Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients

Official Title: “Incidence of Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients Who Receive Rituximab-containing Chemotherapy and Are Previously Infected With Hepatitis B Virus”

This is a single-arm study. Key eligibility criteria include (1) newly diagnosed, diffuse large B-cell or follicular cell non-Hodgkin's lymphoma; (2) negative test for hepatitis B surface antigen (HBsAg) and positive for antibody to hepatitis B core antigen (anti-HBc); (3) adequate bone marrow, liver, and kidney function. All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines. The primary endpoint of this study is the incidence of hepatitis B virus (HBV) reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA during rituximab-CHOP chemotherapy and within 1 year after completion of the last course of rituximab-CHOP chemotherapy.

Patients who have HBV reactivation during the study period will receive free entecavir treatment, one of the standard treatment for chronic hepatitis B, for 48 weeks. The secondary endpoints include the incidence of hepatitis flare, defined as a greater than 3 fold increase of serum alanine aminotransferase (ALT) level that exceeded 100 IU/L, and the efficacy and safety of rituximab-CHOP chemotherapy.

Treatment plan:

A typical course of rituximab-CHOP chemotherapy is as follows:

rituximab 375 mg/m2 i.v., day 1, cyclophosphamide 750 mg/m2 i.v., day 1, doxorubicin 50 mg/m2 i.v., day 1, vincristine 1.4 mg/m2 (maximal 2 mg) i.v., day 1, prednisolone 40 mg/m2/day p.o., day 1 to day 5.

Typically the treatment will be repeated every 3 weeks. If the patients cannot recover from chemotherapy-induced toxicity at the schedule time of the next course of treatment, modification of chemotherapy dosage or delay of chemotherapy administration will be done according to local treatment standard and will be recorded.

The use of component therapy or granulocyte colony-stimulating factor will be at the discretion of individual investigator.

Auxiliary medication, such as anti-emetics, will be given according to local treatment guidelines.

Statistical consideration:

1. Database Management Procedures

Standard module for description of standard operation procedures for data processing to ensure quality and validity of the data.

2. Presentation of Efficacy and safety Endpoints

2.1. The primary endpoint of this study is the incidence of HBV reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA, during rituximab-CHOP chemotherapy and within 1 year after the last course of rituximab-CHOP chemotherapy.

2.2. The secondary endpoints of this study include the incidence of hepatitis flare, defined as a greater than 3 fold increase of serum ALT level that exceeded 100 IU/L, the incidence of severe hepatitis, defined as a hepatitis flare with an increase of ALT to more than 10 fold of ULN or bilirubin to more than 1.5 fold of ULN, during rituximab-CHOP chemotherapy and within 1 year after the last course of rituximab-CHOP chemotherapy.

2.3. The secondary endpoints also include progression-free survival and overall survival for patients who receive rituximab-CHOP chemotherapy. The modality (CT scan, MRI, etc.) and schedule of tumor measurement will be determined according to local treatment guidelines.

3. Hypotheses and Sample Size Determination

It is estimated that in Taiwan the incidence of 'resolved' HBV infection in the general population is about 50%. A recent survey of HbsAg(-)blood donors indicated that 7% of the donors had detectable HBV DNA in serum. The incidence of diffuse large B-cell non-Hodgkin's lymphoma in Taiwan is 700-800 new patients/year (Taiwan Cancer Registry, http://crs.cph.ntu.edu.tw). We plan to enroll 150 patients in three years (50 new patients every year).

4. General Statistical considerations

4.1 Randomization and stratification

This is a single-arm study. No randomization will be done.

4.2 Analysis population

This study will enroll NHL patients with evidence of 'resolved' HBV infection. Eligible subjects must be negative for serum HBV surface antigen (HBsAg) and positive for at least one of the following in the serum: anti-core antigen (anti-HBc), anti-surface antigen (anti-HBs), or HBV DNA. Patients who receive at least 1 dose of rituximab-CHOP chemotherapy will be enrolled in to the intent-to-treat population and safety population. Patients who complete at least 1 course of rituximab-CHOP chemotherapy will be enrolled into the per-protocol analysis. The primary and secondary endpoints described in Section 2.1, 2.2, and 2.3 will be included in the per-protocol analysis.

4.3 Dropout

Taking into account 10% dropout rate, we need to enter 62 patients per year to the trial so that we may finish accrual of patients within 3 years.

4.4 Baseline

Before the first course of rituximab-CHOP chemotherapy, the baseline characteristics for each patient will be measured.

4.5 Multicenter study

This study will be conducted by all participating medical centers to the Lymphoma Disease Committee (14 centers in total). Since the rituximab-CHOP chemotherapy is the standard first-line treatment for patients with diffuse large B-cell NHL and follicular cell NHL, no center interaction on treatment is expected in this study.

4.6 Adjustment for multiple testing

Adjustment because of multiple testing is not needed in this study.

4.7 Subgroup analysis

Pre-specified subgroup analysis for the primary endpoint (HBV reactivation rate) will be done in the following sub-groups:

1. baseline HBV DNA (+) vs. HBV DNA (-);

2. baseline alanine transaminase (ALT) normal vs. abnormal.

4.8 Patient Listings

Individual patient listings should be also provided.

5. Interim analysis and data monitoring

No interim analysis is planned for this study.

6. Final Analysis

For the final statistical analysis, this section should state the specific statistical procedures described in item 6 of this section in the analysis of every primary and secondary efficacy and safety endpoint.

Intervention(s) in this Clinical Trial

• Drug: entecavir
  • All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines. The primary endpoint of this study is the incidence of HBV reactivation, defined by a greater than 10-fold increase, compared with previous nadir levels, of HBV DNA during rituximab-CHOP chemotherapy and within 1 year after completion of the last course of rituximab-CHOP chemotherapy. Patients who have HBV reactivation during the study period will receive free entecavir treatment, one of the standard treatment for chronic hepatitis B, for 48 weeks.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: entecavir
  • All eligible patients will receive rituximab-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) chemotherapy according to current treatment guidelines.

Primary Measures

• enroll 150 patients
  • Time Frame: 3 years
    Safety Issue?: Yes

Inclusion Criteria:

• 1. Histologically proven diffuse large B-cell or follicular B-cell non-Hodgkin's lymphoma, for which chemotherapy with rituximab-CHOP chemotherapy is considered treatment-of-choice.
• 2. Evidence of 'resolved' HBV infection. Eligible subjects must be negative for serum
• HBV surface antigen (HBsAg) and positive for anti-core antibody (anti-HBc).
• 3. Age >18 years.
• 4. Performance status with ECOG score 0-2.
• 5. No previous chemotherapy and radiotherapy, no concurrent glucocorticoid use.
• 6. Absolute neutrophil count (ANC) > 1,500/mm3, platelet > 100,000/mm3 in the peripheral blood.
• 7. Total bilirubin ＜ 2.5 mg/dl. Alanine aminotransferase (ALT) ＜ 3 times UNL (upper limits of normal range).
• 8. Serum creatinine ＜ 1.5 mg/dl. 9.10.Life expectancy 3 months.
• 11.Signed informed consent.

Exclusion Criteria:

• 1. Pregnant or breast-feeding women.
• 2. Patients with history of brain metastasis or CNS involvement.
• 3. Child's class B or C in patients with liver cirrhosis.
• 4. Impaired cardiac function with NYHA (New York Heart Association) classification Gr II.
• 5. History of other liver diseases such as hepatitis C, D, autoimmune hepatitis, primary biliary cirrhosis, Wilsons' disease.
• 6. Other major systemic disease, such as active infection, significant cardiac disease, neurological deficit or psychiatric disorder, that the investigators consider to be significant risk.
• 7. Any concomitant cancer treatment.
• 8. Known hypersensitivity of any of the study drugs (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisolone).
• 9. Known human immunodeficiency virus (HIV) infection.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 75 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Investigator: National Health Research Institutes, Taiwan Other

Overall Clinical Trial Officials and Contacts

Tsang-Wu Liu, Ph.D Study Director National Health Research Institutes, Taiwan  

Information obtained from ClinicalTrials.gov on February 12, 2012

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00931229

Study ID Number: T1408

ClinicalTrials.gov Identifier: NCT00931229

Health Authority: Taiwan: Department of Health