<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/NCT03261349</url>
  </required_header>
  <id_info>
    <org_study_id>201612066MIPB</org_study_id>
    <nct_id>NCT03261349</nct_id>
  </id_info>
  <brief_title>Antiviral Agent HARVONI® for the Treatment of HCV-associated Indolent B-Cell Lymphoma</brief_title>
  <official_title>A Pilot Phase II Study of New Direct-Acting Antiviral Agent, HARVONI® (Ledipasvir/Sofosbuvir), for the Treatment of Genotype 1 or 2 HCV-Associated Indolent B-Cell Non- Hodgkin's Lymphoma</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Taiwan University Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Taiwan University Hospital</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      We and other investigators have revealed an association between Hepatitis C virus (HCV)&#xD;
      seropositivity and an increased risk of developing marginal zone B-cell lymphoma (MZ),&#xD;
      lymphoplasmacytic lymphoma (LPL, also known as Waldenström's macroglobulinemia), follicular&#xD;
      lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). The sustained virologic response&#xD;
      (SVR) to treatment with interferon or pegylated (Peg)IFN with ribavirin was closely&#xD;
      associated with the regression of HCV-associated B-cell NHL (mainly MZL, and LPL).&#xD;
&#xD;
      Currently, the second-generation direct-acting antiviral agents (DAAs), such as sofosbuvir,&#xD;
      have been shown to have a higher cure rate, less side effects, and a shorter duration of&#xD;
      therapy for chronic HCV infection. After the approval of DAA for HCV therapy, several recent&#xD;
      anecdotal case reports showed that indolent low-grade B-cell NHLs regressed after HCV&#xD;
      clearance by DAAs. It is noted that the time to complete remission of these lymphomas was&#xD;
      around 20 to 24 weeks after starting DAAs. These findings indicate that DAAs can eradicate&#xD;
      the trigger of lymphomagenesis by curing chronic HCV infection.&#xD;
&#xD;
      Because DAAs are more potent and efficient than pegylated (Peg) interferon plus ribavirin and&#xD;
      well-tolerated for the treatment of HCV infection, it is reasonable to use DAAs as the&#xD;
      frontline treatment for HCV-positive patients with indolent B-cell NHL, such as MZL, LPL, and&#xD;
      low-grade FL, who do not require immediate cytoreductive therapy. The aim of this proposal is&#xD;
      to assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to&#xD;
      durable complete remission of these lymphomas..&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Although several epidemiological studies, including our study have been demonstrated the link&#xD;
      between HCV and B-cell non-Hodgkin's lymphoma (NHL), the direct evidence of the&#xD;
      HCV-associated-NHL remains uncertain. Direct antiviral agents (DAA) have been shown to have a&#xD;
      higher cure rate, less side effects, and a shorter duration of therapy for chronic HCV&#xD;
      infection. Whether DAA treatment can cure HCV-associated indolent B-cell NHL remains unclear?&#xD;
      If yes, a direct evidence of HCV-associated lymphomagenesis will be approved. Because DAAs&#xD;
      are more potent and efficient than pegylated (Peg) interferon plus ribavirin and&#xD;
      well-tolerated for the treatment of HCV infection, it is reasonable to use DAAs as the&#xD;
      frontline treatment for HCV-positive patients with indolent B-cell NHL, such as MZL, LPL, and&#xD;
      low-grade FL, who do not require immediate cytoreductive therapy. The aim of this proposal is&#xD;
      to assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to&#xD;
      durable complete remission of HCV-associated indolent B-cell NHL.&#xD;
&#xD;
      In the translational part, we will assess the expression pattern of BAFF-related canonical&#xD;
      and non-canonical NF-κB signaling molecules by immunohistochemical (IHC) staining, and&#xD;
      t(11;18)(q21;q21), and t(14;18)(q32;q21) by fluorescence in situ hybridization (FISH) in&#xD;
      pre-treatment tumors samples of patients in prospectively predicting the antiviral&#xD;
      responsiveness of HCV-positive indolent B-cell NHLs. The serum cytokines and chemokines,&#xD;
      IFN-gamma, TNF-alpha, IL-4, IL-5, IL-6, IL-13 and CXCL13, BAFF level, and HCV RNA load before&#xD;
      and after DAA treatment in HCV-associated indolent B-cell NHLs will be examined. The genotype&#xD;
      of the HLA class II, and cloning followed by sequences of the VH region of the immunoglobulin&#xD;
      gene derived from pre-treatment tumor samples will be assessed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">September 1, 2017</start_date>
  <completion_date type="Anticipated">August 15, 2021</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2020</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>New Direct-Acting Antiviral Agent, HARVONI® (ledipasvir/sofosbuvir)</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>The complete remission rate</measure>
    <time_frame>During the first-year, every 3 months to evaluate</time_frame>
    <description>The complete remission rate by using Harvoni® (ledipasvir and sofosbuvir) as the first-line line therapy.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The durability of complete remission (disease-free interval)</measure>
    <time_frame>Follow-up every 3 motnhs for 3 years</time_frame>
    <description>The lymphoma-free</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The overall response rate</measure>
    <time_frame>During the first-year, every 3 months to evaluate</time_frame>
    <description>Complete remission and partial remission rate</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The association between HCV RNA load and response of lymphoma.</measure>
    <time_frame>During the first-year, every 3 months to evaluate</time_frame>
    <description>The assessment of HCV RNA load</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The toxicity of Harvoni®.</measure>
    <time_frame>3 months</time_frame>
    <description>The assessment of toxicity during the first 3 months</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Potential biomarkers predicting the response of Harvoni®.</measure>
    <time_frame>3 years</time_frame>
    <description>Translational study</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">21</enrollment>
  <condition>Indolent Lymphoma</condition>
  <arm_group>
    <arm_group_label>Anti-HCV (Ledipasvir and sofosbuvir)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Harvoni® (90 mg ledipasvir and 400 mg sofosbuvir) one tablet daily for 12 weeks</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Ledipasvir and sofosbuvir</intervention_name>
    <description>To assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to durable complete remission of these lymphomas.</description>
    <arm_group_label>Anti-HCV (Ledipasvir and sofosbuvir)</arm_group_label>
    <other_name>HARVONI®</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patients older than 18 years with histologically proven diagnoses of indolent B-cell&#xD;
             NHLs and with positive genotype 1 or 2 HCV (non-cirrhotic status) were eligible.&#xD;
&#xD;
          2. Indolent B-cell NHLs includes:&#xD;
&#xD;
               -  Low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue&#xD;
                  (MALT) type: known as MALT lymphoma.&#xD;
&#xD;
               -  Splenic marginal zone lymphomas (SMZL)&#xD;
&#xD;
               -  Waldenström's macroglobulinemia (WM, known as lymphoplasmacytic lymphoma) .&#xD;
&#xD;
               -  Grade 1, 2 follicular lymphoma (FL). 3 Stage I to III (modified Ann Arbor stage),&#xD;
                  and non-life threatening IV lymphoma. 4 Patients had not previously been treated&#xD;
                  with chemotherapy or immunotherapy, were eligible. 5 Patients with clinical,&#xD;
                  echographical, or radiological suspicion of lymphoma lesions were eligible.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Evidence of histologic transformation to a high-grade lymphoma (such as grade 3 and 4&#xD;
             follicular lymphoma, and high-grade MALT lymphoma).&#xD;
&#xD;
          2. Life-threatening disseminated lymphoma.&#xD;
&#xD;
          3. Primary gastric lesions were not eligible.&#xD;
&#xD;
          4. Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia&#xD;
             type 1 (CIN1) or localized non-melanomatous skin cancer.&#xD;
&#xD;
          5. Evidence of clinically significant cardiac disease, as defined by history of&#xD;
             symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction&#xD;
             within 12 months before study entry.&#xD;
&#xD;
          6. Evidence of symptomatic central nervous system (CNS) disease.&#xD;
&#xD;
          7. Evidence of active opportunistic infections.&#xD;
&#xD;
          8. Liver cirrhosis B and C (Child-Pugh score)&#xD;
&#xD;
          9. Known HIV infection.&#xD;
&#xD;
         10. Pregnant or lactating status.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>20 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sung-Hsin Kuo, M.D.,Ph.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Department of Oncology, National Taiwan University Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sung-Hsin Kuo, M.D.,Ph.D.</last_name>
    <phone>+886-2323456</phone>
    <phone_ext>67144</phone_ext>
    <email>shkuo101@ntu.edu.tw</email>
  </overall_contact>
  <verification_date>August 2017</verification_date>
  <study_first_submitted>August 9, 2017</study_first_submitted>
  <study_first_submitted_qc>August 23, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 25, 2017</study_first_posted>
  <last_update_submitted>August 23, 2017</last_update_submitted>
  <last_update_submitted_qc>August 23, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">August 25, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Follicular lymphoma</keyword>
  <keyword>MALT lymphoma</keyword>
  <keyword>Waldenström's macroglobulinemia</keyword>
  <keyword>Hepatitis C virus</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lymphoma</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Sofosbuvir</mesh_term>
    <mesh_term>Ledipasvir, sofosbuvir drug combination</mesh_term>
    <mesh_term>Ledipasvir</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/NCT03261349
org study id: 201612066MIPB
nct id: NCT03261349
lead sponsor: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
We and other investigators have revealed an association between Hepatitis C virus (HCV)
      seropositivity and an increased risk of developing marginal zone B-cell lymphoma (MZ),
      lymphoplasmacytic lymphoma (LPL, also known as Waldenström's macroglobulinemia), follicular
      lymphoma (FL), and diffuse large B-cell lymphoma (DLBCL). The sustained virologic response
      (SVR) to treatment with interferon or pegylated (Peg)IFN with ribavirin was closely
      associated with the regression of HCV-associated B-cell NHL (mainly MZL, and LPL).

      Currently, the second-generation direct-acting antiviral agents (DAAs), such as sofosbuvir,
      have been shown to have a higher cure rate, less side effects, and a shorter duration of
      therapy for chronic HCV infection. After the approval of DAA for HCV therapy, several recent
      anecdotal case reports showed that indolent low-grade B-cell NHLs regressed after HCV
      clearance by DAAs. It is noted that the time to complete remission of these lymphomas was
      around 20 to 24 weeks after starting DAAs. These findings indicate that DAAs can eradicate
      the trigger of lymphomagenesis by curing chronic HCV infection.

      Because DAAs are more potent and efficient than pegylated (Peg) interferon plus ribavirin and
      well-tolerated for the treatment of HCV infection, it is reasonable to use DAAs as the
      frontline treatment for HCV-positive patients with indolent B-cell NHL, such as MZL, LPL, and
      low-grade FL, who do not require immediate cytoreductive therapy. The aim of this proposal is
      to assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to
      durable complete remission of these lymphomas..
Although several epidemiological studies, including our study have been demonstrated the link
      between HCV and B-cell non-Hodgkin's lymphoma (NHL), the direct evidence of the
      HCV-associated-NHL remains uncertain. Direct antiviral agents (DAA) have been shown to have a
      higher cure rate, less side effects, and a shorter duration of therapy for chronic HCV
      infection. Whether DAA treatment can cure HCV-associated indolent B-cell NHL remains unclear?
      If yes, a direct evidence of HCV-associated lymphomagenesis will be approved. Because DAAs
      are more potent and efficient than pegylated (Peg) interferon plus ribavirin and
      well-tolerated for the treatment of HCV infection, it is reasonable to use DAAs as the
      frontline treatment for HCV-positive patients with indolent B-cell NHL, such as MZL, LPL, and
      low-grade FL, who do not require immediate cytoreductive therapy. The aim of this proposal is
      to assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to
      durable complete remission of HCV-associated indolent B-cell NHL.

      In the translational part, we will assess the expression pattern of BAFF-related canonical
      and non-canonical NF-κB signaling molecules by immunohistochemical (IHC) staining, and
      t(11;18)(q21;q21), and t(14;18)(q32;q21) by fluorescence in situ hybridization (FISH) in
      pre-treatment tumors samples of patients in prospectively predicting the antiviral
      responsiveness of HCV-positive indolent B-cell NHLs. The serum cytokines and chemokines,
      IFN-gamma, TNF-alpha, IL-4, IL-5, IL-6, IL-13 and CXCL13, BAFF level, and HCV RNA load before
      and after DAA treatment in HCV-associated indolent B-cell NHLs will be examined. The genotype
      of the HLA class II, and cloning followed by sequences of the VH region of the immunoglobulin
      gene derived from pre-treatment tumor samples will be assessed.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: New Direct-Acting Antiviral Agent, HARVONI® (ledipasvir/sofosbuvir)
primary purpose: Treatment
masking: None (Open Label)
measure: The complete remission rate
time frame: During the first-year, every 3 months to evaluate
description: The complete remission rate by using Harvoni® (ledipasvir and sofosbuvir) as the first-line line therapy.
measure: The durability of complete remission (disease-free interval)
time frame: Follow-up every 3 motnhs for 3 years
description: The lymphoma-free
measure: The overall response rate
time frame: During the first-year, every 3 months to evaluate
description: Complete remission and partial remission rate
measure: The association between HCV RNA load and response of lymphoma.
time frame: During the first-year, every 3 months to evaluate
description: The assessment of HCV RNA load
measure: The toxicity of Harvoni®.
time frame: 3 months
description: The assessment of toxicity during the first 3 months
measure: Potential biomarkers predicting the response of Harvoni®.
time frame: 3 years
description: Translational study
arm group label: Anti-HCV (Ledipasvir and sofosbuvir)
arm group type: Experimental
description: Harvoni® (90 mg ledipasvir and 400 mg sofosbuvir) one tablet daily for 12 weeks
intervention type: Drug
intervention name: Ledipasvir and sofosbuvir
description: To assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to durable complete remission of these lymphomas.
arm group label: Anti-HCV (Ledipasvir and sofosbuvir)
other name: HARVONI®
criteria: 
gender: All
minimum age: 20 Years
maximum age: N/A
healthy volunteers: No
last name: Sung-Hsin Kuo, M.D.,Ph.D.
role: Principal Investigator
affiliation: Department of Oncology, National Taiwan University Hospital
last name: Sung-Hsin Kuo, M.D.,Ph.D.
phone: +886-2323456
phone ext: 67144
email: shkuo101@ntu.edu.tw
responsible party type: Sponsor
mesh term: Lymphoma
mesh term: Sofosbuvir
mesh term: Ledipasvir, sofosbuvir drug combination
mesh term: Ledipasvir