Efficacy and Safety of Ibrutinib in Patients With CLL and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers

April 11, 2018 updated by: Professor Yok-lam Kwong, The University of Hong Kong

Efficacy and Safety of Ibrutinib in Patients With Chronic Lymphocytic Leukemia and Other Indolent B-cell Lymphomas Who Are Chronic Hepatitis B Virus Carriers or Occult Hepatitis B Virus Carriers

Efficacy and Safety of ibrutinib in patients with chronic lymphocytic leukemia and other indolent B-cell lymphomas who are chronic hepatitis B virus carriers or occult hepatitis B virus carriers

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

Ibrutinib is a selective oral Burton tyrosine kinase inhibitor. Through interfering with the downstream pathways of B-cell receptor signaling, it inhibits proliferation and induces apoptosis in many B-cell lymphoid malignancies. The clinical benefit of ibrutinib has been demonstrated in patients with relapsed/refractory chronic lymphocytic leukaemia, mantle cell lymphoma, small lymphocytic lymphoma, and other indolent B-cell non-Hodgkin lymphomas.

The pivotal trials of ibrutinib excluded HBsAg+ patients. Therefore, the effects of ibrutinib on HBsAg+ and anti-HBc+ patients remain entirely undefined. In view of the B-cell signaling inhibitory activity of ibrutinib, which might be more potent than rituximab in suppressing B-cells, HBV reactivation in patients exposed previously to HBV infection, including chronic HBV carriers and occult HBV carriers, could be a major clinical problem.

To enable ibrutinib to be prescribed in Asia and other regions of the world where HBV is endemic, evidence-based recommendations on prevention of HBV reactivation in at-risk populations, including chronic HBV carriers (HBsAg+), and occult HBV carriers (HBsAg- but anti-HBc+), are urgently needed.

The following treatment regimens will be adopted. Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily.

Relapsed / refractory mantle cell lymphoma: 560 mg daily. Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily. Treatment is continued until disease progression.

A total of 62 patients will be recruited, including 16 HBsAg+ patients, and 46 occult HBV carriers

Sample size calculation of occult HBV carriers For occult HBV carriers, the sample size is calculated according to the following information, based on our previous observations (as detailed in reference 3). The HBV reactivation rate in HBsAg-, anti-HBc+, anti-HBs+ patients is hypothesized to be 34%, which may increase to 68% in HBsAg-, anti-HBc+, but anti-HBs- patients [3]. Assuming a power of 80% and an alpha-risk of 0.1, together with the ratio of anti-HBs+ : anti-HBs- patients to be 2:1, we expect to recruit 42 HBsAg-, anti-HBc+ patients. With a dropout rate of 10%, the total number of patients to be recruited in this group will be 46.

Sample size calculation of HBsAg+ patients For HBsAg+ patients, the sample size is calculated according to the following information, based on our previous observations (as detailed in reference 3). The ratio of occult carriers (HBsAg-, anti-HBc+) : HBsAg+ patients is about 3: 1.3 Hence, the total number of HBsAg+ to be recruited will be 14 (42 divided by 3). With a drop-out rate of 10%, the total number of patients to be recruited in this group will be 16.

Approximate breakdown of number of patients in each category to be recruited Based on our previous observations on the proportions of low-grade B-cell lymphoid malignancies,8 an approximate breakdown of number of patients is as follows: follicular lymphoma (N=32), chronic lymphocytic leukemia/small lymphocytic lymphoma (N=11), marginal zone B-cell lymphoma (N=11), mantle cell lymphoma (N=5), and Waldenstrom macroglobulinemia (N=5).

Study Type

Interventional

Enrollment (Anticipated)

62

Phase

  • Phase 3

Contacts and Locations

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

Study Locations

  • Hong Kong
      • Hong Kong, Hong Kong
        • Recruiting
        • The University of Hong Kong
        • Sub-Investigator:
          • Eric Tse, MBBS(HK), PhD(Cantab)

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

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Adult patients between age of 18 - 80 years
  2. Patients with indolent B-cell lymphoproliferative neoplasms that have relapsed or are refractory after at least one standard line of therapy that contains rituximab
  3. Pathologically proven B-cell lymphoproliferative neoplasms including chronic lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, marginal-zone B-cell lymphoma, and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma).
  4. Pathologically proven follicular lymphoma, with relapse or disease progression > 12 months after previous rituximab therapy.
  5. Chronic HBV carriers (HBsAg+)
  6. Occult HBV carriers (HBsAg-, anti-HBc+ and HBV DNA-)

  7. Haematology values within the following limits:

    1. Absolute neutrophil count (ANC)1000/mm3 independent of growth factor support
    2. Platelets 100,000/mm3, or 50,000/mm3 if bone marrow is involved, and independent of transfusion support in either situation

  8. Biochemical values within the following limits:

    1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2 x upper limit of normal (ULN)
    2. Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin
    3. Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockcroft Gault) ≥ 40 mL/min/1.73m2
  9. Competent to give an informed consent

Exclusion Criteria:

  1. Concomitant chronic liver diseases not related to HBV
  2. Known history of drug-induced liver injury, chronic active hepatitis C infection, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver and portal hypertension
  3. Known history of drug induced pneumonitis
  4. Known history of inflammatory bowel disease
  5. Woman who are pregnant or breast-feeding
  6. Patients who do not consent to the use of effective contraception during the study
  7. Active infections.
  8. Evidence of ongoing active HBV hepatitis (ALT and/or AST > 2x upper limit of normal, and detectable HBV DNA)
  9. Patients known to have histological transformation of CLL to an aggressive lymphoma
  10. Vaccinated with live, attenuated vaccines within 4 weeks of enrolment

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
Other: Ibrutinib
Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression
Drug: Ibrutinib
Relapsed / refractory chronic lymphocytic leukemia and Waldenstrom macroglobulinaemia (lymphoplasmacytic lymphoma): 420 mg daily Relapsed / refractory mantle cell lymphoma: 560 mg daily Relapsed / refractory indolent B-cell non-Hodgkin lymphoma: 560 mg daily Treatment is continued until disease progression
Other Names:
  • Imbruvica

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Overall response rate (ORR)
Time Frame: 2 years
proportion of patients achieving CR or partial remission (PR)
2 years
Duration of remission
Time Frame: two year
two year
Rates of HBV Reactivation while on Ibrutinib therapy
Time Frame: two year
two year
Adverse events and severe adverse events
Time Frame: two year
Incidence of AE and SAE by severity grading as assessed according to CTCAE v4.03
two year

Collaborators and Investigators

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

Sponsor

The University of Hong Kong

Collaborators

Janssen, LP

Investigators

  • Principal Investigator: Yok Lam Kwong, MD(HK),, The University of Hong Kong

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 (Actual)

November 1, 2016

Primary Completion (Anticipated)

December 1, 2020

Study Completion (Anticipated)

June 1, 2021

Study Registration Dates

First Submitted

December 2, 2016

First Submitted That Met QC Criteria

December 8, 2016

First Posted (Estimate)

December 13, 2016

Study Record Updates

Last Update Posted (Actual)

April 12, 2018

Last Update Submitted That Met QC Criteria

April 11, 2018

Last Verified

April 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HKUBTK01

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

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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