasone 20mg per week for three weeks, every 4 weeks one course. ID will
      be given 6 course as introduction and then one course every 12 weeks for up to 24 months. At
      the last ID course, Zanubrutinib will be stopped. The last ID course is to prevent the bounce
      of IgM because of Zanubrutinib discontinue.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15.
primary purpose: Treatment
masking: None (Open Label)
measure: Deep remission response rate
time frame: up to 5 years
description: ≥VGPR after 6 cycles introduction
measure: Complete response (CR)
time frame: up to 12 months
description: Disappearance of monoclonal protein on immunofixation (both serum and urine); No histologic evidence of bone marrow involvement; Resolution of adenopathy and/or organomegaly on CT; Resolution of clinical signs or symptoms attributed to WM/LPL.
measure: Progress-free survival (PFS)
time frame: up to 5 years
description: the time from treatment initiation until disease progression or death
measure: Duration of response (DoR)
time frame: up to 5 years
description: the time from best response (R) to progression/death (P/D)
measure: Overall survival (OS)
time frame: up to 36 months
description: The percentage of patients in treatment group who are still alive for a certain period of time after they were diagnosed with Waldenstrom's Macroglobulinemia.
measure: Time to next treatment (TTNT)
time frame: up to 5 years
description: time from end of primary treatment to institution of next therapy
measure: Overall response
time frame: up to 5 year
description: minimor response+partial response+VGPR+CR
arm group label: ZID regimen
arm group type: Experimental
description: Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15.
intervention type: Drug
intervention name: Zanubrutinib,Ixazomib and Dexamethasone
description: Zanubrutinib, 160mg orally, twice a day; Ixazomib, 4 mg orally, day 1, 8, 15; Dexamethasone, 20mg orally, days 1, 8, 15；Ixazomib and dexamethasone every 4 weeks of a cycle, with induction of 6 cycles, and then maintain every 12 weeks, up to 6 cycles (96 cycles in total). Zanubrutinib is taken orally twice a day for up to 96 cycles, with a reduction in the last ID cycle. ZID regimen will continue 6 cycles after reaching the maximum response after introduction section.
arm group label: ZID regimen
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Shuhua Yi
role: Principal Investigator
affiliation: Chinese Academy of Medical Sciences and Peking Union Medical College
last name: Shuhua Yi, Dr
phone: 86-22-23909106
email: yishuhua@ihcams.ac.cn
last name: Lugui Qiu, Dr
phone: 86-22-23909172
email: qiulg@ihcams.ac.cn
facility: 
status: Recruiting
contact: 
contact backup: 
country: China
citation: Treon SP, Xu L, Guerrera ML, Jimenez C, Hunter ZR, Liu X, Demos M, Gustine J, Chan G, Munshi M, Tsakmaklis N, Chen JG, Kofides A, Sklavenitis-Pistofidis R, Bustoros M, Keezer A, Meid K, Patterson CJ, Sacco A, Roccaro A, Branagan AR, Yang G, Ghobrial IM, Castillo JJ. Genomic Landscape of Waldenstrom Macroglobulinemia and Its Impact on Treatment Strategies. J Clin Oncol. 2020 Apr 10;38(11):1198-1208. doi: 10.1200/JCO.19.02314. Epub 2020 Feb 21.
PMID: 32083995
citation: Treon SP, Xu L, Hunter Z. MYD88 Mutations and Response to Ibrutinib in Waldenstrom's Macroglobulinemia. N Engl J Med. 2015 Aug 6;373(6):584-6. doi: 10.1056/NEJMc1506192. No abstract available.
PMID: 26244327
citation: Castillo JJ, Meid K, Gustine JN, Dubeau T, Severns P, Hunter ZR, Yang G, Xu L, Treon SP. Prospective Clinical Trial of Ixazomib, Dexamethasone, and Rituximab as Primary Therapy in Waldenstrom Macroglobulinemia. Clin Cancer Res. 2018 Jul 15;24(14):3247-3252. doi: 10.1158/1078-0432.CCR-18-0152. Epub 2018 Apr 16.
PMID: 29661775
responsible party type: Principal Investigator
investigator affiliation: Institute of Hematology & Blood Diseases Hospital, China
investigator full name: Yi Shuhua
investigator title: Professor
mesh term: Waldenstrom Macroglobulinemia
mesh term: Dexamethasone
mesh term: Ixazomib
mesh term: Zanubrutinib
sharing ipd: No