Pembrolizumab in Marginalzone Lymphoma A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II STUDY
Phase: PHASE2
Conditions: Marginal Zone Lymphoma
Sponsor: University of Ulm

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 1 of 130 
 
 
 
 
 
 
POLE-1 
 
Pembrolizumab in MarginalzoneLymphoma 
A MULTICENTER OPEN LABEL SINGLE-ARM PHASE II 
STUDY 
Project Code: 
POLE-1 
Protocol Number 
V-3.0 
Date 
12 April 2021 
EUDRACT Number: 
2018-000187-28 
Included in clinicaltrials.gov 
database 
Yes     
 
   No 
 
NCT-No: NCT04268277 
Substance Identifier (IMP) 
Pembrolizumab (Keytruda®) 
Rituximab (Truxima®) 
Therapeutic Area  
Hematology/Oncology 
Sponsor 
University Hospital Ulm, Ulm, Germany; 
represented by the Chairman of the board 
 
Coordinating Investigator, 
Leiter der klinischen Prüfung 
acc. to German law 
 
Prof. Dr. Christian Buske 
University Hospital of Ulm 
Department of Internal Medicine III 
Albert-Einstein-Allee 23 
D-89081 Ulm 
 
 
 
This document contains confidential information belonging to the Department of Internal Medicine III and the 
Comprehensive Cancer Center Ulm, University of Ulm. Except as may be otherwise agreed to in writing, by accepting or 
reviewing these materials, you agree to hold such information in confidence and not to disclose it to others (except where 
required by applicable law), nor to use it for unauthorized purposes. In the event of actual or suspected breach of this 
obligation, the Ulm University Hospital should be promptly notified. 

Pole-1 Protocol V3.0, dated 12.04.2021 
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Clinical trials office (CTO) 
Project Management 
 
University Hospital of Ulm,  
Department of Internal Medicine III 
Albert-Einstein-Allee 23  
D-89081 Ulm 
 
Statistics/Biometry 
Prof. Dr. Rainer Muche 
Institute of Epidemiology and Medical Biometry 
Ulm University 
Schwabstrasse 13 
D-89075 Ulm 
 
 
Monitoring and Data 
Management 
X-act Cologne Clinical Research GmbH 
Rudi-Conin-Str. 4 
D-50829 Köln 
 
Pharmacovigilance  
 
ZKS Ulm (Zentrum für Klinische Studien Ulm) 
Albert-Einstein-Allee 11 
89081 Ulm 
 
 
Funding 
The study will be funded by an unconditional grant 
of MSD SHARP & DOHME GMBH. 
 
 
 

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2. Synopsis 
STUDY 
Project Code 
POLE-1 
Project Title 
Pembrolizumab in Marginal Zone Lymphoma  
Date 
12 April 2021 
Protocol 
Version 
3.0 
EUDRACT -
Number: 
2018-000187-28  
Included in 
clinicaltrials.gov 
database 
Yes     
 
   No 
 
NCT-No: NCT04268277 
Substance 
Identifier (IMP) 
Pembrolizumab (Keytruda®), Rituximab (Truxima®) 
Sponsor 
University Hospital Ulm 
Trial Design 
Phase II, single arm, multicentric, open label  
Scientific 
Rationale 
For marginal zone lymphoma (MZL) Rituximab in combination with conventional 
chemotherapy is widely used for those patients who fail local therapy or do not 
qualify for such. Depending on the MZL subtype Rituximab/chemotherapy is able 
to induce in part long remissions, but does not prevent relapse later on. In 
addition, chemotherapy associated toxicity is often problematic in MZL patients, 
who are mostly of advanced age. Thus, chemotherapy–free approaches are 
highly attractive for this patient group. Rituximab single agent is a widely used 
chemotherapy – free approach in MZL, but was significantly inferior 
compared to Rituximab/chlorambucil in a large randomized prospective 
clinical trial in treatment naïve MZL with a CR rate of 55,8% vs. 78,8%, 
respectively (P < 0.001)1. Thus, it is the major aim to develop chemotherapy– 
free approaches for MZL, which approach or surpass efficacy of 
Rituximab/chemotherapy combinations, but avoid chemotherapy associated 
toxicities. 
Checkpoint inhibitors such as Pembrolizumab have revolutionized cancer 
treatment and have also shown first encouraging results in Non-Hodgkin 
lymphomas 2-4. Based on these observations it is the aim of this study to test the 
toxicity and efficacy of Pembrolizumab in combination with the anti-CD20 
antibody Rituximab in patients with newly diagnosed or relapsed MZL in need of 
treatment, who are not eligible or failed local therapy, following the assumption 
that this novel chemotherapy – free combination is significantly more effective 
than Rituximab single agent therapy and at least as efficient as 
Rituximab/chemotherapy, but avoids chemotherapy–related toxicity.  

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Objectives 
The objective of this trial is to test the efficacy and toxicity of the treatment of 
Pembrolizumab/Rituximab in patients with MZL in need of treatment, who have 
failed or are not eligible for local therapy or relapsed after local or systemic 
therapy. For efficacy the rate of complete remissions (according to the GELA 
criteria for gastric MALT or to the Cheson 2007 criteria for non-gastric extranodal, 
nodal and splenic MZL) after therapy will be primarily analysed5-7. For toxicity 
assessment treatment associated adverse events, quality of life and cumulative 
incidence of secondary malignancies will be documented.  
Endpoints 
Primary Endpoint: 
• CR rate (CRR) after end of treatment (18 cycles) 
Secondary Endpoint(s): 
• Response rate (CR, PR, CR or PR) 
• Best response 
• Time to best response 
• Time to first response 
• Progression free survival (PFS) 
• Time to treatment failure (TTF) 
• Duration of Response (DR) 
• Cause specific survival (CSS) 
• Overall survival (OS) 
• Quality of life during therapy 
 
Safety Variables: 
Safety variables will include AEs, SAEs, laboratory parameters, ECG and vital 
signs. The severity of AEs will be graded using the NCI-CTCAE version 5.0 
dictionary. An AE is defined as any event arising or worsening from the time a 
signed and dated ICF is obtained until 110 days after the last study drug intake. 
Safety variables will be summarized by means of descriptive statistics and/or 
frequency tables as appropriate. All AEs, drug related AEs, serious AEs will be 
summarized by MedDRA classification and worst CTCAE grade. 
Projected 
Study Design 
European phase II trial, multicenter, single arm, open label 
Projected 
Number of 
Subjects 
maximum of 56 subjects 
Projected 
Number of 
Sites 
Approximately: 15 trial sites in Germany, 3 trial sites in Austria 
Participating 
Countries 
Germany, Austria 
Estimated First 
Patient in – first 
visit date 
Q3 2020 
Anticipated 
Last Patient - 
last visit date 
Q1 2028 
Estimated 
Duration 
of 
Enrollment 
12-18 months 

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Estimated 
individual 
Duration 
of 
Treatment 
54 weeks  
Study Duration 
approximately 7.5 years starting with first patient in (FPI) 
 
Eligibility 
Criteria 
Inclusion Criteria: 
Patients must have a proven pathological diagnosis of MZL, diagnosed by a 
reference pathology center.  
Patients must meet the following inclusion criteria to be eligible for participation 
in this study: 
– 
Confirmed CD20 positive de novo or relapsed MALT Lymphoma in need of 
treatment following or being not eligible for local therapy (including surgery, 
radiotherapy and antibiotics e.g. for H. pylori-positive gastric lymphoma 
arisen at any extranodal site)  
OR 
– 
Confirmed CD20 positive de novo or relapsed splenic MZL in need of 
treatment following or not being eligible for local therapy (including surgery 
and antiviral therapy for Hepatitis C Virus)  
OR 
– 
Confirmed CD20 positive de novo or relapsed nodal MZL in need of 
treatment following or not being eligible for local therapy (radiotherapy). The 
need of treatment is applicable in the case of B symptoms, deterioration of 
peripheral blood counts due to lymphoma infiltration of the bone marrow, 
rapid enlargement of lymph nodes or compression of vital organs by bulky 
disease. 
For nodal MZL and extragastric MALT lymphoma:  
– 
At 
least 
one 
bi-dimensionally 
measurable 
lesion  
 (≥ 1.5 cm in its largest dimension by CT/ PET-CT scan or MRI). Please refer 
to Appendix D. 
 
For splenic MZL (SMZL) 
In patients with splenic MZL, an enlarged spleen on CT scan and lymphoma 
cell infiltration has to be seen in bone marrow and/or peripheral blood. Please 
refer also to Appendix F.  
 
At least one of the following criteria must be fulfilled:  
– 
Bulky progressive or painful splenomegaly 
– 
one of the following symptomatic/progressive cytopenias: Hb < 10 g/dL, or 
Platelet count < 80.000 /µL, or neutropenia < 1000 /µL, whatever the reason 
(autoimmune or hypersplenism or bone marrow infiltration) 
– 
splenectomised 
patients 
with 
rapidly 
raising 
lymphocyte 
counts, 
development of lymphadenopathy or involvement of extranodal sites if not 
being eligible for local therapy 
 
– 
SMZL with concomitant hepatitis C infection which has not responded to or 
has relapsed after Interferon and/or Ribavirin and/or direct antiviral agents 
(patients positive for HCV antibody are eligible only if PCR is negative for 
HCV RNA) 
For gastric MALT Lymphoma: 
 

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– 
For gastric MALT lymhoma, the clinical evidence of the MZL as seen by 
gastroendoscopy is sufficient. There is no need to show a measurable lesion 
by CT scan or MRI. Please refer to Appendix E. 
Inclusion is possible for patients with: 
– 
H. pylori-negative disease de novo or following or being not eligible for local 
therapy (i.e., surgery, radiotherapy or antibiotics) or after systemic therapy 
– 
H. pylori-positive disease that has remained stable, progressed, or relapsed 
following antibiotic therapy 
 
Eligibility 
Criteria 
Others: 
• Age ≥ 18 years 
• Life expectancy >3 months. 
• Meet the following pretreatment laboratory criteria at the Screening visit 
conducted within 28 days of study enrollment (unless due to underlying 
lymphoma): 
– Baseline platelet count  75 109/L (if not due to BM infiltration by the 
lymphoma), absolute neutrophil count  1.5 109/L 
– Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without 
erythropoietin dependency and without packed red blood cell (pRBC) 
transfusion within last 2 weeks) 
– International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × ULN 
unless subject is receiving anticoagulant therapy as long as PT or PTT is 
within therapeutic range of intended use of anticoagulants 
– Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 × ULN unless subject is 
receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 
– ASAT (SGOT):  2,5 times the upper limit of institutional laboratory normal 
value or  5 times the upper limit of institutional laboratory normal value in 
subjects with lymphoma in the liver 
– ALAT (SGPT):  2,5 times the upper limit of institutional laboratory normal 
value or  5 times the upper limit of institutional laboratory normal value in 
subjects with lymphoma in the liver 
– Serum total bilirubin: ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with 
total bilirubin levels > 1.5 ULN (unless clearly related to the disease) 
– Serum creatinine ≤1.5 × ULN OR ≥60 mL/min GFR or CrCl for subjects with 
creatinine levels > 1.5 × institutional ULN 
– Negative HIV antibody 
– Patients with occult or prior HBV infection (defined as negative HBsAg and 
positive total HBcAb) may be included if HBV DNA is undetectable, provided 
that they are willing to undergo monthly DNA testing. Patients who have 
protective titers of HBSAb after vaccination or prior but cured hepatitis B are 
eligible 
– Patients positive for HCV antibody are eligible only if PCR is negative for HCV 
RNA 
– For women of child-bearing potential only: Serum or urine β-HCG must be 
negative during screening and at study enrolment visit. 
• Premenopausal fertile females must agree to use a highly effective method of 
birth control for the duration of the therapy up to 12 months after the last dose 
of Rituximab and through 4 months after the last dose of pembrolizumab. A 

Pole-1 Protocol V3.0, dated 12.04.2021 
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highly effective method of birth control is defined as those which results in a 
low failure rate (i.e. less than 1% per year) when used consistently and 
correctly such as combined (estrogen and progestogen containing) hormonal 
contraception associated with inhibition of ovulation (oral, intravaginal or 
transdermal), progestogen-only hormonal contraception associated with 
inhibition of ovulation (oral, injectable or implantable), intrauterine device 
(IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, 
vasectomised partner or sexual abstinence. Contraception and pregnancy 
testing 
are 
required 
according 
the  
CTFG recommendations 
• Men must agree not to father a child for the duration of therapy and 6 months 
after and must agree to advice a female partner to use a highly effective 
method of birth control. According to CTFG recommendations, men must use 
condoms. 
• Willingness and ability to comply with scheduled visits, drug administration 
plan, imaging studies, laboratory tests, other study procedures, and study 
restrictions 
• Evidence of a personally signed informed consent indicating that the subject 
is aware of the neoplastic nature of the disease and has been informed of the 
procedures to be followed, the experimental nature of the therapy, 
alternatives, potential benefits, possible side effects, potential risks and 
discomforts, and other pertinent aspects of study participation 
 
Exclusion Criteria: 
The presence of any of the following will exclude a subject from enrolment: 
• 
ECOG performance status ≥ 2 
• 
History of a malignancy except for the following: adequately treated local 
basal cell or squamous cell carcinoma of the skin, cervical carcinoma in 
situ, superficial bladder cancer, asymptomatic prostate cancer without 
known metastatic disease and with no requirement for therapy or requiring 
only hormonal therapy and with normal prostate specific antigen for ≥1 year 
prior to study enrolment visit, other malignancy treated with a curative 
intent and currently in complete remission, for ≥3 years 
• 
Central nervous system lymphoma, leptomeningeal lymphoma, or 
histologic evidence of transformation to a high-grade or diffuse large B-cell 
lymphoma 
• 
Has had prior chemotherapy (systemic anti-cancer therapy), targeted small 
molecule therapy, within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or baseline value) from AEs due to a previously 
administered agent 
– Note: Subjects with ≤ Grade 2 neuropathy are an exception to this 
criterion and may qualify for the study 
– Note: If a subject received major surgery, they must have recovered 
adequately from complications from the intervention prior to starting 
therapy 
• Evidence of ongoing systemic bacterial, fungal, or viral infection at the time 
of study enrolment visit 
• Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic 
liver disease, non-alcoholic steatohepatitis, primary biliary cholangitis, 
extrahepatic obstruction caused by cholelithiasis, cirrhosis of the liver, or 
portal hypertension 

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• Treatment with any other investigational agent or participating in another 
clinical trial with an investigational product within 4 weeks prior to entering 
this study or within 5 x the half-life (t1/2) of the investigational product, 
whichever is longer 
• Breastfeeding or Pregnancy 
• Congestive heart failure > New York Heart Association (NYHA) class 2 
• Unstable angina (angina symptoms at rest), new-onset angina (begun 
within the last 3 months) 
• Myocardial infarction less than 6 months before start of study medication  
• Uncontrolled arterial hypertension despite optimal medical management 
• Prior or ongoing clinically significant illness, medical condition, surgical 
history, physical finding, electrocardiogram (ECG) finding, or laboratory 
abnormality that, in the investigator’s opinion, could adversely affect the 
safety of the subject or impair the assessment of study results 
• Vaccination with a live vaccine within 30 days prior to start of therapy 
• Arterial or venous thrombotic or embolic events such as cerebrovascular 
accident (including transient ischemic attacks), deep vein thrombosis or 
pulmonary embolism within 3 months before the start of study medication. 
• Non-healing wound, ulcer, or bone fracture 
• History or concurrent interstitial lung disease of any severity and/or severely 
impaired lung function (as judged by the investigator) 
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 
agent or with an agent directed to another stimulatory or co-inhibitory T-cell 
receptor (e.g., CTLA-4, OX 40, CD137) 
• Has received prior radiotherapy within 2 weeks of start of study treatment. 
Participants must have recovered from all radiation-related toxicities, not 
require corticosteroids, and not have had radiation pneumonitis. A 1-week 
washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to 
non-CNS disease 
• Has known active CNS metastases and/or carcinomatous meningitis. 
Participants with previously treated brain metastases may participate 
provided they are radiologically stable, i.e. without evidence of progression 
for at least 4 weeks by repeat imaging (note that the repeat imaging should 
be performed during study screening), clinically stable and without 
requirement of steroid treatment for at least 14 days prior to first dose of 
study treatment 
• Has a history of non-infectious pneumonitis that required steroids, or 
current pneumonitis 
• History of anaphylaxis in association with previous administration of 
monoclonal antibodies or severe hypersensitivity (≥Grade 3) to the 
investigational medicinal products and/or any of its excipients 
• Has active autoimmune disease that has required systemic treatment in the 
past 2 years (i.e. with use of disease modifying agents, corticosteroids or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, 
or physiologic corticosteroid replacement therapy for adrenal or pituitary 
insufficiency, etc.) is not considered a form of systemic treatment 
• Has a known history of active TB (Bacillus Tuberculosis) 
• Medical history of allogeneic stem cell transplant 

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• Ongoing alcohol or drug addiction or known psychiatric or substance abuse 
disorders that would interfere with cooperation with the requirements of the 
trial 
• Diagnosis of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal 
Necrolysis (TEN)  
Treatment 
Cycle 1 (21 days cycle): 
 
Rituximab: 
375 mg/m2 IV day 1, 8, 15 
 
Pembrolizumab: 
200 mg IV fixed dose day 2 
 
Cycle 2-18 (21 days cycle) or until progression or non-tolerable toxicity: 
 
Rituximab: 
375 mg/m2 IV day 1 every second cycle  
 
Pembrolizumab: 
200 mg IV fixed dose day 1 
Rationale for dosing schedule of rituximab after cycle 1: 
Rituximab single agent is one of the widely used chemotherapy free approaches 
in MZL and has clear anti-lymphoma activity in MZL. This is why we aim at 
continuing Rituximab applications beyond cycle 1 to exploit this activity. In 
addition, conceptually Pembrolizumab as a PD1 inhibitor should increase the 
activity of Rituximab by “re-freshing” ADCC, which is important for Rituximab 
activity. Thus, we anticipate that Rituximab beyond its known activity as a single 
agent, shows increased activity when combined with Pembrolizumab until cycle 
18 in a de-escalated application scheme with one infusion every 8 weeks. 
Follow-up Phase: 
All subjects who enter the trial will continue to be followed every 3 months for 
disease progression, subsequent treatment, and survival for two years after 
completion/ discontinuation of the treatment. Subsequently, patients will be 
monitored every 6 months for three additional years. The follow-up phase will be 
shorter than 5 years if End of Study is reached before this time period. 
 
Safety 
There will be a close safety monitoring of the first 6 included patients. For 
these 6 patients safety evaluations will be performed on day 1, 8 and 15 for cycle 
1 and on day 1 and 15 for cycles 2-6. Safety evaluations include: adverse event 
monitoring, physical examinations, evaluation of changes to concomitant 
medications, and clinical laboratory parameters (hematology, serum chemistry, 
serum immunoglobulin [IgG, IgM, IgA], CRP). The severity of adverse events 
will be assessed using National Cancer Institute Common Terminology Criteria 
for Adverse Events, Version 5.0. Serious adverse events will be reported 
according to applicable legislation. The DSMC will review data regarding safety 
as planned according to the DSMC Charter latest 4 weeks after the 6th patient 
has ended cycle 9. Based on the review of the data of the first 6 patients the 
DSMC will give a risk assessment for the trial and recommendations for 
continuation/discontinuation of the study. 

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Statistical 
Methods 
In MZL a variety of treatment modalities are used such as Rituximab single agent, 
chemotherapy or Rituximab in combination with chemotherapy. It is widely 
accepted that in this non-curative indolent B – cell lymphoma of the mostly elderly 
patient chemotherapy – related toxicity should be avoided and that 
chemotherapy-free approaches are highly attractive in this patient population. So 
far Rituximab single agent is the most frequent chemotherapy-free approach 
used in this entity. Thus, a novel chemotherapy – free treatment approach should 
be at least as efficient as Rituximab monotherapy. In a large randomized study 
Rituximab single agent therapy induced a CRR of 55.8 % compared to 78.8 % 
for the combination of Rituximab and chlorambucil in de novo MZL of the MALT 
type. CR rates in splenic MZL are comparable high at about 60%8, whereas only 
10% of patients with nodal MZL achieve a CRR of around 20%9: As the 
distribution of subtypes is about 70% MALT, 20% splenic, and 10% nodal MZL, 
a CRR which is better than 56% should at least be achieved by a new 
chemotherapy – free approach after end of treatment (18 cycles) for such a 
mixture of the population. 
The goal of this study is to test the efficacy of the chemotherapy - free 
combination Pembrolizumab/Rituximab in treatment – naïve and relapsed 
symptomatic MZL aiming at achieving comparable treatment results compared 
to immuno- chemotherapy. 
 
Sample size/Power Calculation: 
For sample size calculation the one-sided one sample exact binomial test 
was  used. According to the above data, the CRR must be better than 56% after 
end of treatment (18 cycles). Based on a CRR for Pembrolizumab/Rituximab of 
about 75%, a significance level of 2.5% (because of one- sided test) and a power 
of 80%, 48 full evaluable patients will be necessary to show that the chemo-free 
combination 
will 
be 
a 
promising 
candidate 
for 
challenging 
immunochemotherapy (SAS PROC POWER, SAS 9.3; 48 patients is the first 
number of patients with a stable power of more than 80%). It is expected, that 
the rate of withdrawal in the study is smaller than 15%. According to these 
parameters, the study will enroll a maximum of 56 subjects. 
 
Statistical analysis of primary and secondary endpoints: 
The primary parameter CRR will be evaluated in an intention to treat way after 
end of treatment (18 cycles), which means that all eligible patients who received 
at least one cycle of treatment will be included in the analysis of the primary 
endpoint (Core Analysis Population). Only patients who withdraw will be excluded 
from this analysis population (about 15%). This analysis population consists of 
all eligible patients included in the study who received at least one cycle of 
treatment. Patients without staging at regular end of treatment will be defined as 
non-responder (i.e. CR=’NO’). 
The one sample exact binomial test will be used for the analysis of the primary 
endpoint to test the CRR against the fixed value 56% at the 2.5% significance level 
(one-sided). Thus, the decision about the new concept will be based on a 
statistical test of the form: 
 
HA : { CRR > 56%} vs. H0: { CRR ≤ 56%} 
 
Thus, claim of success can be done if 36 (75% of 48 patients) or more complete 
responders (patients with CR) will be observed. Patients who withdraw will be 
included in a separate explorative analysis. Additionally, a one-sided 97.5% 
confidence interval for CRR will be calculated as an effect estimator. Exploratory 
use of univariate logistic regression models will be used to investigate the 
influence of putative risk factors associated with CRR. All secondary endpoints 
will be analyzed exploratory by respective descriptive analysis and 95%- 
confidence intervals. 
 

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TABLE OF CONTENTS   
1. 
SIGNATURES ............................................................................................................................................ 3 
1.1 
SIGNATURE OF SPONSOR, COORDINATING PRINCIPAL INVESTIGATOR (ULM, GERMANY) ....................... 3 
1.2 
COORDINATING INVESTIGATOR (AUSTRIA) ....................................................................................................... 4 
1.3 
STATISTICS ................................................................................................................................................ 5 
2. 
SYNOPSIS ................................................................................................................................................. 6 
3. 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS .............................................................................. 19 
4. 
BACKGROUND INFORMATION AND STUDY RATIONALE ......................................................................... 22 
4.1 
MARGINAL ZONE LYMPHOMA ..................................................................................................................... 22 
4.2 
TREATMENT IN MARGINAL ZONE LYMPHOMA ................................................................................................ 24 
Treatment of MALT lymphoma .................................................................................................................... 24 
Treatment of nodal MZL ............................................................................................................................... 25 
Treatment of splenic MZL ............................................................................................................................. 26 
4.3 
RATIONALE OF THE TRIAL ............................................................................................................................ 27 
5. 
TRIAL OBJECTIVE AND ENDPOINTS ........................................................................................................ 30 
5.1 
PRIMARY OBJECTIVE ................................................................................................................................. 30 
5.2 
PRIMARY ENDPOINT .................................................................................................................................. 30 
5.3 
SECONDARY ENDPOINTS ............................................................................................................................ 30 
5.4 
SAFETY VARIABLES .................................................................................................................................... 32 
6. 
STUDY DESIGN ....................................................................................................................................... 32 
6.1 
ESTIMATED STUDY DURATION ..................................................................................................................... 33 
7. 
STUDY POPULATION .............................................................................................................................. 34 
7.1 
INCLUSION CRITERIA FOR REGISTRATION ........................................................................................................ 34 
7.2 
EXCLUSION CRITERIA FOR REGISTRATION ....................................................................................................... 37 
8. 
TREATMENTS ......................................................................................................................................... 39 
8.1 
STUDY DRUG (IMP) .................................................................................................................................. 39 
8.1.1.1 
Packaging and labeling ........................................................................................................................... 39 
8.1.1.2 
Responsibilities ....................................................................................................................................... 40 
8.1.1.3 
Storage and Handling Requirements ...................................................................................................... 40 
8.1.1.4 
Returns and Reconciliation ..................................................................................................................... 40 
8.1.2 
Pembrolizumab ............................................................................................................................... 41 
8.1.2.1 
Structure and Mechanismen of Action of Pembrolizumab .................................................................... 41 
8.1.2.2 
Pharmaceutical and Therapeutic Background ........................................................................................ 41 
8.1.2.3 
Preclinical and Clinical Trial Data ............................................................................................................ 42 

Pole-1 Protocol V3.0, dated 12.04.2021 
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8.1.2.4 
Pembrolizumab Materials ...................................................................................................................... 43 
8.1.2.5 
Timing of Dose Administration ............................................................................................................... 43 
8.1.3 
Rituximab ........................................................................................................................................ 44 
8.1.3.1 
Formulation Packaging and Labeling ...................................................................................................... 44 
8.1.3.2 
Preparation and Administration of Rituximab IV Formulation ............................................................... 45 
8.1.3.3 
Known serious adverse reactions of Rituximab ...................................................................................... 47 
8.1.3.4 
Undesirable effects ................................................................................................................................. 51 
8.2 
TREATMENT SCHEDULE AND DESIGN ............................................................................................................. 51 
8.3 
DOSE ADJUSTMENTS ................................................................................................................................. 53 
8.3.1 
Pembrolizumab i.v. .......................................................................................................................... 53 
8.3.1.1 
Dose Modification and toxicity management for irAEs associated with Pembrolizumab ...................... 53 
8.3.1.2 
Dose modification and toxicity management of infusion-reactions related to Pembrolizumab ............ 54 
8.3.1.3 
Other dose interruption allowed for Pembrolizumab ............................................................................ 59 
8.3.2 
Rituximab i.v. ................................................................................................................................... 59 
8.4 
PERMITTED MEDICATIONS AND SUPPORTIVE THERAPIES .................................................................................. 59 
8.5 
PROHIBITED CONCOMITANT THERAPY ........................................................................................................... 60 
8.6 
VACCINATIONS ......................................................................................................................................... 61 
9. 
SCHEDULE OF ASSESSMENTS ................................................................................................................. 61 
9.1 
DEFINITION OF (STAGING) EXAMINATIONS ..................................................................................................... 61 
9.1.1 
Pathological diagnostic ................................................................................................................... 61 
9.1.2 
Tumor and Response Evaluation ..................................................................................................... 62 
9.1.3 
Bone marrow examinations ............................................................................................................ 64 
9.1.4 
Demographic and medical history ................................................................................................... 64 
9.1.5 
Physical Examination ....................................................................................................................... 64 
9.1.6 
B Symptoms ..................................................................................................................................... 65 
9.1.7 
Vital Signs ........................................................................................................................................ 65 
9.1.8 
ECOG ............................................................................................................................................... 65 
9.1.9 
Electrocardiograms ......................................................................................................................... 65 
9.1.10 
Laboratory Assessments ............................................................................................................. 65 
9.1.11 
Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym) ......................................... 66 
9.1.12 
Collection of Biological Material for Biobank.............................................................................. 66 
9.2 
SCREENING PROCEDURES............................................................................................................................ 67 
9.3 
ASSESSMENTS DURING TREATMENT ............................................................................................................. 68 
9.4 
THERAPY COMPLETION (EOT) .................................................................................................................... 72 
9.5 
FOLLOW-UP ASSESSMENTS ........................................................................................................................ 74 
10. 
STUDY PROCEDURES .......................................................................................................................... 74 
10.1 
INFORMED CONSENT ................................................................................................................................. 74 
10.2 
REGISTRATION PROCEDURE ........................................................................................................................ 75 

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10.3 
PATIENT STUDY PARTICIPATION CARD ........................................................................................................... 76 
10.4 
CRITERIA FOR PREMATURE DISCONTINUATION OF THE STUDY ............................................................................. 76 
10.4.1 
Early Treatment discontinuation for an individual patient ......................................................... 76 
10.4.2 
Early study termination for an individual patient ....................................................................... 77 
10.4.3 
Early closing of a trial site ........................................................................................................... 77 
10.4.4 
Early termination of the study .................................................................................................... 78 
11. 
ASSESSMENT OF SAFETY .................................................................................................................... 78 
11.1 
MONITORING, RECORDING AND REPORTING OF ADVERSE EVENTS ..................................................................... 78 
11.1.1 
Adverse Event.............................................................................................................................. 78 
11.1.2 
Adverse Event of Special Interest ................................................................................................ 79 
11.1.3 
Adverse Drug Reaction ................................................................................................................ 80 
11.1.4 
Special Situations ........................................................................................................................ 80 
11.2 
EVALUATION OF ADVERSE EVENTS ............................................................................................................... 82 
11.2.1 
Seriousness .................................................................................................................................. 82 
11.2.2 
Severity / Intensity ...................................................................................................................... 83 
11.2.3 
Causality...................................................................................................................................... 84 
11.2.4 
Expectedness ............................................................................................................................... 84 
11.2.5 
Duration ...................................................................................................................................... 85 
11.2.6 
Action Taken ............................................................................................................................... 85 
11.2.7 
Outcome...................................................................................................................................... 85 
11.2.8 
Abnormal Laboratory Values ...................................................................................................... 85 
11.3 
DEFINITION OF AN OVERDOSE OF PEMBROLIZUMAB FOR THIS PROTOCOL AND REPORTING OF OVERDOSE .................. 85 
11.4 
OTHER MALIGNANCIES ............................................................................................................................... 86 
11.5 
PREGNANCY ............................................................................................................................................ 86 
11.6 
REPORTING OF SERIOUS ADVERSE EVENTS ..................................................................................................... 87 
11.6.1 
Reporting period ......................................................................................................................... 87 
11.6.2 
Obligations of the Investigator ................................................................................................... 87 
11.6.3 
Safety Queries ............................................................................................................................. 89 
11.6.4 
Obligations of the sponsor .......................................................................................................... 89 
11.7 
PRODUCT QUALITY COMPLAINT HANDLING ..................................................................................................... 90 
11.8 
BENEFIT/RISK ASSESSMENT OF TREATMENT PROGRAM ..................................................................................... 90 
12. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 91 
12.1 
EXPECTED IMPROVEMENT .......................................................................................................................... 91 
12.2 
SAMPLE SIZE ............................................................................................................................................ 92 
12.3 
ANALYSIS OF THE PRIMARY ENDPOINT .......................................................................................................... 92 
12.4 
ANALYSIS OF THE SECONDARY ENDPOINTS ..................................................................................................... 92 
12.5 
SAFETY ANALYSES ..................................................................................................................................... 93 

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12.6 
ANALYSIS POPULATIONS ............................................................................................................................ 93 
12.6.1 
Core Analysis Population............................................................................................................. 93 
12.6.2 
Safety population ........................................................................................................................ 93 
13. 
INDEPENDENT DATA SAFETY MONITORING COMMITTEE .................................................................. 93 
14. 
STUDY MONITORING AND DATA MANAGEMENT .............................................................................. 94 
14.1 
INVESTIGATORS RESPONSIBILITIES ................................................................................................................ 94 
14.2 
SPONSOR RESPONSIBILITIES ........................................................................................................................ 94 
14.3 
SOURCE DOCUMENT REQUIREMENTS ............................................................................................................ 95 
14.4 
MONITORING VISITS ................................................................................................................................. 95 
14.5 
USE AND COMPLETION OF THE (ELECTRONIC) CASE REPORT FORMS (ECRF) ......................................................... 95 
14.6 
STUDY DRUG MONITORING ........................................................................................................................ 96 
15. 
ETHICAL AND REGULATORY STANDARDS ........................................................................................... 96 
15.1 
ETHICAL PRINCIPLES .................................................................................................................................. 96 
15.2 
LAWS AND REGULATIONS ........................................................................................................................... 97 
15.3 
DATA PROTECTION CONCEPT ...................................................................................................................... 97 
15.4 
ETHICS COMMITTEE AND COMPETENT AUTHORITIES SUBMISSION ....................................................................... 97 
16. 
ADMINISTRATIVE PROCEDURES......................................................................................................... 97 
16.1 
CURRICULUM VITAE .................................................................................................................................. 97 
16.2 
SECRECY AGREEMENT ................................................................................................................................ 97 
16.3 
RECORD RETENTION IN INVESTIGATING TRIAL SITES .......................................................................................... 98 
16.4 
OWNERSHIP OF DATA AND USE OF THE STUDY RESULTS ..................................................................................... 98 
16.5 
PUBLICATION ........................................................................................................................................... 98 
16.6 
INSURANCE COMPENSATION ....................................................................................................................... 99 
16.7 
COMPANY AUDITS AND INSPECTIONS BY REGULATORY AGENCIES ........................................................................ 99 
16.8 
CLINICAL STUDY REPORT ............................................................................................................................. 99 
16.9 
PROTOCOL AMENDMENTS .......................................................................................................................... 99 
16.10 
CONTRACT OF INVESTIGATION .............................................................................................................. 100 
16.11 
FINANCING ....................................................................................................................................... 101 
17. 
REFERENCES .................................................................................................................................... 102 
APPENDICES ................................................................................................................................................. 105 
APPENDIX A: STUDY FLOWCHART ........................................................................................................................... 106 
APPENDIX B: BIOLOGICAL SAMPLES FOR FURTHER ANCILLARY STUDIES ............................................................................ 111 
APPENDIX C: CONTRACEPTIVE GUIDANCE AND PREGNANCY TESTING ............................................................................. 113 
1. 
Contraception Requirements ............................................................................................................. 113 
2. 
Pregnancy Testing ............................................................................................................................. 115 

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APPENDIX D: SELECTION OF LESIONS AND RESPONSE CRITERIA FOR NODAL MARGINAL ZONE LYMPHOMA AND EXTRAGASTRIC 
MALT LYMPHOMA .............................................................................................................................................. 116 
APPENDIX E: RESPONSE CRITERIA FOR EXTRANODAL GASTRIC MARGINAL ZONE LYMPHOMA (MALT) ................................. 120 
APPENDIX F: RESPONSE CRITERIA SPLENIC MARGINAL ZONE LYMPHOMA ....................................................................... 121 
APPENDIX G: ANN ARBOR STAGE ........................................................................................................................... 122 
APPENDIX H: ECOG PERFORMANCE STATUS CRITERIA ............................................................................................... 123 
APPENDIX I: FUNCTIONAL ASSESSMENT OF CANCER THERAPY FOR LYMPHOMA (FACTLYM) (VERSION 4)............................. 124 
APPENDIX J: PATHOLOGY REFERENCE CENTERS ......................................................................................................... 127 
APPENDIX K: DATA SAFETY MONITORING COMMITTEE ............................................................................................... 129 
APPENDIX L: PATIENT INSURANCE ........................................................................................................................... 130 
 
 
 

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3. 
List of abbreviations and glossary of terms 
AE  
 
Adverse Event 
AESI 
 
Adverse Event of Special Interest 
ADR  
 
Adverse Drug Reaction 
ADCC 
 
Antibody Dependent Cell-mediated Cytotoxicity 
ALAT (SGPT) 
ALanine AminoTransferase (Serum Glutamic Pyruvic Transaminase) 
ANC  
 
Absolute Neutrophil Count 
ASAT (SGOT) 
ASpartate AminoTransferase (Serum Glutamic Oxaloacetic Transaminase) 
ASCT 
 
autologous stem cell transplantation 
AUC  
 
Area Under the Curve 
BSA  
 
Body Surface Area 
BM  
 
Bone Marrow 
BW  
 
Body Weight 
CBC  
 
Complete Blood Count 
CHOP 
 
Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone 
CIRS 
 
Cumulative Illness Rating Scale 
CNS  
 
Central Nervous System 
CR  
 
Complete Remission/Response 
CrCL 
 
Creatinine Clearance 
CRO 
 
Contract research organization 
CRP  
 
C-reactive protein 
CRR 
 
Complete Remmision Rate 
CSS  
 
Cause Specific Survival 
CT  
 
Computed Tomography 
CTO  
 
Clinical Trials Office 
CTCAE 
 
Common Toxicity Criteria for Adverse Events 
DFS  
 
Disease-free survival time 
DLT  
 
Dose-limiting toxicity 
DSMC 
 
Data Safety Monitoring Committee 
DR  
 
Duration of Remission 
DRESS 
 
Drug Rash with Eosinophilia and Systemic Symptom 
EC  
 
Ethics Committee 
ECI  
 
Events of Clinical Interest 
ECOG 
 
Eastern Cooperative Oncology Group 
eCRF 
 
electronic Case Report Form 
EOT  
 
End of Treatment 
FISH 
 
Fluorescence In Situ Hybridization 
FL  
 
Follicular Lymphoma 
FPI  
 
First patient in 
GCP 
 
Good Clinical Practice 
GI 
 
 
Gastrointestinal 
GLP  
 
Good Laboratory Practice 

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Hb  
 
Hemoglobin 
HBV  
 
Hepatitis-B-Virus 
HCV  
 
Hepatitis-C-Virus 
HIV  
 
Human Immunodeficiency Virus 
HSCT 
 
Hematopoietic Stem Cell Transplantation 
ICH  
 
International Conference on Harmonisation 
Ig 
 
 
Immunoglobulin 
IMP  
 
Investigational Medicinal Product 
IR 
 
 
immune related 
IRB  
 
Institutional Review Board 
IRR  
 
Infusion-Related Reaction 
ITT  
 
Intention-To-Treat 
IV 
 
 
IntraVenous 
LDH  
 
Lactic DeHydrogenase 
LLN  
 
Lower Limits of Normal 
LPL   
 
Lymphoplasmocytic Lymphoma 
MZL  
 
Marginal Zone Lymphoma 
MTD 
 
Maximal Tolerated Dose 
MRD  
 
Minimal Residual Disease 
NCI  
 
National Cancer Institute 
NFkB 
 
NFkappB 
NHL  
 
Non-Hodgkin’s Lymphoma 
OS  
 
Overall Survival 
ORR 
 
Overall response rate 
PD  
 
Progressive Disease 
PFS  
 
Progression Free Survival 
Plt  
 
Platelets 
PK  
 
Pharmacokinetic 
PR  
 
Partial Remission 
PS  
 
Performance Status 
RNA  
 
Ribonucleic acid 
SAE  
 
Serious Adverse Event 
SC   
 
Subcutaneous 
SD  
 
Stable Disease 
SJS  
 
Stevens-Johnson syndrome 
SmPC 
 
Summary of Product Characteristics 
 
SPD  
 
Sum of the Product of the Diameters  
SSE  
 
Significant safety event 
SUSAR 
 
Suspected Unexpected Serious Adverse Reaction 
T1DM 
 
Type I Diabetes Mellitus 
TEN  
 
Toxic epidermal necrolysis 
TLS  
 
Tumor Lysis Syndrome 
TTF  
 
Time to treament failure 

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ULN  
 
Upper Limit of Normal 
WBC 
 
White blood cells 
WHO 
 
World Health Organization 
WOCBP  
 
Woman of Childbearing Potential 
 
 

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4. 
BACKGROUND INFORMATION AND STUDY RATIONALE 
4.1 
Marginal Zone Lymphoma 
MZL belongs to the group of indolent B – NHL and is characterized by an indolent clinical 
course. MZL is diagnosed in the local or advanced stage and is in this situation a non-curative 
disease. MZL comprises 3 histological entities: splenic (SMZL), nodal (NMZL), and extranodal 
MZL of mucosa-associated lymphoid tissue (MALT) type. The subtypes share a similar 
immunophenotype, but differ with regard to clinical characteristics and prognosis. 
Splenic marginal zone lymphoma (SMZL) infiltrates the spleen, bone marrow and peripheral 
blood and usually occurs in the elderly. Marked splenomegaly as well as thrombocytopenia 
and anemia are the main features at presentation. In SMZL, peripheral lymph nodes and other 
mucosa-associated lymphoid tissue (MALT) are not usually infiltrated, except for the splenic 
hilar lymph nodes. Monoclonal IgM is observed in approximately 1/3 of cases. The diagnosis 
is based usually on spleen tissue samples whose lesions are characterized by a micronodular 
pattern, in which the lymph follicles (white pulps) have increased number and size. 
Characteristic histopathological features of infiltration also may occur in the bone marrow, 
peripheral blood and splenic hilar lymph nodes, which together with clinical findings, often help 
to diagnose the disease correctly 10-12.  
Nodal marginal zone lymphoma (NMZL), whose diagnosis is made only after excluding other 
low-grade lymphomas, is characterized by the presence of a primary lesion in the lymph nodes 
and is a neoplastic counterpart of post-germinal center marginal zone cells. The 
histopathological findings of NMZL overlap with those of other MZLs, including MALT 
lymphoma and SMZL, as well as lymphoplasmacytic lymphoma (LPL), and can be difficult to 
distinguish from these lymphoma subtypes with secondary lymph node infiltration. Lymph node 
involvement of NMZL can be localized or systemic; infiltration into the bone marrow or 
peripheral blood is rare. Plasmacytoid differentiation is observed but generally without 
monoclonal 
IgM, 
differentiating 
it 
from 
Waldenström’s 
Macroglobulinemia. 
The 
histopathological features of NMZL resemble those of MALT type and SMZL. Lymphoma cells 
proliferate in a marginal zone pattern in the lymph nodes 9, 13-15.  
In Mucosa- Associated Lymphoid Tissue (MALT Lymphoma), infiltration occurs in a variety of 
extranodal organs, with digestive organs accounting for about half (of which about 85% of 
cases have gastric involvement). Virtually every organ can be affected by MALT lymphoma 
infiltration and can include the lung (14%), head and neck (14%), ocular adnexa (12%), skin 
(11%) and thyroid gland (4%). Monoclonal IgM paraproteinemia appears in 1/3 of cases. MALT 

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lymphoma presents a variety of histological findings which can make it difficult to distinguish 
MALT lymphoma with prominent colonization from FL 16.  
Several prognostic factors have been identified for MZL: thus, the „Integruppo Italiano Linfomi“ 
carried out a study to assess the outcomes of SMZL to identify prognostic factors in 309 
patients. Using three variables, hemoglobin level less than 12 g/dl, LDH level greater than 
normal and albumin level less than 3.5 g/dl, they grouped patients into three prognostic 
categories: low-risk group (41%) with no adverse factors, intermediate-risk group (34%) with 
one adverse factor and high-risk group (25%) with two or three adverse factors. The 5-year 
cause specific survival (CSS) rate was 88% for the low-risk group, 73% for the intermediate-
risk group and 50% for the high-risk group 10. Subsequently, an international study of 593 
SMZL patients identified hemoglobin, platelet count, high lactate dehydrogenase level, and 
extrahilar lymphadenopathy as parameters independently associated with lymphoma-specific 
survival (LSS). Three risk groups were identified with significantly different 5-year LSS (94%, 
78%, and 69%, respectively) 17. In a subsequent study that aimed at optimizing prognostication 
clinically acceptable cut points were established: 9.5 g/dL for hemoglobin, and 80x109/L for 
platelet count. The patients were allocated into 3 groups: low risk (36%) with 0 points, 
intermediate risk (56%) with 1 or 2 factors, and high risk (8%) with 3 or 4 factors. The 3 groups 
had a 5-year LSS of 95%, 87%, and 68%, respectively 18.  
For extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) a 
prognostic index was built by Cox regression, using data from 401 patients enrolled in the 
international randomized International Extranodal Lymphoma Study Group 19 (IELSG-19) trial. 
A validation set, including 633 patients, was obtained by merging 3 independent cohorts of 
MALT lymphoma patients. The 3 individual features maintaining the greatest prognostic 
significance for event-free survival (EFS, the main endpoint of the IELSG-19 trial) were age > 
70 years (hazard ratio [HR], 1.72; 95% confidence interval [CI], 1.26-2.33), Ann Arbor stage III 
or IV (HR, 1.79; 95% CI ,1.35-2.38), and an elevated lactate dehydrogenase level (HR, 1.87; 
95% CI, 1.27-2.77). The prognostic index (MALT-IPI) constructed using these 3 parameters 
identified 3 groups: low, intermediate, and high risk (corresponding to the presence of 0, 1, or 
≥ 2 of these factors, respectively). The 5-year EFS rates in the low-, intermediate-, and high-
risk groups were 70%, 56%, and 29%, respectively. The MALT-lymphoma International 
Prognostic Index (MALT-IPI) also significantly discriminated between patients with different 
progression-free, overall, and cause-specific survival. The prognostic utility was retained in 
gastric and nongastric lymphomas, in each treatment arm (chlorambucil, Rituximab, and 
Rituximab plus chlorambucil), and was confirmed in the validation set 19.  
 
 

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4.2 
Treatment in Marginal Zone Lymphoma 
Treatment of MALT lymphoma 
Local Treatments 
Although surgical resection of tumors may be curative in many patients with MALT lymphoma, 
the use of this strategy is progressively decreasing. This is because postsurgical sequels and 
organ dysfunction are more injurious than the lymphoma itself. Therefore, surgery is mostly 
limited to diagnostic procedures for histopathologic diagnosis, management of therapeutic 
complications, or treatment of relapsing disease in patients who are not candidates for other 
treatments. Gastrectomy, for example, is currently being used as a salvage or palliative 
approach to bleeding or perforation, both of which are extremely rare in gastric MALT 
lymphoma. It is noteworthy that some cases of pulmonary MALT lymphoma are completely 
resected, because radiologic assessment initially suspected a diagnosis other than lymphoma 
(i.e., lung carcinoma). Complete excision can be performed in many conjunctival and lacrimal 
gland MALT lymphomas, especially in pseudoencapsulated lesions. However, additional 
efforts to completely resect lymphomatous lesions should be avoided considering that the 
extent of surgical resection does not influence survival. Radiotherapy is used as salvage 
therapy in patients with gastric MALT lymphoma who do not respond to or who relapse after 
HP eradication. The best disease control is attained in lymphomas arising in the thyroid gland, 
whereas up to 40% of patients with ocular adnexal MALT lymphoma experience contralateral 
or distant relapse. Most irradiated patients with stage I MALT lymphoma achieve an objective 
response that is slow and gradual. In-field relapses are uncommon. Patients with ocular 
adnexal MALT lymphoma often develop a cataract 2 to 5 years after treatment. Irradiated 
patients with gastric MALT lymphoma develop transient anorexia and malaise and occasional 
nausea or dyspepsia. Radiotherapy is associated with significant residual xerostomia in 
patients with Sjörgen Syndrome and MALT lymphoma of the salivary glands; this complication 
is often symptomatic and requires permanent dietary modifications. Radiation pneumonitis, 
presenting as permanent but nonprogressive fibrosis, occurs in patients with lung MALT 
lymphoma, even when low doses are used; this event is usually asymptomatic. Rare cases of 
in-field second cancers have been reported 16. 
Systemic treatments 
Patients with (mostly advanced) MALT lymphoma had been and still are included in trials 
mostly encompassing follicular lymphomas. The first paper to single out MALT lymphoma 
patients treated with the oral alkylating agents chlorambucil and cyclophosphamide was 
published in 1995, showing a 75% complete response rate (CRR) after a median duration of 
therapy of 12 months 20. Since then, several mostly small, uncontrolled trials using various 

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agents and combinations in MALT lymphoma have been published, although few randomized 
data currently exist. Two randomized trials exist, including the International Extranodal 
Lymphoma Study Group (IELSG)-19 study on chlorambucil versus Rituximab plus 
chlorambucil 1, 21 and a randomized study on wait and see versus chlorambucil in patients with 
gastric MALT lymphoma after HP eradication 22. Interestingly, the latter study, which 
randomized 110 patients, could not establish a benefit for chlorambucil monotherapy after HP 
eradication. The 5-year recurrence rate was 21% in the “wait-and-see” arm versus 11% in the 
chlorambucil arm (p = .15), and it is also interesting that no benefit was seen with chlorambucil 
in patients who had residual lymphoma after antibiotics. To date, the randomized, multicenter 
IELSG-19 trial is the largest prospectively randomized trial in MALT lymphoma, including a 
total of 231 patients, comparing chlorambucil versus Rituximab-chlorambucil. Chlorambucil 
was given orally at 6 mg/m2 for 42 consecutive days (weeks 1-6), followed by chlorambucil for 
2 weeks every 28 days up to 4 cycles. The response rate was 87% for the chlorambucil arm 
and 94% for the combination arm (P = .069), whereas both the CRR and the 5-year event-free 
survival rate were significantly higher with the combination (78% vs 65% [P = .025] and 68% 
vs 50%, respectively) in both gastric and extragastric MALT lymphoma. However, the long-
term outcome was not significantly improved, questioning the need for combining chlorambucil 
and Rituximab in asymptomatic patients. As a consequence, the study was extended to include 
a Rituximab-monotherapy arm to allow for further comparison of activity between Rituximab 
and chlorambucil monotherapy. Rituximab single agent therapy was inferior to the combination 
with a CR rate of 55.8% and an EFS at 5 years of 50% (95% CI, 42 to 59), but with similar 
overall survival in all three arms1.  
The Spanish Lymphoma/Autologous Marrow Transplant Study Group (GELTAMO) has 
included 60 patients with treatment-naïve MALT lymphoma in a trial of Rituximab 375 
mg/m2 intravenously on day 1 and Bendamustine 90 mg/m2 (R-Benda) on days 1 and 2 23. The 
protocol was designed to expose patients to minimal necessary therapy; thus, patients in 
complete remission after 3 courses were given only 4 cycles, whereas other patients 
underwent 6 cycles. In this study, a 100% response rate was seen, with no relapses occurring 
after a median follow-up of 14 months. In addition, an Austrian retrospective series has also 
shown responses in heavily pretreated patients with extragastric MALT lymphoma, underlining 
the high potential of R-Benda 24. In view of these findings, the combination of R-Benda appears 
to be attractive for use outside of clinical trials, if a chemotherapy is planned in these patients. 
Treatment of nodal MZL 
As of today, there are no standard recommended treatments for NMZL. Typically, the same 
strategy as that used for follicular lymphoma is applied in NMZL patients. Patients with strictly 

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localized disease may be considered for localized radiation therapy. In cases of low tumor 
burden, a watchful waiting strategy is usually employed, whereas in disseminated-stage 
disease, immunochemotherapy (Rituximab plus chemotherapy with or without an 
anthracycline) is considered an appropriate option. Current combinations include 
Rituximab/cyclophosphamide/vincristine/prednisone 
(R-CVP), Rituximab/fludarabine 
(FR), and fludarabine/cyclophosphamide/Rituximab (FCR), (although only a limited number of 
patients have been treated), with reported overall response rates (ORRs) >85% and 3-year 
PFS in the range of 60% to 90%. Of note, in the trial evaluating FR, excessive toxicity was 
reported and only 58% of these MZL patients completed the planned protocol 9, 12. 
As the most common treatment of all lymphomas, anthracycline-containing chemotherapy 
(Rituximab/cyclophosphamide/doxorubicin/vincristine/prednisone [R-CHOP]) is commonly 
used to treat NMZL patients; however, there are no convincing data justifying its 
recommendation in this patient population. Bendamustine-Rituximab (BR) was tested as first-
line therapy in a multicenter, randomized, phase 3 study comparing the efficacy and safety of 
BR vs R-CHOP in 549 indolent lymphomas (including 67 MZL, 41 lymphoplasmacytic 
lymphoma, 21 small lymphocytic lymphoma) 25. In the overall study population, after a median 
follow-up of 45 months, median PFS was longer in the BR group than with R-CHOP (69.5 vs 
31.2 months; hazard ratio, 0.58; 95% confidence interval, 0.44-0.74; P < .0001). BR was less 
frequently associated with serious adverse events than R-CHOP (19% vs 29%), notably 
severe infectious complications with fatal outcomes. The very small proportion of MZL patients 
included limits unequivocal extrapolation of this data to NMZL patients.  
Treatment of splenic MZL 
Consensus guidelines recommend treating SMZL only in the presence of symptomatic 
splenomegaly, cytopenias, systemic symptoms, or progressive nodal disease. Autoimmune 
cytopenias should be specifically treated 26. No randomized trials have been conducted in 
SMZL and, as consequence, there is no consensus on how to treat newly diagnosed and 
relapsed patients. The therapeutic options for SMZL have a wide range and include 
splenectomy, chemotherapy, and Rituximab alone or Rituximab with chemotherapy. In 
addition, antiviral treatment should be considered in patients with SMZL and concurrent 
chronic infection with HCV-related hepatitis who do not need immediate conventional 
treatment against the lymphoma. 
Splenectomy 
As a therapeutic approach, surgical removal of large spleens may eliminate a significant 
amount of disease by ameliorating abdominal discomfort and resolving cytopenias that result 
from splenic sequestration. After surgery, patients can remain free from treatment for many 

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years. Because cytopenias resulting from marrow failure do not resolve after splenectomy, a 
BM biopsy is advisable during the workup to define the burden of BM infiltration by the disease. 
One additional advantage of splenectomy is that it allows a definitive diagnosis of SMZL. 
Drawbacks of splenectomy are short-term (perioperative events) and long-term (immune 
suppression and infections) complications. Perioperative complications were registered in one 
quarter of a recent series of 41 splenectomized patients: pulmonary dysfunction in 8 (19.5%), 
deep vein thrombosis in 1 (2.4%), portal vein thrombosis in 1 (2.4%), and major bleeding in 9 
(21.9%). Infections caused by encapsulated bacteria are the major risk associated with 
splenectomy, and vaccination against capsulated bacteria is mandatory at least 2 weeks 
before elective splenectomy. Splenectomy should be contraindicated in cases with 
disseminated lymphoma with nodal involvement outside the splenic hilum 8, 26, 27.  
Rituximab-based treatment 
Rituximab monotherapy yield results similar to those of splenectomy, avoid the toxicity of 
chemotherapy, and potentially eradicate the disease at the molecular level. Kalpadakis et 
al reported 58 patients treated with Rituximab once per week for 6 weeks, followed by a 
maintenance phase once every 2 months for 1 to 2 years. At the end of the induction phase, 
the CR rate was 45%, unconfirmed CR 26%, and partial response 24%; the 5-year overall 
survival and progression-free survival (PFS) were 92% and 73%, respectively. According to 
the European Society for Medical Oncology guidelines, Rituximab monotherapy is a 
reasonable first-line therapy and a less traumatic alternative to splenectomy. The combination 
of Rituximab with chemotherapy is considered standard therapy for symptomatic, indolent B-
cell NHL. In SMZL, this approach is indicated for eligible patients with disseminated 
disease, constitutional symptoms, and/or signs of high-grade transformation. The combination 
of Rituximab with Bendamustine (BR) is effective in indolent NHL, although it has never been 
tested in a dedicated trial of SMZL. In the Bright study, the overall response rate to BR was 
92% in 25 patients with MZL. In the StiL trial, the PFS for BR therapy was not longer than that 
for Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) 
among patients with MZL, but the study was not powered to find differences in the MZL subset 
8, 15.  
4.3 
Rationale of the trial 
As pointed out above there is no standard treatment for patients with MZL and systemic 
treatment approaches range from Rituximab single agent therapy to more intense 
immunochemotherapies such as Rituximab-Bendamustine or Rituximab-CHOP. With the latter 
approaches high remission rates and long responses are induced, but the dilemma here is, 
that data do not convincingly show that patients live longer with dose intense approaches 

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compared with less intensive treatments. Furthermore, it has taken into account that none of 
the dose intense approaches are curative and that the majority of patients suffering from MZL 
are elderly, quite often having non-lymphoma related co-morbidities. Thus, mild chemo-free 
approaches are highly attractive in this disease and the feasibility of this approach has been 
recently shown for the BTK – inhibitor Ibrutinib. The drug showed comparably low toxicity and 
anti-lymphoma activity in patients with relapsed MZL, leading to the approval of the drug by 
the FDA for patients with relapsed/refractory MZL, which have received a Rituximab containing 
regimen before. However, the disadvantage of this treatment approach is that the drug has to 
be given continuously and that overall response and the CR rates were moderate with 48% 
and 3%, respectively. Median progression-free survival was 14.2 months. Probably the most 
widely used chemofree approach is Rituximab single agent in patients with MZL. As described 
above Rituximab monotherapy is well tolerated, safe and has reasonable anti-lymphoma 
activity in all three subtypes of MZL. The largest randomised trial, the IELSG-19 trial, assigned 
patients towards Chlorambucil, Rituximab/Chlorambucil and Rituximab single agent in patients 
with treatment naïve MALT lymphoma 1. In this trial ORR was 78.3% with 55.8% CR and 22.5% 
PR 
for 
Rituximab 
single 
agent 
compared 
to 
94.7%, 
78.8 
and 
15.9% 
for 
Rituximab/Chlorambucil. The event free survival at 5 years was 50% for Rituximab single agent 
treatment compared to 68% with the combination. These data show that Rituximab efficacy 
can be further augmented by adding chemotherapy such as Chlorambucil, but at the cost of 
chemotherapy associated toxicities such as haematological toxicity.  
The hypothesis of this study is that adding Pembrolizumab to Rituximab is superior to 
Rituximab single agent and is approaching the efficacy of Rituximab/Chlorambucil without 
exposing the patient to chemotherapy associated toxicity. This hypothesis is based on recently 
reported data, which demonstrated high activity of Pembrolizumab in different types of B-cell 
lymphomas: Thus, safety and antitumor activity of Pembrolizumab was tested in relapsed and 
refractory peripheral mediastinal B-cell lymphoma as part of the KEYNOTE-013 multicohort 
phase 1b trial. At time of data cutoff, 18 patients (median age 30 years; median 3 prior lines of 
therapy) had been enrolled and treated, of whom 17 were included in the efficacy analyses. 
Eleven patients (61%) experienced drug-related adverse events (mostly grade 1-2); none 
discontinued treatment due to adverse events. ORR was 41% (7/17); 6 additional patients 
(35%) had stable disease. Of patients evaluable by imaging, 13 out of 16 (81%) had decreases 
in target lesions. With a median follow-up of 11.3 months, median duration of response was 
not reached. Two patients reached the maximum 2-year treatment duration and remain in 
remission. Median overall survival was not reached for treated patients overall; all responders 
were still alive at data cutoff. These results in heavily pretreated rrPMBCL patients 
demonstrated that PD-1 blockade with Pembrolizumab has a manageable safety profile and 
promising antitumor activity28 . In a phase II study the efficacy and safety of Pembrolizumab 

Pole-1 Protocol V3.0, dated 12.04.2021 
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were tested at a dose of 200 mg every 3 weeks in transformed CLL. Twenty-five patients 
including 16 relapsed CLL and 9 RT (all proven diffuse large cell lymphoma) patients were 
enrolled, and 60% received prior ibrutinib. Objective responses were observed in 4 out of 9 RT 
patients (44%). All responses were observed in RT patients who had progression after prior 
therapy with ibrutinib. After a median follow-up time of 11 months, the median overall survival 
in the RT cohort was 10.7 months, but was not reached in RT patients who progressed after 
prior ibrutinib. Treatment-related grade 3 or above adverse events were reported in 15 (60%) 
patients and were manageable. Overall, Pembrolizumab exhibited selective efficacy in CLL 
patients with RT29. In relapsed or refractory classic Hodgkin lymphoma a single-arm phase II 
study of Pembrolizumab in three cohorts of patients with rrHL, defined on the basis of 
lymphoma progression after (1) autologous stem cell transplantation (ASCT) and subsequent 
brentuximab vedotin (BV); (2) salvage chemotherapy and BV, and thus, ineligible for ASCT 
because of chemoresistant disease; and (3) ASCT, but without BV after transplantation, were 
performed. Patients received Pembrolizumab 200 mg once every 3 weeks. Response was 
assessed every 12 weeks. The primary end points were ORR by central review and safety. A 
total of 210 patients were enrolled and treated (69 in cohort 1, 81 in cohort 2, and 60 in cohort 
3). At the time of analysis, patients received a median of 13 treatment cycles. Per central 
review, the ORR was 69.0% (95% CI, 62.3% to 75.2%), and the complete response rate was 
22.4% (95% CI, 16.9% to 28.6%). By cohort, ORRs were 73.9% for cohort 1, 64.2% for cohort 
2, and 70.0% for cohort 3. Thirty-one patients had a response of 6 months. The safety profile 
was largely consistent with previous Pembrolizumab studies4. In a study for NK/T-cell 
lymphoma, seven male patients with NK/T-cell lymphoma, for whom a median of 2 (range, 1-
5) regimens (including L-asparaginase regimens and allogeneic hematopoietic stem-cell 
transplantation in 2 cases) failed, were treated with Pembrolizumab. All patients responded, 
according to various clinical, radiologic (positron emission tomography), morphologic, and 
molecular (circulating Epstein-Barr virus [EBV] DNA) criteria. Two patients achieved complete 
response (CR) in all parameters. Three patients achieved clinical and radiologic CRs, with two 
having molecular remission. Two patients achieved partial response. After a median of 7 cycles 
of Pembrolizumab and a follow-up of a median of 6 months, all five CR patients were still in 
remission. The only adverse event was grade 2 skin graft-versus-host disease in one patient 
with previous allogeneic HSCT30. In a recent report at the annual Meeting of the American 
Society of Hematology the efficacy of Pembrolizumab in combination with Rituximab in 
relapsed/refractory follicular lymphoma was tested. Patients received Rituximab (375 mg/m2 
IV) on days 1, 8, 15, and 22 of cycle 1 and Pembrolizumab (200mg IV) every 3 weeks for up 
to 16 infusions starting on day 2 of cycle 1. 32 subjects were enrolled with a median follow-up 
of 13.8 months. Overall response rate was 67% with a high CR rate of 50%. The median 
duration of response was 14.1 months. There were three grade 3 or grade 4 immune related 

Pole-1 Protocol V3.0, dated 12.04.2021 
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adverse events 31. Please refer to the current investigator brochure for all available 
Pembrolizumab data. 
In summary, these data showed high anti-lymphoma activity in pretreated indolent B – NHL by 
Pembrolizumab, providing the rationale to test this drug in combination with Rituximab in this 
lymphoma subtype with the goal to increase efficacy of Rituximab single agent, but to avoid 
chemotherapy associated toxicities.  
In this study, no comparator arm is included. The reason is that MZL is a rare disease and a 
comparator arm would require the inclusion of a large number of patients. Importantly, despite 
being a single arm study, this trial will give important information about the efficacy and toxicity 
of the Pembrolizumab/Rituximab combination, However, in case the results of this trial are 
encouraging and the risk-benefit ratio is justifiable a subesequent larger phase III trial with a 
comparator arm will be considered as an international trial. 
5. 
Trial Objective and endpoints  
5.1 
Primary Objective  
The objective of the trial is to test the efficacy of treatment with Pembrolizumab and Rituximab 
in patients with MZL in need of treatment, who have failed or are not eligible for local therapy 
or relapsed. For efficacy the rate of complete remissions (according to the GELA criteria for 
gastric MALT or to the Cheson 2007 criteria for nodal and splenic MZL) after end of treatment 
(18 cycles) will be primarily analyzed.  
5.2 
Primary Endpoint  
Primary endpoint is the complete response (CR rate (CRR) determined after end of treatment 
(18 cycles). Patients who progress before EOT will be treated as CR=’NO’ and will be included 
in the calculation of the primary endpoint. No primary endpoint will be determined for patients 
who withdraw. These patients will be excluded from the confirmatory data analysis but will be 
analyzed in a separate exploratory sensitivity analysis of the primary endpoint.  
For further information about the statistical analysis of the primary endpoint, see section 12. 
5.3 
Secondary Endpoints 
The following parameters are the secondary endpoints: 
• 
Response rate 
The response rates (complete response (CR), partial response (PR)) and overall 
response rate (CR or PR) are evaluated 4 weeks after the end of treatment. 
• 
Best response 

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Best response is determined in the time interval from the start of therapy to end of 
follow-up 
 
• 
Time to best response 
Time to best response is defined as the time from the start of therapy to best response 
the patient achieves (CR, PR) 
• 
Time to first response 
Time to first response is defined as the time from the start of therapy to first response 
(CR, PR). 
• 
Progression free survival (PFS) 
Progression free survival (PFS) is defined as the time from registration to the first 
occurrence of progression or relapse as assessed by the investigator, or death from 
any cause. PFS for patients without disease progression, relapse, or death will be 
censored at the time of the last tumor assessment. 
• 
Time to treatment failure (TTF) 
Time to treatment failure (TTF) is defined as the time of registration to discontinuation 
of therapy for any reason including death from any cause, progression, toxicity or add-
on of new anti-cancer therapy. Patients alive without treatment failure are censored at 
the latest tumor assessment date.  
• 
Duration of Response (DR) 
Duration of Response will be calculated in patients with response (CR, PR) to therapy 
from diagnosis of response to the date of progression, relapse or death from any cause. 
Patients alive without progression and relapse will be censored at the latest tumor 
assessment date or the stopping date.  
• 
Cause specific survival (CSS) 
Cause specific survival is defined as the period from the study registration to death from 
lymphoma or lymphoma related cause; death unrelated to MZL is considered as a 
competing event. 
• 
Overall survival (OS) 
Overall survival is defined as the period from the induction registration to death from 
any cause. Patients who have not died until the time of the analysis will be censored at 
their last contact date.  
• 
Quality of life during trial 
Quality of life will be measured by the FACT Lym (see Appendix I) before start of 
treatment and during trial participation. 

Pole-1 Protocol V3.0, dated 12.04.2021 
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5.4 
Safety Variables 
Safety variables will include AEs, SAEs, laboratory parameters, ECG and vital signs. The 
severity of AEs will be graded using the NCI-CTCAE version 5.0 dictionary. An AE is defined 
as any event arising or worsening after start of study drug administration until 110 days (based 
on five times the terminal elimination half-life of Rituximab and Pembrolizumab) after the last 
study drug intake. Safety variables will be summarized by means of descriptive statistics and/or 
frequency tables as appropriate. All AEs, drug related AEs, serious AEs will be summarized 
by MedDRA classification and worst CTCAE grade. 
6. 
Study Design 
This study is a European multicenter, single-arm, open-label, phase II trial of 18 cycles of 
Pembrolizumab and Rituximab in patients aged ≥ 18 years with previously untreated or 
relapsed MZL in need of treatment.  
The study flow will be as follows: 
- 
Previously untreated or relapsed patients will be screened for eligibility for the trial. If the 
patient is eligible for the study, the patient will be registered before the first cycle of 
treatment. 
- 
Patients who progress at any time point during treatment are considered as treatment 
failure. They will be followed up for overall survival until end of follow up period or death.  
- 
Patients, who achieve at least a SD after treatment will be followed up for response until 
progression/relapse and for overall survival until death. 

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Fig.1: Study Design 
 
6.1 
Estimated Study Duration 
It is expected that a total of 56 patients at approximately 15 investigator trial sites in Germany 
and 3 trial sites in Austria will be registered. Every patient will receive treatment over a time 
period of 18 cycles (each cycle lasts 3 weeks). Subsequently, patients will be monitored every 
3 months for 2 additional years, subsequently every 6 months for three additional years. 
Patients will be recruited over a period of 12-18 months. 
1st patient registered (estimated):  
Q3 2020 
Last patient registered (estimated):  
Q1 2022 
Maximal duration of study therapy/patient: 
18 cycles 
(18 cycles with 21 days = 378 days resp. 54 weeks) 
Duration of follow-up/patient: 
up to 5 years (until End of Study is 
reached) 
End of study:  LPLV 7.5 years (=90 months) after the first patient is included in the study 
Considering a recruitment period of 12 – 18 months and a treatment period of 54 weeks, after 
7.5 years all patients will either be in Follow-Up or will already have completed Follow-up. In 
the 90th month after FPI Follow-up Visits that were scheduled for this month can still take 
place. Sites will be notified in advance about EOS so that they can plan the Follow-up visits 
accordingly. 

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After finishing all study relevant procedures, therapy and follow-up period, the patient will be 
followed in terms of routine aftercare and treated if necessary by the primary responsible 
hematologic-oncologic center. 
7. 
Study Population 
Patients must have a proven pathological diagnosis of MZL, diagnosed by a reference 
pathology center.  
7.1 
Inclusion criteria for Registration 
Patients must have a proven pathological diagnosis of MZL, diagnosed by a reference 
pathology center.  
Patients must meet the following inclusion criteria to be eligible for participation in this study: 
– 
Confirmed CD20 positive de novo or relapsed MALT Lymphoma in need of treatment 
following or being not eligible for local therapy (including surgery, radiotherapy and 
antibiotics e.g. for H. pylori-positive gastric lymphoma arisen at any extranodal site)  
OR 
– 
Confirmed CD20 positive de novo or relapsed splenic MZL in need of treatment 
following or not being eligible for local therapy (including surgery and antiviral therapy 
for Hepatitis C Virus)  
OR 
– 
Confirmed CD20 positive de novo or relapsed nodal MZL in need of treatment following 
or not being eligible for local therapy (radiotherapy). The need of treatment is applicable 
in the case of B symptoms, deterioration of peripheral blood counts due to lymphoma 
infiltration of the bone marrow, rapid enlargement of lymph nodes or compression of 
vital organs by bulky disease. 
For nodal MZL and extragastric MALT lymphoma: 
At 
least 
one 
bi-dimensionally 
measurable 
lesion 
(≥ 1.5 cm in its largest dimension by CT/ PET-CT scan or MRI). Please refer to Appendix 
D. 
For splenic MZL (SMZL): 
In patients with splenic MZL, an enlarged spleen on CT scan and lymphoma cell infiltration 
has to be seen in bone marrow and/or peripheral blood. Please refer also to Appendix F.  
At least one of the following criteria must be fulfilled:  

Pole-1 Protocol V3.0, dated 12.04.2021 
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– 
Bulky progressive or painful splenomegaly 
– 
one of the following symptomatic/progressive cytopenias: Hb < 10 g/dL, or Platelet 
count < 80.000 /µL, or neutropenia < 1000 /µL, whatever the reason (autoimmune or 
hypersplenism or bone marrow infiltration) 
– 
splenectomised patients with rapidly raising lymphocyte counts, development of 
lymphadenopathy or involvement of extranodal sites if not being eligible for local 
therapy 
– 
SMZL with concomitant hepatitis C infection which has not responded to or has 
relapsed after Interferon and/or Ribavirin and/or direct antiviral agents (patients positive 
for HCV antibody are eligible only if PCR is negative for HCV RNA) 
For gastric MALT Lymphoma:  
For gastric MALT lymphoma, the clinical evidence of the MZL as seen by gastroendoscopy 
is sufficient. There is no need to show a measurable lesion by CT scan or MRI. Please refer 
to Appendix E. 
Inclusion is possible for patients with: 
– 
H. pylori-negative disease de novo or following or being not eligible for local therapy 
(i.e., surgery, radiotherapy or antibiotics) or after systemic therapy. 
– 
H. pylori-positive disease that has remained stable, progressed, or relapsed following 
antibiotic therapy 
Others: 
• 
Age ≥ 18 years 
• 
Life expectancy > 3 months 
• 
Meet the following pretreatment laboratory criteria at the Screening visit conducted 
within 28 days of study enrollment (unless due to underlying lymphoma): 
– 
Baseline platelet count  75 109/L (if not due to BM infiltration by the lymphoma), 
absolute neutrophil count  1.5 109/L. 
– 
Hemoglobin ≥ 9.0 g/dL or ≥ 5.6 mmol/L (Criteria must be met without erythropoietin 
dependency and without packed red blood cell (pRBC) transfusion within last 2 weeks) 
– 
International Normalized Ratio (INR) or Prothrombin Time (PT): ≤ 1.5 × ULN unless 
subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic 
range of intended use of anticoagulants 

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– 
Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 × ULN unless subject is receiving 
anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use 
of anticoagulants 
– 
ASAT (SGOT): ≤ 2,5 times the upper limit of institutional laboratory normal value or ≤ 
5 times the upper limit of institutional laboratory normal value in subjects with lymphoma 
in the liver 
– 
ALAT (SGPT): ≤ 2,5 times the upper limit of institutional laboratory normal value or ≤ 5 
times the upper limit of institutional laboratory normal value in subjects with lymphoma 
in the liver 
– 
Serum total bilirubin: ≤ 1.5 × ULN OR Direct bilirubin ≤ ULN for subjects with total 
bilirubin levels > 1.5 ULN (unless clearly related to the disease) 
– 
Serum creatinine ≤ 1.5 × ULN OR ≥ 60 mL/min GFR or CrCl for subjects with creatinine 
levels > 1.5 × institutional ULN 
– 
Negative HIV antibody 
– 
Patients with occult or prior HBV infection (defined as negative HBsAg and positive 
total HBcAb) may be included if HBV DNA is undetectable, provided that they are willing 
to undergo monthly DNA testing. Patients who have protective titers of HBSAb after 
vaccination or prior but cured hepatitis B are eligible.  
– 
Patients positive for HCV antibody are eligible only if PCR is negative for HCV RNA. 
– 
For women of child-bearing potential only: Pregnancy β-HCG negative. Serum or urine 
β-HCG must be negative during screening and at study enrolment visit. 
• 
Premenopausal fertile females must agree to use a highly effective method of birth 
control for the duration of the therapy up to 12 months after the last dose of 
Rituximab and through 4 months after the last dose of Pembrolizumab. A highly 
effective method of birth control is defined as those which results in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly such as combined 
(estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal or transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable or implantable), 
intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral 
tubal occlusion, vasectomised partner or sexual abstinence. Contraception and 
pregnancy 
testing 
are 
required 
according 
the 
CTFG 
recommendations 
(http://www.hma.eu/fileadmin/dateien/Human_Medicines/01-
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf) 

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• 
Men must agree not to father a child for the duration of therapy and 6 months after 
and must agree to advice a female partner to use a highly effective method of birth 
control. According to CTFG recommendations, men must use condoms. 
• 
Willingness and ability to comply with scheduled visits, drug administration plan, 
imaging studies, laboratory tests, other study procedures, and study restrictions 
• 
Evidence of a personally signed informed consent indicating that the subject is 
aware of the neoplastic nature of the disease and has been informed of the 
procedures to be followed, the experimental nature of the therapy, alternatives, 
potential benefits, possible side effects, potential risks and discomforts, and other 
pertinent aspects of study participation 
7.2 
Exclusion Criteria for Registration 
The presence of any of the following will exclude a subject from enrolment: 
• 
ECOG performance status ≥ 2 
• 
History of a malignancy except for the following: adequately treated local basal cell 
or squamous cell carcinoma of the skin, cervical carcinoma in situ, superficial 
bladder cancer, asymptomatic prostate cancer without known metastatic disease 
and with no requirement for therapy or requiring only hormonal therapy and with 
normal prostate specific antigen for ≥ 1 year prior to study enrolment visit, other 
malignancy treated with a curative intent and currently in complete remission, for ≥ 
3 years 
• 
Central nervous system lymphoma, leptomeningeal lymphoma, or histologic 
evidence of transformation to a high-grade or diffuse large B-cell lymphoma 
• 
Has had prior chemotherapy (systemic anti-cancer therapy), targeted small molecule 
therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not 
recovered (i.e., ≤ Grade 1 or baseline value) from AEs due to a previously 
administered agent 
o Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and 
may qualify for the study 
o Note: If a subject received major surgery, they must have recovered adequately 
from complications from the intervention prior to starting therapy 
• 
Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of study 
enrolment visit 

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• 
Ongoing drug-induced liver injury, chronic active hepatitis B (HBV), alcoholic liver 
disease, non-alcoholic steatohepatitis, primary biliary cholangitis, extrahepatic 
obstruction caused by cholelithiasis, cirrhosis of the liver, or portal hypertension 
• 
Treatment with any other investigational agent or participating in another clinical trial 
with an investigational product within 4 weeks prior to entering this study or within 5 
x the half-life (t1/2) of the investigational product, whichever is longer 
• 
Breastfeeding or Pregnancy 
• 
Congestive heart failure > New York Heart Association (NYHA) class 2 
• 
Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 
3 months) 
• 
Myocardial infarction less than 6 months before start of study medication  
• 
Uncontrolled arterial hypertension despite optimal medical management 
• 
Prior or ongoing clinically significant illness, medical condition, surgical history, 
physical finding, electrocardiogram (ECG) finding, or laboratory abnormality that, in 
the investigator’s opinion, could adversely affect the safety of the subject or impair 
the assessment of study results 
• 
Vaccination with a live vaccine within 30 days prior to start of therapy 
• 
Arterial or venous thrombotic or embolic events such as cerebrovascular accident 
(including transient ischemic attacks), deep vein thrombosis or pulmonary embolism 
within 3 months before the start of study medication 
• 
Non-healing wound, ulcer, or bone fracture 
• 
History or concurrent interstitial lung disease of any severity and/or severely 
impaired lung function (as judged by the investigator) 
• 
Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD L2 agent or with 
an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-
4, OX 40, CD137) 
• 
Has received prior radiotherapy within 2 weeks of start of study treatment. 
Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis. A 1-week washout is 
permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease 
• 
Has known active CNS metastases and/or carcinomatous meningitis. Participants 
with previously treated brain metastases may participate provided they are 

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radiologically stable, i.e. without evidence of progression for at least 4 weeks by 
repeat imaging (note that the repeat imaging should be performed during study 
screening), clinically stable and without requirement of steroid treatment for at least 
14 days prior to first dose of study treatment 
• 
Has a history of non-infectious pneumonitis that required steroids, or current 
pneumonitis 
• 
History of anaphylaxis in association with previous administration of monoclonal 
antibodies or severe hypersensitivity (≥Grade 3) to the investigational medicinal 
products and/or any of its excipients 
• 
Has active autoimmune disease that has required systemic treatment in the past 2 
years 
(i.e. 
with 
use 
of 
disease 
modifying 
agents, 
corticosteroids 
or 
immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, 
etc.) is not considered a form of systemic treatment 
• 
Has a known history of active TB (Bacillus Tuberculosis) 
• 
Medical history of allogeneic stem cell transplant 
• 
Ongoing alcohol or drug addiction or known psychiatric or substance abuse 
disorders that would interfere with cooperation with the requirements of the trial 
• 
Diagnosis of Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis 
(TEN)  
8. 
Treatments 
8.1 
Study drug (IMP) 
8.1.1.1 Packaging and labeling 
MSD will supply Pembrolizumab and Celltrion Healthcare Co., LTD will supply Rituximab. 
All study drugs will be labeled according to the requirements of local law and legislation. The 
label text will be approved according to the sponsor’s agreed procedures, and a copy of the 
labels will be made available to the study site upon request. For all study drugs, a system of 
numbering in accordance with all requirements of Good Manufacturing Practice (GMP) will be 
used, ensuring that each dose of study drug can be traced back to the respective bulk batch 
of the ingredients. A complete record of batch numbers and expiry dates of all study treatment 
as well as the labels will be maintained in the sponsor’s study file. An approved representative 

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at the site will ensure that all received study drugs are stored in a secured area on site, under 
recommended storage conditions and in accordance with applicable regulatory requirements. 
8.1.1.2 Responsibilities  
Supplies have to be obtained by sending a drug order form. 
All drug packages are to be inspected upon receipt at the study site prior to being drawn up. If 
any particulate matter is detected, the packaging is not to be used. Damaged packaging is to 
be reported to the sponsor and stored until instructions have been given.  
The Investigator, the Hospital Pharmacist, or other personnel allowed to store and dispense 
the IMP will be responsible for ensuring that the IMP used in the clinical trial are securely 
maintained as specified by the Sponsor and in accordance with the applicable regulatory 
requirements. All IMPs must be stored in accordance with labeling and shall be dispensed in 
accordance with the Investigator's prescription and it is the Investigator's responsibility to 
ensure that an accurate record of IMP issued and returned is maintained. Any quality issue 
noticed with the receipt or use of an IMP (deficient IMP in condition, appearance, pertaining 
documentation, labeling, expiry date, etc.) should be promptly notified to the Sponsor, who will 
initiate a complaint procedure. Under no circumstances will the Investigator supply the IMP to 
a third party, allows the IMP to be used other than as directed by this Clinical Trial Protocol, or 
dispose of the IMP in any other manner. 
 
8.1.1.3 Storage and Handling Requirements 
Clinical supplies must be stored in a secure, limited-access location under the storage 
conditions specified on the label. Receipt and dispensing of trial medication must be recorded 
by an authorized person at the trial site. Clinical supplies may not be used for any purpose 
other than that stated in the protocol. 
8.1.1.4 Returns and Reconciliation 
The investigator or pharmacist will inventory and acknowledge receipt of all shipments of the 
IMP. The investigator or pharmacist will also keep accurate records of the quantities of the 
study treatments dispensed and used for each patient. Used vials can be destroyed directly 
after preparation of the infusion for safety reasons. The study monitor will periodically check 
the supplies of IMP held by the investigator or pharmacist to verify accountability of all IMP 
used. All unused treatments will also be verified by the Sponsor/Monitor. A detailed treatment 
log of the returned IMP will be established with the Investigator (or the pharmacist) and 
countersigned by the Investigator and the Monitoring Team. The Investigator will not destroy 
the unused IMP unless the Sponsor/monitor provides written authorization. The investigator is 

Pole-1 Protocol V3.0, dated 12.04.2021 
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responsible for keeping accurate records of the clinical supplies received, the amount 
dispensed to and returned by the participants and the amount remaining at the conclusion of 
the trial.  
Upon completion or termination of the study, all unused and/or partially used investigational 
product will be destroyed at the site per institutional policy. It is the Investigator’s responsibility 
to arrange for disposal of all empty containers, provided that procedures for proper disposal 
have been established according to applicable federal, state, local and institutional guidelines 
and procedures, and provided that appropriate records of disposal are kept. 
A potential defect in the quality of the IMP may be subject to initiation by the Sponsor of a recall 
procedure. In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall the IMP and eliminate potential hazards. 
8.1.2 Pembrolizumab 
8.1.2.1 Structure and Mechanismen of Action of Pembrolizumab 
Pembrolizumab is a potent humanized immunoglobulin G4 (IgG4) monoclonal antibody (mAb) 
with high specificity of binding to the programmed cell death 1 (PD 1) receptor, thus inhibiting 
its interaction with programmed cell death ligand 1 (PD-L1) and programmed cell death ligand 
2 (PD-L2). Based on preclinical in vitro data, Pembrolizumab has high affinity and potent 
receptor blocking activity for PD 1. Pembrolizumab has an acceptable preclinical safety profile 
and is in clinical development as an intravenous (IV) immunotherapy for advanced 
malignancies. Keytruda® (Pembrolizumab) is indicated for the treatment of patients across a 
number of indications because of its mechanism of action to bind the PD-1 receptor on the T 
cell. For more details on specific indications refer to the Investigator brochure. 
8.1.2.2 Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance function in controlling outgrowth of neoplastic 
transformations has been known for decades [Disis, 2010]. Accumulating evidence shows a 
correlation between tumor-infiltrating lymphocytes in cancer tissue and favorable prognosis in 
various malignancies. In particular, the presence of CD8+ T-cells and the ratio of CD8+ effector 
T cells/FoxP3+ regulatory T-cells (T-regs) correlates with improved prognosis and long-term 
survival in solid malignancies, such as ovarian, colorectal, and pancreatic cancer; 
hepatocellular carcinoma; malignant melanoma; and renal cell carcinoma. Tumor-infiltrating 
lymphocytes can be expanded ex vivo and reinfused, inducing durable objective tumor 
responses in cancers such as melanoma [Dudley et al., 2005; Hunder et al., 2008]. 

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The PD-1 receptor-ligand interaction is a major pathway hijacked by tumors to suppress 
immune control. The normal function of PD-1, expressed on the cell surface of activated T cells 
under healthy conditions, is to down-modulate unwanted or excessive immune responses, 
including autoimmune reactions. PD-1 (encoded by the gene Pdcd1) is an immunoglobulin (Ig) 
superfamily member related to cluster of differentiation 28 (CD28) and cytotoxic T-lymphocyte-
associated protein 4 (CTLA-4) that has been shown to negatively regulate antigen receptor 
signaling upon engagement of its ligands (PD L1 and/or PD-L2) [Greenwald et al., 2005; 
Okazaki et al., 2001]. 
The structure of murine PD-1 has been resolved [Zhang et al., 2004]. PD-1 and its family 
members are type I transmembrane glycoproteins containing an Ig-variable–type (IgV type) 
domain responsible for ligand binding and a cytoplasmic tail responsible for the binding of 
signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based signaling motifs, 
an immunoreceptor tyrosine-based inhibition motif, and an immunoreceptor tyrosine-based 
switch motif. Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases, SHP-1 and 
SHP-2, to the immunoreceptor tyrosine-based switch motif within its cytoplasmic tail, leading 
to the dephosphorylation of effector molecules such as CD3 zeta (CD3ζ), protein kinase C-
theta (PKCθ), and zeta-chain-associated protein kinase (ZAP70), which are involved in the 
CD3 T-cell signaling cascade [Okazaki et al., 2001; Chemnitz et al., 2004; Sheppard et al., 
2004; and Riley, 2009]. The mechanism by which PD-1 down-modulates T cell responses is 
similar to, but distinct from, that of CTLA-4, because both molecules regulate an overlapping 
set of signaling proteins [Parry et al., 2005; Francisco, 2010]. As a consequence, the PD 1/PD-
L1 pathway is an attractive target for therapeutic intervention in Marginal zone lymphoma. 
8.1.2.3 Preclinical and Clinical Trial Data 
Please refer to the Investigator’s Brochure for all Preclinical and Clinical data.  
In hematological neoplasms Pembrolizumab was tested in different lymphomas and multiple 
myeloma. Pembrolizumab in combination with Pomalidomide and Dexamethasone were given 
in the KN183 trial in subjects with refractory or relapsed and refractory multiple myeloma in 
comparison to the control arm with Pomalidomide and Dexamethasone alone. In the KN185 
trial Subjects with newly diagnosed and treatment naive multiple myeloma were treated with 
Pembrolizumab in combination with Lenalidomide and Dexamethasone in comparison to the 
control arm with Lenalidomide and Dexamethasone. A full safety analysis based on June 2, 
2017 data cutoff date was conducted for both studies. 249 randomized participants were 
included in the KN183 study. The median follow-up was 8.1 months. Objective response rate 
was 34% in the investigational arm compared to 40% in the control arm. In the safety analysis, 
there was an increase of Grade 3-5 events (83% vs. 65%, investigational vs. control arm). The 

Pole-1 Protocol V3.0, dated 12.04.2021 
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incidence of serious adverse events was 63% vs. 46%, respectively. At the cutoff date 301 
randomized participants were included in the KN185 study. The median follow-up was 6.6 
months. Objective response rate was 64% in the investigational arm compared to 62% in the 
control arm. In the safety analysis, there was an increase of Grade 3-5 events (72% vs. 50%, 
investigational vs. control arm). The incidence of serious adverse events was 54% vs. 39 %, 
respectively. These data demonstrated that the combination of Pembrolizumab with so called 
immunomodulatory agents such as pomalidomide and lenalidomide induce considerable 
toxicity and should be avoided.  
8.1.2.4 Pembrolizumab Materials 
Please refer to IB for Pembrolizumab for more details regarding drug properties and 
formulation.  
Pembrolizumab will be provided by MSD as summarized here: 
Pembrolizumab 100 mg/ 4mL 
solution for infusion 
Pembrolizumab solution for infusion 100 mg/vial is a liquid Drug Product (DP) (manufactured 
using the fully formulated Drug Substance (DS) with L-histidine as a buffering agent, 
polysorbate 80 as a surfactant, and sucrose as a stabilizer/tonicity modifier and Water for 
Injection as Solvent). 
The solution is stored under refrigerated conditions (2°C to 8°C). The liquid is intended for IV 
administration.  
It is a clear to opalescent solutions, essentially free of visible particles and is intended for IV 
administration. The color of the solution is colorless to slightly yellow. At the point of use, 
Pembrolizumab DP is diluted with 0.9% sodium chloride injection, USP (normal saline) or 5% 
dextrose injection, USP (5% dextrose) to 1 to 10 mg/mL before IV administration through an 
infusion filter. Liquid DP is compatible with the IV bag and infusion-line materials. Reconstituted 
vials should be used immediately to prepare the infusion solution in the IV bag, and the infusion 
solution should be administered immediately. Do not freeze the diluted solution. If the diluted 
Pembrolizumab solution is not used immediately, it may be stored for no more than 24 hours 
at 2°C to 8°C. This 24-hour total hold time may include up to 6 hours at room temperature (at 
or below 25°C). If refrigerated, the vials and/or IV bags must be allowed to come to room 
temperature before use. 
8.1.2.5 Timing of Dose Administration 
Pembrolizumab 200 mg will be administered as a 30 minutes IV infusion every 3 weeks. Sites 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 

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However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
The Pharmacy Manual contains specific instructions for the preparation of the Pembrolizumab 
infusion fluid and administration of infusion solution. 
Shelf life of reconstituted vials 
Reconstituted vials should be used immediately to prepare the infusion solution in the IV bag, 
and the infusion solution should be administered immediately. If the diluted Pembrolizumab 
solution is not used immediately, it may be stored for no more than 24 hours at 2°C to 8°C. 
This 24-hour total hold time from reconstitution may include up to 6 hours at room temperature 
(at or below 25°C). Any additional hold time must be at 2°C to 8°C. If refrigerated, the vials 
and/or intravenous bags must be allowed to come to room temperature prior to use. 
Premedication 
Premedication with antipyretic and antihistamine may be considered. 
8.1.3 Rituximab  
Rituximab (Truxima®) will be applied IV and will be supplied by Celltrion Healthcare Co., LTD.  
8.1.3.1 Formulation Packaging and Labeling  
Formulation, Packaging and Labeling 
Truxima 100 mg concentrate for solution for infusion. 
Truxima 500 mg concentrate for solution for infusion. 
Qualitative and quantitative composition 
Each vial contains 100 mg or 500 mg of Rituximab. Each mL of concentrate contains 10 mg of 
Rituximab. 
Rituximab is a genetically engineered chimeric mouse/human monoclonal antibody 
representing a glycosylated immunoglobulin with human IgG1 constant regions and murine 
light-chain and heavy-chain variable region sequences. The antibody is produced by 
mammalian (Chinese hamster ovary) cell suspension culture and purified by affinity 
chromatography and ion exchange, including specific viral inactivation and removal 
procedures. 
Excipient with known effect: 
This medicinal product contains up to 23.06 mmol (or 530.1 mg) sodium per dose. To be taken 
into consideration by patients on a controlled sodium diet. 

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Incompatibilities 
No incompatibilities between Truxima and polyvinyl chloride or polyethylene bags or infusion 
sets have been observed. 
Shelf life 
Unopened vial 
For unopened vials 3 years. 
Diluted solution 
The prepared infusion solution of Truxima is physically and chemically stable for 24 hours at 
2°C - 8°C and subsequently 12 hours at room temperature (≤25°C). 
From a microbiological point of view, the prepared infusion solution should be used 
immediately. If not used immediately, in-use storage times and conditions prior to use are the 
responsibility of the user and would normally not be longer than 24 hours at 2°C - 8°C, unless 
dilution has taken place in controlled and validated aseptic conditions. 
Special precautions for storage 
Store in a refrigerator (2°C – 8°C). Keep the container in the outer carton in order to protect 
from light. For storage conditions after dilution of the medicinal product, see above. 
 
Nature and contents of container 
10 mL vial: Clear Type I glass vials with butyl rubber stopper containing 100 mg of Rituximab 
in 10 ml.  
50 mL vial: Clear Type I glass vials with butyl rubber stopper containing 500 mg of Rituximab 
in 50 ml.  
8.1.3.2 Preparation and Administration of Rituximab IV Formulation  
Special precautions for disposal and other handling 
Truxima is provided in sterile, preservative-free, non-pyrogenic, single use vials. Aseptically 
withdraw the necessary amount of Truxima, and dilute to a calculated concentration of 1 to 4 
mg/mL Rituximab into an infusion bag containing sterile, pyrogen-free sodium chloride 9 
mg/mL (0.9%) solution for injection or 5% D-Glucose in water. For mixing the solution, gently 
invert the bag in order to avoid foaming. Care must be taken to ensure the sterility of prepared 
solutions. Since the medicinal product does not contain any anti-microbial preservative or 
bacteriostatic agents, aseptic technique must be observed. Parenteral medicinal products 
should be inspected visually for particulate matter and discolouration prior to administration. 

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Any unused medicinal product or waste material should be disposed of in accordance with 
local requirements. 
Administration 
Truxima should be administered under the close supervision of an experienced healthcare 
professional, and in an environment where full resuscitation facilities are immediately available. 
Premedication consisting of an analgesic/ anti-pyretic and an antihistaminic, e.g. paracetamol 
and diphenhydramine, should always be given before each administration of Truxima. In 
patients with non-Hodgkin's lymphoma and chronic lymphocytic leukaemia (CLL), 
premedication with glucocorticoids should be considered if Truxima is not given in combination 
with glucocorticoid-containing chemotherapy. In patients with rheumatoid arthritis, 
premedication with 100 mg intravenous methylprednisolone should be completed 30 minutes 
prior to Truxima infusions to decrease the incidence and severity of infusion related reactions 
(IRRs). In patients with granulomatosis with polyangiitis (Wegener's) or microscopic 
polyangiitis, methylprednisolone given intravenously for 1 to 3 days at a dose of 1,000 mg per 
day is recommended prior to the first infusion of Truxima (the last dose of methylprednisolone 
may be given on the same day as the first infusion of Truxima). This should be followed by oral 
prednisone 1 mg/kg/day (not to exceed 80 mg/day, and tapered as rapidly as possible based 
on clinical need) during and after Truxima treatment. 
 
Method of administration 
Truxima is for intravenous use. The prepared Truxima solution should be administered as an 
intravenous infusion through a dedicated line. It should not be administered as an intravenous 
push or bolus. Patients should be closely monitored for the onset of cytokine release 
syndrome. Patients who develop evidence of severe reactions, especially severe dyspnoea, 
bronchospasm or hypoxia should have the infusion interrupted immediately. Patients with non-
Hodgkin's lymphoma should then be evaluated for evidence of tumor lysis syndrome including 
appropriate laboratory tests and, for pulmonary infiltration, with a chest X-ray. In all patients, 
the infusion should not be restarted until complete resolution of all symptoms, and 
normalization of laboratory values and chest X-ray findings. At this time, the infusion can be 
initially resumed at not more than one-half the previous rate. If the same severe adverse 
reactions occur for a second time, the decision to stop the treatment should be seriously 
considered on a case by case basis. Mild or moderate infusion-related reactions (IRR) usually 
respond to a reduction in the rate of infusion. The infusion rate may be increased upon 
improvement of symptoms. 
First infusion 

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The recommended initial rate for infusion is 50 mg/h; after the first 30 minutes, it can be 
escalated in 50 mg/h increments every 30 minutes, to a maximum of 400 mg/h.  
Subsequent infusions  
Subsequent doses of Truxima can be infused at an initial rate of 100 mg/h, and increased by 
100 mg/h increments at 30 minute intervals, to a maximum of 400 mg/h. 
Please refer to the IB for further formulation, storage and handling instructions for Rituximab 
IV. 
8.1.3.3 Known serious adverse reactions of Rituximab 
Contraindications 
Contraindications for use in non-Hodgkin’s lymphoma and chronic lymphocytic leukaemia: 
Hypersensitivity to the active substance or to murine proteins, or to any of the other excipients. 
Active, severe infections. Patients in a severely immunocompromised state.  
Contraindications for use in rheumatoid arthritis, granulomatosis with polyangiitis and 
microscopic polyangiitis: Hypersensitivity to the active substance or to murine proteins, or to 
any of the other excipients. Active, severe infections. Patients in a severely 
immunocompromised state. Severe heart failure (New York Heart Association Class IV) or 
severe, uncontrolled cardiac disease. 
Special warnings and precautions for use 
In order to improve traceability of biological medicinal products, the tradename of the 
administered product should be clearly recorded in the patient file. 
Progressive multifocal leukoencephalopathy 
All patients treated with Truxima for rheumatoid arthritis, granulomatosis with polyangiitis and 
microscopic polyangiitis must be given the patient alert card with each infusion. The alert card 
contains important safety information for patients regarding potential increased risk of 
infections, including progressive multifocal leukoencephalopathy (PML). Very rare cases of 
fatal PML have been reported following use of Rituximab. Patients must be monitored at 
regular intervals for any new or worsening neurological symptoms or signs that may be 
suggestive of PML. If PML is suspected, further dosing must be suspended until PML has been 
excluded. The clinician should evaluate the patient to determine if the symptoms are indicative 
of neurological dysfunction, and if so, whether these symptoms are possibly suggestive of 
PML. Consultation with a Neurologist should be considered as clinically indicated. If any doubt 
exists, further evaluation, including MRI scan preferably with contrast, cerebrospinal fluid 
(CSF) testing for JC Viral DNA and repeat neurological assessments, should be considered. 

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The physician should be particularly alert to symptoms suggestive of PML that the patient may 
not notice (e.g. cognitive, neurological or psychiatric symptoms). Patients should also be 
advised to inform their partner or caregivers about their treatment, since they may notice 
symptoms that the patient is not aware of. If a patient develops PML, the dosing of Truxima 
must be permanently discontinued. Following reconstitution of the immune system in 
immunocompromised patients with PML, stabilisation or improved outcome has been seen. It 
remains unknown if early detection of PML and suspension of Rituximab therapy may lead to 
similar stabilisation or improved outcome. 
Non-Hodgkin's lymphoma and chronic lymphocytic leukaemia 
Infusion related reactions 
Rituximab is associated with infusion-related reactions, which may be related to release of 
cytokines and/or other chemical mediators. Cytokine release syndrome may be clinically 
indistinguishable from acute hypersensitivity reactions. This set of reactions which includes 
syndrome of cytokine release, tumor lysis syndrome and anaphylactic and hypersensitivity 
reactions are described below. Severe infusion-related reactions with fatal outcome have been 
reported during post-marketing use of the Rituximab intravenous formulation, with an onset 
ranging within 30 minutes to 2 hours after starting the first Rituximab intravenous infusion. 
They were characterized by pulmonary events and in some cases included rapid tumor lysis 
and features of tumor lysis syndrome in addition to fever, chills, rigors, hypotension, urticaria, 
angioedema and other symptoms. Severe cytokine release syndrome is characterised by 
severe dyspnoea, often accompanied by bronchospasm and hypoxia, in addition to fever, 
chills, rigors, urticaria, and angioedema. This syndrome may be associated with some features 
of tumor lysis syndrome such as hyperuricaemia, hyperkalaemia, hypocalcaemia, 
hyperphosphataemia, acute renal failure, elevated lactate dehydrogenase (LDH) and may be 
associated with acute respiratory failure and death. The acute respiratory failure may be 
accompanied by events such as pulmonary interstitial infiltration or oedema, visible on a chest 
X-ray. The syndrome frequently manifests itself within one or two hours of initiating the first 
infusion. Patients with a history of pulmonary insufficiency or those with pulmonary tumor 
infiltration may be at greater risk of poor outcome and should be treated with increased caution. 
Patients who develop severe cytokine release syndrome should have their infusion interrupted 
immediately and should receive aggressive symptomatic treatment. Since initial improvement 
of clinical symptoms may be followed by deterioration, these patients should be closely 
monitored until tumor lysis syndrome and pulmonary infiltration have been resolved or ruled 
out. Further treatment of patients after complete resolution of signs and symptoms has rarely 
resulted in repeated severe cytokine release syndrome. 

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Patients with a high tumor burden or with a high number (≥ 25 x 109/L) of circulating malignant 
cells such as patients with CLL, who may be at higher risk of especially severe cytokine release 
syndrome, should be treated with extreme caution. These patients should be very closely 
monitored throughout the first infusion. Consideration should be given to the use of a reduced 
infusion rate for the first infusion in these patients or a split dosing over two days during the 
first cycle and any subsequent cycles if the lymphocyte count is still > 25 x 109/L. 
Infusion related adverse reactions of all kinds have been observed in 77% of patients treated 
with Rituximab (including cytokine release syndrome accompanied by hypotension and 
bronchospasm in 10% of patients). These symptoms are usually reversible with interruption of 
Rituximab infusion and administration of an anti-pyretic, an antihistaminic, and, occasionally, 
oxygen, intravenous saline or bronchodilators, and glucocorticoids if required. Please see 
cytokine release syndrome above for severe reactions. Anaphylactic and other hypersensitivity 
reactions have been reported following the intravenous administration of proteins to patients. 
In contrast to cytokine release syndrome, true hypersensitivity reactions typically occur within 
minutes after starting infusion. Medicinal products for the treatment of hypersensitivity 
reactions, e.g., epinephrine (adrenaline), antihistamines and glucocorticoids, should be 
available for immediate use in the event of an allergic reaction during administration of 
Rituximab. Clinical manifestations of anaphylaxis may appear similar to clinical manifestations 
of the cytokine release syndrome (described above). Reactions attributed to hypersensitivity 
have been reported less frequently than those attributed to cytokine release. Additional 
reactions reported in some cases were myocardial infarction, atrial fibrillation, pulmonary 
oedema and acute reversible thrombocytopenia. Since hypotension may occur during 
Rituximab administration, consideration should be given to withholding antihypertensive 
medicinal product 12 hours prior to the Truxima infusion. 
Cardiac disorders 
Angina pectoris, cardiac arrhythmias such as atrial flutter and fibrillation, heart failure and/or 
myocardial infarction have occurred in patients treated with Rituximab. Therefore, patients with 
a history of cardiac disease and/or cardiotoxic chemotherapy should be monitored closely. 
Haematological toxicities 
Although Rituximab is not myelosuppressive in monotherapy, caution should be exercised 
when considering treatment of patients with neutrophils < 1.5 x 109/L and/or platelet counts < 
75 x 109/L as clinical experience in this population is limited. Rituximab has been used in 21 
patients who underwent autologous bone marrow transplantation and other risk groups with a 
presumable reduced bone marrow function without inducing myelotoxicity. Regular full blood 
counts, including neutrophil and platelet counts, should be performed during Truxima therapy. 

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Infections 
Serious infections, including fatalities, can occur during therapy with Rituximab. Truxima 
should not be administered to patients with an active, severe infection (e.g. tuberculosis, sepsis 
and opportunistic infections). 
Physicians should exercise caution when considering the use of Truxima in patients with a 
history of recurring or chronic infections or with underlying conditions which may further 
predispose patients to serious infection. 
Cases of hepatitis B reactivation have been reported in subjects receiving Rituximab including 
fulminant hepatitis with fatal outcome. The majority of these subjects were also exposed to 
cytotoxic chemotherapy. Limited information from one study in relapsed/refractory CLL 
patients suggests that Rituximab treatment may also worsen the outcome of primary hepatitis 
B infections. Hepatitis B virus (HBV) screening should be performed in all patients before 
initiation of treatment with Truxima. At minimum this should include HBsAg-status and HBcAb-
status. These can be complemented with other appropriate markers as per local guidelines. 
Patients with active hepatitis B disease should not be treated with Truxima. Patients with 
positive hepatitis B serology (either HBsAg or HBcAb) should consult liver disease experts 
before start of treatment and should be monitored and managed following local medical 
standards to prevent hepatitis B reactivation. 
Very rare cases of progressive multifocal leukoencephalopathy (PML) have been reported 
during post-marketing use of Rituximab in NHL and CLL. The majority of patients had received 
Rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant. 
Immunisations 
The safety of immunisation with live viral vaccines, following Rituximab therapy has not been 
studied for NHL and CLL patients and vaccination with live virus vaccines is not recommended. 
Patients treated with Truxima may receive non-live vaccinations. However, with non-live 
vaccines response rates may be reduced. In a non-randomised study, patients with relapsed 
low-grade NHL who received Rituximab monotherapy when compared to healthy untreated 
controls had a lower rate of response to vaccination with tetanus recall antigen (16% vs. 81%) 
and Keyhole Limpet Haemocyanin (KLH) neoantigen (4% vs. 76% when assessed for > 2-fold 
increase in antibody titer). For CLL patients similar results are assumable considering 
similarities between both diseases but that has not been investigated in clinical trials. Mean 
pre-therapeutic antibody titres against a panel of antigens (Streptococcus pneumoniae, 
influenza A, mumps, rubella, varicella) were maintained for at least 6 months after treatment 
with Rituximab. 
Skin reactions 

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Severe skin reactions such as Toxic Epidermal Necrolysis (Lyell's syndrome) and Stevens-
Johnson syndrome, some with fatal outcome, have been reported. In case of such an event, 
with a suspected relationship to Rituximab, treatment should be permanently discontinued. 
Sodium 
This medicinal product contains up to 23.06 mmol (or 530.1 mg) sodium per dose. To be taken 
into consideration by patients on a controlled sodium diet. 
8.1.3.4 Undesirable effects 
Experience from non-Hodgkin's lymphoma and chronic lymphocytic leukaemia 
Summary of the safety profile 
The overall safety profile of Rituximab in non-Hodgkin's lymphoma and chronic lymphocytic 
leukaemia is based on data from patients from clinical trials and from post-marketing 
surveillance. These patients were treated either with Rituximab monotherapy (as induction 
treatment or maintenance treatment following induction treatment) or in combination with 
chemotherapy. 
The most frequently observed adverse drug reactions (ADRs) in patients receiving Rituximab 
were IRRs which occurred in the majority of patients during the first infusion. The incidence of 
infusion-related symptoms decreases substantially with subsequent infusions and is less than 
1% after eight doses of Rituximab. 
Infectious events (predominantly bacterial and viral) occurred in approximately 30-55% of 
patients during clinical trials in patients with NHL and in 30-50% of patients during clinical trials 
in patients with CLL. 
The most frequent reported or observed serious adverse drug reactions (ADRs) were: 
• IRRs (including cytokine-release syndrome, tumor-lysis syndrome) 
• Infections 
• Cardiovascular events 
Other serious ADRs reported include hepatitis B reactivation and PML. 
8.2 
Treatment schedule and design 
Cycle 1 (21 days cycle): 
Rituximab: 
375 mg/m2 IV day 1, 8, 15 

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Pembrolizumab: 
200 mg IV fixed dose day 2 
Cycle 2-18 (21 days cycle) or until progression or non-tolerable toxicity: 
Rituximab: 
375 mg/m2 IV day 1 every second cycle 
Pembrolizumab: 
200 mg IV fixed dose day 1 
Trial 
treatment 
should 
be 
administered 
on 
Day 
1 
of 
each 
cycle 
after 
all 
procedures/assessments have been completed as detailed on the Trial Flow Chart (Appendix 
A).  
All trial treatments will be administered on an outpatient basis. 
 
Sequence of treatment:  
On days when both Pembrolizumab and Rituximab are administered, Pembrolizumab will be 
administered first IV, subsequently Rituximab will be applied IV. There should be at least a 30 
min break between the infusions. Pre-medication for Rituximab will be applied before the start 
of Pembrolizumab as described in section 8.1.3 and according to the center’s standard 
procedures. The administration will take place under the close supervision of an experienced 
healthcare professional and patients will be closely monitored for adverse reactions like 
cytokine release syndrome.  
Rationale for dosing schedule of rituximab after cycle 1: 
Rituximab single agent is one of the widely used chemotherapy free approaches in MZL and 
has clear anti-lymphoma activity in MZL. This is why we aim at continuing Rituximab 
applications beyond cycle 1 to exploit this activity. In addition, conceptually Pembrolizumab as 
a PD1 inhibitor should increase the activity of Rituximab by “re-freshing” ADCC, which is 
important for Rituximab activity. Thus, we anticipate that Rituximab beyond its known activity 
as a single agent, shows increased activity when combined with Pembrolizumab until cycle 18 
in a de-escalated application scheme with one infusion every 8 weeks. 
 
Follow-up Phase 
All subjects who enter the trial will continue to be followed every 3 months for disease 
progression, subsequent treatment, and survival for two years after completion/discontinuation 

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of the treatment. Subsequently, patients will be monitored every 6 months for three additional 
years. The follow-up phase will be shorter than 5 years if End of Study is reached before this 
time period. 
Patients with disease progression at any time will be followed every 6 months (after early 
completion visit) until the end of the study (app of 7.5 years starting with first patient in) for the 
following: 
- 
New anti-lymphoma therapy 
- 
Survival 
8.3 
Dose adjustments 
In general, the following rules should be adhered to: 
• 
In case of several toxicities, the most severe reaction is to be taken for dose 
reductions. 
• 
Patients must have at least a hemoglobin value 7.5 g/dL, an ANC 0.5  109/L, 
and a platelet count 30  109/L before continuing treatment. 
• 
Delays of cycles will be done by regimen and not by individual compound. 
• 
Dose reductions will be done by individual compounds as described below. 
• 
If there is the necessity to stop application of single compounds, treatment can be 
continued omitting the individual drug with the other compounds of the regimen. 
• 
If there is a delay in treatment of > 3 weeks, contact the ‘Clinical trials office (Ulm)’. 
8.3.1 Pembrolizumab i.v. 
8.3.1.1 Dose Modification and toxicity management for irAEs associated with Pembrolizumab 
and combination therapy 
AEs associated with Pembrolizumab exposure, including coadministration with additional 
compounds, may represent an immunologic etiology. These immune-related AEs (irAEs) may 
occur shortly after the first dose or several months after the last dose of Pembrolizumab/ 
combination treatment and may affect more than one body system simultaneously. Therefore, 
early recognition and initiation of treatment is critical to reduce complications. Based on 
existing clinical study data, most irAEs were reversible and could be managed with 
interruptions of Pembrolizumab/ combination treatment, administration of corticosteroids 
and/or other supportive care. For suspected irAEs, ensure adequate evaluation to confirm 
etiology or exclude other causes. Additional procedures or tests such as bronchoscopy, 
endoscopy, skin biopsy may be included as part of the evaluation. Based on the severity of 
irAEs, withhold or permanently discontinue Pembrolizumab and administer corticosteroids. 

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Dose modification and toxicity management guidelines for irAEs associated with 
Pembrolizumab/ combination treatment are provided in Table 1. 
Attribution of Toxicity: 
When study interventions are administered in combination, attribution of an adverse event to 
a single component is likely to be difficult.  Therefore, while the investigator may attribute a 
toxicity event to the combination, to rituximab alone or to pembrolizumab alone, for adverse 
events listed in Table 1, both interventions must be held according to the criteria in Table 1. 
Holding Study Interventions: 
When study interventions are administered in combination, if the AE is considered immune-
related, both interventions should be held according to recommended dose modifications. 
Restarting Study Interventions: 
Participants may not have any dose modifications (no change in dose or schedule) of 
pembrolizumab in this study, as described in Table 1. 
• 
If the toxicity does not resolve or the criteria for resuming treatment are not met, the 
participant must be discontinued from all study interventions. 
• 
If the toxicities do resolve and conditions are aligned with what is defined in Table 1, 
the combination of rituximab and pembrolizumab may be restarted at the discretion of 
the investigator 
 
8.3.1.2 Dose modification and toxicity management of infusion-reactions related to 
Pembrolizumab 
Pembrolizumab may cause severe or life-threatening infusion-reactions including severe 
hypersensitivity or anaphylaxis. Signs and symptoms usually develop during or shortly after 
drug infusion and generally resolve completely within 24 hours of completion of infusion. Dose 
modification and toxicity management guidelines on Pembrolizumab associated infusion 
reaction are provided in Table 2.  

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Table 1: Dose modification and toxicity management guidelines for immune-related AEs associated with Pembrolizumab monotherapy 
and immuno-oncology combinations 
General instructions: 
1. Corticosteroid taper should be initiated upon AE improving to Grade 1 or less and continue to taper over at least 4 weeks. 
2. For situations where study intervention has been withheld, study intervention can be resumed after AE has been reduced to Grade 1 or 0 and corticosteroid 
has been tapered. Study intervention should be permanently discontinued if AE does not resolve within 12 weeks of last dose or corticosteroids cannot be 
reduced to ≤10 mg prednisone or equivalent per day within 12 weeks.  
3. For severe and life-threatening irAEs, IV corticosteroid should be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if irAEs cannot be controlled by corticosteroids. 
4. For signs or symptoms of SJS or TEN, withhold pembrolizumab and refer the patient for specialized care for assessment and treatment. If SJS or TEN is 
confirmed, permanently discontinue pembrolizumab. 
 
Immune-related 
AEs 
Toxicity grade 
(CTCAEv5.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or other 
therapies  
Monitoring and follow-up  
Pneumonitis  
Grade 2 
Withhold  
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
• Add prophylactic antibiotics for 
opportunistic infections 
 
• 
Monitor participants for signs and symptoms of 
pneumonitis 
• 
Evaluate participants with suspected pneumonitis with 
radiographic imaging and initiate corticosteroid 
treatment 
Grade 3 or 4, or 
recurrent Grade 2 
Permanently 
discontinue 
Diarrhea / Colitis  Grade 2 or 3 
Withhold 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
 
• 
Monitor participants for signs and symptoms of 
enterocolitis (i.e., diarrhea, abdominal pain, blood or 
mucus in stool with or without fever) and of bowel 
perforation (i.e., peritoneal signs and ileus). 
• 
Participants with ≥ Grade 2 diarrhea suspecting colitis 
should consider GI consultation and performing 
endoscopy to rule out colitis.  
• 
Participants with diarrhea/colitis should be advised to 
drink liberal quantities of clear fluids. If sufficient oral 
fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. 
Recurrent Grade 3 
or Grade 4 
Permanently 
discontinue 
AST / ALT 
elevation or 
Grade 2a 
Withhold 
• Administer corticosteroids (initial 
dose of 0.5- 1 mg/kg prednisone or 
equivalent) followed by taper 
• 
Monitor with liver function tests (consider weekly or 
more frequently until liver enzyme value returned to 
baseline or is stable) 

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Increased 
bilirubin 
Grade 3b or 4c  
Permanently 
discontinue 
• Administer corticosteroids (initial 
dose of 1-2 mg/kg prednisone or 
equivalent) followed by taper 
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of -cell 
failure 
Withholdd 
• Initiate insulin replacement 
therapy for participants with 
T1DM  
• Administer anti-hyperglycemic in 
participants with hyperglycemia  
 
• 
Monitor participants for hyperglycemia or other signs 
and symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
• Administer corticosteroids and 
initiate hormonal replacements as 
clinically indicated. 
 
• 
Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal insufficiency)  
Grade 3 or 4  
Withhold or 
permanently 
discontinued  
Hyperthyroidism  
Grade 2 
Continue  
• Treat with non-selective beta-
blockers (e.g., propranolol) or 
thionamides as appropriate  
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinued 
Hypothyroidism 
Grade 2-4 
Continue  
• Initiate thyroid replacement 
hormones (e.g., levothyroxine or 
liothyroinine) per standard of care 
• 
Monitor for signs and symptoms of thyroid disorders.  
 
Nephritis: 
Grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold  
• Administer corticosteroids 
(prednisone 1-2 mg/kg or 
equivalent) followed by taper. 
• 
Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 

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Myocarditis 
Grade 1  
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or DRESS 
Withhold 
• Based on severity of AE 
administer corticosteroids 
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
Confirmed SJS, 
TEN, or DRESS 
Permanently 
discontinue 
All other 
immune-related 
AEs 
Persistent Grade 2 
Withhold 
• Based on type and severity of AE 
administer corticosteroids  
• 
Ensure adequate evaluation to confirm etiology and/or 
exclude other causes 
 
Grade 3 
Withhold or 
discontinue based 
on the type of 
event. e 
Grade 4 or 
recurrent Grade 3  
Permanently 
discontinue 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline if 
baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, pembrolizumab 
may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs. 
 
 
 
 
 

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Table 2: Pembrolizumab Infusion Reaction Dose modification and Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at 
Subsequent Dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
None 
Grade 2 
Requires therapy or infusion 
interruption but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDs, narcotics, IV 
fluids); prophylactic medications 
indicated for ≤24 hrs 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Increase monitoring of vital signs as medically indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
If symptoms resolve within 1 hour of stopping drug infusion, the infusion may be restarted at 50% of 
the original infusion rate (e.g. from 100 mL/hr to 50 mL/hr). Otherwise dosing will be held until 
symptoms resolve and the participant should be premedicated for the next scheduled dose. 
Participants who develop Grade 2 toxicity despite adequate premedication should be 
permanently discontinued from further study drug treatment 
Participant may be 
premedicated 1.5h (± 
30 minutes) prior to 
infusion of 
Pembrolizumab with: 
Diphenhydramine 50 
mg po (or equivalent 
dose of antihistamine). 
Acetaminophen 500-
1000 mg po (or 
equivalent dose of 
analgesic). 
Grades 3 or 4 
Grade 3: 
Prolonged (i.e., not rapidly responsive 
to symptomatic medication and/or brief 
interruption of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization indicated 
for other clinical sequelae (e.g., renal 
impairment, pulmonary infiltrates) 
Grade 4: 
Life-threatening; pressor or ventilatory 
support indicated 
Stop Infusion. 
Additional appropriate medical therapy may include but is not limited to: 
Epinephrine** 
IV fluids 
Antihistamines 
NSAIDs 
Acetaminophen 
Narcotics 
Oxygen 
Pressors 
Corticosteroids 
Increase monitoring of vital signs as medically indicated until the participant is deemed medically 
stable in the opinion of the investigator. 
Hospitalization may be indicated. 
**In cases of anaphylaxis, epinephrine should be used immediately. 
Participant is permanently discontinued from further study drug treatment. 
No subsequent dosing 
Appropriate resuscitation equipment should be available at the bedside and a physician readily available during the period of drug administration. 
For further information, please refer to the Common Terminology Criteria for Adverse Events v 4.0 (CTCAE) at http://ctep.cancer.gov 

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8.3.1.3 Other dose interruption allowed for Pembrolizumab  
Pembrolizumab may be interrupted for situations other than treatment-related AEs such as 
medical / surgical events or logistical reasons not related to study therapy. Participants should 
be placed back on study therapy within 3 weeks of the scheduled interruption, unless otherwise 
discussed with the Sponsor. The reason for interruption should be documented in the patient's 
study record. 
8.3.2 Rituximab i.v. 
If any NCI CTCAE (v 5.0) grade 1 or 2 infusion-related reaction (IRR) occurs during an infusion, 
infusion should be slowed or interrupted (at the discretion of the investigator) and supportive 
treatment instituted. The infusion rate can be increased or restarted on resolution of the 
symptoms. 
If any NCI CTCAE (v 5.0) grade 3 or 4 IRR occurs during an infusion, infusion will be 
discontinued immediately and not restarted until resolution of the symptoms. Treatment can 
be reinitiated (at half the original infusion rate) at the discretion of the investigator, but if the 
same adverse event appears again with the same severity, treatment must be permanently 
discontinued. 
If bronchospasm or dyspnea occurs in the patient during the infusion, the infusion should be 
stopped immediately. Medication such as anti-histamines or steroids should be given for 
symptomatic relief. The infusion should not be re-started until symptoms have resolved 
completely and should be given at half the original infusion rate. Neutropenia and 
thrombocytopenia could be due to the course of the disease and it may be necessary to delay 
the dose of Rituximab until they are resolved, up to a maximum of 2 weeks. 
Please also consider section “8.1.3.3 Serious adverse reactions”. 
8.4 
Permitted Medications and Supportive Therapies  
• Standard therapies for concurrent medical conditions  
• Treatment 
with 
non-conventional 
therapies 
(for 
example 
acupuncture), 
and 
vitamin/mineral supplements is acceptable provided that they do not interfere with the 
study endpoints, in the opinion of the Investigator.  
• Bisphosphonates 
• Patients who are therapeutically treated with an agent such as warfarin or heparin will be 
allowed to participate provided that their medication dose and INR/PTT is stable. Close 
monitoring is recommended according to standard of care. If either of these values is 
above the therapeutic range, the doses should be modified and the assessments should 

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be repeated weekly until it is stable. 
• Antiemetics: Prophylactic anti-emetics may be administered according to standard 
practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as 
granisetron, ondansetron, or an equivalent agent, is allowed as needed. The use of 
corticosteroids as antiemetics prior to Pembrolizumab administration will be not allowed. 
• Palliative and supportive care for the other disease-related symptoms (with the exception 
of radiotherapy) and for toxicity associated with treatment will be offered to all patients in 
this trial. 
• Patients may receive palliative and supportive care for any underlying illness (with the 
exception of radiotherapy). 
• Low-dose aspirin (maximum 100 mg/day) and low-dose heparin are permitted. 
• Patients taking narrow therapeutic index medications should be monitored proactively, if 
these medications cannot be avoided. These medications may include quinidine and 
digoxin. 
 
The following medications and supportive therapies are examples of support therapies that 
may be used if needed during this study:  
• Platelet, and packed red blood cell transfusions are permitted, as necessary; 
• Granulocyte-Colony Stimulating Factor, Erythropoietin;  
• Medications to prevent and treat Rituximab related infusion reactions (i.e. Acetaminophen, 
Diphenhydramine, glucocorticoids, Ranitidine or Cimetidine).  
8.5 
Prohibited concomitant therapy  
• Any treatment responsible for lymphocyte depletion and live-attenuated vaccines are not 
permitted  
• Antineoplastic systemic chemotherapy or biological therapy  
• This list is not comprehensive and is only meant to be used as a guide: 
− 
Herbal medications/preparations (except for vitamins). Herbal medications include, 
but not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko biloba, 
dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh, mistletoe 
and ginseng. Patients should stop using all herbal medications at least 7 days prior to 
first dose of study treatment. 
− 
Other investigational and antineoplastic therapies 
− 
Anti-arrhythmic therapy other than beta blockers or digoxin 
− 
Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or 
equivalent. Previous corticosteroid therapy must be stopped or reduced to the allowed 

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dose at least 7 days prior to the screening CT/MRI). If a patient is on chronic 
corticosteroid therapy, corticosteroids should be de-escalated to the maximum 
allowed dose before the screening. Patients may be using topical or inhaled 
corticosteroids. Short-term systemic corticosteroids above 15 mg prednisolone or 
equivalent will be allowed. The use of corticosteroids as antiemetics prior to 
Pembrolizumab administration will not be allowed 
− 
Ongoing immunosuppressive therapy  
− 
Concomitant radiotherapy (it is assumed that radiation would be indicated only in case 
of progression, when the patient would come off study medication anyway)  
− 
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during therapy.  
The therapies listed above are not prohibited anymore 110 days after last study drug 
administration (based on five times the terminal elimination half-life of Rituximab and 
Pembrolizumab). In case of disease progression the patient can receive a new anti-
lymhoma treatment before this time period, the decision is at the discretion of the 
treating physician. 
8.6 
Vaccinations 
• Immunizations status of eligible patients must be checked at the inclusion. National 
recommendations for adult immunization policy must be fulfilled before Rituximab delivery. 
• Pneumococal and hemophilus B vaccines are recommended in the absence of 
contraindications before Rituximab therapy. The interval of time between any 
immunization and the first Rituximab delivery should be at least of 28 days. 
9. 
Schedule of assessments  
9.1 
Definition of (staging) examinations 
9.1.1 Pathological diagnostic 
Tissue diagnostic procedures must be performed within 12 months prior to study entry and 
have to include diagnostics by a reference pathology center. Biopsy material from an excisional 
or core biopsy must be submitted for retrospective central confirmation. Tissue samples dated 
> 12 months prior to informed consent can be accepted only if tissue material is available for 
retrospective confirmation, if there is no clinical indication for transformation of disease, and if 
the request for additional biopsy would be unethical treatment of the patient. 
A local pathological diagnosis of MZL is obligatory before registration into the clinical trial. In 
addition, a reference pathological confirmation of the diagnosis MZL has to be available at the 

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end of the screening period and before initiation of treatment. The pathological review will be 
centralized nationally in each participating country in their national reference laboratories. The 
review will be done without knowledge of patient outcome and will comprise the confirmation 
of the diagnosis of MZL including specification of the MZL sub-type. Preferably, all the 
requested tumor paraffin embedded blocks from the formalin fixed sample (that was used for 
diagnosis) will be sent to one of the Pathology Reference Centers named in Appendix J. If this 
is not possible at least 10 unstained slides should be sent. As part of the central pathological 
review also the MYD88 mutation will be assessed. Furthermore, PD-L1 expression of 
lymphoma cells will be assessed by a validated method. The block remains at the central 
reference pathologist if patient gave his informed consent for that. The central reference 
pathologist will send the reference pathology report to the study site and the local pathologist 
that submitted the case for review. Histopathology central review process has become in the 
last years a common and prerequisite procedure for clinical trials in the field of lymphomas. It 
requires both a histopathological and immunohistochemical approach using an appropriate 
panel of antibodies according to the morphological pattern and, in some instances, further 
molecular or genetic analysis. 
9.1.2 Tumor and Response Evaluation 
All measurable disease must be documented at baseline and re-assessed according to 
assessment 
schedule 
provided 
in 
Appendix 
A.  
Initial CT/MRI scans used for screening evaluation should not be older than 6 weeks before 
start of treatment.  
Response assessments will be performed by the investigator, based on physical examinations, 
CT/MRI scans, hematology, laboratory results, and bone marrow examinations, through use 
of Response Criteria for nodal, extranodal and splenic MZL (see Appendix D-F). CT scans 
(with contrast) should include chest, abdomen, and pelvis scans; CT scans of the neck should 
be included if clinically indicated (i.e., if evidence of disease on physical examination) and must 
be followed throughout the trial if there is disease involvement at baseline. MRIs of the chest, 
abdomen, and pelvis with a non-contrast CT scan of the chest may be used in patients for 
whom CT scans with contrast are contraindicated (i.e., patients with contrast allergy or 
impaired renal clearance). If MRI is used at screening, then MRI should be used throughout 
the study (same method during the entire study). In addition, the CT portion of a combined 
FDG-PET/CT scan may be used and collected with resolution sufficient to allow accurate and 
consistent comparison of target lesion measurements with subsequent CT scans. Use of FDG-
PET/CT when clinically indicated and must be conducted always beforehand Pembrolizumab 
administration. Any time the investigator suspects disease progression, a full tumor 

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assessment must be performed, including a CT scan (limited to areas of prior involvement if 
required by local authorities). 
In case of several lesions, the 6 largest ones should be measured and used as baseline value 
(if possible, the lesions should be from disparate regions of the body and should include 
mediastinal and retroperitoneal areas of disease whenever these sites are involved). If only a 
splenomegaly has been diagnosed, the spleen should also be measured by ultrasound so that 
the spleen can be monitored by ultrasound only to avoid unnecessary radiation. 
 
In patients with gastric extranodal MZL, the initial staging should include a gastroduodenal 
endoscopy with multiple biopsies from the stomach, duodenum, gastroesophageal junction, 
and any site that seems abnormal and must not be older than 12 weeks before start of 
treatment. If any disease sites are identified in this manner at screening, a subsequent 
gastroduodenal endoscopy and biopsy are required to confirm a CR. In addition, if other sites 
are involved at baseline, they should be appropriately staged at baseline and re-evaluated 
during follow-up. For response evaluation endoscopy should be performed at C10D1 and at 
the end of treatment. H. pylori status must be evaluated. Endoscopic ultrasound to evaluate 
the regional lymph nodes and gastric wall infiltration should be performed.  
 
In patients with non-gastric extranodal MZL, the initial staging should be adapted to the 
affected site as follows and according to local practice:  
 
• 
Small intestine (immunoproliferative small intestinal disease, IPSID): Campylobacter 
Jejuni 
search 
in 
the 
tumor 
biopsy 
by 
polymerase 
chain recation 
(PCR), 
immunohistochemistry or in situ hybridization may be carried out. 
• 
Large intestine: colonoscopy. 
• 
Lung: Bronchoscopy + bronchoalveolar lavage. 
• 
Salivary glands: Ear/nose/throat examination and ultrasound. To eliminate association 
with Sjögren syndrome anti-SSA or anti-SSB antibodies should be investigated. 
• 
Thyroid: echography ± computer tomography (CT) scan of the neck and thyroid function 
tests. 
• 
Ocular adnexa: MRI (or CT scan) and ophthalmologic examination. Chlamydia psittaci in 
the tumor biopsy and blood mononuclear cells by PCR may be considered. 
• 
Breast: mammography and MRI (or CT scan). 
• 
Skin: Borrelia Burgdorferi in the tumor biopsy by PCR (in endemic areas) may be 
considered. 

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For all patients with extranodal MZL the MALT-IPI should be determined. It is the decision of 
the investigator to conduct a FDG-PET-CT. Investigations must not be older than 12 weeks 
before start of treatment. If any disease sites are identified in this manner at screening, a 
subsequent investigation is required to confirm a CR. For response evaluation investigations 
should be performed at C10D1 and at the end of treatment. 
9.1.3 Bone marrow examinations 
Bone marrow examinations should include a biopsy for morphology and an aspirate for local 
hematology (optional, if part of standard of care at site). Bone marrow examinations are 
required at screening for staging purposes in all patients (CR definition requires clearing of a 
previously infiltrated bone marrow) and must not be older than 12 weeks before start of 
treatment. If there was bone marrow infiltration at screening, then a subsequent bone marrow 
biopsy at the completion of cycle 9 is required for clinical response evaluation for all patients 
who may have achieved a CR. In patients with a PR and continued bone marrow involvement, 
a subsequent bone marrow examination may be required to confirm a CR at a later time point. 
An additional bone marrow aspirate may be done if that is standard of care at the site. 
9.1.4 Demographic and medical history 
Demographic data will include year of birth, gender and ethnic origin. 
The investigator or designee will collect a complete medical and surgical history from 
5 years before the screening through to the time of informed consent. Medical history will 
include information on the subject’s concurrent medical conditions.  
Relevant medical history, including previous chemotherapy/immunotherapy or radiotherapy, 
antecedent hematologic or oncologic disease, other diseases/symptoms such as fatigue, 
bleeding, and infection (only ongoing events) will be collected. Lymphoma history must date 
back to the initial diagnosis and any response duration must be recorded. Additionally the Ann 
Arbor Stage (Appendix G) will be determined.  
9.1.5 Physical Examination 
A complete physical examination should include an evaluation of head, eye, ear, nose, and 
throat and the cardiovascular, dermatological, musculoskeletal, respiratory, gastrointestinal, 
and neurological systems. As part of tumor assessment, physical examinations should also 
include the evaluation of the presence and degree of enlarged lymph nodes, hepatomegaly, 
and splenomegaly. At screening a complete physical examination will be performed. At the 
other timepoints physical examination should only include systems of most clinical relevance.  

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9.1.6 B Symptoms 
At least the following B Symptoms have to be assessed: fever, night sweats and weight loss 
(unintentional loss of weight; e.g. more than 10% of body weight within the last 6 months).  
9.1.7 Vital Signs 
The assessment of vital signs must include height (only screening), weight, blood pressure, 
pulse and temperature.  
9.1.8 ECOG 
The ECOG Performance Status is one of two widely used methods to assess the functional 
status of a patient. The scale for evaluation is shown in appendix H.  
9.1.9 Electrocardiograms 
A 12-lead ECG and an echocardiography is required at screening and when clinically 
indicated. ECGs for each patient should be obtained from the same machine whenever 
possible, echocardiogram to measure LVEF 
9.1.10 Laboratory Assessments 
During treatment laboratory tests prior to each infusion may be performed either the day before 
or on the planned day of infusion. For dosing criteria, see Section 8.3. 
Laboratory assessments will include the following: 
• 
Hematology (hemoglobin, hematocrit, platelet count, red blood cell (RBC) count, white 
blood cell count, and percent or absolute differential count [total neutrophils, segmented 
neutrophils, banded neutrophils, eosinophils, lymphocytes, monocytes, basophils, 
malignant lymphocytes (e.g., villous lymphocytes in splenic MZL), other cells]) 
• 
Serum chemistries (sodium, potassium, chloride, bicarbonate, BUN, creatinine, calcium, 
magnesium, total bilirubin, total protein, albumin, CRP, LDH, ALT, AST, GGT, alkaline 
phosphatase, uric acid, glucose, BUN/creatinine ratio, lipase, amylase and β2 
microglobulin (β2 microglobulin required only at screening). Phosphate, total cholesterol, 
LDL and triglycerides will be determined at Screening, on Day 1 of every 2nd cycle (2, 
4, 6 etc.) and at the EOT visit. On these days patients must be fasting prior to sampling 
according to local standards. If a patient cannot adhere to fasting requirements, the 
evaluation of lipid-panels including triglycerides is considered not feasible. 
• 
Quantitative immunoglobulins (IgG, IgA, and IgM) 

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• 
Serum electrophoresis (albumin, alpha 1, alpha 2, beta, gamma), relative and absolute 
determination of M protein if present. If M protein is present, immunofixation for detection 
of Ig subtype (IgG, IgA, IgM, IgD, light-chain kappa or lambda)  
• 
Thyroid hormones: T3, T4, TSH 
• 
Urine analysis: In a fresh sample of midstream urine, a dipstick testing for proteinuria is 
required (and microscopy including protein, specific gravity, glucose and blood). 
• 
Urine Protein to Creatinine Ratio (UPCR) measurement. 
• 
GFR calculation according to MDRD abbreviated formula 
• 
Leukocyte immunophenotyping (FACS) PB and Bone Marrow Aspirate; Mandatory CD5, 
CD10, CD19, CD20, CD23, CD27, CD43, FMC7, kappa/lambda light chains.  
• 
Coagulation (PTT or aPTT, prothrombin time, INR) 
• 
Pregnancy test: All women of childbearing potential (including those who have had a 
tubal ligation) will have a pregnancy test at screening. WOCBP should only be included 
after a negative highly sensitive urine or serum pregnancy test. Following initiation of 
treatment, pregnancy testing will be performed whenever an expected menstrual cycle 
is missed or when pregnancy is otherwise suspected; at the time points specified in the 
Schedule of Activities and may be performed more frequently if required by local 
legislation. If a urine pregnancy test is positive, dosing will be delayed until the patient’s 
status is determined by a serum pregnancy test. 
• 
Viral serology and detection: Hepatitis B (HBsAg and total HBcAb and HBSAb) HBV 
DNA should be monitored every 4 weeks by real-time PCR with a limit of quantification 
of at least 29 IU/mL until at least 1 year after the last treatment cycle in patients who are 
HBsAg negative and HBcAb positive. If a patient is HBsAg negative and HBcAb positive 
during screening, additional serology for hepatitis B surface antibody (HBsAb) is required 
prior to Day 1 of Cycle 1. HCV antibody (also HCV RNA by PCR in a local laboratory if 
the patient is HCV antibody positive).  
9.1.11 Functional Assessment of Cancer Therapy - Lymphoma (FACT-Lym)  
To address health-related quality-of-life (HRQL) issues for Non-Hodgkin’s lymphoma (NHL) 
patients. Patient completes the questionnaire at the start of treatment (Cycle 1 Day 1) and 
afterwards at Day 1 of every third cycle, before contact with the investigator or other 
investigative site personnel. 
9.1.12 Collection of Biological Material for Biobank 
Only German study sites will participate in the biological sampling project. 

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The patient’s consent and signature at the “Transfer of Ownership Agreement” is prerequisite 
for biological sampling. The required materials, amounts and procedures for the management 
of biological samples will be explained in Appendix B. 
If any patients will withdraw his/her consent to further biological sampling and storage during 
study participation, no further collection of biological samples will take place and already stored 
samples will be destroyed if possible and wished by the patient. This does not affect the 
patient’s participation in the clinical study in any other respect. 
9.2 
Screening procedures 
Written informed consent for participation in the study must be obtained before performing any 
study-specific screening tests or evaluations. Informed Consent Forms for patients who are 
not subsequently enrolled will be maintained at the study site. Screening tests and evaluations 
will be performed within 28 days prior to Day 1 of Cycle 1 (defined as the day of the first dose 
of Rituximab). Results of standard-of-care tests or examinations performed within 14 days prior 
obtaining informed consent may be used; such tests do not need to be repeated for screening. 
All screening evaluations must be completed and reviewed to confirm that patients meet all 
eligibility criteria before initiation of study treatment. Please see the Study Flowcharts provided 
in Appendix A for schedules of screening and pretreatment assessments. 
At the end of the screening period a reference pathology report has to be available 
before start of treatment. 
After the patient signs the study informed consent, any new finding discovered not present in 
the patient’s medical history or a worsening of a prior medical history finding must be recorded 
as an adverse event. Certain results from diagnostic testing performed as part of the standard 
of practice prior to the informed consent date and time may be used to fulfill screening criteria. 
This includes fresh tissue, CT (or MRI) scans, endoscopy with biopsies, bone marrow sample, 
echocardiogram and hepatitis testing which may be used provided they fall into the protocol 
specified window (see section 9.1). However, these historical results can only be used after 
the patient gives informed consent to use them. 
The following procedures will be conducted at the Screening visit (after obtaining informed 
consent): 
• 
Discussion of fertility issues and sperm banking should be performed in patients at 
childbearing age 
• 
Demographic, Medical History and Ann Arbor Stage 
• 
Complete physical examination, vital signs and ECOG performance status 
• 
Initial staging procedures: iter alia imaging and bone marrow examinations (for details 
see section 9.1) 

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• 
Presence of B–symptoms (fever, weight loss, night sweat)  
• 
12-lead ECG and Echocardiography 
• 
Laboratory: 
o Hematology 
o Serum chemistry 
o electrophoresis 
o If M protein is present: Serum protein immunofixation 
o Coagulation 
o Thyroid hormones  
o Urine analysis 
o Urine Protein to Creatinine Ratio (UPCR) measurement 
o GFR calculation according to MDRD abbreviated formula 
o Quantitative immunoglobulins (IgG, IgA, and IgM) 
o Leukocyte immunophenotyping (FACS) PB and Bone Marrow Aspirate  
o Viral serology and detection 
• 
Concomitant medication 
• 
All women of childbearing potential will have a pregnancy test at screening  
Once screening studies are complete and patient eligibility for this study is established, the 
provided inclusion checklist form will be completed for registration of the patient.  
9.3 
Assessments during Treatment 
Local laboratory assessments may be performed within 4 days prior to study drug 
administration on Day 1 of each cycle. Results must be reviewed and the review documented 
prior to study drug administration. During treatment, all visits must occur within ± 4 days from 
the scheduled date, unless otherwise noted. Assessments scheduled on the day of study drug 
administration should be performed prior to study drug infusion, unless otherwise noted. 
Please see the Study Flowcharts provided in Appendix A for schedules of assessments to be 
performed during treatment. 
Treatment – Cycle 1 
Cycle 1, Day 1 
The following assessments should be performed on Cycle 1 Day 1 before receiving study drug 
unless otherwise specified in the protocol.  
• 
Complete physical examination, including vital signs 
• 
ECOG Performance Status 
• 
Laboratory tests 

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o Hematology 
o Serum Chemistry (excluding phosphate, total cholesterol, LDL and triglycerides) and 
electrophoresis 
o Women of childbearing potential: negative urine pregnancy test  
• 
Safety assessment (see Section 8.3 and 11). AE reporting period starts with informed 
consent signature 
• 
Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• 
Quality of life questionnaire (FACT-Lym) 
Cycle 1, Day 2 
• 
Vital signs 
• 
Safety assessment 
• 
Concomitant medication review 
Cycle 1 Day 8 
The following assessments should be performed on Cycle 1 Day 8 before receiving study drug 
unless otherwise specified in the protocol. 
• 
Vital signs 
• 
Laboratory: 
o Hematology 
o Serum Chemistry (excluding phosphate, total cholesterol, LDL and triglycerides) and 
electrophoresis 
o Urine Protein to Creatinine Ratio (UPCR) measurement when clinically indicated 
• 
Safety assessment (see Section 8.3 and 11). 
• 
Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
Cycle 1, Day 15 
The following assessments should be performed on Cycle 1 Day 15 before receiving study 
drug unless otherwise specified in the protocol. 
• 
Vital signs 
• 
Laboratory: 
o Hematology 

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o Serum Chemistry (excluding phosphate, total cholesterol, LDL and triglycerides) and 
electrophoresis 
o Urine Protein to Creatinine Ratio (UPCR) measurement when clinically indicated 
• 
Safety assessment (see Section 8.3 and 11). 
• 
Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
Cycle 2 and higher, Day 1 
The following assessments should be performed on Cycle 2 and higher, Day 1 before receiving 
study drug unless otherwise specified in the protocol. 
• 
Physical examination, including vital signs 
• 
ECOG Performance Status 
• 
Laboratory: 
o Hematology 
o Serum 
Chemistry 
and 
electrophoresis. 
Phosphate, total cholesterol, LDL and triglycerides will be determined at Screening, 
on Day 1 of every 2nd cycle (2, 4, 6 etc.) and at the EOT visit. On these days patients 
must be fasting prior to sampling according to local standards. If a patient cannot 
adhere to fasting requirements, the evaluation of lipid-panels including triglycerides 
is considered not feasible. 
o GFR 
o Coagulation panel 
o Urinalysis (dipstick). Microscopy as clinically indicated 
o Urine Protein to Creatinine Ratio (UPCR) measurement when clinically indicated 
o HBV DNA PCR in patients who are HBsAg negative and HBcAb positive  
• 
Safety assessment (see Section 8.3 and 11). 
• 
Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• 
B-Symptoms on Day 1 of each third cycle (i.e. on Day 1 of Cycles 1, 3, 6, 9 etc. and 
Cycle 10) 
• 
QoL questionnaire (FACT-Lym) on Day 1 of each third cycle (i.e. on Day 1 of Cycles 1, 
3, 6, 9 etc.)  
Please see the Study Flowcharts provided in Appendix A for schedules of assessments to be 
performed during Treatment phases. 

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Safety monitoring of the first 6 included patients 
There will be a close safety monitoring of the first 6 included patients. For these 6 patients 
safety evaluations will be performed on: 
• 
Cycle 1 day 1, day 8 and day 15  
• 
Cycles 2 to 6 day 1 and day 15 
All included patients will have study visits as described above. For these 6 first patients 
additionally the visits C2D15, C3D15, C4D15, C5D15 and C6D15 have to be scheduled. 
The following assessments should be performed:  
• 
physical examinations 
• 
Laboratory: 
o Hematology 
o Serum Chemistry and electrophoresis 
o CRP 
o serum immunoglobulin [IgG, IgM, IgA] 
• 
adverse event monitoring 
• 
concomitant medications 
End of Cycle 9 (Cycle 10 Day 1) or Early Termination Visit 
Patients who complete Cycle 9 will be asked to return to the clinic within 4−6 weeks after Cycle 
9 Day 1 for C10D1 visit. Patients who discontinued treatment early will be asked to return to 
the clinic for Early Termination Visit. An early termination visit should occur within 4−8 weeks 
after last dose (in case of early termination due to adverse event) or within 2−8 weeks after 
last dose (in case of early termination due to clinical disease progression). Please see the 
Study Flowcharts provided in Appendix A for schedules of assessments to be performed at the 
induction completion/early termination visit. 
The following assessments should be performed on Cycle 10 Day 1 before receiving study 
drug or on Early Termination Visit unless otherwise specified in the protocol: 
• 
In patients with gastric extranodal MZL: Gastroduodenal endoscopy 
• 
Tumor Assessment: by CT/PET-CT/MRI and/or Bone Marrow aspirate and biopsy and/or 
Immunophenotyping PB and BM  
• 
Complete physical examination, including vital signs 
• 
ECOG Performance Status 
• 
Laboratory: 
o Quantitative Immunglobulins (IgA, IgG, IgM) 
o Serum Protein Immunofixation if initially positive for monoclonal Ig 

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o Leukocyte immunophenotyping (FACS) PB (and Bone Marrow Aspirate);  
o Hematology 
o Serum Chemistry and electrophoresis 
o Coagulation 
o HBV DNA PCR in patients who are HBsAg negative and HBcAb positive 
o Urinalysis (dipstick). Microscopy as clinically indicated 
o Urine Protein to Creatinine Ratio (UPCR) measurement when clinically indicated 
o GFR 
o Women of childbearing potential: negative urine pregnancy test  
• 
12-lead ECG and an echocardiography when clinically indicated 
• 
Safety assessment (see Section 8.3 and 11). 
• 
Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• 
In case of Early Termination Visit: new anti-lymphoma treatment 
Please see the Study Flowcharts provided in Appendix A for schedules of assessments to be 
performed during Treatment phases. 
Patients with at least SD will continue study treatment as specified above until end of cycle 18 
or until PD is determined.  
9.4 
Therapy Completion (EOT) 
Patients who complete the treatment period will be asked to return to the clinic 4 weeks after 
Cycle 18 Day 1 for an EOT visit. The visit at which a response assessment showed disease 
progression may be used as the early termination visit (see above).  
The following assessments should be performed at the End of Treatment (EOT): 
• 
In patients with gastric extranodal MZL: gastroduodenal endoscopy 
• 
Tumor Assessment: by CT/PET-CT/MRI and/or Bone Marrow aspirate and biopsy and/or 
Immunophenotyping PB and BM  
• 
Complete physical examination, including vital signs 
• 
ECOG Performance Status 
• 
Laboratory: 
o Quantitative Immunglobulins (IgA, IgG, IgM) 
o Serum Protein Immunofixation if initially positive for monoclonal Ig 
o Leukocyte immunophenotyping (FACS) PB (and Bone Marrow Aspirate);  
o Hematology 
o Serum Chemistry and electrophoresis 

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o HBV DNA PCR in patients who are HBsAg negative and HBcAb positive 
o Urinalysis (dipstick). Microscopy as clinically indicated 
o Urine Protein to Creatinine Ratio (UPCR) measurement when clinically indicated 
o GFR 
o Women of childbearing potential: negative urine pregnancy test  
• 
12-lead ECG and an echocardiography when clinically indicated 
• 
Safety assessment (see Section 8.3 and 11). 
• 
Concomitant medication review. Please note: contrast media does not need to be 
recorded as concomitant medication unless there is an AE related to its administration 
(e.g. allergic reaction). 
• 
New anti-lymphoma treatment 
• 
B-Symptoms 
• 
QoL questionnaire (FACT-Lym)  
 
 

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9.5 
Follow-Up Assessments 
Neither in the case of CR/SD nor in the case of PD is it necessary to provide the study 
medication beyond the end of the study. In the case of PD, treatment is continued with a 
different treatment regimen. 
a. Patients with response or stable disease 
For patients who have at least SD at the EOT visit, disease assessments will continue every 3 
months ± 14 days for 2 years (with CT/PET-CT/MRI if initially positive or indicated every 6 
months) and then every 6 months ± 14 days for 3 years (with CT/PET-CT/MRI if initially positive 
or indicated every year) until the end of the study or until disease progression, whichever 
occurs first. This assessment is consistent with both NCCN and ESMO guidelines. Patients 
will then be followed twice per year until the end of the study for the following: 
• 
New anti-lymphoma therapy 
• 
Survival 
Patients who start a new anti-lymphoma therapy or discontinue study drug in the absence of 
disease progression should be followed according to the above schedule. 
 
b. Patients with disease progression 
Patients with disease progression at any time will be followed every 6 months (after early 
completion visit) until the end of the study (approximately 7.5 years after inclusion of first 
patient) for the following: 
• 
New anti-lymphoma therapy 
• 
Survival 
10. Study procedures 
10.1 
Informed consent 
All subjects must sign and date the most current IRB/IEC approved informed consent form. It 
is the responsibility of the investigator or a designated physician who is part of the study team 
to obtain informed consent in compliance with national requirements from each subject prior 
to any study related procedures or, where relevant, prior to evaluating the patient's suitability 
for the study. 
The informed consent document used by the investigator for obtaining subject's informed 
consent must be reviewed and approved by the sponsor prior to IRB/IEC submission. 
The investigator must explain to a potential patient the aims, methods, reasonable anticipated 
benefits and potential hazards of the trial and any discomfort it may entail. Patients will be 

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informed that they are free not to participate in the trial and that they may withdraw consent to 
participate at any time. They will be told which alternative treatments are available if they refuse 
to take part and that such refusal or withdrawal will not prejudice future treatment.  
Confirmation that the informed consent form has been signed should occur before any study-
specific procedures are performed and before patient registration. All subjects who receive 
protocol-specified therapy or specified treatment should be re-informed and should re-consent 
with at least every safety relevant updated version of the IRB/IEC approved informed consent 
form during study participation as applicable and per institutional guidelines.  
Withdrawal in case the patients experiences an adverse event which indicates to the 
investigator that continued participation is not in the best interest of the patient is performed 
by the investigator. All data collected before the time point of withdrawal remain within the 
study database (according to AMG §40 (2a) 3) Consent will be sought from the patient, in 
order to be allowed to 
o 
report further major outcome information (e.g. efficacy data) 
o 
guarantee the safety of a patient 
o 
comply with requirements to submit complete documents for authorisation 
Documentation that informed consent occurred prior to the study subject’s entry into the study 
and of the informed consent process should be recorded in the study subject’s source 
documents including the date. 
The original informed consent document signed and dated by the study subject and by the 
person having informed and obtained consent from the study subject prior to the study 
subject’s entry into the study, must be maintained in the Investigator’s study files and a copy 
will be given to the study subject. In addition, if a protocol is amended and it impacts on the 
content of the informed consent, the informed consent document must be revised. 
No compensation will be paid to the patients. 
10.2 
Registration Procedure 
The Informed Consent has to be signed by all parties before starting of any trial related 
procedures. 
Patients have to be registered in a web-based system when informed consent signature is 
obtained and as soon as Eligibility Criteria are fulfilled to generate the unique trial identification 
number. Registration must occur prior to initiation of treatment. 
Following data must be provided in the web-based system: 
• 
Name of pathological reference investigator 

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• 
Patient's birth date (month/year) 
• 
Eligibility criteria 
• 
Electronic signature of the responsible investigator for confirmation of inclusion and 
exclusion criteria 
10.3 
Patient Study Participation card  
All participating patients will receive a study participation card, on which the study title and 
study drug are indicated. Furthermore, the address and telephone number of the investigator 
is listed in case of emergency. The patients should always carry this card with them.  
10.4 
Criteria for premature discontinuation of the study 
10.4.1 Early Treatment discontinuation for an individual patient 
Per-protocol treatment of the patient must be discontinued for the following reasons: 
• pregnancy 
• disease progression at any time 
• intercurrent illness that would, in the judgment of the Investigator, affect assessment of 
clinical status to a significant degree 
• recurrent Grade 2 pneumonitis 
• repeated clinically relevant violation of the protocol 
• non-compliance by the patient with protocol requirements 
• excessive and unexpected toxicity of the treatment 
• patient’s decision to stop her/his participation in the trial or study treatment 
• decision by the treating physician for medical reasons 
• discontinuation of the whole study at the request of sponsor 
• Patient is lost to follow-up. If a patient does not return for scheduled visits, every effort 
should be made to re-establish contact. In any circumstance, every effort should be 
made to document patient outcome, if possible. 
In summary, a patient should be withdrawn from the trial treatment if, in the opinion of the 
investigator, it is medically necessary, or if it is the wish of the patient. 
The reason for the early termination of the per-protocol treatment must be documented and 
the ’Coordinating Investigator’ must be informed in written form e.g. on the respective eCRF. 
Patients who stop per-protocol therapy early must be documented and followed-up according 
to protocol. Early termination should be avoided. In case of an early termination of therapy, 
reasons / circumstances and if applicable the final disease status of the patient have to be 

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documented. If the patient does not withdraw the consent for further follow-up, he or she 
should be followed-up as planned.  
10.4.2 Early study termination for an individual patient 
The only reason for the exclusion of a patient from the study is his or her 
withdrawal of consent. Patients can withdraw their informed consent to this study at any 
time and this does not interfere with their right of treatment by the local investigator (physician). 
In case of cessation of the study-treatment a final statement concerning the treatment effect 
and the causes of premature study-termination have to be given by the local investigator.  
In case it becomes evident ex post that a patient did not qualify for the study (e. g. did not fulfill 
all inclusion criteria nor had an exclusion criterion at the time of registration) the physician 
treating the patient with ex-post non-qualification will be informed by the Clinical Trial Office 
Ulm on the ex post non-qualification of a patient. A thorough benefit risk assessment has to be 
performed by the investigator together with the sponsor to decide if the patient with ex-post 
non-qualification should continue study treatment and the result has to be documented. The 
patient with ex post non-qualification is only allowed to continue study treatment if it is 
concluded that in this case for the patient benefits will outweigh risks. The documentation and 
follow up of patients with ex post non-qualification must continue as planned in the protocol, 
because the documentation of such patients is not different from the documentation of qualified 
patients. 
10.4.3 Early closing of a trial site 
The closing of a given trial site will be considered if: 
• it does not meet the technical requirements of the protocol, 
• the recruitment rate is not sufficient, 
• inaccurate or incomplete data collection 
• detected fraud, 
• GCP noncompliance, 
• the conduct of the study is not compliant with the protocol, or 
• the data quality is not sufficient. 
The early closing of a site will be decided by the Coordinating Investigator after consultation 
with the responsible Data Safety Monitoring Committee. Investigators and trial sites deciding 
not to take part in the trial any longer have to inform the Coordinating Investigator immediately. 
The decision should be well-founded. Details on further treatment and follow-up of patients 
already on study have to be discussed with the Principal Investigator.  

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10.4.4 Early termination of the study 
Early termination of the entire study may be necessary for the following reasons: 
• the occurrence of serious unexpected side effects of treatment 
• excessive treatment-related mortality 
• insufficient efficacy of study treatment  
• relevant pertaining new information from other studies or publications 
• inadequate recruitment rate 
• excessive number of deviations from the study protocol 
• logistic and / or financial reasons 
• any other fact which would change the risk-benefit analysis of this trial 
The Data Safety Monitoring Committee (see Appendix K) will monitor the study conduct and 
the safety aspects of the trial on a regular basis, and will give recommendations to the 
Coordinating Investigator of the trial whether to stop the trial or to change the trial protocol. 
The Coordinating Investigator will then decide on the actions to be taken. Basis for his decision 
are the Development Safety Update Reports and the recommendations of the Data Safety 
Monitoring Committee. These recommendations take into consideration the time course of the 
recruitment, characteristics of the study population, execution of the therapy per protocol, 
adherence to protocol and frequency of adverse and serious adverse events. The decision on 
an early termination of the study is a complex action which has to consider in addition to 
statistical also medical and ethical as well as organizational and financial aspects. Finally, 
according to the National drug laws, the trial may be suspended or early terminated by decision 
of the respective National Authorities. All Federal Authorities and the ethics committee in 
charge will be notified about the early termination of the trial. 
11. Assessment of Safety 
11.1 
Monitoring, Recording and Reporting of Adverse Events 
11.1.1 Adverse Event 
An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may 
appear or worsen in a subject during the course of a study. It may be a new intercurrent illness, 
a worsening concomitant illness, an injury, or any concomitant impairment of the subject’s 
health, including laboratory test values (as specified by the criteria below), regardless of 
etiology. Any worsening (i.e., any clinically significant adverse change in the frequency or 
intensity of a pre-existing condition) should be considered an AE. A diagnosis or syndrome 
should be recorded on the AE page of the eCRF rather than the individual signs or symptoms 
of the diagnosis or syndrome.  

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An overdose, accidental or intentional, whether or not it is associated with an AE, or abuse, 
withdrawal, sensitivity or toxicity to an investigational product should be recorded as an AE. If 
an overdose is associated with an AE, the overdose and adverse event should be recorded as 
separate terms. 
All subjects will be monitored for AEs during the study. Assessments may include monitoring 
of any or all of the following parameters: the subject’s clinical symptoms, laboratory, 
pathological, radiological or surgical findings, physical examination findings, or other 
appropriate tests and procedures. 
All AEs and special situations will be recorded by the Investigator from the time a signed and 
dated ICF is obtained until 110 days after the last dose of study drug.  
All adverse events and special situations, regardless of seriousness, severity, or presumed 
relationship to study drug, must be recorded using medical terminology (CTCAE, Version 5.0) 
in the source document and the eCRF. Whenever possible, diagnoses should be given when 
signs and symptoms are due to a common etiology (e.g. cough, runny nose, sneezing, sore 
throat, and head congestion should be reported as "upper respiratory infection"). Investigators 
must record in the eCRF their opinion concerning the relationship of the adverse event to study 
therapy. All measures required for adverse event management must be recorded in the source 
document. 
All SAEs must be reported to the Sponsor/ZKS, within 24 hours of the Investigator’s knowledge 
of the event by email to
 using the SAE Report Form. 
11.1.2 Adverse Event of Special Interest 
AESIs (serious or non-serious) are a subset of Events to Monitor (EtMs) of scientific and 
medical concern specific to the IMP or to the Sponsor’s product or research, for which ongoing 
monitoring and rapid communication by the Investigator to the Sponsor is required. Such an 
event might require further investigation in order to characterize and understand it. Depending 
on the nature of the event, rapid communication by the trial Sponsor to other parties (e.g., 
MAH, Regulatory Authorities) may also be warranted. 
Adverse events of special interest (AESI) (synonym: Events of Clinical Interest (ECI)) either 
serious or non-serious, are required to be reported by the investigator to the Sponsor/ZKS in 
the SAE form immediately (i.e., no more than 24 hours after learning of the event) and will be 
recorded on the AE page of the eCRF additionally. Adverse events of special interest for this 
study include the following: 
 
 

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Table 3: Adverse Event of Special Interest 
Adverse Events of Special Interest 
An elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of 
normal and an elevated total bilirubin lab value that is greater than or equal to 2X the upper 
limit of normal and, at the same time, an alkaline phosphatase lab value that is less than 2X 
the upper limit of normal, as determined by way of protocol-specified laboratory testing or 
unscheduled laboratory testing.* 
 
*Note: These criteria are based upon available regulatory guidance documents. The purpose 
of the criteria is to specify a threshold of abnormal hepatic tests that may require an additional 
evaluation for an underlying etiology. 
AESIs (ECI) must be reported within 1 working day after becoming aware by the Sponsor to 
MSD 
Pharmacovigilance 
Germany 
 
 
 
 
 
For the time period beginning when the consent form is signed until treatment allocation, any 
AESI (ECI), or follow up to an AESI (ECI), that occurs to any participant must be reported 
within 1 working day after becoming aware by the Sponsor to MSD Pharmacovigilance 
Germany if it causes the participant to be excluded from the trial, or is the result of a protocol-
specified intervention, including but not limited to washout or discontinuation of usual therapy, 
diet, placebo treatment or a procedure. 
For the time period beginning at treatment allocation through 110 days following cessation of 
treatment, or 30 days following cessation of treatment if the participant initiates new anticancer 
therapy, whichever is earlier, any AESI (ECI), or follow up to an AESI (ECI), whether or not 
related to MSD product, must be reported within 1 working day after becoming aware by the 
Sponsor to MSD Pharmacovigilance Germany 
11.1.3 Adverse Drug Reaction 
An adverse drug reaction (ADR) is any noxious and unintended response to a medicinal 
product related to any dose. The phrase "responses to a medicinal product" means that a 
causal relationship between a medicinal product and an adverse event is at least a reasonable 
possibility. An ADR should be recorded on the AE page of the eCRF. 
11.1.4 Special Situations 
Uses of the IMP outside what is foreseen in the protocol and defined below as „special 
situations“ are subject to the same obligation to report as adverse reactions. All special 

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situations, even in absence of an AE, that occur during the defined study period must be 
recorded on the source documentation, transcribed into the eCRF and in addition reported to 
the Sponsor/ZKS on the „Report form for SAEs, AESIs and Special Situations“.  
Note: All instances of incorrect medication not in accordance with the study protocol should be 
additionally categorized as deviation in the eCRF. 
• 
Pregnancy/Breast feeding 
see section 11.5 
• 
Overdose* 
Any administration of a quantity of a medicinal product given per administration or 
cumulatively that results in drug exposure exceeding that which is defined in the 
protocol. 
• 
Abuse  
Intentional, non-therapeutic use of a drug product or substance, even once, to achieve 
a desired psychological or physiological effect. Therefore, abuse potential refers to the 
likelihood that abuse will occur with a particular drug product or substance with CNS 
activity. Desired psychological effects can include euphoria, hallucinations and other 
perceptual distortions, alterations in cognition, and changes in mood. 
• 
Misuse 
Any intentional therapeutic use of a drug product in an inappropriate way. Inappropriate 
use should be considered in the context of the clinical trial protocol. 
• 
Medication Error 
An unintended failure in the drug treatment process. 
Examples include administration of a drug product in the wrong dose, by an incorrect 
route, or to the wrong person; administration of a drug product resulting in a drug 
interaction due to drugs or foods that are known to interact; administration of the 
wrong drug product; or inadvertently consuming a greater than prescribed dose of a 
drug product (e.g. double dose) due to memory lapse. Therapeutic errors may be 
made by the patient, physician, pharmacist, clinical study staff etc. 
• 
Occupational exposure 
Exposure to an IMP, as a result of one´s professional or non-professional occupation. 
• 
Lack of therapeutic efficacy 
Although MZL is a serious and life-threatening disease, patients will receive approved 
therapies while participating in this study. Efficacy of Rituximab/Pembrolizumab 
combination treatment has yet to be demonstrated in the MZL population. Therefore, 
lack of therapeutic efficacy is not the scope of this study.  
*an overdose of MSD product, as defined in Section 11.3.  

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11.2 
Evaluation of Adverse Events 
A qualified Investigator will evaluate all adverse events as to:  
11.2.1 Seriousness  
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes or actions: 
• 
Results in death; 
• 
Is life-threatening (i.e., in the opinion of the Investigator, the subject is at immediate risk 
of death from the AE); it does not refer to an event which hypothetically might have 
caused death if it were more severe 
• 
Requires inpatient hospitalization or prolongation of existing hospitalization 
(hospitalization is defined as an inpatient admission, regardless of length of stay); 
• 
Results in persistent or significant disability/incapacity (a substantial disruption of the 
subject’s ability to conduct normal life functions); 
• 
Is a congenital anomaly/birth defect; 
• 
Any other event that the Investigator judges to be an important medical event  
• 
adverse event associated with an overdose of IMP 
Important medical events are defined as those occurrences that may not be immediately life 
threatening or result in death, hospitalization, or disability, but may jeopardize the subject or 
require medical or surgical intervention to prevent one of the other outcomes listed above. 
Medical and scientific judgment should be exercised in deciding whether such an AE should 
be considered serious. Suspected transmission of an infectious agent by a medicinal product 
will be reported as a serious adverse event.  
If an AE is considered serious, both the AE page/screen of the eCRF and the SAE Report 
Form must be completed. 
For each SAE, the Investigator will provide at least information on severity, start and stop 
dates, relationship to IMP, action taken regarding IMP, and outcome. 
Events excluded from SAE reporting are hospitalizations for: 
• 
A standard procedure for protocol therapy administration. However, hospitalization or 
prolonged hospitalization for a complication of therapy administration will be reported 
as an SAE.  
• 
Routine treatment or monitoring of the studied indication not associated with any 
deterioration in condition. 

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• 
The administration of blood or platelet transfusion as routine treatment of studied 
indication. However, hospitalization or prolonged hospitalization for a complication of 
such transfusion remains a reportable SAE. 
• 
A procedure for protocol/disease-related investigations (e.g., surgery, scans, 
endoscopy, sampling for laboratory tests, bone marrow sampling). However, 
hospitalization or prolonged hospitalization for a complication of such procedures 
remains a reportable SAE. 
• 
A procedure or hospitalization for progression/relapse investigations (e.g., surgery, 
scans, endoscopy, sampling for laboratory tests, bone marrow sampling). 
• 
Hospitalization or prolongation of hospitalization for technical, practical, or social 
reasons, in absence of an AE. 
• 
A procedure that is planned (i.e., planned prior to signing informed consent); must be 
documented in the source document and the eCRF. Hospitalization or prolonged 
hospitalization for a complication remains a reportable SAE. 
• 
Emergency outpatient treatment or observation that does not result in admission, 
unless fulfilling other seriousness criteria above. 
• 
Sign, symptoms and physical findings indicative of progression of lymphoma are not to 
be reported as “Serious Adverse Event”.  
• 
“Alopecia” toxicity (any grade) will never be reported as “Serious Adverse Event”. 
• 
Serious adverse events will not be recorded 30 days after the start of a new 
chemotherapy treatment, with the exception of second primary malignancies or if it is 
related to the study drug as assessed by the investigator. 
11.2.2 Severity / Intensity 
For both AEs and SAEs, the Investigator must assess the severity / intensity of the event.  
The severity / intensity of AEs will be graded based upon the subject’s symptoms according to 
the current active minor version of National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE, Version 5.0):  
AEs that are not defined in the NCI CTCAE (v 5.0) should be evaluated for severity / intensity 
according to the following scale: 
• Grade 1 = Mild – transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required 
• Grade 2 = Moderate – mild to moderate limitation in activity, some assistance may be 
needed; no or minimal medical intervention/therapy required 

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• Grade 3 = Severe – marked limitation in activity, some assistance usually required; 
medical intervention/therapy required, hospitalization is possible 
• Grade 4 = Life threatening – extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy required, hospitalization or hospice 
care probable 
• Grade 5 = Death - the event results in death 
Specific NCI Working Group or other criteria pertinent to the indication may also be used as 
applicable. 
The term “severe” is often used to describe the intensity of a specific event (as in mild, 
moderate or severe myocardial infarction); the event itself, however, may be of relatively minor 
medical significance (such as severe headache). This criterion is not the same as “serious” 
which is based on subject/event outcome or action criteria associated with events that pose a 
threat to a subject’s life or functioning. 
Seriousness, not severity, serves as a guide for defining regulatory obligations. 
11.2.3 Causality  
The Investigator must determine the relationship between the administration of the IMPs and 
the occurrence of an AE/SAE as Not Related or Related as defined below: 
Not related: 
A causal relationship is unlikely or remote between the adverse event 
and study drug administration and other medications, therapeutic 
interventions, or underlying conditions provide a sufficient explanation for 
the observed event 
Related: 
A causal relationship is possible between the adverse event and study 
drug administration and other medications, therapeutic interventions, or 
underlying conditions do not provide a sufficient explanation for the 
observed event 
11.2.4 Expectedness 
A serious adverse event that is not included in the Adverse Reaction Section of the relevant 
Reference Safety Information (RSI) by its specificity, severity or outcome is considered an 
unexpected adverse event. The reference safety information for this study are the respective 
sections of the IB of Pembrolizumab and of the SmPC of Rituximab. For the purpose of SUSAR 
reporting, the version of the IB in force at the time of occurrence of the SUSAR applies. 

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11.2.5 Duration 
For both AEs and SAEs, the Investigator will maintain a record of the start and stop dates of 
the event. 
11.2.6 Action Taken 
The Investigator will report the action taken with IMP as a result of an AE or SAE, as applicable 
(e.g., discontinuation or reduction of IMP, as appropriate) and report if concomitant and/or 
additional treatments were given for the event.  
11.2.7 Outcome 
The investigator will report the outcome of the event for both AEs and SAEs. 
All SAEs that have not resolved upon discontinuation of the subject’s participation in the study 
must be followed until recovered, recovered with sequelae, not recovered (death due to 
another cause) or death (due to the SAE).  
11.2.8 Abnormal Laboratory Values 
Abnormal laboratory values in laboratory tests that are performed for safety surveillance and 
are not needed for assessment of any efficacy variables will be captured as adverse events, 
rather than capturing the raw laboratory values. 
An abnormal laboratory value is considered to be an AE if the abnormality: 
• 
results in discontinuation from the study; 
• 
requires treatment, modification/ interruption of IMP dose, or any other therapeutic 
intervention; or 
• 
is judged to be of significant clinical importance. 
Regardless of severity grade, only laboratory abnormalities that fulfill a seriousness criterion 
need to be documented as a serious adverse event. 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the 
diagnosis or syndrome should be recorded on the AE page/screen of the eCRF. If the 
abnormality was not a part of a diagnosis or syndrome, then the abnormal laboratory value 
should be recorded as the AE. 
11.3 
Definition of an Overdose of Pembrolizumab for this Protocol and 
Reporting of Overdose  
For purposes of this study, an overdose of Pembrolizumab will be defined as any dose of 1,000 
mg or greater (≥5 times the indicated dose). No specific information is available on the 

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treatment of overdose of Pembrolizumab. In the event of overdose, the participant should be 
observed closely for signs of toxicity. Appropriate supportive treatment should be provided if 
clinically indicated. 
If an adverse event(s) is associated with the overdose of a MSD product, the adverse event(s) 
is reported as a serious adverse event, even if no other seriousness criteria are met. 
If a dose of MSD’s product meeting the protocol definition of overdose is taken without any 
associated clinical symptoms or abnormal laboratory results, the overdose is reported as 
Special Reporting Situation, using the terminology “accidental or intentional overdose without 
adverse effect.” 
All reports of overdose with and without an adverse event must be reported within 24 hours to 
the Sponsor and within 1 working day after becoming aware by the Sponsor to MSD 
Pharmacovigilance 
Germany 
 
 
 
 
  
11.4 
Other malignancies 
In addition to all routine AE reporting, all new malignant tumors, including solid tumors, skin 
malignancies and hematologic malignancies, are to be reported for the duration of study 
treatment and during any protocol-specified follow-up periods including postprogression follow-
up for overall survival. 
11.5 
Pregnancy 
Any pregnancy in a female subject or in a female partner of a male subject diagnosed during 
the treatment period or within 12 months after last study treatment (Rituximab and 
Pembrolizumab) administration must be reported immediately to the Sponsor/ZKS. Follow-up 
information on the subject and her pregnancy outcome should be communicated by the 
investigator to the Sponsor as soon as available. 
If a participant inadvertently becomes pregnant while on treatment, the participant will be 
immediately discontinued from study treatment. The investigator should counsel the subject or 
the partner of the subject, discuss the risks of continuing the pregnancy, and possible effects 
on the foetus. Monitoring of the patient should continue until up to 8 weeks of age of the 
newborn. The site will contact the participant at least monthly and document the participant’s 
status until the pregnancy has been completed or terminated. 
Pregnancy should be reported on the Pregnancy Report Form. If the outcome of the 
pregnancy meets the criteria for immediate classification as a SAE (i.e., spontaneous or 
therapeutic abortion, any congenital anomaly [including that in an aborted fetus], stillbirth, 

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neonatal death), the investigator should follow the procedures for reporting SAEs. All neonatal 
deaths that occur within 30 days of birth should be reported, without regard to causality, as 
SAEs. In addition, any infant death after 30 days that the investigator suspects as related to 
the in utero exposure to the study drug should also be reported as SAE. 
Such events must be reported within 24 hours to the Sponsor and within 1 working day after 
becoming aware by the Sponsor to MSD Pharmacovigilance Germany (
).  
If a male participant impregnates his female partner, the study personnel at the site must be 
informed immediately and the pregnancy must be reported to Sponsor within 24 hours. The 
pregnant female partner should be advised to call their healthcare provider immediately.  
11.6 
Reporting of Serious Adverse Events 
11.6.1 Reporting period  
All events that meet one or more criteria of seriousness that occurred from the time the 
patient’s signed informed consent up to 110 days after the last study drug 
administration, regardless the relationship to the study treatment requires the completion of 
an SAE Report Form in addition to being recorded on the AE page of the eCRF.  
A Serious Adverse Event that occurs after this time, including during the follow-up period, if 
considered related to the study medication, will be reported regardless of the time between 
the last drug administration and the event onset.  
11.6.2 Obligations of the Investigator 
The Investigator is required to ensure that the data on these forms is accurate and consistent. 
This requirement applies to all SAEs (regardless of relationship to study drugs) that occur 
during the study (from the time the patient signs informed consent to 110 days after the last 
dose of study drug(s)), and those made known to the Investigator at any time thereafter that 
are considered to be related study drugs.  
All serious adverse events that have not resolved by the end of the study, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs: 
• 
The event resolves 
• 
The event stabilizes 
• 
The event returns to baseline, if a baseline value/status is available 

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• 
The event can be attributed to agents other than the study drug or to factors 
unrelated to study conduct 
• 
It becomes unlikely that any additional information can be obtained (subject or 
health care practitioner refusal to provide additional information, lost to follow-
up after demonstration of due diligence with follow-up efforts) 
Additionally, any serious adverse event, considered by an investigator who is a qualified 
physician to be related to MSD product that is brought to the attention of the investigator at 
any time following consent through the end of the specified safety follow-up period specified in 
the paragraph above, or at any time outside of the time period specified in the previous 
paragraph also must be reported immediately according to SAE reporting requirements 
mentioned above. Events concerning secondary malignancy need to be reported during follow-
up period regardless of causality. 
All participants with serious adverse events must be followed up for outcome. 
In case of serious adverse events, AESI and special situations the Investigator must 
immediately report by sending the scanned and signed the SAE form to:  
Recipients: ZKS and CTO (Ulm)  
 
All SAE forms must be dated and signed by the responsible Investigator or one of 
his/her authorized staff Members. 
• The SAE report should provide a detailed description of the SAE specifying the date of 
onset, severity, action taken regarding trial medication, corrective therapy given, 
outcome of all serious adverse events and his opinion as to whether the serious adverse 
event can be related to the study drugs. Whenever possible, symptoms should be 
grouped as a single syndrome or diagnosis. 
• Information about results of any examinations carried out including laboratory tests that 
are important for the diagnosis, assessment, or treatment of a SAE and the dates on 
which these examinations were performed should be given within the SAE form. For 
laboratory tests the respective normal reference range should be provided as well.  
• Information for final description and evaluation of a case report may not be available 
within the required time frames for reporting outlined above. Nevertheless, for regulatory 
purposes, initial reports should be submitted within the prescribed time as long as the 
following minimum criteria are met: an identifiable patient; a suspect medicinal product; 
an identifiable reporting source (the identity of the Investigator: name, address, site 
number and email/telephone number); an event or outcome assessed as reportable; 

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investigator causality assessment (in case the investigator causality is missing, the 
causality will be considered related and the case may qualify as a SUSAR). Follow-up 
information should be actively sought and submitted as it becomes available. 
• Additional information to any SAE should be provided by the investigator on a 
subsequent SAE-Report Follow up form and sent by e-mail to Sponsor/ZKS as soon as 
they become available, but not later than 3 days. If a subject died and an autopsy has 
been performed, copies of the autopsy report and death certificate are to be sent as soon 
as these become available. A translation of the autopsy report and death certificate into 
English language has to be provided, if written in a language other than English or 
German. 
• For the time period beginning at treatment allocation through 110 days following 
cessation of treatment, or 30 days following cessation of treatment if the participant 
initiates new anticancer therapy, whichever is earlier, any serious adverse event, or 
follow up to a serious adverse event, including death due to any cause whether or not 
related to the MSD product, must be reported within 24 hours to the Sponsor and by the 
Sponsor within 1 working day to MSD Pharmacovigilance Germany 
 
Where required by local regulation, the Investigator is responsible for informing the IRB/EC of 
the SAE and providing them with all relevant initial and follow-up information about the event. 
The Investigator must keep copies of all SAE information on file including correspondence with 
the Sponsor/ZKS and the IRB/EC. 
11.6.3 Safety Queries 
Queries pertaining to SAEs will be communicated from the Sponsor/ZKS to the site via 
facsimile or electronic mail. The response time is expected to be no more than 1 calendar day 
(urgent queries) or three (3) business days (non-urgent queries). Urgent queries (e.g., missing 
causality assessment) may be handled by phone. 
11.6.4 Obligations of the sponsor 
SAE reports and any other relevant safety information must be reported from the Sponsor to 
MSD 
Pharmacovigilance 
Germany 
(
 
 
 
 
 within 1 working day after becoming aware by the Sponsor if 
it causes the participant to be excluded from the trial, or is the result of a protocol-specified 
intervention, including but not limited to washout or discontinuation of usual therapy, diet, 
placebo treatment or a procedure. It has to be reported by facsimile, or other appropriate 

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method, using the SAE Report Form. This instruction pertains to initial SAE reports as well as 
any follow-up reports.  
During the course of the study, the Sponsor will report in a pseudonymized, expedited manner 
all SAEs that are both unexpected and suspected to be related to study drugs, to the 
Competent Authorities, concerned Ethic Committees in each country in accordance with 
international and local regulations, and to the Investigators: 
• within 7 days of first knowledge by the sponsor of such a case for fatal or life-threatening 
events. Relevant missing information for fatal or life-threatening cases will be 
subsequently submitted within an additional eight days  
• and within 15 days of first knowledge by the sponsor for other serious adverse events. 
The expectedness of an adverse reaction will be determined by the Sponsor according to the 
reference safety information (e.g. Investigator’s Brochure or SmPC) of the trial medication. 
Expedited reporting (SUSAR, New Safety Issues) and submission of Development Safety 
Update Reports to the relevant Competent Authorities and to the Ethics Committees according 
to local regulation will be performed by ZKS Ulm and CTO. 
11.7 
Product quality complaint handling 
A product quality complaint (PQC) is defined as any suspicion of a product defect related to 
manufacturing, labeling, or packaging, i.e., any dissatisfaction relative to the identity, quality, 
durability, or reliability of a product, including its labeling or package integrity. A PQC may have 
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting 
and analysis of PQC information from studies are crucial for the protection of subjects, 
investigators, and the sponsor, and are mandated by regulatory agencies worldwide. All initial 
PQCs of an IMP must be reported to Sponsor/ZKS by the study-site personnel within 24 hours 
after being made aware of the event. The sponsor is responsible to report the PQC to either 
MSD Pharmacovigilance Germany or Pharmacovigilance Mundipharma 
(depending on the IMP concerned). If the defect is combined with a serious adverse event, the 
investigational staff must report the PQC to Sponsor/ZKS according to the serious adverse 
event reporting timelines. A sample of the suspected product if possible should be maintained 
for further investigation.  
11.8 
Benefit/Risk assessment of treatment program 
MZL is a subtype of cancer with a normally indolent clinical course. Despite this the disease is 
life threatening and leads to continuous deterioration of the patient’s clinical situation without 

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adequate treatment. In this trial only patients will be included who are in need of treatment for 
whom local therapy is not feasible, for whom local therapy did not result in disease control or 
who relapsed after systemic treatment. In this situation the treatment program with 
Pembrolizumab/Rituximab represents a chemo-free approach, which promises high efficacy 
without major toxicity. The assumption of high efficacy is based on the experience with 
Pembrolizumab single agent in partly heavily pretreated relapsed/refractory B-Non-Hodgkin’s 
lymphoma and on experience with Pembrolizumab in combination with Rituximab in relapsed 
follicular lymphoma, demonstrating high efficacy and clinically manageable toxicity. In addition, 
there is a large body of evidence, that Rituximab single agent is well tolerated and has anti-
lymphoma activity in patients with MZL. Adequate pre-medication is obligatory in this trial and 
there will be close monitoring for toxicity of the first 6 patients included. Taken together, the 
risk for the patients to experience unexpected serious toxicity will be low and has to be 
balanced with the high likelihood to receive a chemo-free treatment, which will allow disease 
control for a longer time period, thereby delaying the need for the patient to accept more dose 
intense chemotherapy. Thus, the benefit of the treatment program is expected to be superior 
to the potential short and long term toxicities.  
12. Statistical Considerations 
12.1 
Expected Improvement 
In MZL a variety of treatment modalities are used such as Rituximab single agent, 
chemotherapy or Rituximab in combination with chemotherapy. It is widely accepted that in 
this non-curative indolent B – cell lymphoma of the mostly elderly patient chemotherapy – 
related toxicity should be avoided and that chemotherapy-free approaches are highly attractive 
in this patient population. So far Rituximab single agent is the most frequent chemotherapy-
free approach used in this entity. Thus, a novel chemotherapy – free treatment approach 
should be at least as efficient as Rituximab monotherapy. In a large randomized study 
Rituximab single agent therapy induced a CRR of 55.8% compared to 78.8% for the 
combination of Rituximab and chlorambucil in de novo MZL of the MALT type 1. CR rates in 
splenic MZL are comparable high at about 60% 8, 11, whereas patients with nodal MZL achieve 
a CRR of around 20%9. As the distribution of subtypes is about 70% MALT, 20% splenic, and 
10% nodal MZL, a CRR which is better than 56% for the total population with MZL should at 
least be achieved by a new chemotherapy – free approach after end of treatment (18 cycles 
after start of therapy) for such a mixture of the population.  
The goal of this study is to test the efficacy of the chemotherapy - free combination 
Pembrolizumab/Rituximab in treatment – naïve and relapsed symptomatic MZL aiming at 
achieving comparable treatment results compared to immuno- chemotherapy.  

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12.2 
Sample Size 
For sample size calculation the one-sided one sample exact binomial test was used. According 
to the above data, the CRR for the total group of the different subtypes of MZL must be better 
than 56% after end of treatment (18 cycles). Anticipating a CRR for Pembrolizumab/Rituximab 
of about 75%, a significance level of 2.5% (because of one- sided test) and a power of 80%, 
48 full evaluable patients will be necessary to show that the combination will be a promising 
candidate for challenging immuno- chemotherapy (PROC POWER, SAS 9.3; 48 patients is the 
first number of patients with a stable power of more than 80%). It is expected, that the rate of 
withdrawal in the study is smaller than 15%. According to these parameters, the study will enrol 
56 subjects. The distribution between the sexes is not relevant, because neither incidence of 
MZL is differed between sexes nor clinically outcome measures such as response, progression 
free and overall survival has been shown to be related to sexes. 
12.3 
Analysis of the Primary Endpoint 
The primary endpoint (CRR) will be evaluated after end of treatment (18 cycles) after the last 
recruited patient has started her/his treatment. The primary parameter CRR will be evaluated 
in a modified intention to treat way, which means that all patients for whom the primary 
endpoint CRR is measured after end of treatment will be included in the analysis of the primary 
endpoint (Core Analysis Population, see subsection 12.6). Only patients who withdraw will be 
excluded (about 15% are expected). The one sample exact binomial test will be used for the 
analysis of the primary endpoint to test the CRR against the fixed value 56% at the 2.5% 
significance level (one-sided). Thus, the decision about the new concept will be based on a 
statistical test of the form: 
HA: {CRR > 56%} vs. H0: {CRR ≤ 56%} 
Thus, claim of success can be done if 36 (75% of 48 patients) or more responders (patients 
with CR) will be observed. Patients who withdraw will be included in a separate explorative 
analysis. Additionally, a one-sided 97.5% confidence interval for CRR will be calculated as an 
effect estimator. Exploratory use of univariate logistic regression models will be used to 
investigate the influence of putative risk factors associated with CRR.  
Subgroup analyses in the subtype (MALT lymphoma, splenic MZL, nodal MZL) will be 
performed as further exploratory analyses. 
12.4 
Analysis of the Secondary Endpoints 
Details of the secondary endpoints are described in section 5.3. All secondary endpoints will 
be analyzed exploratory by respective descriptive analysis and 95%- confidence intervals.  

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12.5 
Safety Analyses 
Safety evaluations include: adverse event monitoring, physical examinations, evaluation of 
changes to concomitant medications, and clinical laboratory parameters (hematology, serum 
chemistry, serum immunoglobulin [IgG, IgM, IgA], CRP). The severity of adverse events will 
be assessed using National Cancer Institute Common Terminology Criteria for Adverse 
Events, Version 5.0. Serious adverse events will be reported according to applicable 
legislation. The DSMC will review data regarding safety as planned according to the DSMC 
Charter. 
12.6 
Analysis Populations 
12.6.1 Core Analysis Population 
As this study is a trial with only one treatment arm, all analyses will be performed only for one 
analysis population, the Core Analysis Population. This analysis population consists of all 
eligible patients included in the study who received at least one cycle of treatment. Patients 
without staging at regular end of treatment will be defined as non-responder (i.e. CR=’NO’). 
The results on efficacy in the Core Analysis Population were considered to be the main efficacy 
results (confirmatory results). Forty eight patients are planned to belong to the Core Analysis 
Population, see part 12.3 above. 
12.6.2 Safety population 
The safety population and the Core Analysis Population are identical in this trial. 
13. Independent Data Safety Monitoring Committee 
An independent external Data Safety Monitoring Committee (DSMC) will review ongoing safety 
data throughout the study. The Data Safety Monitoring Board will include at least three 
independent members (2 experts in MZL and one independent statistician). Review of the 
safety data by the DSMC will take place based on the safety analyses after the first 6 patients 
and after the first 28 patients (50% of patient recrural) and 56 patients (100% patient recrural) 
have completed cycle 9 of treatment. All data presented at the meeting will be considered 
confidential. In addition, a review will be performed, when the last patient has ended treatment. 
Following each meeting the DSMC will prepare a report and may recommend changes in the 
conduct of the trial. Details on the work of the board will be described in a specific DSMC 
charter, to be jointly agreed upon the board and the sponsor. 

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14. Study monitoring and Data Management 
14.1 
Investigators Responsibilities  
Investigator responsibilities are set out in the ICH Guideline for Good Clinical Practice and in 
the local regulations. The sponsor staff or an authorized representative will evaluate and 
approve all investigators. The investigator is responsible to provide an adequate number of 
qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial 
properly and safely. 
The investigator is responsible for supervising any individual or party to whom the investigator 
delegates trial-related duties and functions conducted at the trial site. 
The investigator should ensure that all persons assisting with the study are adequately 
informed about the protocol, amendments, study treatments, as well as study-related duties 
and functions. The investigator should maintain a list of sub-investigators and other 
appropriately qualified persons to whom he or she has delegated significant study-related 
duties. 
The investigator is responsible for keeping a record of all patients who sign an informed 
consent document and are screened for entry into the study. Patients who fail screening must 
have the reason(s) recorded in the subject’s source documents. 
The investigator, or a designated member of the investigator’s staff, must be available during 
monitoring visits to review data, resolve queries and allow direct access to subject records 
(e.g., medical records, office charts, hospital charts, and study-related charts) for source data 
verification. The Investigator must ensure timely and accurate completion of eCRFs and 
queries. 
14.2 
Sponsor Responsibilities  
The sponsor (University Hospital Ulm) or an authorized representative of this study has 
responsibilities towards the legislator to take all reasonable steps to ensure the proper conduct 
of the study as regards patient safety, ethics, study adherence, integrity and validity of the data 
recorded on the case report forms. Thus, the main duty of the project leader and of his clinical 
research support team is to help the investigator maintain a high level of ethical, scientific, 
technical and regulatory quality in all aspects of the study. 
At regular intervals during the study, the trial site will be contacted, through site visits, letters 
or telephone calls, by a representative of the monitoring team to review study progress, 
investigator and subject adherence to study requirements and any emergent problems.  

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During monitoring visits, the following points will be scrutinized with the investigator: subject 
informed consent, inclusion and exclusion criteria, subject recruitment and follow-up, subject 
compliance to the study treatment, study treatment accountability (if applicable), concomitant 
therapy use, evaluations of response, serious/non serious adverse event documentation and 
reporting, and quality of data.  
14.3 
Source document requirements 
According to the guidelines on Good Clinical Practice, the study monitor has to check the case 
report form entries against the source documents. The consent form will include a statement 
by which the patients allow the sponsor's duly authorized personnel (e.g. trial monitoring team) 
to have direct access to source data which supports data on the case report forms (e.g. 
patient's medical file, appointment books, original laboratory records, etc.). These personnel, 
bound by professional secrecy, will not disclose any personal identity or personal medical 
information. 
14.4 
Monitoring Visits 
Monitoring visits to the trial site will be made periodically during the trial to ensure that GCP 
and all aspects of the protocol are followed. The CRO will announce independent special 
trained monitors who will check on site on the basis of the patients records the fulfillment of 
e.g. inclusion/exclusion criteria, of diagnostic procedures at study entry, the presence of an 
informed consent, handling of remission criteria, performance of treatment and adverse events 
and correct documentation of patient’s data in the eCRF (Source Data Verification). The 
number of contacts will depend on the characteristics of the respective trial site, e.g., the 
number of recruited patients. Source documents will be reviewed for verification of agreement 
with data on case report forms. Details on the extent of data verification are described in the 
trial specific monitoring manual. The investigator/institution guarantees direct access to source 
documents by the representative of the CRO and appropriate regulatory authorities. 
14.5 
Use and completion of the (electronic) Case Report Forms (eCRF) 
A professional study database and eCRF will be provided by a specialized CRO contracted 
and supervised by the sponsor. Study data will be processed and stored in the EU only. 
A case report form will be completed for each study patient. It is the responsibility of the 
investigator to ensure the accuracy, completeness, legibility and timeliness of the data reported 
in the patient’s eCRF which have been designed by the sponsor to record all observations and 
other pertinent data to the clinical investigation.  

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Source documentation supporting the eCRF data should indicate the patient’s participation in 
the study and should document the dates and details of study procedures, adverse events and 
patient status. 
The investigator, or designated representative, should complete the eCRF pages as soon as 
possible after information is collected, preferably on the same day that a study patient is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
All data entry and corrections are recorded in the audit trail (date of data entry/correction, name 
of person, type of action). 
14.6 
Study Drug Monitoring 
Accountability for IMP Pembrolizumab and Rituximab at the clinical site is the responsibility of 
the investigator. The investigator will ensure that Pembrolizumab and Rituximab is used only 
in accordance with this protocol. Where allowed, the investigator may choose to assign some 
of the drug accountability responsibilities to a pharmacist or other appropriate individual.  
Drug accountability records for the IMP indicating the drug’s delivery date to the site, inventory 
at the site, use by each patient, or disposal of the drug will be maintained by the clinical site. 
These records will adequately document that the patients were provided the doses as specified 
in the protocol. The monitors assigned by the sponsor will review drug accountability at the site 
on an ongoing basis during monitoring visits. 
All unused IMP will be retained at the site until they are inventoried by the monitor. All used, 
unused or expired IMP will be treated and disposed of as hazardous waste in accordance with 
governing regulations. 
15. Ethical and regulatory standards 
15.1 
Ethical principles 
This study is in accordance with the principles laid down by the 18th World Medical Assembly 
(Helsinki, 1964) and amendments laid down by the 29th (Tokyo, 1975), the 35th (Venice, 1983) 
and the 41st (Hong Kong, 1989), the 48th (Somerset West, 1996), the 52nd (Edinburg, 2000) 
World Medical Assemblies, notes for clarification added by the WMA General Assembly on 
paragraph 29 (Washington 2002) and on Paragraph 30 (Tokyo 2004) and amendment laid 
down by the 59th (Seoul, October 2008) World Medical Assemblies and the 64th WMA General 
Assembly, Fortaleza, Brazil, October 2013.  

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15.2 
Laws and regulations 
This study is also in accordance with laws and regulations of the country(ies) in which the trial 
is performed, as well as any applicable guidelines. 
15.3 
Data Protection concept 
The data protection concept stipulates that patients are only included in this clinical trial after 
they have been informed and after having signed the Informed Consent Form (ICF). The 
sponsor provides a data protection management and an information security management 
system. The Clinical Trial Centers are contractually obliged to comply with the GDPR and other 
data protection regulations, in particular the implementation of appropriate technical and 
organizational measures (Art. 32 GDPR). This also applies to involved third parties who are 
contractually obliged in accordance with Art. 28 GDPR to guarantee the implementation of 
appropriate technical and organisational measures in such a manner that the processing will 
meet the requirements of the Regulation and ensure the protection of the rights of the data 
subject. The data will not be used for any other purpose than the research project described 
in this protocol. It is guaranteed that the data protection provisions are followed. 
15.4 
Ethics Committee and competent authorities submission 
The sponsor must submit this study to country central ethics review committee, and to 
competent authorities and it is required to forward a copy of written approvals / advices signed 
to the investigators. 
16. Administrative procedures 
16.1 
Curriculum vitae 
An updated copy of the curriculum vitae of each investigator and sub-investigator will be 
provided to the sponsor prior to the beginning of the study. 
16.2 
Secrecy agreement 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the investigators (or any company acting on their behalf), inclusive of this study and of the 
patient case report forms are the exclusive property of the sponsor. 
They may not be given or disclosed by the investigator or by any person within his authority 
either in part or in totality to any unauthorized person without the prior written formal consent 
of the sponsor. 

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It is specified that the submission of this study and other necessary documentation to the Ethics 
Committee or a like body is expressly permitted, the Ethics Committee members having the 
same obligation of confidentiality. 
The investigator shall take all necessary measures to ensure that there is no breach of 
confidentiality in respect of all information accumulated, acquired or deduced in the course of 
the trial, other than that information to be disclosed by law. 
16.3 
Record retention in investigating trial sites 
The investigator must maintain all study records including the investigator site file, patient files 
and other source data for the maximum period of time permitted by the hospital, institution or 
private practice. 
However national regulations should be taken into account, the longest time having to be 
considered. 
The investigator is required to arrange for the retention of the patient identification codes for at 
least 15 years after the completion or discontinuation of the trial. 
Any trial site will notify the sponsor before destroying any data or records. 
The sponsor is responsible for archiving the trial master file according to applicable regulations. 
16.4 
Ownership of data and use of the study results 
The sponsor has the ownership of all data and results collected during this study. In 
consequence the sponsor reserves the right to use the data of the present study, either in the 
form of case report forms, or in the form of a report, with or without comments and with or 
without analysis, in order to submit them to the competent authorities. 
16.5 
Publication 
The final publication of the trial results will be written by the coordinating investigator on the 
basis of the statistical analysis performed at the Biometry (Institute of Epidemiology and 
Medical Biometry Ulm University). A draft manuscript will be submitted to the Biometry and all 
co-authors for review. After revision by the Biometry and the other co-authors, the manuscript 
will be sent to a peer reviewed scientific journal. Authors of the manuscript will include the 
coordinating investigator, investigators who have included more than 3% of the evaluable 
patients in the trial (by order of inclusion), the statistician, and others who have made significant 
scientific contributions. 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 99 of 130 
 
Interim publications or presentations of the study may include demographic data, overall 
results and prognostic factor analyses, but no efficacy or safety data may be published before 
the recruitment is discontinued. 
Any publication, abstract or presentation based on patients included in this study must be 
approved by the coordinating investigator. This is applicable to any individual patient registered 
in the trial, or any subgroup of the trial patients. Such a publication cannot include an analysis 
of any of the study end-points unless the final results of the trial have already been published.  
16.6 
Insurance compensation 
The sponsor of the study will obtain insurance coverage for each patient for eventually 
occurring damage caused by the treatment or any actions taken according to the treatment 
plan, a certificate of insurance will be provided to the investigator.  
16.7 
Company audits and inspections by regulatory agencies 
For the purpose of ensuring compliance with good clinical practice and regulatory agency 
guidelines it may be necessary to conduct a site audit or an inspection. 
By signing this study, the investigator agrees to allow the sponsor and its representative, and 
drug regulatory agencies to have direct access to his study records for review. These 
personnel, bound by professional secrecy, will not disclose any personal identity or personal 
medical information. 
These audits involve review of source documents supporting the adequacy and accuracy of 
data gathered in eCRF, review of documentation required to be maintained, and checks on 
drug accountability. 
The sponsor will in all cases help the investigator prepare for an inspection by any regulatory 
agency. 
16.8 
Clinical study report 
The sponsor will inform of the end of the trial the Competent Authorities and Ethics Committees 
according to law following the end of the study. A study report will be prepared under the 
responsibility of the sponsor less than one year after the end of the study and forwarded to the 
Competent Authorities and Ethics Committees 
16.9 
Protocol amendments 
No changes or amendments to this study may be made by the investigator or by the sponsor 
after the study has been agreed to and signed by both parties unless such change(s) or 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 100 of 130 
 
amendment(s) have been fully discussed and agreed upon by the Study Coordinators and the 
sponsor.  
Any change agreed upon will be recorded in writing, the written amendment will be signed by 
the coordinating investigators and by the sponsor and the signed amendment will be appended 
to this protocol. 
Approval / advice of amendments by Ethics Committee and Competent Authorities are 
required prior to their implementation, unless there are overriding safety reasons. 
If the change or deviation increases risk to the study population, or adversely affects the validity 
of the clinical investigation or the subject's rights, full approval / advice must be obtained prior 
to implementation. For changes that do not involve increased risk or affect the validity of the 
investigation or the subject's rights, approval / advice may be obtained by expedited review, 
where applicable. 
In some instances, an amendment may require a change to a consent form. The investigator 
must receive approval / advice of the revised consent form prior to implementation of the 
change. In addition, changes to the case report forms, if required, will be incorporated in the 
amendment. 
Prior to initiating the changes, study amendment must be submitted to regulatory agencies, 
where applicable, except under emergency conditions. 
16.10 
Contract of Investigation 
The participating institutions are selected by the coordinating investigator, based on the proven 
qualification in the framework of previous trials in the cooperative groups. The clinical trial sites 
will document their appropriate qualification and capacities for taking part in the trial, in order 
to allow for a qualified decision of the (local) ethical committee on the participation 
The local investigator of every participating trial site has to sign the contract of investigation 
before start of the study. With this contract the local investigator agrees to treat all patients 
who have been admitted to the participating trial site during active study-recruitment fulfilling 
the inclusion criteria and not the exclusion criteria after giving an informed consent and 
registration at the study office within the present study. Additionally, he agrees to document 
the basic and treatment data according the specific eCRFs. 
Every participating trial site has the duty to be cooperative if inspections will be performed at 
the trial site. 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 101 of 130 
 
16.11 
Financing 
The coordinating investigator and the sponsor will take care of the financing/funding of the 
study. The study will be funded in part by MSD SHARP & DOHME GMBH. The study drug, 
“Pembrolizumab” will be provided by MSD SHARP & DOHME GMBH free of charge, Truxima 
will be provided free of charge by Celltrion Healthcare Co., LTD.  
 
 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 102 of 130 
 
17. REFERENCES 
1. 
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of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue 
Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus 
Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy. J Clin Oncol 
2017 Jun 10; 35(17): 1905-1912. 
 
2. 
Chan TS, Khong PL, Kwong YL. Pembrolizumab and lenalidomide induced remission 
in refractory double-hit lymphoma. Ann Hematol 2016 Oct; 95(11): 1917-1918. 
 
3. 
Chan TS, Khong PL, Kwong YL. Pembrolizumab for relapsed anaplastic large cell 
lymphoma after allogeneic haematopoietic stem cell transplantation: efficacy and 
safety. Ann Hematol 2016 Oct; 95(11): 1913-1915. 
 
4. 
Chen R, Zinzani PL, Fanale MA, Armand P, Johnson NA, Brice P, et al. Phase II Study 
of the Efficacy and Safety of Pembrolizumab for Relapsed/Refractory Classic Hodgkin 
Lymphoma. J Clin Oncol 2017 Jul 1; 35(19): 2125-2132. 
 
5. 
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007 Feb 10; 25(5): 579-586. 
 
6. 
Matutes E, Oscier D, Montalban C, Berger F, Callet-Bauchu E, Dogan A, et al. Splenic 
marginal zone lymphoma proposals for a revision of diagnostic, staging and therapeutic 
criteria. Leukemia 2008 Mar; 22(3): 487-495. 
 
7. 
Copie-Bergman C, Gaulard P, Lavergne-Slove A, Brousse N, Flejou JF, Dordonne K, 
et al. Proposal for a new histological grading system for post-treatment evaluation of 
gastric MALT lymphoma. Gut 2003 Nov; 52(11): 1656. 
 
8. 
Arcaini L, Rossi D, Paulli M. Splenic marginal zone lymphoma: from genetics to 
management. Blood 2016 Apr 28; 127(17): 2072-2081. 
 
9. 
Thieblemont C, Molina T, Davi F. Optimizing therapy for nodal marginal zone 
lymphoma. Blood 2016 Apr 28; 127(17): 2064-2071. 
 
10. 
Arcaini L, Lazzarino M, Colombo N, Burcheri S, Boveri E, Paulli M, et al. Splenic 
marginal zone lymphoma: a prognostic model for clinical use. Blood 2006 Jun 15; 
107(12): 4643-4649. 
 
11. 
Thieblemont C, Davi F, Noguera ME, Briere J, Bertoni F, Zucca E, et al. Splenic 
marginal zone lymphoma: current knowledge and future directions. Oncology (Williston 
Park) 2012 Feb; 26(2): 194-202. 
 
12. 
Thieblemont C, Davi F, Noguera ME, Briere J. Non-MALT marginal zone lymphoma. 
Curr Opin Hematol 2011 Jul; 18(4): 273-279. 
 

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13. 
Traverse-Glehen A, Bertoni F, Thieblemont C, Zucca E, Coiffier B, Berger F, et al. 
Nodal marginal zone B-cell lymphoma: a diagnostic and therapeutic dilemma. 
Oncology (Williston Park) 2012 Jan; 26(1): 92-99, 103-104. 
 
14. 
Arcaini L, Lucioni M, Boveri E, Paulli M. Nodal marginal zone lymphoma: current 
knowledge and future directions of an heterogeneous disease. Eur J Haematol 2009 
Sep; 83(3): 165-174. 
 
15. 
Dreyling M, Thieblemont C, Gallamini A, Arcaini L, Campo E, Hermine O, et al. ESMO 
Consensus conferences: guidelines on malignant lymphoma. part 2: marginal zone 
lymphoma, mantle cell lymphoma, peripheral T-cell lymphoma. Ann Oncol 2013 Apr; 
24(4): 857-877. 
 
16. 
Raderer M, Kiesewetter B, Ferreri AJ. Clinicopathologic characteristics and treatment 
of marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). 
CA Cancer J Clin 2016 Mar-Apr; 66(2): 153-171. 
 
17. 
Montalban C, Abraira V, Arcaini L, Domingo-Domenech E, Guisado-Vasco P, Iannitto 
E, et al. Risk stratification for Splenic Marginal Zone Lymphoma based on haemoglobin 
concentration, platelet count, high lactate dehydrogenase level and extrahilar 
lymphadenopathy: development and validation on 593 cases. Br J Haematol 2012 Oct; 
159(2): 164-171. 
 
18. 
Montalban C, Abraira V, Arcaini L, Domingo-Domenech E, Guisado-Vasco P, Iannitto 
E, et al. Simplification of risk stratification for splenic marginal zone lymphoma: a point-
based score for practical use. Leuk Lymphoma 2014 Apr; 55(4): 929-931. 
 
19. 
Thieblemont C, Cascione L, Conconi A, Kiesewetter B, Raderer M, Gaidano G, et al. 
A MALT lymphoma prognostic index. Blood 2017 Sep 21; 130(12): 1409-1417. 
 
20. 
Hammel P, Haioun C, Chaumette MT, Gaulard P, Divine M, Reyes F, et al. Efficacy of 
single-agent chemotherapy in low-grade B-cell mucosa-associated lymphoid tissue 
lymphoma with prominent gastric expression. J Clin Oncol 1995 Oct; 13(10): 2524-
2529. 
 
21. 
Zucca E, Conconi A, Laszlo D, Lopez-Guillermo A, Bouabdallah R, Coiffier B, et al. 
Addition of rituximab to chlorambucil produces superior event-free survival in the 
treatment of patients with extranodal marginal-zone B-cell lymphoma: 5-year analysis 
of the IELSG-19 Randomized Study. J Clin Oncol 2013 Feb 10; 31(5): 565-572. 
 
22. 
Hancock BW, Qian W, Linch D, Delchier JC, Smith P, Jakupovic I, et al. Chlorambucil 
versus observation after anti-Helicobacter therapy in gastric MALT lymphomas: results 
of the international randomised LY03 trial. Br J Haematol 2009 Feb; 144(3): 367-375. 
 
23. 
Salar A, Domingo-Domenech E, Panizo C, Nicolas C, Bargay J, Muntanola A, et al. 
First-line response-adapted treatment with the combination of bendamustine and 
rituximab in patients with mucosa-associated lymphoid tissue lymphoma (MALT2008-
01): a multicentre, single-arm, phase 2 trial. Lancet Haematol 2014 Dec; 1(3): e104-
111. 
 

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24. 
Kiesewetter B, Mayerhoefer ME, Lukas J, Zielinski CC, Mullauer L, Raderer M. 
Rituximab plus bendamustine is active in pretreated patients with extragastric marginal 
zone B cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma). 
Ann Hematol 2014 Feb; 93(2): 249-253. 
 
25. 
Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grunhagen U, Losem C, et 
al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for 
patients with indolent and mantle-cell lymphomas: an open-label, multicentre, 
randomised, phase 3 non-inferiority trial. Lancet 2013 Apr 06; 381(9873): 1203-1210. 
 
26. 
Zucca E, Copie-Bergman C, Ricardi U, Thieblemont C, Raderer M, Ladetto M, et al. 
Gastric marginal zone lymphoma of MALT type: ESMO Clinical Practice Guidelines for 
diagnosis, treatment and follow-up. Ann Oncol 2013 Oct; 24 Suppl 6: vi144-148. 
 
27. 
Arcaini L, Paulli M. Splenic marginal zone lymphoma: hydra with many heads? 
Haematologica 2010 Apr; 95(4): 534-537. 
 
28. 
Zinzani PL, Ribrag V, Moskowitz CH, Michot JM, Kuruvilla J, Balakumaran A, et al. 
Safety and tolerability of pembrolizumab in patients with relapsed/refractory primary 
mediastinal large B-cell lymphoma. Blood 2017 Jul 20; 130(3): 267-270. 
 
29. 
Ding W, LaPlant BR, Call TG, Parikh SA, Leis JF, He R, et al. Pembrolizumab in 
patients with CLL and Richter transformation or with relapsed CLL. Blood 2017 Jun 29; 
129(26): 3419-3427. 
 
30. 
Kwong YL, Chan TSY, Tan D, Kim SJ, Poon LM, Mow B, et al. PD1 blockade with 
pembrolizumab is highly effective in relapsed or refractory NK/T-cell lymphoma failing 
l-asparaginase. Blood 2017 Apr 27; 129(17): 2437-2442. 
 
31. 
Nastoupil L, Westin JR, Fowler NH, Fanale MA, Samaniego F, Oki Y, et al. Blood 2017: 
414. 
 
32. 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, et al. Toxicity 
and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 
1982 Dec; 5(6): 649-655. 
 
 
 
 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 105 of 130 
 
APPENDICES 
 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 106 of 130 
 
Appendix A: Study Flowchart 
Treatment – Phase 
 
 
Screening 
Treatment Period (1 cycle = 21 days) 
EOT/ ET Visit 
(4 weeks after 
C18/D1 )  
Section 
SD 
-28 
C1/D1 
 
C1/D2 
 
C1/D8 + 
D15 
C2/D1 – 
C9/D1  
C10D1 
C11/D1 – 
C18/D1 
Informed consent incl. discussion 
of fertility issues and sperm 
banking (in patients of childbearing 
age)* 
10.1 
X 
 
 
 
 
 
 
 
Verify Inclusion/exclusion criteria* 
7.1 + 7.2 
X 
X 
 
 
 
 
 
 
Pathological diagnosis (local and 
reference pathology –  
incl. MYD88 and PD-L1*)  
9.1.1 
Within 12 months 
before C1D1 
 
 
 
 
 
 
 
Demographics, Medical history and 
Ann Arbor Stage* 
9.1.4 
X 
 
 
 
 
 
 
 
Patients with gastric extranodal 
MZL: Gastroduodenal endoscopy a  
9.1.2 
Within 12 weeks 
before C1D1 
 
 
 
 
Xc 
 
Xc 
Patients with non-gastric 
extranodal MZL: Assessments 
according section 9.1.2 
9.1.2 
Within 12 weeks 
before C1D1 
 
 
 
 
Xc 
 
Xc 
Bone marrow aspirate and biopsy b 
9.1.3 
Within 12 weeks 
before C1D1 
 
 
 
 
Xb 
 
Xb 
CT/MRI scan and tumor 
assessment 
9.1.2 
Within 6 weeks 
before C1D1 
 
 
 
 
Xc 
 
Xc 
12-lead ECG + Echocardiography 
9.1.9 
X 
 
 
 
 
Xd 
 
Xd 
B Symptoms 
9.1.6 
X 
X 
 
 
Xl 
Xl 
Xl 
X 
Physical examination e 
9.1.5 
X 
(X) 
 
 
(X) 
X 
(X) 
X 
Vital signs  
9.1.7 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status* 
9.1.8 
X 
X 
 
 
X 
X 
X 
X 
Concomitant medication 
9.3 – 9.4 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events / Toxicity 
11 
 
X 
X 
X 
X 
X 
X 
X 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 107 of 130 
 
Treatment – Phase (continued) 
 
 
Screening 
Treatment Period (1 cycle = 21 days) 
EOT/ ET Visit  
(4 weeks after 
C18/D1 ) 
 
Section 
SD 
-28 
C1/D1 
 
C1/D2 
 
C1/D8 + 
D15 
C2/D1 – 
C9/D1  
C10D1 
C11/D1 – 
C18/D1 
Laboratory Assessments 
9.1.10 
 
 
HIV, HBV, HCV testing f 
9.1.10 
X 
 
 
 
Xf 
Xf 
Xf 
Xf 
 
Pregnancy test 
9.2 – 9.4  
+ App. C 
X 
X 
 
 
X 
X 
X 
X 
 
Hematology 
9.1.10 
X 
X 
 
X 
X 
X 
X 
X 
 
Serum chemistry g, h 
9.1.10 
X 
X 
 
X 
X 
X 
X 
X 
 
Electrophoresis  
 
(If M Protein present: add. 
 
Serum Protein Immunofixation) 
9.1.10 
X 
X 
 
X 
X 
X 
X 
X 
 
Coagulation 
9.1.10 
X 
 
 
 
X 
X 
X 
 
 
Thyroid hormones 
9.1.10 
X 
 
 
 
Xm 
Xm 
Xm 
 
 
Leukocyte immunophenotyping 
 
(FACS)j 
9.1.10 
X 
 
 
 
 
X 
 
X 
 
Quantitative Immunoglobulins 
 
(IgG, IgA, IgM) 
9.1.10 
X 
 
 
 
 
X 
 
X 
 
Urine analysis i 
9.1.10 
X 
 
 
 
Xi 
Xi 
Xi 
Xi 
 
UPCR 
9.1.10 
X 
Xd 
 
Xd 
Xd 
Xd 
Xd 
Xd 
 
GFR (acc. MDRD formula) 
9.1.10 
X 
 
 
 
X 
X 
X 
X 
QoL questionnaire (FACT-Lym)* 
9.1.11 
 
X 
 
 
X (Day 1 of every third cycle) 
X 
Tumor tissue sample at time of 
relapse or transformation 
9.1.2 
 
 
 
 
(X)k 
New anti-lymphoma treatment 
9.5 
 
 
 
 
 
 
 
X 
Biological Material for Biobank 
(optional)* 
9.1.12  
+ App. B 
X 
 
 
 
 
X 
 
X 
 
 
 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 108 of 130 
 
Treatment – Phase (continued) 
C=Cycle; CT=computed tomography; D=Day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EOT=End of Treatment; ET=early termination; 
FACS=fluorescence-activated cell sorter; HBV=hepatitis B virus; HCV=hepatitis C virus; IPI=International Prognostic Index; MRI=magnetic resonance imaging; UPCR= 
Urine Protein to Creatinine Ratio (UPCR) measurement.  
 
Only activities/procedures marked with an asterisk (*) are study specific. All other activities/procedures are performed according to routine/guidelines.  
 
Notes: On treatment days, all assessments should be performed prior to dosing unless otherwise noted. The C1, D1 visit should be scheduled to allow subsequent 
visits to occur without delay. Study visits during treatment should occur on the scheduled day (±3 days), with the exception of delays resulting from toxicities.  
 
a In patients with gastric extranodal MZL, the initial staging should include a gastroduodenal endoscopy with multiple biopsies from the stomach, duodenum, 
gastroesophageal junction, and any site that seems abnormal. If any disease sites are identified in this manner at screening, a subsequent gastroduodenal endoscopy 
and biopsy are required to confirm a CR. H. pylori status must be evaluated. Endoscopic ultrasound to evaluate the regional lymph nodes and gastric wall infiltration 
should be performed. 
b A bone marrow examination must be performed at screening unless performed within 12 weeks prior to C1, D1. If positive at screening, a subsequent bone marrow 
examination is required at completion of cycle 9 (C10D1) for all patients who may achieved a CR and at the EOT visit for patients to confirm a CR. In patients with 
continued bone marrow involvement, a subsequent bone marrow examination may be required to confirm a CR at a later timepoint. Any additional (unscheduled) bone 
marrow examinations performed during the study will be at the discretion of the investigator.  
c If initially positive 
d When clinically indicated 
e At Screening a complete physical examination includes all systems described in Section 9.1.5. As part of tumor assessment including assessment of lymph nodes, 
hepatomegaly, and splenomegaly. At other timepoints physical examination should only include systems of most clinical relevance = (X)  
f CxD1 HBV DNA PCR in patients who are HBsAG neg. and HBcAb pos. 
g ß2 microglobulin only at screening;  
h Phosphate, total cholesterol, LDL and triglycerides will be determined at Screening, on Day 1 of every 2nd cycle (2, 4, 6 etc.) and at the EOT visit. On these days patients 
must be fasting prior to sampling according to local standards. If a patient cannot adhere to fasting requirements, the evaluation of lipid-panels including triglycerides is 
considered not feasible. 
i At Screening in a fresh sample of midstream urine, a dipstick testing for proteinuria is required and microscopy including protein, specific gravity, glucose and blood. For 
further urine testing only dipstick, microscopy as clinically indicated 
j PB and bone marrow aspirate will be taken for the assessment of circulating lymphoma cells: mandatory: CD5, CD10, CD19, CD20, CD23, CD27, CD43, FMC7, 
kappa/lambda light chains.  
k an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that time. 
l B-Symptoms on Day 1 of each third cycle (i.e. on Day 1 of Cycles 1, 4, 7, 10, 13 and 17) 
m TSH is assessed before each treatment cycle, T3 and T4 only in case of labortatory abnormalities. 
 
 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 109 of 130 
 
Follow-up – Phase for patients who have CR, PR or SD at the EOT visit 
After last treatment cycle or after 
early termination  
 
Follow-up Year 1 + 2 
(every 3 months ± 14 days) 
Follow-up Year 3 - 5 
(every 6 months ± 14 days)  
At the end of 
study or time of 
progression 
FU1 FU2 FU3 FU4 FU5 FU6 FU7 FU8 FU9 FU10 FU11 FU12 FU13 FU14 
Physical examination a 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG Performance Status 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
B symptoms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Serum chemistry b  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine analysis c 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
HBV DNA PCR d 
(X) 
(X) 
(X) 
(X) 
 
 
 
 
 
 
 
 
 
 
 
New anti-lymphoma treatment e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Survival follow-up e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CT/MRI scan and tumor assessment 
(if initially positive) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Gastroduodenal endoscopy f 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
Leukocyte immunophenotyping 
(FACS) g 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
Quantitative immunoglobulins  
(IgA, IgG, IgM) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
Serum protein immunofixation  
(if initially positive) 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
X 
Bone marrow aspirate and biopsy h 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Tumor tissue sample at time of 
relapse 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X)i 
Adverse events j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
QoL questionnaire (FACT-Lym) 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
X 
X 
Biological Material for Biobank 
(optional) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (at progress) 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 110 of 130 
 
 
Follow-up – Phase (continued) 
 
CT=computed tomography; ECOG=Eastern Cooperative Oncology Group; FACS=fluorescence-activated cell sorter; HBV=hepatitis B virus; SAE=serious adverse 
event. 
 
(x)=conditional/optional; refer to footnote for details.  
 
a The physical examination should only include systems of most clinical relevance. 
b Without Phosphate, total cholesterol, LDL and triglycerides 
c For further urine testing only dipstick, microscopy as clinically indicated 
d Only if clinically indicated. HBV DNA levels will be measured by real-time PCR using an assay with a sensitivity of at least 10 IU/mL. 
e Patients with disease progression will be followed for new anti-lymphoma treatment and survival twice per year until the end of the study. 
f In patients with gastric extranodal MZL. If clinically indicated it may be performed even more often. If there were no disease sites detectable at the last investigation, 
endoscopy should be performed every 6 months in year 1 to 2, and then once a year in year 3, 4 and 5 of follow-up. In the case of persistent disease sites endoscopy 
should be performed every three months until negativity. 
g A blood sample will be taken for the assessment of circulating lymphoma cells: mandatory: CD5, CD10, CD19, CD23, CD27, CD43, FMC7, kappa/lambda light chains 
h If initially positive or clinically indicated or in the case of progression 
i If an additional biopsy is done as part of the standard of care at the time of relapse or transformation, a tissue sample will be collected at that time. 
j All AEs will be recorded up to 110 days after the last dose of study drug, study drug–related SAEs will be recorded indefinitely (even if the study has been closed).  
 
 
 
 
 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 111 of 130 
 
Appendix B: Biological samples for further ancillary studies 
Only German study sites will participate in the biological sampling project.  
 
In the case of patient’s consent, the following biological samples will be obtained:  
a) Bone marrow cells  
- before start of treatment  
- during treatment/ at EOT only in those patients in whom bone marrow aspiration is 
performed to confirm CR or to document delayed response (see Appendix A).  
 
b) Cheek swab  
- once before start of treatment  
 
c) Peripheral blood and serum  
- at different time points as indicated below and in case of progression at any time of the study. 
 
Questions and notifications regarding biological sampling should be sent via e-mail to: 
gla.biosampling@uni-ulm.de 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Time points 
 
Four eligible time points are described for bio-sampling: 
1. Prior to treatment 
2. C10D1 (during treatment) 
3. EOT (month 18) 
4. When in progress 

Pole-1 Protocol V3.0, dated 12.04.2021 
Page 112 of 130 
 
 
 
 
 
The biological samples should be sent as follows: 
Sample 
Delivery 
30 ml of peripheral 
blood  
Peripheral Blood should be collected on site in CELL-FREE DNA blood 
collection tubes (BCT®) (Streck), which will be provided by the Sponsor. 
Tubes will be sent to the University of Ulm at ambient temperature with 
overnight carrier for next day delivery 
15 ml of bone 
marrow aspirate 
EDTA tube at ambient temperature should be sent to the University of Ulm 
with overnight carrier for next day delivery 
1 x 10 ml of serum  
Serum tubes at ambient temperature with overnight carrier for next day 
delivery  
1 x 10 ml EDTA 
EDTA tubes at ambient temperature with overnight carrier for next day 
delivery 
Cheek swab 
DNA of non-hematological cells will be collected by cheek swabs and the 
Whatman® FTA® card technology (Sigma-Aldrich). The kit will be provided 
by the Sponsor. Genomic DNA stored on FTA Cards at room temperature is 
stable for years. FTA cards will be sent to the University of Ulm with 
overnight carrier for next day delivery 
 
All the collected biological samples are common property and are open for scientific projects 
performed by the participants of this trial. Transport costs will be covered by the sponsor of the 
trial. 
 
Sample 
Usage 
30 mL of peripheral blood in CELL-
FREE DNA blood collection tubes 
(BCT®) (Streck)  
Storage of plasma for cell free DNA (cfDNA), storage of 
DNA (cell pellet) for MRD measurement 
15 mL of bone marrow  
- 
Storage of freshly isolated cells 
- 
Storage of DNA and RNA from sorted bone marrow 
B cells 
10 mL of serum  
Storage of serum proteins 
10 mL EDTA 
Storage of DNA (cell pellet) for MRD 
Cheek swab 
Storage of DNA of non-hematopoietic cells (FTA cards)  

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Appendix C: Contraceptive Guidance and Pregnancy Testing 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal 
unless permanently sterile (see below)  
Women in the following categories are not considered WOCBP: 
● 
Premenarchal 
● 
Premenopausal female with 1 of the following: 
○ Documented hysterectomy 
○ Documented bilateral salpingectomy 
○ Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s review of the participant’s 
medical records, medical examination, or medical history interview. 
● 
Postmenopausal female 
○ A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause.  
○ A high follicle stimulating hormone (FSH) level in the postmenopausal range may be 
used to confirm a postmenopausal state in women not using hormonal contraception 
or hormonal replacement therapy (HRT). However, in the absence of 12 months of 
amenorrhea, confirmation with two FSH measurements in the postmenopausal range 
is required.  
○ Females on HRT and whose menopausal status is in doubt will be required to use 
one of the non-hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
1. Contraception Requirements 
Male Participants: 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to one of the following during the protocol defined time frame:  
● Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long term and persistent basis) and agree to remain abstinent 
● Use a male condom plus partner use of a contraceptive method with a failure rate of <1% 
per year as described in Table 9 when having penile-vaginal intercourse with a woman of 
childbearing potential who is not currently pregnant. 

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○ 
Note: Men with a pregnant or breastfeeding partner must agree to remain abstinent 
from penile vaginal intercourse or use a male condom during each episode of penile 
penetration. 
 
Female Participants: 
Female participants of childbearing potential are eligible to participate if they agree to use 
a highly effective method of contraception consistently and correctly as described in Table 
4 during the protocol-defined time frame in.  
 
Table 4 
Highly Effective Contraception Methods 
Highly Effective Contraceptive Methods That Are User Dependent a  
Failure rate of <1% per year when used consistently and correctly. 
● Combined (estrogen- and progestogen- containing) hormonal contraception associated 
with inhibition og ovulationb, 
○ Oral  
○ Intravaginal  
○ Transdermal  
● Progestogen-only hormonal contraception associated with inhibition og ovulationb, 
○ Oral  
○ Injectable  
Highly Effective Methods That Have Low User Dependency  
Failure rate of <1% per year when used consistently and correctly. 
● Progestogen- only contraceptive implant  
● Intrauterine hormone-releasing system (IUS)  
● Intrauterine device (IUD) 
● Bilateral tubal occlusion 
● Vasectomized partner  
A vasectomized partner is a highly effective contraception method provided that the partner is 
the sole male sexual partner of the WOCBP and the absence of sperm has been confirmed. If 
not, an additional highly effective method of contraception should be used.  
● Sexual abstinence  
Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study treatment. 
The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
study and the preferred and usual lifestyle of the participant.)  
Notes:  
Use should be consistent with local regulations regarding the use of contraceptive methods for 
participants of clinical studies.  

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a) Typical use failure rates are lower than perfect-use failure rates (i.e. when used 
consistently and correctly).  
b) If hormonal contraception efficacy is potentially decreased due to interaction with study 
treatment, condoms must be used in addition to the hormonal contraception during the 
treatment period and for at least 110 days after the last dose of study treatment. 
 
 
Please note: If a patient experiences nausea or diarrhea, oral contraception is not considered 
a reliable method. 
Combined contraceptive methods (additional use of condoms for female participants and 
their partners) are recommended. 
 
2. Pregnancy Testing 
WOCBP should only be included after a negative highly sensitive urine or serum pregnancy 
test.  
Following initiation of treatment, pregnancy testing will be performed whenever an expected 
menstrual cycle is missed or when pregnancy is otherwise suspected; at the time points 
specified in the Schedule of Activities, and as required locally. 

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Appendix D: Selection of Lesions and Response Criteria for Nodal Marginal 
Zone Lymphoma and Extragastric MALT Lymphoma 
Response should be determined on the basis of radiographic and clinical evidence of disease 
adapting the modified 2007 Cheson criteria below5. 
Selection of Target Lesions 
Up to six of the largest dominant nodes or tumor masses selected according to all of the 
following: 
• 
Clearly measurable in at least two perpendicular dimensions at baseline 
All nodal lesions must measure: 
− 
1.5 cm in greatest transverse diameter (GTD) regardless of short axis 
measurement, or 
− 
If the GTD measures between 1.1-1.5 cm, the short axis must measure > 1.0 cm. 
• 
All extranodal lesions must measure ≥ 1.5 cm in the GTD. 
• 
If possible, the lesions should be from disparate regions of the body 
• 
Should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved 
• 
Extranodal lesions within the liver or spleen must be at least 1.5 cm in two 
perpendicular dimensions. 
 
Selection of Nontarget Lesions 
Nontarget lesions will be qualitatively assessed at each subsequent time point. All of the sites 
of disease present at baseline and not classified as target lesions will be classified as nontarget 
lesions, including any measurable lesions that were not chosen as target lesions. Examples of 
nontarget lesions include: 
• All bone lesions, irrespective of the modality used to assess them 
• Lymphangitis of the skin or lung 
• Cystic lesions 
• Splenomegaly and hepatomegaly  
• Measurable lesions beyond the maximum number of six 
• Groups of lesions that are small and numerous 
• Pleural/pericardial effusions and/or ascites with cytological evidence of malignancy 
 
Reporting Conventions 
 
Lesion not assessable 
This category is reserved for target and non-target lesions that are deemed “not assessable” 
because: 
• 
One or more target/nontarget cannot be assessed (e.g., inadequate scan coverage, 
contrast, artifacts, or other factors). 
• 
One or more target/non-target lesions were excised or irradiated and have not 
reappeared or increased. 
Examples of lesions not assessable are a lung lesion in the hilum obstructing the bronchus 
and causing atelectasis of the lobe or a hypodense liver lesion that becomes surrounded by 
fatty infiltration. In both examples, the boundaries of the lesion can be difficult to distinguish. 
Every effort should be made to assign measurements to lesions that develop less distinct 
margins because they become much smaller. 
 
 

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Effects of Lesions not Assessable on Response Assessment 
If a target lesion is classified as not assessable after baseline, the sum of the product of the 
diameters (SPD)/area (whichever applies) of the target lesions cannot accurately be 
determined for that time point. In this case the clinical judgment of the investigator together 
with the measurements of all other assessable lesions is necessary to record the timepoint 
response. 
PD can be determined without evaluation of all sites of disease on the basis of the GTD, area 
or SPD for target lesions, evaluation of unequivocal progression in nontarget lesions, or 
observation of a new lesion within the available radiographic or clinical assessments. 
 
Response Criteria for Nodal Marginal Zone lymphoma and extragastric MALT lymphoma 
and for measurable disease (≥1.5 cm) shown by radiographic evidence. For the 
assessment of extranodal gastric MALT lymphoma and splenic MZL, see Appendices E and F 
in addition to the information below. 
 
Complete Response (CR) 
1. Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present prior to therapy. 
2. Variably FDG-avid lymphomas/FDG avidity unknown: In patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative: all lymph nodes 
and nodal masses must have regressed on CT to normal size (< 1.5 cm in their greatest 
transverse diameter for nodes 1.5 cm prior to therapy). Previously involved nodes that 
were 1.1-1.5 cm in their long axis and >1.0 cm in their short axis prior to treatment must 
have decreased to < 1.0 cm in their short axis after treatment. 
3. The spleen and/or liver, if considered enlarged prior to therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination and 
should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is not 
always reliable as a spleen considered normal in size may still contain lymphoma, 
whereas an enlarged spleen may reflect variations in anatomy, blood volume, the use 
of hematopoietic growth factors, or other causes rather than lymphoma. 
4. If the bone marrow was involved by lymphoma prior to treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). If the 
sample is indeterminate by morphology, it should be negative by immuno-
histochemistry. A sample that is negative by immuno-histochemistry but demonstrating 
a small population of clonal lymphocytes by flow cytometry will be considered a CR 
until data become available demonstrating a clear difference in patient outcome. 
 
Partial Response (PR) 
1. >50% decrease in sum of the product of the diameters (SPD) of up to 6 of the largest 
dominant nodes or nodal masses. These nodes or masses should be selected 
according to all of the following: (a) they should be clearly measurable in at least 2 
perpendicular dimensions; (b) they should be from disparate regions of the body; (c) 
they should include mediastinal and retroperitoneal areas of disease whenever these 
sites are involved. 
2. No increase in the size of other nodes, liver or spleen 
3. Splenic and hepatic nodules must regress by ≥ 50% in their SPD or, for single nodules, 
in the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
usually evaluable and not measurable disease. 

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5. Bone marrow assessment is irrelevant for determination of a PR if the sample was 
positive prior to treatment. However, if positive, the cell type should be specified, e.g. 
large-cell lymphoma or small neoplastic B cells. Patients who achieve a complete 
remission by the above criteria, but who have persistent morphologic bone marrow 
involvement will be considered partial responders. In cases where the bone marrow 
was involved prior to therapy that resulted in a clinical CR, but with no bone marrow 
assessment following treatment, patients should be considered as partial responders. 
6. No new sites of disease 
7. Variably FDG-avid lymphomas/FDG-avidity unknown; for patients without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, standard CT 
criteria should be used. 
 
Stable Disease (SD) 
1. Failing to attain the criteria needed for a CR or PR, but not fulfilling those for progressive 
disease (see below). 
2. Variably FDG-avid lymphomas/FDG-avidity unknown 
For patients without a pretreatment PET scan or if the pretreatment PET was 
negative, there must be no change in the size of the previous lesions on the post 
treatment CT scan. 
 
Progressive Disease (PD) 
Lymph nodes should be considered abnormal if the long axis is >1.5 cm regardless of the short 
axis. If a lymph node has a long axis of 1.1-1.5 cm it should only be considered abnormal if its 
short axis is >1.0. Lymph nodes < 1.0 cm x <1.0 cm will not be considered as abnormal for 
relapse or progressive disease. 
 
Appearances of any new lesion > 1.5 cm in any axis during or at the end of therapy, even if 
others are decreasing in size. Increased FDG uptake in a previously 
1. unaffected site should only be considered relapsed or progressive disease after 
confirmation with other modalities. In patients with no prior history of pulmonary 
lymphoma, new lung nodules identified by CT are mostly benign. Thus, a therapeutic 
decision should not be made solely on the basis of the PET without histological 
confirmation. 
2. >50% increase from nadir in the SPD of any previously involved nodes, or in a single 
involved node, or the size of other lesions (e.g., splenic or hepatic nodules). To be 
considered progressive disease, a lymph node with a diameter of the short axis of < 
1.0 cm must increase by ≥ 50% and to a size of 1.5 x 1.5 cm or > 1.5 cm in the long 
axis. 
3. 50% increase in the longest diameter of any single previously identified node >1 cm in 
its short axis. 
4. Lesions should be PET-positive if a typical FDG-avid lymphoma or one that was PET-
positive prior to therapy unless the lesion is too small to be detected with current PET 
systems (<1.5 cm in its long axis by CT). 
 
Please note, that PET is not part of the regular tumor assessment in this trial and that PET 
should only be done if medically indicated; so in regular cases judgement about response has 
to be done without PET information. 
 
 
 
 

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Matrix for Timepoint Response Evaluation 
Target 
Lesions 
Non-Target 
Lesions 
New Lesions 
Timepoint 
Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
CR 
No 
PR 
PR 
SD 
No 
PR 
SD 
CR 
No 
SD 
SD 
SD 
No 
SD 
PD 
Any 
Yes/No 
PD 
Any 
PD 
Yes/No 
PD 
Any 
Any 
Yes 
PD 
 

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Appendix E: Response Criteria for Extranodal Gastric Marginal Zone 
lymphoma (MALT) 
 
The histological grading system of the GELA for posttreatment evaluation of gastric 
MALT lymphoma should be used7. If there is a measurable extragastric extranodal or nodal 
disease, it should be documented additionally on the basis of radiographic and clinical 
evidence of disease using the modified 2007 Cheson criteria (see Appendix D). 
GELA histological grading system for post-treatment evaluation of gastric MALT lymphoma 
Score 
Lymphoid infiltrate 
LEL 
Stromal changes 
CR  
Absent or scattered plasma cells and small 
lymphoid cells in the LP 
Absent 
Normal or empty LP 
and/orfibrosis 
pMRD  
Aggregates of lymphoid cells or lymphoid 
nodules in the LP/MM and/or SM 
Absent 
Empty LP and/or 
fibrosis 
rRD  
Dense, diffuse, or nodular extending 
around glands in the LP 
Focal LEL or 
absent 
Focal empty LP and/or 
fibrosis 
NC  
Dense, diffuse, or nodular 
Present, “may 
be absent” 
No changes 
CR = complete remission, pMRD = probable minimal residual disease, rRD= responding residual disease, NC = 
no change, MM, muscularis mucosa; LP, lamina propria; SM, submucosa; LEL, lymphoepithelial lesions. 
 
According to this histological scoring system, criteria for treatment response in GMZL can be 
defined as follow:  
1. Complete remission (CR) is defined as normalization of endoscopic findings and 
negative histology (CR or pMRD) in two subsequent follow-up investigations.  
2. Partial remission (PR) is defined as normalization or reduction of macroscopic findings, 
histological signs of lymphoma regression (rRD) and no signs of progressive disease.  
3. Stable disease (SD) is characterized by unmodified gastroscopic findings and/or 
unmodified histology (NC).  
4. Progressive disease (PD) is defined by worsening of macroscopic findings or 
dissemination of gastric MALT lymphoma or transformation into diffuse large B-cell 
lymphoma.  
5. Relapse is defined as the re-occurrence of histologically- confirmed lymphoma after a 
CR was previously documented. 

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Appendix F: Response Criteria Splenic Marginal Zone lymphoma 
The following criteria should be used for response evaluation6, 15. Splenomegaly as 
well as nodal or extranodal disease should be documented using the modified 2007 
Cheson criteria5 (see Appendix D). 
 
Response Criteria for Splenic MZL  
 
Response Category  
 
Definition  
 
Complete response (CR)  
 
• Resolution of organomegaly, normalization of the 
blood counts (Hb >12 g /dl; platelets > 100 x 109/l; 
neutrophils >1.5 x 109/l and no evidence of circulating 
clonal B cells). No evidence or minor BM infiltration 
detected by immunohistochemistry.  
 
 
Partial response (PR)  
 
• 50% or greater improvement in the disease 
manifestations. This should include resolution or 
decrease in spleen size, improvement on cytopenias 
and resolution or decrease in lymphadenopathy if 
present. BM should show a decrease in the level of 
lymphoid infiltration and improvement of the 
hemopoietic reserve.  
 
 
No response (Stable Disease (SD))*  
 
• No response: Less than 10% improvement on the 
disease manifestations  
Progressive Disease (PD)* 
• Progressive disease: Deterioration of the above, i.e. 
> 50% of measurable signs of the disease from nadir. 
 
 
Splenectomy:  
Response will be considered when there is at least 50% improvement on the blood counts, non-
progressive lymphocytosis and no change or improvement in the degree of BM infiltration.  
 
*: Based on (Dreyling, 2013), this category will be split into two separate response categories 
 
 
 

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Appendix G: Ann Arbor Stage 
 
Ann Arbor Stage 
Stage I:  
 
– I = Involvement of a single lymph node region. 
– IE = Localized involvement of a single extralymphatic organ or site. 
Stage II:   
• 
II = Involvement of 2 or more lymph node regions on the same side of the diaphragm. 
• 
IIE = Localized involvement of a single associated extralymphatic organ or site and its 
regional lymph nodes with or without other lymph node regions on the same side of the 
diaphragm. 
Stage III:   
• 
III = Involvement of lymph node regions on both sides of the diaphragm. 
• 
IIIE = Involvement of lymph node regions on both sides of the diaphragm accompanied 
by localized involvement of an extralymphatic organ or site. 
• 
IIIS = Involvement of lymph node regions on both sides of the diaphragm accompanied 
by involvement of the spleen*. 
• 
IIIS+IIIE = Both IIIS+IIIE  
 
Stage IV:   
• 
IV = Disseminated (multifocal) involvement of 1 or more extralymphatic sites with or 
without associated lymph node involvement or isolated extralymphatic organ 
involvement with distant (non-regional) nodal involvement. 
• 
IVE = Extranodal lymphoid malignancies arise in tissues separate from, but near, the 
major lymphatic aggregates. 

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Appendix H: ECOG Performance Status Criteria 
The following table presents the ECOG performance status scale32: 
 
ECOG Performance Status Scale 
0 
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction 
1 
Symptoms but ambulatory. Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (eg, 
light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable 
to carry out any work activities. Up and about more than 50% of waking 
hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined to bed 
or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
 
 

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Appendix I: Functional Assessment of Cancer Therapy for Lymphoma 
(FACTLym) (Version 4) 
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days. 
 
 
 
PHYSICAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GP1 
I have a lack of energy 
0 
1 
2 
3 
4 
GP2 
I have nausea 
0 
1 
2 
3 
4 
GP3 
Because of my physical condition, I have trouble 
meeting the needs of my family 
 
0 
 
1 
 
2 
 
3 
 
4 
GP4 
I have pain 
0 
1 
2 
3 
4 
GP5 
I am bothered by side effects of treatment 
0 
1 
2 
3 
4 
GP6 
I feel ill 
0 
1 
2 
3 
4 
GP7 
I am forced to spend time in bed 
0 
1 
2 
3 
4 
 
 
SOCIAL/FAMILY WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GS1 
I feel close to my friends 
0 
1 
2 
3 
4 
GS2 
I get emotional support from my family 
0 
1 
2 
3 
4 
GS3 
I get support from my friends 
0 
1 
2 
3 
4 
GS4 
My family has accepted my illness 
0 
1 
2 
3 
4 
GS5 
I am satisfied with family communication about my 
illness 
 
0 
 
1 
 
2 
 
3 
 
4 
GS6 
I feel close to my partner (or the person who is my 
main support) 
 
0 
 
1 
 
2 
 
3 
 
4 
Q1 
Regardless of your current level of sexual activity, please 
answer the following question. If you prefer not to answer 
it, please mark this box and go to the next section. 
 
 
 
 
 

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Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
EMOTIONAL WELL-BEING 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GE1 
I feel sad 
0 
1 
2 
3 
4 
GE2 
I am satisfied with how I am coping with my illness 
0 
1 
2 
3 
4 
GE3 
I am losing hope in the fight against my illness 
0 
1 
2 
3 
4 
GE4 
I feel nervous 
0 
1 
2 
3 
4 
GE5 
I worry about dying 
0 
1 
2 
3 
4 
GE6 
I worry that my condition will get worse 
0 
1 
2 
3 
4 
 
 
 
FUNCTIONAL WELL-BEING 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite
a bit 
Very 
much 
 
GF1 
I am able to work (include work at home) 
0 
1 
2 
3 
4 
GF2 
My work (include work at home) is fulfilling 
0 
1 
2 
3 
4 
GF3 
I am able to enjoy life 
0 
1 
2 
3 
4 
GF4 
I have accepted my illness 
0 
1 
2 
3 
4 
GF5 
I am sleeping well 
0 
1 
2 
3 
4 
GF6 
I am enjoying the things I usually do for fun 
0 
1 
2 
3 
4 
GF7 
I am content with the quality of my life right now 
0 
1 
2 
3 
4 
 
 
 
 
 
GS7 
I am satisfied with my sex life 
0 
1 
2 
3 
4 

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Please circle or mark one number per line to indicate your response as it applies 
to the past 7 days. 
 
ADDITIONAL CONCERNS 
 
Not 
at all 
A little 
bit 
Some-
what 
Quite 
a bit 
Very 
much 
P2 
I have certain parts of my body where I experience pain
0 
1 
2 
3 
4 
LEU1 
I am bothered by lumps or swelling in certain parts of 
my body (e.g., neck, armpits, or groin)
 
0 
 
1 
 
2 
 
3 
 
4 
BRM3 
I am bothered by fevers (episodes of high body 
temperature)
 
0 
 
1 
 
2 
 
3 
 
4 
ES3 
I have night sweats
0 
1 
2 
3 
4 
LYM1 
I am bothered by itching
0 
1 
2 
3 
4 
LYM2 
I have trouble sleeping at night
0 
1 
2 
3 
4 
BMT6 
I get tired easily
0 
1 
2 
3 
4 
C2 
I am losing weight
0 
1 
2 
3 
4 
Ga1 
I have a loss of appetite
0 
1 
2 
3 
4 
HI8 
I have trouble concentrating
0 
1 
2 
3 
4 
N3 
I worry about getting infections
0 
1 
2 
3 
4 
LEU6 
I worry that I might get new symptoms of my illness
0 
1 
2 
3 
4 
LEU7 
I feel isolated from others because of my illness or 
treatment
 
0 
 
1 
 
2 
 
3 
 
4 
BRM9 
I have emotional ups and downs
0 
1 
2 
3 
4 
LEU4 
Because of my illness, I have difficulty planning for the 
future
 
0 
 
1 
 
2 
 
3 
 
4 
 

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Appendix J: Pathology Reference Centers 
Country 
Name of institution and address 
Germany 
Prof. Dr. med. Alfred Feller 
 
 
 
 
 
Prof. Dr. med. Falko Fend 
 
  
 
 
Prof. Dr. med. Dr. h.c. Martin-Leo Hansmann 
 
 
Prof. Dr. med. Wolfram Klapper 
 
 
 
 
 
Prof. Dr. med. Peter Möller 
 
 
 
 
Prof. Dr. med. German Ott 
 

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Prof. Dr. med. Andreas Rosenwald 
 
 
Prof. Dr. med. Dr. h.c. Harald Stein 
 
 
 
 
 
 
Austria 
 
Prof. Dr. Ingrid Simonitsch-Klupp  
 
  
  
 

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Appendix K: Data Safety Monitoring Committee 
Name, institution and address 
 
Prof. Dr. med. Eva Kimby 
 
 
 
  
 
 
 
ao Univ. Prof. Dr. med. Alexander Egle 
 
 
 
 
 
Dr. rer. nat. Michael Unterhalt 
 
 
 
 
 
 
 
 

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Appendix L: Patient Insurance 
If required according to the national regulations for each participating country, the 
sponsor of the study will obtain insurance coverage for eventually occurring damage 
caused by the treatment or any actions taken according to the treatment plan. A 
certificate of insurance will be provided to the investigator in countries in which this 
document is required. The investigator, or an individual who is designated by the 
investigator, will inform the patient of the existence of the insurance, including the 
obligations arising from it. The study patients must be given access to the insurance 
documents and, on request, a copy of the general conditions of insurance.