Antiviral Agent HARVONI® for the Treatment of HCV-associated Indolent B-Cell Lymphoma

Sponsor
National Taiwan University Hospital (Other)
Overall Status
Unknown status
CT.gov ID
NCT03261349
Collaborator
(none)
21
1
47.4

Study Details

Study Description

Brief Summary

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..

Condition or Disease Intervention/Treatment Phase
  • Drug: Ledipasvir and sofosbuvir
Phase 2

Detailed Description

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.

Study Design

Study Type:
Interventional
Anticipated Enrollment :
21 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Intervention Model Description:
New Direct-Acting Antiviral Agent, HARVONI® (ledipasvir/sofosbuvir)New Direct-Acting Antiviral Agent, HARVONI® (ledipasvir/sofosbuvir)
Masking:
None (Open Label)
Primary Purpose:
Treatment
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
Anticipated Study Start Date :
Sep 1, 2017
Anticipated Primary Completion Date :
Dec 31, 2020
Anticipated Study Completion Date :
Aug 15, 2021

Arms and Interventions

Arm Intervention/Treatment
Experimental: Anti-HCV (Ledipasvir and sofosbuvir)

Harvoni® (90 mg ledipasvir and 400 mg sofosbuvir) one tablet daily for 12 weeks

Drug: Ledipasvir and sofosbuvir
To assess whether Harvoni® (ledipasvir and sofosbuvir) could eradicate HCV and lead to durable complete remission of these lymphomas.
Other Names:
  • HARVONI®
  • Outcome Measures

    Primary Outcome Measures

    1. The complete remission rate [During the first-year, every 3 months to evaluate]

      The complete remission rate by using Harvoni® (ledipasvir and sofosbuvir) as the first-line line therapy.

    Secondary Outcome Measures

    1. The durability of complete remission (disease-free interval) [Follow-up every 3 motnhs for 3 years]

      The lymphoma-free

    2. The overall response rate [During the first-year, every 3 months to evaluate]

      Complete remission and partial remission rate

    3. The association between HCV RNA load and response of lymphoma. [During the first-year, every 3 months to evaluate]

      The assessment of HCV RNA load

    4. The toxicity of Harvoni®. [3 months]

      The assessment of toxicity during the first 3 months

    5. Potential biomarkers predicting the response of Harvoni®. [3 years]

      Translational study

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    20 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    1. Patients older than 18 years with histologically proven diagnoses of indolent B-cell NHLs and with positive genotype 1 or 2 HCV (non-cirrhotic status) were eligible.

    2. Indolent B-cell NHLs includes:

    • Low-grade marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) type: known as MALT lymphoma.

    • Splenic marginal zone lymphomas (SMZL)

    • Waldenström's macroglobulinemia (WM, known as lymphoplasmacytic lymphoma) .

    • Grade 1, 2 follicular lymphoma (FL). 3 Stage I to III (modified Ann Arbor stage), and non-life threatening IV lymphoma. 4 Patients had not previously been treated with chemotherapy or immunotherapy, were eligible. 5 Patients with clinical, echographical, or radiological suspicion of lymphoma lesions were eligible.

    Exclusion Criteria:
    1. Evidence of histologic transformation to a high-grade lymphoma (such as grade 3 and 4 follicular lymphoma, and high-grade MALT lymphoma).

    2. Life-threatening disseminated lymphoma.

    3. Primary gastric lesions were not eligible.

    4. Prior diagnosis of neoplasm within 5 years, except cervical intraepithelial neoplasia type 1 (CIN1) or localized non-melanomatous skin cancer.

    5. Evidence of clinically significant cardiac disease, as defined by history of symptomatic ventricular arrhythmias, congestive heart failure or myocardial infarction within 12 months before study entry.

    6. Evidence of symptomatic central nervous system (CNS) disease.

    7. Evidence of active opportunistic infections.

    8. Liver cirrhosis B and C (Child-Pugh score)

    9. Known HIV infection.

    10. Pregnant or lactating status.

    Contacts and Locations

    Locations

    No locations specified.

    Sponsors and Collaborators

    • National Taiwan University Hospital

    Investigators

    • Principal Investigator: Sung-Hsin Kuo, M.D.,Ph.D., Department of Oncology, National Taiwan University Hospital

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    National Taiwan University Hospital
    ClinicalTrials.gov Identifier:
    NCT03261349
    Other Study ID Numbers:
    • 201612066MIPB
    First Posted:
    Aug 25, 2017
    Last Update Posted:
    Aug 25, 2017
    Last Verified:
    Aug 1, 2017
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Product Manufactured in and Exported from the U.S.:
    Yes
    Keywords provided by National Taiwan University Hospital
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of Aug 25, 2017