A Phase II Study of Bendamustine Plus Rituximab (BR) in Patients With Relapsed or Progressive Marginal Zone B-cell Lymphoma (MZBCL)
Phase: PHASE2
Conditions: Marginal Zone B-cell Lymphoma
Sponsor: Seoul National University Hospital

KCSG LY14-09_Protocol v.3.0_2017.09.20 
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Protocol Title 
 
A phase II study of bendamustine plus rituximab (BR)  
in patients with relapsed or progressive  
marginal zone B-cell lymphoma (MZBCL) 
 
 
 
 
 
 
 
 
 
 
Activation date: August 2013 
Recent version: Version 3.0 
Version date: 20th September 2017 

KCSG LY14-09_Protocol v.3.0_2017.09.20 
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PROTOCOL SYNOPSIS 
Study Owner: 
Seoul National University Hospital 
Protocol Title:  
A phase II study of bendamustine plus rituximab (BR) in 
patients with relapsed or progressive marginal zone B-cell 
lymphoma (MZBCL) 
Principal Investigator 
Dae Seog Heo, MD, PhD 
Principal Investigator 
Contact Information: 
Department of Internal Medicine, Seoul National University 
Hospital, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea; 
heo1013@snu.ac.kr  
Institution Name(s): 
Seoul National University Hospital  
Sub-Investigator 
Name(s), if applicable: 
  No  
  Yes  
Plan on using other 
Institutions or centers 
to conduct study: 
If yes, please list 
name(s) and 
address(es): 
 No  
 Yes   
Seoul National University Hospital, Seoul National University Bu
ndang Hospital, Korean Cancer Study Group, the Lymphoma su
bcommittee 
Rationale: 
Bendamustine consists of a 2-chloroethylamine alkylating 
group, a benzimidazole ring, and a butyric acid side chain and 
shows both alkyla ting and antimetabolite properties. 
Bendamustine confers a progression-free survival (PFS) benefit 
in indolent B-cell lymphoid malignancies. In addition, 
bendamustine plus rituximab (BR) is highly active against 
relapsed/refractory indolent B-cell and mantle cell lymphomas 
(overall response rate [ORR]=92% and complete remission 
[CR]=55%) and chronic lymphocytic leukemia (CLL) (ORR=59% 
and CR=9%). Furthermore, a front-line BR demonstrates a 
significant PFS benefit and tolerability compared with R-CHOP 
in untreated indolent and mantle cell lymphomas except 
marginal zone B-cell lymphoma (MZBCL) (StiL NHL1 study).  
The 3rd nationwide study with 3,998 lymphoma patients 
between 2005 and 2006 revealed a relatively higher rates and 

KCSG LY14-09_Protocol v.3.0_2017.09.20 
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increasing incidence of MZBCL (769 [19%] of 3,998) as 
compared with the 2nd nationwide study (252 [16%] of 1,548) in 
Korea. Although 1st-line R-CVP is the standard treatment of 
advanced MZBCL in Korea (ORR=88% and CR=60%), nearly 
40% of MZBCL progress at 3 years. Bendamustine alone is 
effective against rituximab-refractory MZBCL (ORR=81% [13/16] 
and CR=25% [4/16]) and 1st-line BR shows similar outcome to 
R-CHOP (N=67, median PFS 57.2 vs 47.2 month; P=.3249) as a 
subgroup population analysis. However, the efficacy of BR has 
not been well elucidated in relapsed or progressive MZBCL. 
Therefore, this study will be conducted to evaluate the efficacy 
of BR in patients with relapsed or progressive MZBCL. 
Study Design: 
 
Multi-center trial, Phase II, non-randomized, open-label, single-
arm study with combined therapy of bendamustine and 
rituximab in patients with MZBCL who has relapsed or 
progressive to prior chemotherapy or chemo-radiotherapy. 
Bendamustine + rituximab combination chemotherapy 
 
Bendamustine 90mg/m2 IV on days 1-2 up to 6th cycle 
 
Rituximab 375mg/m2 IV on day 1 at 1st cycle  
 
Rituximab 1400mg SC on day 1 from 2nd cycle every 4 
weeks up to 8th cycle, disease progression, or 
intolerable toxicities. 
 
Objectives:  
Primary: ORR 
Secondary: CR rate, ORR according to prior chemo-sensitivity 
(CR+PR vs. SD+PD), PFS, OS, safety, response duration, 
biomarker correlative study 
Subjects: 
Total patients: 24 +3 (10% drop-out rate) = 27patients 

KCSG LY14-09_Protocol v.3.0_2017.09.20 
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Inclusion Criteria:  
1. Histologically confirmed CD20-positive nodal or extranodal 
MZBCL 
2. MZBCL patients who relapsed or progressed: have to meet a+b 
or a+c of the following criteria: 
a. 
At least one and a maximum of four prior lines of 
chemotherapy  
b. 
progression 
or 
relapsed 
during 
or 
after 
previous 
chemotherapy, except for rituximab treatment. 
c. progression or relapsed after 6 months of the last dose of 
previous chemotherapy including rituximab treatment. 
3. Patients age ≥ 18 years 
4. ECOG PS 0-2 (appendix A) 
5. At least one bidimensionally measurable disease (>1.5cm  
defined by CT scan) 
6. Adequate hematologic, renal, and hepatic functions as defined 
by: 
1) hemoglobin ≥ 9 g/dL, absolute neutrophil count ≥ 1.5 x 109/L, 
and platelets ≥ 75 x 109/L (absolute neutrophil count ≥ 1.0 x 
109/L, platelets ≥ 50 x 109/L if bone marrow involvement or 
hypersplenism due to the splenic involvement present) 
2) Serum creatinine ≤ 1.5 x ULN or calculated CrCL ≥ 40 mL/min 
(Cockcroft Gault fomula) 
3) Total bilirubin ≤ 1.5 x ULN  (total bilirubin ≤ 3.0 x ULN in 
patient with Gilbert’s syndrome) 
7. Women of child-bearing potential should use two appropriate 
methods of contraception during the study (diaphragm, use of 
condom by partner, intrauterine contraceptive device, sponge or 
spermicide) or in the status of surgical sterilization or maintain 
abstinence. 
Men 
should 
use 
appropriate 
method 
of 
contraception; such as use of condom and etc. 
8. Written informed consent 
Exclusion Criteria: 
1. Not all of the above inclusion criteria are met. 
2. Prior chemotherapy within 4 weeks or radiotherapy within 6 
weeks 
3.Corticosteroids 
during 
last 
28 
days 
except 
chronic 

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administration of prednisolone at a dose of < 20mg/day for 
indications other than lymphomas 
4. Evidence of CNS involvement by lymphomas 
5. Active HBV/HCV infections, known HIV infection. However, 
HBsAg-positive subject must be under the standard antiviral 
agent treatment and under the condition that HBV DNA should 
not be detected. HBcAb-positive subject should be checked the 
condition closely through trial period. 
6. Prior diagnosis of cancers within 5 years, except cervical 
intraepithelial neoplasia type 1, localized non-melanoma skin 
cancer, or small differentiated thyroid cancer 
7. Serious concurrent disease: 
1) myocardial infarction and any cardiovascular events within 6 
months prior to enrollment 
2) uncontrolled hypertension despite adequate medication 
3) serious congestive heart failure (NYHA functional 
classification III or V) 
8. Patients who are pregnant or lactating 
Study Drug Regimens: 
Bendamustine 90mg/m2 on days 1and 2 plus subcutaneous 
Rituximab 1,400mg on day 1 every 4 weeks as a cycle up to 8th 
cycles (rituximab 375mg/m2 IV on day 1 at 1st cycle only) 
 Other Therapy:  
N/A 
Efficacy Measures:  
Response evaluation every 8 weeks during BR chemotherapy, 
and followed by every 3 months after completion of last BR 
chemotherapy for 2 years, and then every 6 months after 2 
years using revised response criteria for malignant lymphoma  
Safety Measures: 
Adverse events using NCI CTCAE version 4.03: treatment-
emergent and treatment-related / discontinuation  
Correlative Science: 
FcγRIII polymorphism and baseline NK cell quantification before 
BR 

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Statistical Analysis: 
MinMax Simon’s two-stage design 
α P0=0.60; P1=0.80 (ORR) 
Significant level=0.05; power=0.80 
Stage 1: 8/13 (≥9 responses are required to move to stage 2) 
Stage 2: 25/35 (26 or more responses are required to reject the 
null hypothesis) 
Total expected number of  subjects (dropout rate: 10%) = 35 + 4 
= 39 patients 
At least 35 subjects are required to achieve 80% of the power (39 in 
consideration of dropout rate). 
However the target number of trial is difficult to practice. 
Data Collection: 
CRF 
Estimated Start Date: 
Activation:           Feb 2015 
Estimated Length of 
Enrollment: 
First patient in:       Mar 2015 
Last patient in:       Apr 2018 
Last patient out:      Apr 2020 
Description of Site 
Enrollment Capabilities: 
Most sites use first-line R-CVP in stage III/IV MALT lymphoma 
in Korea. Nearly 90 patients with stage IV disease might receive 
R-CVP per year in this center. However, some disease relapsed 
or progressed after prior chemotherapy or chemo-radiotherapy. 
Estimated Study 
Duration: 
65 months 
Planned Written 
Outcomes of This Study 
(check all that apply): 
 Final Study Report 
 Submit for presentation at scientific conference  
 Submit for full publication 
 Submit abstract/poster at scientific conference 
Publication Plan (if 
applicable): 
Jun 2020/ J Clin Oncol  
Intellectual Property 
Disclosure: 
 No  
 Yes  
Study Insurance: 
Covered by the study site as the local/national requirements for 
conducting clinical trial in Korea. 

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Past History and 
Experience: 
 No  
 Yes BR regimen is used in relapsed DLBCL and MCL patients 
in Korea. This center has many experiences in rituximab-based 
trials in malignant lymphomas. It also has bendamustine 
experience in treating indolent lymphoma.   
STUDY DRUG SUPPLY 
Study Drug Requested 
from Roche Per Patient: 
Mabthera IV/SC - maximum 1/7 cycles treatment per patients 
- 500mg/vial x1 + 200mg/vial x 1 (or 2) = 1 cycle per patient 
(IV) 
- 1400mg/vial x 7 cycles = 7 vials per patient (SC) 
39 planned patients x 8 vials/patient = 312 vials (total) 
Other Sources of Study 
Drug(s): 
Bendamustine 100mg/vial by Eisai Korea