Trial Information

A Randomized Study of Lamivudine Prophylaxis or Treatment Against Hepatitis B Reactivation in Non-Hodgkin's Lymphoma Patients Carrying Hepatitis B Surface Antigen

- TREATMENT PLANS

1. Systemic chemotherapy with CHOP regimen Schedule and Dose for CHOP
Cyclophosphamide 750 mg/m2 i.v. Day 1 Doxorubicin 50 mg/m2 i.v. Day 1 Vincristine
1.4 mg/m2/d i.v. Day 1 Prednisolone 60 mg/m2/d p.o. Day 1-7 1.1 Courses will be
repeated every 21 days. 1.2 For patients with CR, give at least 2 additional
courses for a minimum of 6 courses.

1.3 For patients with maximal response as PR or SD, change to second-line
chemotherapy. The regimens for second-line chemotherapy are at the discretion of
the investigators. Local radiotherapy is allowed for residual localized 1.4 For
patients with PD, change to second-line chemotherapy. The regimens of the latter
are at the discretion of the investigators.

2.1 Arm I Patients take lamivudine 100 mg P.O. qd, starting from Day 1 of the
first course of CHOP, and until 2 months after the completion of chemotherapy.
Lamivudine is to be maintained no matter hepatitis occurred or not during
chemotherapy. If second-line chemotherapy is used, lamivudine with the same dose
and schedule will be continued until 2 months after completion of the second-line
chemotherapy.

If third-line chemotherapy is needed, the use of lamivudine will be at the 2.2 Arm
II Patients are treated with CHOP alone. If the patients develop clinical
hepatitis, as defined in section 7.2, lamivudine 100 mg, P.O., qd., will be given,
and continued until hepatitis is resolved. Prophylactic lamivudine is not to be
given in subsequent chemotherapy. (Our previous study has indicated that nearly
all clinical hepatitis developed in HBV carriers during systemic chemotherapy is
caused by HBV reactivation. Therefore, for practical reason, the investigators
are not advised to wait for the results of HBV DNA serology examination before
starting lamivudine treatment. )

3.0 DOSE MODIFICATION 3.1 Hematological Toxicity* Drug administration is postponed
if there is no full hematological recovery (AGC ＞ 2,000/mm3 and Platelet ＞
100,000/mm3 ) from prior course at scheduled treatment day. Full doses will be
given as soon as the hematological recovery is documented. If two weeks after the
due day recovery is still incomplete, the treatment may be started and the dosage
be reduced according to the following

schedule:

AGC*/mm3Platelet/mm3 1,500-2,00075,000-100,000 1,000-1,49950,000-74,999
＜1,000＜50,000 Cyclophosphamide 80% 60% ** Doxorubicin 80% 60% **

- G-CSF is allowed to be used prophylactically for older ( > 60 years old) patients and
for patients with previous or ongoing prolonged myelosuppression.

- Postpone for another week. If the counts remain AGC＜1,500 or Platelet ＜75,000
three weeks after the due day, patients should be off study.

3.2 Hepatotoxicity For patients with normal prechemotherapy serum ALT, hepatitis flare-up is
defined as ALT elevation greater than 1.5 fold of upper normal limit. For patients with
abnormal prechemotherapy serum ALT, hepatitis flare-up is defined as 2.0 fold or greater
increase of serum ALT level. The hepatitis or hepatitis flare-up is attributed to
reactivation of HBV when there is a sudden elevation (＞10-fold) in serum HBV DNA level or
reappearance of HBV DNA and/or HBeAg in the serum.

Since results of our previous study has indicated that nearly all clinical hepatitis
developed in HBV carrier during chemotherapy is caused by HBV reactivation, and serum HBV
DNA data are not readily available in most hospitals, all patients with hepatitis flare-up
are considered HBV reactivation until proved otherwise. For patients in the second arm,
biochemical hepatitis will prompt a start of daily lamivudine, even before a definite
documentation of 10-fold increase of HBV DNA. For patients with only minor hepatic
dysfunction (total bilirubin ＜3.0 mg/dl and ALT ＜200 I.U./L), full-dose chemotherapy is
recommended on the scheduled treatment day without delay. For patients with more severe
hepatic dysfunction (total bilirubin ≧ 3.0 mg/dl or ALT ≧ 200 I.U./L), subsequent course is
postponed for 1 week and the dosage modified as followings if the values remain abnormal
after 1 week:

Total Bilirubin (mg/dl) ＜3.0 3.0 ~ 4.9 5.0 ~ 7.5 ＞7.5 ALT (I.U./L) ＜200 200 ~ 399 400 ~ 800
＞800 Doxorubicin 100% 75% 50% *

- Wait until recovery with serum levels below these values. Patients will be off study if
Bil ＞ 7.5 mg/dl or ALT ＞ 800 I.U/L, 3 weeks after the due day.

3.3 Gastrointestinal Toxicity In case of severe (≧ NCI Gr III) anorexia, nausea, vomiting,
diarrhea, stomatitis or abdominal pain, all therapy should be delayed until improvement of
symptoms to ≦ GrII.

Patients will be off study if ≧ Gr III toxicity persists ≧ 3 weeks after due day. Patients
are allowed to use H3-blockers in the subsequent courses for severe nausea and vomiting. If
gastrointestinal toxicity is still ≧ Gr III during the next course, doses of
cyclophosphamide and doxorubicin should be reduced by 25% in the subsequent courses. If no
further episodes of severe reaction, the doses can be escalated, 12.5% each time, and back
to 100%.

3.4 Cardiotoxicity In case of NCI grade II cardiotoxicity, doxorubicin should be reduced by
50%. If cardiotoxicity is resolved, the dose may be carefully deescalated, 12,5% each time,
in the subsequent courses. If severe (≧ NCI grade III) cardiotoxicity develops, doxorubicin
should be discontinued and should not be used again in the subsequent courses.

3.5 Multiple Toxicity In the event of multiple toxicity, dose modification should be based
on the guideline that requires the greatest reduction of doses.

4.0 CRITERIA FOR REMOVAL FROM STUDY

All patients who are still under or have completed protocol treatments (1st-line or
2nd-line) should be continuously followed-up for all study end points. Patients are removed
from study if they have major violation of the protocol due to the following reasons:

1. Completion of assigned therapy and observation.

2. Progressive of disease.

3. Excessive of complication or toxicity.

4. Patient death.

5. Patient withdrawal or refusal.

5.0 MEASUREMENT OF EFFECT ： Authorized physicians or research nurses must call Ms. Yueh-Ling
Ho at the TCOG Operations Office (Tel: 02-26534401 ext 6655) for patients registration and
randomization.

A permuted block randomization will be used to generate the list by the Statistical Center
housed at the Division of Biostatistics, NHRI. Treatment assignment is given only when the
patient passes the eligibility check.

6.0 REPORT OF ADVERSE EFFECT : Adverse effect of treatments should be reported to TCOG
Operations Office at 02-26534401 ext 6655, 6657, 6658 and FAX: 02-2782-3755, within 48
hours. See appendix for the TCOG ADR (Adverse Drug Reaction) Form of reporting adverse
effect.