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

August 23, 2017 updated by: National Taiwan University Hospital

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

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..

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

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 Type

Interventional

Enrollment (Anticipated)

21

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

20 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / 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®

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The complete remission rate
Time Frame: 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.
During the first-year, every 3 months to evaluate

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
The durability of complete remission (disease-free interval)
Time Frame: Follow-up every 3 motnhs for 3 years
The lymphoma-free
Follow-up every 3 motnhs for 3 years
The overall response rate
Time Frame: During the first-year, every 3 months to evaluate
Complete remission and partial remission rate
During the first-year, every 3 months to evaluate
The association between HCV RNA load and response of lymphoma.
Time Frame: During the first-year, every 3 months to evaluate
The assessment of HCV RNA load
During the first-year, every 3 months to evaluate
The toxicity of Harvoni®.
Time Frame: 3 months
The assessment of toxicity during the first 3 months
3 months
Potential biomarkers predicting the response of Harvoni®.
Time Frame: 3 years
Translational study
3 years

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

National Taiwan University Hospital

Investigators

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

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Anticipated)

September 1, 2017

Primary Completion (Anticipated)

December 31, 2020

Study Completion (Anticipated)

August 15, 2021

Study Registration Dates

First Submitted

August 9, 2017

First Submitted That Met QC Criteria

August 23, 2017

First Posted (Actual)

August 25, 2017

Study Record Updates

Last Update Posted (Actual)

August 25, 2017

Last Update Submitted That Met QC Criteria

August 23, 2017

Last Verified

August 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • 201612066MIPB

Drug and device information, study documents

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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