Conditions: Waldenstrom Macroglobulinemia
Keywords: Waldenstrom Macroglobulinemia Relapsed Refractory Rituximab Pembrolizumab
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 17
Healthy volunteers: no

Brief summary:
This study is for patients who have previously been treated for Waldenström's macroglobulinaemia (WM) and their disease has either not responded (known as refractory disease) or has returned (known as relapsed disease). Through this study, the researchers would like to find out whether treating these patients with drugs called rituximab and pembrolizumab is a safe and effective combination for this disease.

In this study, pembrolizumab and rituximab will be given together. In other studies pembrolizumab has been shown to be effective at treating diseases similar to WM. The researchers want to test whether giving pembrolizumab and rituximab together is safe and effective.

Detailed description:

Arms:
arm 1: None

Interventions: intervention 1: Pembrolizumab intervention 2: Rituximab
Intervention descriptions: intervention 1: 200 mg IV dose given on day 1 of a three week cycle intervention 2: 375 mg/m2 IV dose given up to 8 times in the trial

Protocol document:
Prot_SAP_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A phase II trial to investigate the safety and efficacy of 
rituximab and pembrolizumab in relapsed/refractory 
Waldenström’s macroglobulinaemia 
 
 
 
 
 
 
Trial Sponsor: 
University College London 
Trial Sponsor reference: 
UCL/18/0131 
Trial funder: 
Merck Sharp and Dohme Ltd 
Funder reference: 
MISP # 56775 
ISRCTN/Clinicaltrials.gov no: 
NCT03630042 
EUDRACT no: 
2018-001767-23  
IRAS no: 
244929 
 
 
 
 
Protocol version no: 
2.0 
Protocol version date: 
27/07/2021 
 
 
 
 
 
 
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Protocol v2.0 27/07/2021 Authorisation signatures: 
 
Name & Role: 
Signature: 
Date authorised: 
 
Chief Investigator: 
 
Dr Jaimal Kothari 
Consultant Haematologist  
Oxford University Hospitals 
NHS Foundation Trust 
----------------------------------------------- ----------------------- 
 
For the Sponsor: 
 
 
 
 
 
 
Dr Laura Clifton-Hadley 
Trials Group Lead 
UCL CTC 
----------------------------------------------- ----------------------- 
 
 
Please note: This trial protocol must not be applied to patients treated outside the 
Pembro WM trial. Cancer Research UK & UCL Cancer Trials Centre (UCL CTC) can only 
ensure that approved trial investigators are provided with amendments to the protocol. 
We thank the patient representatives who reviewed the protocol for their input into the 
trial design and patient information sheet.   
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COORDINATING CENTRE: 
For general queries, supply of trial documentation and central data management please 
contact: 
Pembro WM Trial Coordinator 
Cancer Research UK & UCL Cancer Trials Centre 
90 Tottenham Court Road 
London 
 
W1T 4TJ 
United Kingdom 
 
Tel:  
+44 (0) 20 7679 9860 
09:00 to 17:00 Monday to Friday, excluding Bank Holidays (UK time) 
 
Email: 
ctc.pembroWM@ucl.ac.uk  
Other trial contacts: 
Chief Investigator: 
Dr Jaimal Kothari 
Address: 
Churchill Hospital,  
Oxford University Hospitals NHS Foundation Trust 
 
Old Road, Headington 
 
Oxford 
 
 
OX3 7LE 
 
 
 
 
Trial Management Group (TMG): 
 
Name 
Job title 
Organisation 
 
Dr Jaimal Kothari 
 
Dr Rebecca Auer  
Dr Shirley D’Sa  
Dr Toby Eyre   
 
Dr Guy Pratt  
 
Dr Roger Owen      
Dr Suzanne Arulogun 
Dr Harriet Scorer 
Dr Michael Northend 
Laura Clifton-Hadley    
William Wilson 
Darren Edwards 
Jessica Hunt 
Chief Investigator 
 
Co-Investigator 
Co-Investigator 
Co-Investigator 
 
Co-Investigator 
 
Co-Investigator 
Co-Investigator 
Patient Representative 
Clinical Research Fellow 
Trial Group Lead 
Statistician 
Senior Trial Coordinator 
Trial Coordinator 
Oxford University Hospitals NHS 
Foundation Trust  
Barts Health NHS Trust 
UCLH NHS Foundation Trust 
Oxford University Hospitals NHS 
Foundation Trust 
University Hospitals Birmingham 
NHS Trust 
HMDS Leeds 
UCLH NHS Foundation TrustCR 
UK and UCL CTC 
CR UK and UCL CTC 
CR UK and UCL CTC 
CR UK and UCL CTC 
CR UK and UCL CTC 
CR UK and UCL CTC 
 
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TABLE OF CONTENTS 
1. 
Protocol Summary .......................................................................................................................... 11 
1.1. 
Summary of Trial Design ................................................................................................................................................ 11 
1.2. 
Trial Schema ......................................................................................................................................................................... 16 
2. 
Introduction ..................................................................................................................................... 17 
2.1. 
Background ............................................................................................................................................................................ 17 
2.1.1. 
Waldenström’s macroglobulinemia ................................................................................. 17 
2.1.2. 
Clinical need in WM ......................................................................................................... 17 
2.1.3. 
New potential drug therapies in WM ............................................................................... 18 
2.1.4. 
Limitations in recent studies of targeted agents .............................................................. 18 
2.1.5. 
PD-1/PD-L1 as a target in WM ........................................................................................ 19 
2.1.6. 
Clinical experience of pembrolizumab............................................................................. 19 
2.1.7. 
Scientific rationale for combining Pembrolizumab and Rituximab in WM ....................... 20 
3. 
Trial Design ..................................................................................................................................... 22 
3.1. 
Trial Objectives .................................................................................................................................................................... 22 
3.1.1. 
Primary Objective ............................................................................................................ 22 
3.1.2. 
Secondary Objectives ..................................................................................................... 22 
3.1.3. 
Exploratory Objective ...................................................................................................... 22 
3.2. 
Trial Endpoints ..................................................................................................................................................................... 23 
3.2.1. 
Primary end-points: ......................................................................................................... 23 
3.2.2. 
Secondary end-points: .................................................................................................... 23 
3.2.3. 
Exploratory endpoints: ..................................................................................................... 23 
3.3. 
Trial Activation ...................................................................................................................................................................... 24 
4. 
Selection of Sites/Site Investigators ............................................................................................. 25 
4.1. 
Site Selection ........................................................................................................................................................................ 25 
4.1.1. 
Selection of Principal Investigator and other investigators at sites ................................. 25 
4.1.2. 
Training requirements for site staff .................................................................................. 25 
4.2. 
Site initiation and Activation .......................................................................................................................................... 26 
4.2.1. 
Site initiation .................................................................................................................... 26 
4.2.2. 
Required documentation ................................................................................................. 26 
4.2.3. 
Site activation .................................................................................................................. 26 
5. 
Informed consent ............................................................................................................................ 27 
6. 
Selection of Patients ...................................................................................................................... 28 
6.1. 
Screening Log ...................................................................................................................................................................... 28 
6.2. 
Patient Eligibility .................................................................................................................................................................. 28 
6.2.1. 
Inclusion criteria ............................................................................................................... 28 
6.2.2. 
Exclusion criteria ............................................................................................................. 29 
6.3. 
Pregnancy and birth control .......................................................................................................................................... 30 
6.3.1. 
Pregnancy and birth control ............................................................................................ 30 
6.3.2. 
Risk of exposure to trial treatment during pregnancy ...................................................... 31 
6.3.3. 
Pregnancy testing ............................................................................................................ 31 
6.3.4. 
Contraceptive Advice....................................................................................................... 32 
6.3.5. 
Action to be taken in the event of a pregnancy ............................................................... 33 
7. 
Registration Procedures ................................................................................................................ 34 
7.1. 
Pre-Registration .................................................................................................................................................................. 34 
7.2. 
Registration ............................................................................................................................................................................ 35 
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7.3. 
Initial Trial Drug Supply ................................................................................................................................................... 35 
8. 
Trial Treatment ................................................................................................................................ 36 
8.1. 
Investigational Medicinal Products ............................................................................................................................ 36 
8.2. 
Treatment Summary ......................................................................................................................................................... 36 
8.3. 
Trial Treatment Details .................................................................................................................................................... 37 
8.3.1. 
Criteria to receive treatment ............................................................................................ 37 
8.3.2. 
Moving treatment for logistical reasons ........................................................................... 38 
8.3.3. 
Administration for IgM flare ............................................................................................. 38 
8.3.4. 
Pembrolizumab administration ........................................................................................ 38 
8.3.5. 
Rituximab administration ................................................................................................. 39 
8.4. 
Management of Adverse Events ................................................................................................................................ 40 
8.4.1. 
General considerations ................................................................................................... 40 
8.4.2. 
Pembrolizumab and combination therapy related adverse events ................................. 41 
8.4.3. 
Pembrolizumab Infusion-related reactions ...................................................................... 44 
8.4.4. 
Other pembrolizumab related adverse events ................................................................ 45 
8.4.5. 
Rituximab related adverse events and Infusion related reactions .................................. 45 
8.4.6. 
IgM flare ........................................................................................................................... 45 
8.5. 
Treatment discontinuation ............................................................................................................................................. 46 
8.6. 
Management of Overdoses, Trial treatment error, or Occupational Exposure .................................. 46 
8.6.1. 
Overdose ......................................................................................................................... 46 
8.6.2. 
Medication error ............................................................................................................... 47 
8.6.3. 
Occupational exposure .................................................................................................... 47 
8.7. 
Supportive Care .................................................................................................................................................................. 47 
8.8. 
Contraindications ................................................................................................................................................................ 48 
8.9. 
Pharmacy Responsibilities ............................................................................................................................................ 49 
8.9.1. 
Temperature Excursions ................................................................................................. 49 
8.9.2. 
IMP accountability ........................................................................................................... 50 
8.10. 
24 Hour/Out-of-Office Hours Emergency Drug-Specific Advice ................................................................ 50 
8.11. 
Clinical Management after Treatment Discontinuation .................................................................................. 50 
8.12. 
Drug Provision after the End of the Trial ................................................................................................................ 50 
9. 
Assessments ................................................................................................................................... 51 
9.1. 
Registration Assessments ............................................................................................................................................. 51 
9.2. 
Assessments during Treatment .................................................................................................................................. 52 
9.2.1. 
Assessments prior to each cycle of treatment ................................................................ 52 
9.2.2. 
Disease response assessments ...................................................................................... 53 
9.3. 
Assessments after Disease Progression ............................................................................................................... 53 
9.4. 
Assessments after treatment discontinuation (for reasons other than disease progression) .... 54 
10. Exploratory Biological Studies ...................................................................................................... 55 
10.1. 
Lymph node and bone marrow trephine formalin fixed paraffin embedded blocks – optional to 
patient……………………………………………………………………………………………………………………………………………………….56 
10.2. 
Bone marrow samples – optional to patient ......................................................................................................... 56 
10.3. 
Peripheral blood samples – optional to patient .................................................................................................. 57 
11. Data Management and Data Handling Guidelines ....................................................................... 58 
11.1. 
Completing Case Report Forms ................................................................................................................................. 58 
11.2. 
Missing Data.......................................................................................................................................................................... 58 
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11.3. 
Timelines for Data Return .............................................................................................................................................. 58 
11.4. 
Data Queries ......................................................................................................................................................................... 59 
12. Pharmacovigilance ......................................................................................................................... 60 
12.1. 
Definitions ............................................................................................................................................................................... 60 
12.2. 
Reporting Procedures ...................................................................................................................................................... 61 
12.2.1. 
Reporting of Adverse Events (AEs) ................................................................................. 62 
12.2.2. 
Reporting of Serious Adverse Events (SAEs) ................................................................. 62 
12.3. 
SUSARs................................................................................................................................................................................... 65 
12.4. 
Adverse events of special interest ............................................................................................................................. 65 
12.5. 
Urgent events ....................................................................................................................................................................... 66 
12.6. 
Safety Monitoring ................................................................................................................................................................ 66 
12.7. 
Pregnancy .............................................................................................................................................................................. 67 
12.8. 
Development Safety Update Reports (DSURs) ................................................................................................. 68 
13. Incident Reporting and Serious Breaches ................................................................................... 69 
13.1. 
Incident Reporting .............................................................................................................................................................. 69 
13.2. 
Serious Breaches ............................................................................................................................................................... 69 
14. Trial Monitoring and Oversight ..................................................................................................... 70 
14.1. 
On-Site and Remote Monitoring ................................................................................................................................. 70 
14.2. 
Centralised Monitoring ..................................................................................................................................................... 71 
14.3. 
’Triggered’ On-Site/Remote Monitoring .................................................................................................................. 71 
14.4. 
Escalation of Monitoring Issues .................................................................................................................................. 71 
14.5. 
Oversight Committees ..................................................................................................................................................... 72 
14.5.1. 
Trial Management Group (TMG) ..................................................................................... 72 
14.5.2. 
Trial Steering Committee (TSC) ...................................................................................... 72 
14.5.3. 
Independent Data Monitoring Committee (IDMC) ........................................................... 72 
14.5.4. 
Role of UCL CTC ............................................................................................................. 72 
15. Withdrawal of Patients ................................................................................................................... 73 
15.1. 
Patients who do not start Trial Treatment ............................................................................................................. 73 
15.2. 
Discontinuation of Trial Treatment ............................................................................................................................ 73 
15.3. 
Withdrawal of Consent ..................................................................................................................................................... 74 
15.3.1. 
Withdrawal of consent for follow up................................................................................. 74 
15.3.2. 
Withdrawal of consent for data collection ........................................................................ 74 
15.3.3. 
Withdrawal of consent for use of samples ...................................................................... 74 
15.4. 
Losses to Follow-Up ......................................................................................................................................................... 75 
16. Trial Closure .................................................................................................................................... 76 
16.1. 
End of Trial ............................................................................................................................................................................. 76 
16.2. 
Archiving of Trial Documentation ............................................................................................................................... 76 
16.3. 
Early Discontinuation of Trial ....................................................................................................................................... 76 
16.4. 
Withdrawal from Trial Participation by a Site ....................................................................................................... 76 
17. Statistics .......................................................................................................................................... 77 
17.1. 
Sample Size Calculation ................................................................................................................................................. 77 
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17.2. 
Statistical analysis .............................................................................................................................................................. 77 
17.2.1. 
Analysis of primary endpoint ........................................................................................... 77 
17.2.2. 
Analysis of secondary endpoints and secondary analyses ............................................. 77 
17.3. 
Interim analyses .................................................................................................................................................................. 79 
18. Ethical and Regulatory Considerations........................................................................................ 80 
18.1. 
Ethical Approval .................................................................................................................................................................. 80 
18.2. 
Regulatory Approval ......................................................................................................................................................... 80 
18.3. 
Site Approvals ...................................................................................................................................................................... 80 
18.4. 
Protocol Amendments ...................................................................................................................................................... 81 
18.5. 
Patient Confidentiality & Data Protection ............................................................................................................... 81 
19. Sponsorship and Indemnity .......................................................................................................... 82 
19.1. 
Sponsor Details ................................................................................................................................................................... 82 
19.2. 
Indemnity ................................................................................................................................................................................. 82 
20. Funding ............................................................................................................................................ 83 
21. Publication Policy ........................................................................................................................... 84 
22. References ....................................................................................................................................... 85 
Appendix 1: Quick Reference Guide to Patient Visits ......................................................................... 87 
Appendix 2: ECOG Performance Status ............................................................................................... 90 
Appendix 3: Response assessment ...................................................................................................... 91 
Appendix 4: Protocol Version History ................................................................................................... 92 
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Abbreviations 
ABPI 
Association of British Pharmaceutical Industry  
ADL 
Activities of Daily Living 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest  
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute Neutrophil Count 
AR 
Adverse Reaction 
AST 
Aspartate aminotransferase 
CI 
Chief Investigator 
 
CR 
Complete Response 
CRF 
Case Report Form 
CT 
Computerised Tomography 
CTA 
Clinical Trial Authorisation  
CTCAE 
Common Terminology Criteria for Adverse Events 
DPA 
Data Protection Act 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylene Diamine Tetra Acetate 
EudraCT 
European Clinical Trials Database 
FBC 
Full Blood Count 
G-CSF 
Granulocyte Colony Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GMO 
Genetically Modified Organisms 
Hb 
Haemoglobin 
HRA 
Health Research Authority 
IB 
Investigator’s Brochure  
ICH GCP 
International Conference of Harmonisation-Good Clinical Practice 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
ISRCTN 
International Standard Randomised Controlled Trial Number 
IV 
Intravenous 
LCRN 
Local Clinical Research Network 
LDH 
Lactate Dehydrogenase 
LFT 
Liver Function Tests 
LLN 
Lower Limit of Normal 
MHRA 
Medicines and Healthcare products Regulatory Agency 
mNCA 
Model Agreement for Non-Commercial Research 
NCRI 
National Cancer Research Institute 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
PI 
Principal Investigator 
PO 
By mouth 
PR 
Partial Response 
REC 
Research Ethics Committee 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reaction 
SD 
Stable Disease 
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SPC 
Summary of Product Characteristics 
SSA 
Site Specific Assessment 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TMF 
Trial Master File  
TMG 
Trial Management Group 
TSC 
Trial Steering Committee 
UCL CTC 
CR UK and UCL Cancer Trials Centre 
U&E 
Urea and Electrolytes 
ULN 
Upper Limit of Normal 
VGPR 
Very Good Partial Response 
WBC 
White Blood Cells 
 
 
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1. 
PROTOCOL SUMMARY 
1.1. 
Summary of Trial Design  
 
Title: 
A Phase II trial to investigate the safety and efficacy 
of 
rituximab 
and 
pembrolizumab 
in 
relapsed/refractory 
Waldenström’s 
macroglobulinaemia 
Short Title/acronym: 
PembroWM 
EUDRACT no: 
2018-001767-23 
Sponsor name & reference: 
UCL18/0131 
Funder name & reference: 
Merck Sharp and Dohme Ltd; MISP# 56775 
ISRCTN/Clinicaltrials.gov no: 
NCT03630042 
Design: 
Single arm, phase II trial, non-randomised 
Overall aim: 
To determine the safety, tolerability and efficacy of 
pembrolizumab in combination with rituximab for the 
treatment of relapsed/refractory Waldenström’s 
macroglobulinaemia (WM) 
Primary endpoint: 
Percentage of patients achieving an overall 
response rate (defined as complete response (CR), 
very good partial response (VGPR), partial response 
(PR) or minor response (MR) i.e. a greater than 25% 
reduction in the serum IgM level) at 24 weeks post 
commencing treatment. 
Secondary endpoints: 
 Safety and tolerability of pembrolizumab in 
combination with rituximab 
 Complete response (CR) rate at 24 weeks post 
commencing treatment 
 Very good partial response (VGPR) rate at 24 
weeks post commencing treatment 
 Time to maximal response to treatment 
 Time to next treatment 
 Progression free survival (PFS) at 1 and 2 years 
 Overall survival (OS) at 1 and 2 years 
 Change in quality of life (QoL) at 24 weeks post 
commencing treatment 
Exploratory Biological 
Studies: 
 Assessment of PD-1 and PD-L1/ PD-L2 
expression by fluorescence in situ hybridisation 
(FISH) and immunohistochemistry (IHC) 
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 IHC to assess baseline and on-treatment 
changes to distribution and composition of 
immune response cells in the microenvironment 
 Analysis of baseline biopsies to elucidate 
potential mechanisms of action of tumour 
response 
 Assessment of treatment outcome according to 
tumour genotype 
 Correlation of bone marrow response with 
reduction in serum IgM level 
 Quantification of bone marrow involvement by 
morphologic assessment of trephine and flow 
cytometric assessment of aspirate for MRD 
Target accrual: 
42 patients 
Inclusion & exclusion criteria: 
 
(Refer to section 6.2 for the full list of 
eligibility criteria)  
 
Inclusion criteria 
 
 Patients >18 years old  
 Eastern Cooperative Oncology Group (ECOG) 
performance status 0-2 (see appendix 3) 
 Presence of measurable disease, (defined as a 
detectable level of  IgM paraprotein) and fulfils 
other 
World 
Health 
Organisation 
(WHO) 
diagnostic criteria for WM  
 Relapsed or refractory WM who have received 
≥1 prior lines of therapy 
 Adequate renal function: estimated creatinine 
clearance ≥30ml/min as calculated using the 
Cockroft-Gault equation 
 Adequate liver function, including:  
o Bilirubin ≤1.5 x the upper limit of normal 
(ULN) 
o Aspartate or alanine transferase (AST or 
ALT) ≤2.5x ULN 
 Adequate organ and bone marrow function:  
o Neutrophils ≥0.5x109/L 
o Platelets ≥25109/L  
Note: Growth factor and/or transfusion support is 
permissible to stabilize participant prior to study 
treatment if needed. No lower limit if cytopenia is 
related to WM infiltration in the bone marrow. 
 Willing 
to 
comply 
with 
contraceptive 
requirements of the trial (see section 6.3.4) 
 Negative serum or highly sensitive urine 
pregnancy test for women of childbearing 
potential (WOCBP) 
 Written informed consent 
 
 
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Exclusion criteria 
 
 Refractory 
to 
rituximab 
as 
defined 
by 
progression on/within 6 months of finishing a 
rituximab based regimen 
 Women who are pregnant or breastfeeding, or 
males expecting to conceive or father children at 
any point from the start of treatment until 4 
months 
after 
the 
last 
administration 
of 
pembrolizumab 
 Clinically significant cardiac disease (see section 
6.2 of the protocol for details) 
 History of significant cerebrovascular disease in 
the last 6 months 
 Known 
central 
nervous 
system 
(CNS) 
involvement of WM 
 Clinically significant active infection requiring 
antibiotic or antiretroviral therapy 
 Significant concurrent, uncontrolled medical 
condition (see section 6.2 of protocol for details) 
 Has a known additional malignancy that is 
progressing 
or 
requires 
active 
treatment. 
Exceptions include basal cell carcinoma of the 
skin, squamous cell carcinoma of the skin, or in 
situ cervical cancer that has 
undergone 
potentially curative therapy  
 Active autoimmune disease apart from: 
o Type I diabetes or thyroid disease, 
controlled on medication 
o Skin conditions such as psoriasis, vitiligo 
or 
alopecia 
not 
requiring 
systemic 
treatment  
o Auto-immune thrombocytopenia, thought 
to be secondary to WM, provided that the 
platelet count meet the criteria specified 
above on daily doses of corticosteroid of 
<10mg prednisolone or equivalent 
 Prior history of haemolytic anaemia (either warm 
or cold) 
 History of non-infective colitis 
 History of (non-infectious) pneumonitis that 
required steroids or has current pneumonitis 
 Systemic anti-cancer therapy within 4 weeks 
prior to trial registration (except for BTK 
inhibitors, which may continue until 48 hours 
prior to the start of cycle 1, day 1 of trial therapy) 
 Received a T cell depleting antibody (e.g. 
Campath) within 3 months prior to starting 
treatment 
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 Received a live vaccine or live-attenuated 
vaccine within 30 days prior to starting treatment 
 Chronic or ongoing active infectious disease 
requiring systemic treatment (see section 6.2 of 
the protocol for details) 
 Patients who have received treatment with any 
non-marketed drug substance or experimental 
therapy within 4 weeks prior to starting treatment 
(unless prior agreed with the TMG) 
 Patients known or suspected of not being able to 
comply with the study protocol 
 Positive serology for Hepatitis B defined as a 
positive test for HepB surface antigen (HBsAg).  
Note: patients who are HepB core antibody 
(HBcAb) positive will only be eligible for the study 
if the HepB virus deoxyribonucleic acid (DNA) 
test is negative and patients are willing to 
undergo monthly monitoring for HBV reactivation 
 Positive serology for Hepatitis C defined as a 
positive test for HCV antibody 
 Major surgery within 4 weeks prior to trial 
registration  
 Prior therapy with an anti-PD-1,anti-PD-L1 or 
CTLA4 monoclonal antibody  
 Prior allogeneic bone marrow transplant  
 Diagnosis of prior immunodeficiency or organ-
transplant requiring immunosuppressive therapy 
or known HIV or acquired immunodeficiency 
syndrome (AIDS)-related illness 
 Current or prior use of immunosuppressive 
therapy within 7 days prior to start of treatment 
except the following: intranasal, inhaled, topical 
steroids or local steroid injections (e.g. Intra-
articular injections); a short course of oral 
prednisolone (a maximum of 10mg/day for 5 
days) can be used within 7 days of cycle 1 day 1 
if there are concerns around IgM flare, following 
BTK inhibitor discontinuation 
 Known 
or 
suspected 
hypersensitivity 
to 
components of pembrolizumab or rituximab (or 
other CD20 monoclonal antibodies) 
 
Number of sites: 
10 UK sites 
 
 
 
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Treatment summary: 
Eligible patients will be treated with rituximab 
375mg/m2 IV infusion and pembrolizumab 200mg IV 
infusion on a 3 weekly cycle, for a maximum of 18 
cycles (1 year): 
 
 Cycle 1: 
o Rituximab 375mg/m2 - days 1, 8 and 15  
o Pembrolizumab 200mg - day 2 
 Cycle 2: 
o Rituximab 375mg/m2 - day 1  
o Pembrolizumab 200mg - day 1 
 After cycle 2:  
o Rituximab 375mg/m2 - 12 weekly on day 1 
(cycle 6, 10, 14 & 18) 
o Pembrolizumab 200mg - day 1 of every cycle  
 
Duration of recruitment: 
27 months 
 
Duration of follow up: 
Patients will be followed up for a minimum of 2 years 
post registration into the study 
Definition of end of trial: 
The end of trial will be declared when the final data 
item from the final patient is received (i.e. it is 
anticipated that this will be when the final patient 
completes their 2-year follow-up visit).  
 
 
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1.2. 
Trial Schema 
 
 
 
 
 
1
•CONSENT
2
•SCREENING
3
•PRE-REGISTRATION and FULL REGISTRATION
4
•TREATMENT
• Cycle 1:
Rituximab 375mg/m2 - days 1, 8 and 15 & Pembrolizumab 200mg - day 2
• Cycle 2: 
Rituximab 375mg/m2 - day 1 & Pembrolizumab 200mg - day 1
• After cycle 2: Rituximab 375mg/m2 - 12 weekly on day 1 (cycle 6, 10, 14 & 18) and       
(18 cycles total)
Pembrolizumab 200mg - day 1 of every cycle
5
•RESPONSE ASSESSMENTS
•Week 12
•Week 24
•1 year
6
•FOLLOW UP
•Patients will be followed up for at least 2 years post registration into the study.  Following 
this patients will be followed up annually for ongoing remission status and late toxicity 
assessment until the EoT is declared.
•If patients discontinue treatment (for reasons other than disease progression) they will 
be followed up at day 60 post treatment discontinuation and will then be followed up 
annually for disease response/late toxicities
•If patients discontinue due to disease progression will be followed up annually
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2. 
INTRODUCTION 
2.1. 
Background 
2.1.1.  Waldenström’s macroglobulinemia 
Waldenström’s macroglobulinemia (WM) is a rare low grade B-cell malignancy, 
characterised by bone marrow infiltration with monoclonal immunoglobulin M secreting 
lymphoplasmacytic cells. The incidence is 5-8 cases per million, with about 1,000-1,500 
new patients diagnosed in the USA annually. Incidence increases with age with a median 
age at diagnosis of 70 years for Caucasians, and slightly lower in other ethnic groups. 
There is a male to female preponderance, and an incidence higher in Caucasians than 
Africans or Asians (Gertz et al 2000; Gertz et al 2015).  
Activating mutations in the MYD88 gene (MYD88MUT), which trigger downstream IRAK- 
mediated NF-κB signaling (Treon et al 2012), are seen in approximately 90% of cases. 
A second set of mutations with prognostic significance is found at CXCR4, the receptor 
for SDF-1a, which are either frameshift or nonsense mutations, are similar to those seen 
in the immunodeficiency syndrome WHIM (warts, hypogammaglobulinemia, infections 
and myelokathexis), and also lead to constitutive activation. Either or both of these 
mutations can be found in patients and lead to different clinical pictures, outcomes, and 
response to therapy (Treon, et al 2014). 
According to the International Prognostic scoring system for WM (ISSWM), patients are 
stratified into low, intermediate, and high risk groups with respective 5-year survival rates 
of 87%, 68%, and 36%, based upon age, IgM level, β2-microglobulin level, hemoglobin, 
and platelet count (Morel et al 2009). 
About 75% of initially asymptomatic WM patients will require therapy within 15 years of 
follow-up, with a median time to initiation of therapy of over 7 years; a lower Hgb, 
extensive bone marrow infiltration, serum paraprotein, and β2-microglobulin levels are 
significant predictors of an eventual need for therapy (Gertz et al 2015). Indications for 
treatment as per the IWWM-8 consensus meeting are either clinical symptoms or 
laboratory findings. Clinical indications include the combination of fever, night sweats, 
weight loss and fatigue, hyperviscosity syndrome, bulky/symptomatic lymphadenopathy, 
significant hepatomegaly or splenomegaly, other symptomatic organomegaly, or 
peripheral neuropathy. Laboratory indications for therapy include symptomatic 
cryoglobulinemia, cold agglutinin anemia, immune hemolytic cytopenias, nephropathy, 
amyloidosis, or significant anemia/thrombocytopenia due to marrow replacement 
(Leblond et al 2016). 
2.1.2. Clinical need in WM 
Current treatment strategies include single agent rituximab or rituximab combination 
approaches.  In the upfront setting, both Bendamustine plus rituximab, and 
Dexamethasone, cyclophosphamide and rituximab have shown to be effective 
approaches (Rummel et al, 2013; Kastritis et al, 2015). Proteasome inhibitor 
combinations with rituximab have also been studied in both the upfront and relapse 
setting (Gavriatopoulou et al, 2017; Treon et al, 2014).   
 
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Treatment at relapse is less standardised, however patients generally remain responsive 
to therapy, including rituximab combination approaches. Responses appear less durable 
with a median progression free survival (PFS) of 16-24 months, up until the advent of 
ibrutinib, which appears to give better results, with a median PFS of at least 4 years 
(Treon et al, 2015 Treon el al, 2017). There is now also evidence for combining rituximab 
with ibrutinib in the upfront and relapsed setting, and emerging data on small numbers 
of patients who have been treated with ibrutinib in the upfront setting (Dimopoulous et al, 
2018; Treon et al 2018). However, relapse is inevitable and there is therefore a need for 
more effective drugs/combinations that can induce deeper and more durable responses, 
especially as there are some concerns about the nature and tempo of relapses following 
discontinuation/progression after ibrutinib (Gustine et al, 2017). 
The need for recurrent treatment, the advanced median age at diagnosis, and the 
underlying biology of the condition, means that there is a relatively high rate of treatment-
related complications, including infection, secondary malignancy and myelosuppression.  
Therefore the further development of chemotherapy-free regimes is attractive, and 
logical partners for combination therapy would include rituximab and ibrutinib. 
2.1.3. New potential drug therapies in WM 
Increased understanding of the biology of WM has catalysed the development of new 
targeted therapeutic agents. MYD88 acts as an adaptor protein for interleukin-1R (IL-1R) 
and Toll-Like receptor (TLR) signaling pathways and recruits kinases that lead to 
activation of NFkB and secretion of cytokines which are implicated in WM cell survival 
and proliferation (Treon et al, 2014). These kinases include IL-R associated kinase 4 
(IRAK-4) and IRAK-1 as well as Bruton Tyrosine Kinase (BTK), the target for ibrutinib 
and other BTK inhibitors. The MYD88L265P mutation causes constitutive signaling 
through this pathway in WM. 
Ibrutinib is becoming a standard of care in relapsed WM, and further BTK inhibitors 
including Acalabrutinib and Zanubrutinib are in development. CXCR4 and IRAK-1 
inhibitors have shown some pre-clinical activity and are under development (Kuhne et al, 
2014, Yang et al, 2017). 
Other attractive targets include the anti-apoptotic protein, BCL2, as this is upregulated in 
WM, making the small molecule inhibitor, venetoclax (ABT-199) a promising potential 
therapy: in a phase I trial 3 out of 4 WM patients achieved a response, including one with 
a complete remission (CR) (Davids et al, 2017). The mammalian target of rapamycin 
(MTOR) inhibitor, everolimus, which blocks pathways involved in WM cell growth and 
proliferation, showed a major response rate of 50% in previously treated WM patients 
(Ghobrial et al, 2017) 
2.1.4. Limitations in recent studies of targeted agents 
However impressive these results, these new, targeted therapies have their own 
limitations. For example, there are no complete responses seen with ibrutinib. 
Phosphoflow analysis of bone marrow lymphoplasmacytic cells taken from WM patients 
showed highly active IRAK1 and IRAK4 but not BTK suggesting partial escape through 
this alternative signaling pathway. Moreover wild type MYD88 WM responds significantly 
less well to ibrutinib [Treon et al, 2017]. This partial resistance, either inherent or 
acquired, is likely to be seen with other agents that target a specific pathway.  
Moreover, while these targeted agents are undoubtedly less myelotoxic, they have their 
own associated toxicity. For example, bortezomib can be associated with severe 
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peripheral neuropathy, which can be particularly challenging in the WM patient group, 
who may have disease-associated neuropathy. Similarly ibrutinib is associated with side 
effects such as increased risk of atrial fibrillation and bleeding. This may be particularly 
problematic in an elderly group of patients, who may require anti-coagulation for other 
indications or who may have an acquired coagulopathy due to the WM itself. ‘Real-world’ 
data suggests approximately 20% of WM patients may discontinue Ibrutinib within a year, 
secondary to toxicity (Gustine et al, 2018) and novel, and ideally non-toxic approaches 
are required to treat these patients.  
Finally, non standardised measurement of response, small patient numbers, and failure 
to separate out first- line versus relapsed/refractory patients makes it difficult to compare 
the efficacy of novel agents across trials. Definition of consensus response criteria by the 
International Workshop on WM should improve this to some degree (Owen et al, 2014). 
With the burgeoning number of new agents, it is therefore an important time for further 
rigorously conducted clinical trials in WM.   
2.1.5. PD-1/PD-L1 as a target in WM 
PD-1 inhibitors are thought to overcome immune anergy by blocking interaction between 
the inhibitory receptor, PD-1, on T cells and its ligands, PD-L1 and PD-L2, which are 
over-expressed in some tumour cells and the tumour micro-environment. PD-1 inhibitors, 
such as pembrolizumab and nivolumab, have shown impressive clinical results in 
relapsed lymphoid malignancies, especially in Hodgkin lymphoma (Bröckelmann et al, 
2017). 
There is a clear role for the bone marrow microenvironment in the pathophysiology of 
WM and PD-1 and PDL-1 is widely expressed in the BMs of patients with WM (Ansell, 
2014) and complex cellular and stromal  interplay is partly controlled by the expression 
and secretion of a number of cytokines, including IL-6 and IL-21 (Hodge et al, 2012).  
Interaction between PD-1 and its ligands may at least partially mediate the permissive 
role of the bone marrow microenvironment in WM: co-culture of PD-1 expressing WM 
cells with PD-L1/ PD-L2 overexpressing stromal cells increased WM cell viability and 
proliferation (Ansell, 2014). 
More recent data indicates that soluble PD-1 Ligands Regulate T-Cell Function in WM, 
with IL-6 and IL-21 leading to an upregulation of both PD-L1 and PD-L2 expression (Jalali 
et al, 2017). This upregulation appears to increase expression of soluble, rather than cell-
surface PD-L1 and PD-L2, but this appears to inhibit T-cell function. Thus, there is 
adequate preclinical data to postulate that PD-1 blocking antibodies may be an effective 
therapeutic intervention in WM. Moreover, as compared with ibrutinib and other BTK 
inhibitors, it is unlikely that response to PD-1 inhibitors will be as restricted to specific 
genomic subtypes (i.e. MYD88/ CXCR mutant versus wild type).     
2.1.6. Clinical experience of pembrolizumab 
Pembrolizumab is a potent and highly selective humanised monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2. Available pharmacokinetic (PK) results in patients with 
melanoma, non-small cell lung cancer (NSCLC), and other solid tumour types support a 
lack of meaningful difference in PK exposures obtained at a given dose among tumour 
types. An open-label Phase 1 trial (PN001) in melanoma patients has been conducted 
to evaluate the safety and clinical activity of single agent pembrolizumab. The dose 
escalation portion of this trial evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10 
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mg/kg, administered every 2 weeks (Q2W) in patients with advanced solid tumours 
(Patnaik et al, 2015). All three dose levels were well tolerated and no dose-limiting 
toxicities were observed. This first in human study of pembrolizumab showed evidence 
of target engagement and objective evidence of tumour size reduction at all dose levels. 
No maximum tolerated dose (MTD) has been identified. 
In KEYNOTE-001, two randomized cohort evaluations of melanoma patients receiving 
pembrolizumab at a dose of 2 mg/kg versus 10 mg/kg every 3 weeks (Q3W) have been 
completed [ref]. The clinical efficacy and safety data demonstrate a lack of clinically 
important differences in efficacy response or safety profile at these doses.   For example, 
in Cohort B2, advanced melanoma patients who had received prior ipilimumab therapy 
were randomized to receive pembrolizumab at 2 mg/kg versus 10 mg/kg Q3W.   The 
overall response rate (ORR) was 26% (21/81) in the 2 mg/kg group and 26% (25/79) in 
the 10 mg/kg group (full analysis set (FAS)).   The proportion of patients with drug-related 
adverse events (AEs), grade 3-5 drug-related AEs, serious drug-related AEs, death or 
discontinuation due to an AE was comparable between groups or lower in the 10 mg/kg 
group.    
Available pharmacokinetic results in patients with melanoma, NSCLC, and other solid 
tumour types support a lack of meaningful difference in pharmacokinetic exposures 
obtained at a given dose among tumour types. Population PK analysis has been 
performed and has confirmed the expectation that intrinsic factors do not affect exposure 
to pembrolizumab to a clinically meaningful extent. Taken together, these data support 
the use of lower doses (with similar exposure to 2 mg/kg Q3W) in all solid tumour 
indications.  
Selection of 200 mg as the appropriate dose for a switch to fixed dosing is based on 
simulation results indicating that 200 mg will provide exposures that are reasonably 
consistent with those obtained with 2 mg/kg dose and importantly will maintain individual 
patient exposures within the exposure range established in melanoma as associated with 
maximal clinical response.   A population PK model, which characterized the influence of 
body weight and other patient covariates on exposure, has been developed using 
available data from 476 patients from PN001. The distribution of exposures from the 200 
mg fixed dose are predicted to considerably overlap those obtained with the 2 mg/kg 
dose, with some tendency for individual values to range slightly higher with the 200 mg 
fixed dose.  The slight increase in PK variability predicted for the fixed dose relative to 
weight-based dosing is not expected to be clinically important given that the range of 
individual exposures is well contained within the range of exposures shown in the 
melanoma studies of 2 and 10 mg/kg to provide similar efficacy and safety.  
Pembrolizumab efficacy in relapsed indolent lymphomas as a single agent (with WM 
patients treated) has recently been assessed in a phase 2 trial, which has been published 
in abstract form (Ding et al, 2017). In 23 patients receiving pembrolizumab monotherapy, 
responses were seen (including a minor response in a patient with WM) and the toxicity 
profile was acceptable. 
2.1.7. Scientific rationale for combining Pembrolizumab and Rituximab in WM  
The manageable tolerability of anti-PD-1 mAb pathway blockers and their unique 
mechanism of action are encouraging but to increase the response rate and depth of 
response combination therapy approaches appear to be required. Given the proven 
efficacy, well understood toxicity and proven ability to combine with other agents 
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(including cytotoxic chemotherapy and targeted small molecules such as ibrutinib and 
idelalisib) rituximab is attractive partner for such immunotherapy combinations.  
Rituximab has proven clinical efficacy in WM and is widely used in the relapsed/refractory 
setting. In general, there is evidence of enhanced efficacy of rituximab combination 
therapy compared with monotherapy alone (Santos-Lozano et al, 2016). There is some 
rationale to hypothesise that pembrolizumab and rituximab could have a synergistic 
effect. Antibody and complement dependent cell mediated cytotoxicity may generate 
neo-antigens and create an inflammatory milieu, which may further prime T-cell 
activation. Also, the apparent limited activity of pembrolizumab as a single agent would 
inform a combination as a more logical approach, especially in the presence of some 
recently presented data looking at this combination in relapsed follicular lymphoma 
(Nastoupil et al, 2017). 30 patients treated with the combination led to an overall 
response rate of 64% and a CR rate of 48%, with a manageable toxicity profile, with 
immune AEs generally being grade 1-2. 
 
The aim of this trial is to investigate the safety and efficacy of rituximab in combination 
with pembrolizumab in patients with relapsed WM. 
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3. 
TRIAL DESIGN 
 
This is a phase II, non-randomised, single arm, open label study to determine the safety, 
tolerability and efficacy (assessed by response rate) of pembrolizumab in combination 
with rituximab for the treatment of relapsed/refractory WM.  
 
Patients with relapsed/refractory WM meeting the eligibility criteria will be recruited to the 
study.  Patients will be treated on a 3 weekly cycle with the following: 
 Rituximab 375mg/m2 IV infusion on days 1, 8 and 15 for cycle 1 
 Rituximab 375mg/m2 IV infusion day 1 of cycle 2, then 
 Rituximab 375mg/m2 IV infusion given 12 weekly for a further 4 doses (total 
duration of rituximab treatment is 1 year) 
 Pembrolizumab 200mg IV infused on day 2 of cycle 1, and day 1 of subsequent 
cycles for a maximum of 18 cycles (1 year) or until disease progression, 
discontinuation due to toxicity or any other cause (whichever occurs sooner) 
 
Patients will be assessed for disease response (by serum IgM measurement) at 12 and 
24 weeks post commencing treatment and at 1 year.   
 
3.1. 
Trial Objectives  
3.1.1. Primary Objective 
 To determine the efficacy (overall response rate at 24 weeks) of the combination 
of rituximab and pembrolizumab in relapsed/refractory WM 
 
3.1.2. Secondary Objectives 
 To determine the safety and tolerability of the combination of rituximab and 
pembrolizumab in relapsed/refractory WM 
 To assess the depth of response to rituximab and pembrolizumab and duration of 
response 
 To determine the time to best response and time to next therapy 
 To determine the effect of rituximab and pembrolizumab on quality of life 
 
3.1.3. Exploratory Objective 
• To investigate immune biomarkers of response to the combination of rituximab 
and pembrolizumab 
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3.2. 
Trial Endpoints 
3.2.1. Primary end-points: 
• Percentage of patients achieving an overall response rate (defined as complete 
response (CR), very good partial response (VGPR), partial response (PR) or 
minor response (MR) i.e. a greater than 25% reduction in the serum IgM level) at 
24 weeks post commencing treatment 
 
3.2.2. Secondary end-points: 
• Safety and tolerability of pembrolizumab and rituximab as assessed by the 
frequency of serious and non-serious adverse events, graded according to 
CTCAE v5.0 
• Complete response (CR) rate at 24 weeks post commencing treatment (see 
appendix 4)  
• Very good partial response (VGPR) rate at 24 weeks post commencing treatment 
(see appendix 4) 
• Time to maximal response, as determined by the time of registration to the 
maximal disease response  
• Time to next treatment, as determined by the time from registration to the next line 
of therapy  
• Progression free survival (PFS) at 1 and 2 years 
• Overall survival (OS) at 1 and 2 years 
• Change in quality of life (QoL) at 24 weeks post commencing treatment 
 
3.2.3. Exploratory endpoints: 
• Assessment of PD-1 and PD-L1/ PD-L2 expression by fluorescence in situ 
hybridisation (FISH) and immunohistochemistry (IHC).   
• IHC to assess baseline and on-treatment changes to distribution and composition 
of immune response cells in the microenvironment 
• Analysis of baseline biopsies to elucidate potential mechanisms of action of 
tumour response 
• Assessment of treatment outcome according to tumour genotype, as determined 
by sequencing assays for MYD88L265P and CXCR4 mutations  
• Correlation of bone marrow response with reduction in serum IgM level.  
• Quantification of bone marrow involvement by morphologic assessment of 
trephine and flow cytometric assessment of aspirate for MRD 
 
 
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3.3. 
Trial Activation 
UCL CTC will ensure that all trial documentation has been reviewed and approved by all 
relevant bodies and that the following have been obtained prior to activating the trial: 
• Health Research Authority (HRA) approval, including Research Ethics Committee 
approval 
• Clinical Trial Authorisation from the Medicines and Healthcare products 
Regulatory Agency (MHRA) 
• ‘Adoption’ into NIHR portfolio 
• Adequate funding for central coordination 
• Confirmation of sponsorship 
• Adequate insurance provision 
 
 
 
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4. 
SELECTION OF SITES/SITE INVESTIGATORS 
4.1. 
Site Selection 
In this protocol trial ‘site’ refers to a hospital where trial-related activities are conducted. 
Sites must be able to comply with: 
• Trial treatment, imaging, clinical care, follow up schedules and all requirements of 
the trial protocol 
• Requirements of the UK Policy Framework for Health and Social Care Research, 
issued by the Health Research Authority and the Medicines for Human Use 
Clinical Trials Regulation (SI 2004/1031), and all amendments 
• Data collection requirements, including adherence to CRF submission timelines 
as per section 11.3 (Timelines for Data Return) 
• Biological sample collection, processing and storage requirements  
• Monitoring requirements, as outlined in protocol section 14 (Trial Monitoring and 
Oversight)  
• Obtaining relevant license(s) for medical radiation exposure, and renewing as 
necessary 
4.1.1. Selection of Principal Investigator and other investigators at sites 
Each site must appoint an appropriate Principal Investigator (PI), i.e. a health care 
professional authorised by the site to lead and coordinate the work of the trial on behalf 
of a site. Co-investigators must be trained and approved by the PI. All PIs and co-
investigators must be medical doctors and have experience of immune-oncology agents 
and treating WM. The PI is responsible for the conduct of the trial at their site and for 
ensuring that any amendments are implemented in a timely fashion. If a PI plans to take 
a leave of absence UCL CTC must be informed promptly. For absences greater than 
three months or where the PI is no longer able to perform his/her, duties at the site UCL 
CTC may terminate recruitment at site. A new suitable replacement PI must be identified 
by the site and UCL CTC notified.  
UCL CTC may terminate recruitment at a site where a suitable replacement PI has not 
been identified within three months. 
4.1.2. Training requirements for site staff 
All site staff must be appropriately qualified by education, training and experience to 
perform the trial related duties allocated to them, which must be recorded on the site 
delegation log. 
CVs for all staff must be kept up-to-date, signed and dated and copies held in the 
Investigator Site File (ISF). A current, signed copy of the CV with evidence of GCP 
training (or copy of GCP certificate) for the PI must be forwarded to UCL CTC upon 
request. 
GCP training is required for all staff responsible for trial activities. The frequency of repeat 
training may be dictated by the requirements of their employing institution, or 2 yearly 
where the institution has no policy, and more frequently when there have been updates 
to the legal or regulatory requirements for the conduct of clinical trials. 
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4.2. 
Site initiation and Activation 
4.2.1. Site initiation 
Before a site is activated, the UCL CTC trial team will arrange a site initiation with the 
site which the PI, the pharmacy lead and site research team must attend. The site will be 
trained in the day-to-day management of the trial and essential documentation required 
for the trial will be checked. 
Site initiation will be performed for each site by telephone/videoconference with site.  Re-
initiating sites may be required where there has been a significant delay between 
initiation and enrolling the first patient..  
4.2.2. Required documentation 
The following documentation must be submitted by the site to UCL CTC prior to a site 
being activated by the UCL CTC trial team: 
• Site Registration Form (identifying relevant local staff) 
• Relevant institutional approvals 
• A completed site delegation log that is initialled and dated by the PI (with all tasks 
and responsibilities delegated appropriately) 
• Completed site contacts form (with contact information for all members of local 
staff) 
• A signed and dated copy of the PI’s current CV (with documented up-to-date GCP 
training, or copy of GCP training certificate) 
• Trial specific prescription 
In addition, the following agreements must be in place: 
• A signed Model Agreement for Non-Commercial Research (mNCA) between the 
Sponsor and the relevant institution (usually an NHS Trust/Health Board) 
4.2.3. Site activation 
Once the UCL CTC trial team has received all required documentation and the site has 
been initiated, a site activation letter will be issued to the PI, at which point the site may 
start to approach patients. 
Refer to the Summary of Drug Arrangements document for details of the initial supplies 
of Pembrolizumab. 
Following site activation, the PI is responsible for ensuring: 
• adherence to the most recent version of the protocol 
• all relevant site staff are trained in the protocol requirements 
• appropriate recruitment and medical care of patients in the trial 
• timely completion and return of CRFs (including assessment of all adverse events) 
• prompt notification and assessment of all serious adverse events 
• that the site has facilities to provide 24 hour medical advice for trial patients 
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5. 
INFORMED CONSENT 
Sites are responsible for assessing a patient’s capacity to give informed consent. 
Sites must ensure that all patients have been given the current approved version of the 
patient information sheet, are fully informed about the trial and have confirmed their 
willingness to take part in the trial by signing the current approved consent form.  
Sites must assess a patient’s ability to understand verbal and written information in 
English and whether or not an interpreter would be required to ensure fully informed 
consent. If a patient requires an interpreter and none is available, the patient should not 
be considered for the trial. 
The PI, or, where delegated by the PI, other appropriately trained site staff, are required 
to provide a full explanation of the trial and all relevant treatment options to each patient 
prior to trial entry. During these discussions, the current approved patient information 
sheet for the trial should be discussed with the patient. 
A minimum of twenty four (24) hours should be allowed for the patient to consider and 
discuss participation in the trial. 
Written informed consent on the current approved version of the consent form for the trial 
must be obtained before any trial-specific procedures are conducted. The discussion and 
consent process must be documented in the patient medical notes. 
Site staff are responsible for: 
• checking that the current approved version of the patient information sheet and 
consent form are used 
• checking that information on the consent form is complete and legible 
• checking that the patient has initialled all relevant sections and signed and dated 
the form 
• checking that an appropriate member of staff has countersigned and dated the 
consent form to confirm that they provided information to the patient 
• checking that an appropriate member of staff has made dated entries in the 
patient’s medical notes relating to the informed consent process (i.e. information 
given, consent signed etc.) 
• following pre-registration, adding the patients’ trial number to all copies of the 
consent form, which should be filed in the patient’s medical notes and investigator 
site file. 
• giving the patient a copy of their signed consent form, patient information sheet, 
and upon full registration, giving the patient a patient contact card 
The right of the patient to refuse to participate in the trial without giving reasons must be 
respected. All patients are free to withdraw at any time. Also refer to section 15 
(Withdrawal of Patients). 
 
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6. 
SELECTION OF PATIENTS  
6.1. 
Screening Log 
A screening log must be maintained and appropriately filed at site. Sites should record 
each patient screened for the trial and the reasons why they were not registered in the 
trial if this is the case. The log must be sent to UCL CTC when requested. 
6.2. 
Patient Eligibility 
There will be no exception to the eligibility requirements at the time of full registration. 
Queries in relation to the eligibility criteria must be addressed prior to full registration. 
Patients are eligible for the trial if all the inclusion criteria are met and none of the 
exclusion criteria applies.  
Patients’ eligibility must be confirmed by an investigator who is suitably qualified and who 
has been allocated this duty, as documented on the site staff delegation log, prior to 
registering the patient. Confirmation of eligibility must be documented in the patients’ 
medical notes and on the registration CRF. 
Patients must give written informed consent before any trial specific screening 
investigations may be carried out. Refer to section 9.1 (Registration Assessments) for 
the list of assessments and procedures required to evaluate the suitability of patients 
prior to entry. 
6.2.1. Inclusion criteria 
 
1. Patients ≥18 years old  
2. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (see 
appendix 3) 
3. Presence of measurable disease, (defined as a detectable level of IgM 
paraprotein) and fulfils other World Health Organisation (WHO) diagnostic 
criteria for WM   
4. Relapsed or refractory WM who have received ≥1 prior lines of therapy 
5. Adequate renal function: estimated creatinine clearance ≥ 30ml/min as 
calculated using the Cockroft-Gault equation 
6. Adequate liver function, including:  
o Bilirubin ≤1.5 x the upper limit of normal (ULN) 
o Aspartate or alanine transferase (AST or ALT) ≤2.5 x ULN 
7. Adequate organ and bone marrow function:  
o Neutrophils ≥0.5x109/L 
o Platelets ≥25x109/L  
Note: Growth factor and/or transfusion support is permissible to stabilize 
participant prior to study treatment if needed. No lower limit if cytopenia is 
related to WM infiltration in the bone marrow. 
8. Willing to comply with the contraceptive requirements of the trial (see section 
6.3.4) 
9. Negative serum or highly sensitive urine pregnancy test for women of childbearing 
potential (WOCBP)  
10. Written informed consent  
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6.2.2. Exclusion criteria 
 
1. Refractory to rituximab as defined by progression on/within 6 months of finishing 
a rituximab based regimen 
2. Women who are pregnant or breastfeeding, or males expecting to conceive or 
father children at any point from the start of treatment until 4 months after the last 
administration of pembrolizumab  
3. Clinically significant cardiac disease within 6 months prior to registration including 
unstable angina or myocardial infarction, uncontrolled congestive heart failure 
(NYHA class III-IV), and unstable arrhythmias requiring therapy, with the 
exception of extra systoles or minor conduction abnormalities. Stable and 
controlled atrial fibrillation is not an exclusion.  
4. History of significant cerebrovascular disease in last 6 months 
5. Known central nervous system involvement of WM 
6. Clinically significant active infection requiring antibiotic or antiretroviral therapy  
7. Significant concurrent, uncontrolled medical condition including, but not limited to, 
renal, 
hepatic, 
haematological, 
gastrointestinal, 
endocrine, 
pulmonary, 
neurological, cerebral or psychiatric disease 
8. Has a known additional malignancy that is progressing or requires active 
treatment. Exceptions include basal cell carcinoma of the skin, squamous cell 
carcinoma of the skin, or in situ cervical cancer that has undergone potentially 
curative therapy 
9. Active autoimmune disease apart from: 
o Type I diabetes or thyroid disease, controlled on medication 
o Skin conditions such as psoriasis, vitiligo or alopecia not requiring 
systemic treatment 
o Auto-immune thrombocytopenia, thought to be secondary to WM, 
provided that platelet count meet the criteria specified above, on daily 
doses of corticosteroid ≤10mg prednisolone or equivalent 
10. Prior history of haemolytic anaemia (either warm or cold) 
11. History of non-infective colitis  
12. History of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis 
13. Systemic anti-cancer therapy within 4 weeks prior to trial registration (except for 
BTK inhibitors, which may continue until 48 hours prior to the start of cycle 1, 
day 1 of trial treatment) 
14. Received a T cell depleting antibody (e.g. Campath) within 3 months prior to 
starting treatment 
15. Received a live vaccine or live-attenuated vaccine within 30 days prior to starting 
treatment  
16. Chronic or ongoing active infectious disease requiring systemic treatment such 
as, but not limited to, chronic renal infection, chronic chest infection with 
bronchiectasis, tuberculosis and active hepatitis 
17. Patients who have received treatment with any non-marketed drug substance or 
experimental therapy within 4 weeks prior to starting treatment (unless prior 
agreement with the TMG)  
18. Patients known or suspected of not being able to comply with a study protocol 
(e.g. due to alcoholism, drug dependency or psychological disorder) 
19. Positive serology for Hepatitis B defined as a positive test for HepB surface 
antigen (HBsAg).  Note: patients who are HepB core antibody (HBcAb) positive 
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will only be eligible for the study if the HepB virus deoxyribonucleic acid (HBV 
DNA) test is negative and patients are willing to undergo monthly monitoring for 
HBV reactivation 
20. Positive serology for Hepatitis C defined as a positive test for HCV antibody 
21. Major surgery within 4 weeks prior to trial registration  
22. Prior therapy with an anti-PD-1,anti-PD-L1 or CTLA4 monoclonal antibody  
23. Prior allogeneic bone marrow transplantation 
24. Diagnosis of prior immunodeficiency or organ-transplant requiring 
immunosuppressive therapy or known HIV or acquired immunodeficiency 
syndrome (AIDS)-related illness 
25. Current or prior use of immunosuppressive therapy within 7 days prior to start of 
treatment except the following: intranasal, inhaled, topical steroids or local 
steroid injections (e.g. Intra-articular injections); a short course of oral 
prednisolone (a maximum of 10mg/day for 5 days) can be used within 7 days of 
cycle 1 day 1 if there are concerns around IgM flare, following BTK inhibitor 
discontinuation  
26. Known or suspected hypersensitivity to components of pembrolizumab and/or 
rituximab (or other CD20 monoclonal antibody) 
 
6.3. 
Pregnancy and birth control  
6.3.1. Pregnancy and birth control 
Definition of women of childbearing potential (WOCBP) and fertile men 
A woman of childbearing potential (WOCBP) is a sexually mature woman (i.e. any female 
who has experienced menstrual bleeding) who: 
• has not undergone a hysterectomy or bilateral oophorectomy/salpingectomy 
• has not had premature ovarian failure confirmed by a specialist gynaecologist 
• is not postmenopausal (i.e. a post-menopausal woman is a female who has not 
had menses at any time in the preceding 12 consecutive months without an 
alternative medical cause) 
o 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.  
o 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 enrolment. 
A man is considered fertile after puberty unless permanently sterile by bilateral 
orchidectomy. 
 
 
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6.3.2. Risk of exposure to trial treatment during pregnancy 
The risk of exposure to trial treatment has been evaluated using the safety information 
available in the IB for the IMP (pembrolizumab) and the SPC for the IMP (rituximab).  
There are no data on the use of pembrolizumab in pregnant women.  
Pembrolizumab 
Animal reproduction studies have not been conducted with pembrolizumab; however, in 
murine models of pregnancy blockade of PD-L1 signalling has been shown to disrupt 
tolerance to the foetus and to result in an increased foetal loss. These results indicate a 
potential risk, based on its mechanism of action, that administration of pembrolizumab 
during pregnancy could cause foetal harm, including increased rates of abortion or 
stillbirth. Human immunoglobulins G4 (IgG4) are known to cross the placental barrier and 
pembrolizumab is an IgG4; therefore, pembrolizumab has the potential to be transmitted 
from the mother to the developing foetus. Pembrolizumab should not be used during 
pregnancy unless the clinical condition of the woman requires treatment with 
pembrolizumab.  Furthermore, it is not known if pembrolizumab has transient adverse 
effects on the composition of semen. 
Rituximab 
Developmental toxicity studies (using Mabthera) have been performed in cynomolgus 
monkeys at doses up to 100 mg/kg (treatment on gestation days 20-50) and have 
revealed no evidence of toxicity to the foetus due to rituximab. However, dose dependent 
pharmacologic depletion of B cells in the lymphoid organs of the foetuses was observed, 
which persisted post-natally and was accompanied by a decrease in IgG level in the 
newborn animals affected. B cell counts returned to normal in these animals within 6 
months of birth and did not compromise the reaction to immunisation. 
Rituximab can be retained for a long time in B cell depleted patients and therefore 
WOCBP should be advised to use effective contraceptive methods during and for 12 
months after treatment with rituximab.   
Overall, the trial treatment has been assessed as having a high risk of 
teratogenicity/fetotoxicity. 
6.3.3. Pregnancy testing 
All female participants who are WOCBP must have a negative serum or highly sensitive 
urine pregnancy test (minimum sensitivity 25 IU/I or equivalent units of HCG) pre-
registration and within 72 hours prior to the first dose of trial treatment.  Pregnancy testing 
should be repeated before each cycle of trial treatment. Pregnancy testing should be 
performed whenever an expected menstrual cycle is missed or when pregnancy is 
otherwise suspected. 
 
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6.3.4. Contraceptive Advice 
All female participants who are WOCBP must consent to use one of the following methods 
of highly effective contraception from the start of treatment until 12 months after the last 
administration of an IMP.  Methods with low user dependency are preferable, particularly 
where introduced as a result of participation in the trial. 
 combined (estrogen and progestogen containing) hormonal contraception 
associated with inhibition of ovulation 
 oral 
 intravaginal 
 transdermal 
 progestogen-only hormonal contraception associated with inhibition of ovulation1: 
 oral (e.g. desogestrel) 
 injectable 
 implantable1 
 intrauterine device (IUD)1 
 intrauterine hormone-releasing system (IUS)1 
 bilateral tubal occlusion1 
 vasectomised partner1,2 
 sexual abstinence3 
1. Contraception methods that are considered to have low user dependency. 
2. Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual partner of the 
WOCBP trial participant and that the vasectomised partner has received medical assessment of the surgical success. 
3. 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 treatments. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject. 
Requirement for male patients with female partners who are pregnant or WOCBP 
Due to the risk of genotoxicity and/or risk to the foetus from exposure to seminal fluid: 
 Male patients (including male patients who have had vasectomies) must consent 
to use condoms with female partners who are WOCBP or partners who are 
pregnant, from the start of treatment until 4 months after the last administration of 
an IMP. 
 Male patients must also advise their female partners who are WOCBP of the 
requirement for contraceptive requirements as listed for female patients who are 
WOCBP. 
 
For female and male patients: 
 
 The method(s) of contraception used must be stated in the patient medical 
notes. The medical notes of male participants should include a statement that 
the female partner has been informed about contraception advice. 
 
 
 
 
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6.3.5. Action to be taken in the event of a pregnancy 
Female patients: 
If a female patient becomes pregnant:  
• prior to initiating treatment or during treatment, the patient will be withdrawn from 
the trial/further treatment and, if they consent to pregnancy monitoring, followed 
up until pregnancy outcome. It is recommended that the patient be followed up on 
a monthly basis. 
• after the end of the treatment, until 12 months after the last administration of an 
IMP, the patient will be followed up until pregnancy outcome if they consent to 
pregnancy monitoring. It is recommended that the patient be followed up on a 
monthly basis. 
 
Male patients:  
If a female partner of a male patient becomes pregnant between the patient’s start of 
treatment and 4 months after the last administration of an IMP, the male participant can 
continue with the study whilst their female partner will be followed up if they have given 
consent to pregnancy monitoring. It is recommended that the pregnant partner be 
followed up on a monthly basis. 
 
Notification to UCL CTC – refer to Pregnancy Report Processing (see section 12.7) 
 
 
 
 
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7. 
REGISTRATION PROCEDURES 
7.1. Pre-Registration 
The purpose of preliminary registration is to allow patients likely to be eligible for the trial 
but where final confirmation of eligibility based on their bone marrow biopsy is pending, 
to be allocated a trial number for use when sending baseline tissue samples to the central 
laboratory (see section 10 for further details on required samples). Samples without a 
trial number will not be accepted by the central laboratory. 
 
In order to undertake preliminary registration, the following criteria must be met: 
 The patient must have given written informed consent for the trial 
 The site investigator must have confirmed the patient is potentially eligible 
based on assessments performed to date 
 
The site must then complete the preliminary registration form and send it to the UCL 
CTC via email, before sending samples to the central laboratory. 
 
N.B. When emailing forms, patient identifiable information from the form (e.g. initials, day 
and month of birth) must be redacted before it is emailed to ctc.pembroWM@ucl.ac.uk. 
The identifiable information must be provided to the UCL CTC via telephone so that UCL 
CTC can transcribe this information on to the form. The un-redacted form must then be 
posted to the UCL CTC, and a copy kept in the patient file at site. 
 
 
Registration telephone number: 
+44 (0)20 7679 9860 
Registration email address: 
 
ctc.pembroWM@ucl.ac.uk  
UCL CTC Office hours: 
09:00 to 17:00 Monday to Friday, 
excluding Bank Holidays  
 
 
Once the UCL CTC has confirmed that the patient has been consented appropriately and 
is provisionally eligible for the trial, they will assign a unique trial number for the patient 
and email confirmation of the trial number to the main contact for the site. 
 
This trial number will remain the patient’s unique trial identifier throughout the trial, and 
should be used in all communications sent during the trial. 
 
 
The patient must under no circumstances start any trial treatment until the patient has 
completed the full registration process (see section 7.2) and the UCL CTC have 
confirmed that the patient may start trial treatment. 
 
If, after being allocated a trial number, a patient is found to be ineligible for the trial, and 
will not be proceeding to full registration, the site must inform the UCL CTC, quoting the 
patient’s unique trial number and date of sample dispatch. The UCL CTC will then contact 
the central laboratory to request destruction of the patient’s samples and will email the 
site to confirm destruction. 
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7.2. 
Registration 
Full patient registration will be undertaken centrally at UCL CTC and this must be 
performed prior to commencement of any trial treatment. Registration evaluations 
should be carried out at sites as detailed in section 9.1 (Registration Assessments). 
Following -registration evaluations, confirmation of eligibility and consent of a patient at 
a site, the registration eligibility checklist and full registration CRF form must be fully 
completed and emailed to UCL CTC. These will be used to confirm patient eligibility. If 
further information is required UCL CTC will contact the person requesting registration to 
discuss the patient and request updated forms to be faxed. 
Once eligibility has been confirmed UCL CTC will email confirmation of the patient’s 
inclusion in the trial to the PI, main contact and pharmacy. 
Registration telephone number: 
+44 (0)20 7679 9860 
Registration email address: 
 
ctc.pembroWM@ucl.ac.uk  
UCL CTC Office hours: 
09:00 to 17:00 Monday to Friday, 
excluding Bank Holidays  
 
Once a patient has been fully registered onto the trial they must be provided with the 
following: 
• A patient contact card. Site contact details for 24 hour medical care must be added 
to this card and patients advised to carry this with them at all times while 
participating in the trial 
After full registration has been confirmed the PembroWM GP letter must also be 
completed and sent to the patient’s GP. 
7.3. 
Initial Trial Drug Supply 
Merck Sharp & Dohme (MSD) Limited will provide pembrolizumab free of charge for the 
duration of the study for appropriately enrolled subjects.  
Refer to Summary of Drug Arrangements document for details of initial supply of 
pembrolizumab for the trial.   
Rituximab is to be supplied from Hospital Commercial Stock as detailed in the Summary 
of Drug Arrangements document. 
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8. 
TRIAL TREATMENT 
Investigational Medicinal Products (IMPs)  
For the purpose of this protocol, the IMPs are: 
 Pembrolizumab (MK 3475) 
 Rituximab (note: biosimilars are allowed) 
Please also refer to Summary of Drug Arrangements document (SoDA) for full 
arrangements for the trial. 
8.1. 
Investigational Medicinal Products 
Supplied IMP 
Pembrolizumab (also referred to as MK-3475) (clear to slightly opalescent, colourless to 
slightly yellow solution for infusion [100 mg / 4 ml vial]) is supplied free of charge by MSD 
Limited.  Pembrolizumab is not licensed for this indication.     
Please refer to the Summary of Drug Arrangements document for further details of supply, 
packaging and storage conditions etc. 
 
IMP from hospital stock 
Rituximab (colourless concentrate for solution for infusion [100 mg / 10 ml vial or 500 mg 
/ 50 ml vial]) is to be provided from hospital commercial stock.  Pharmacies must ensure 
adequate supplies for the trial.  Biosimilar (e.g. Truxima) products are permitted in the 
trial. 
Please refer to local policy and the relevant SPC for handling and storage conditions. 
8.2. 
Treatment Summary 
Patients with relapsed/refractory WM meeting the eligibility criteria will be fully registered 
into the study.  Patients will be treated with rituximab 375mg/m2 IV infusion and 
pembrolizumab 200mg IV infusion on a 3 weekly cycle, for a maximum of 18 cycles on 
the following days: 
 Cycle 1: 
o Rituximab 375mg/m2 - days 1, 8 and 15  
o Pembrolizumab 200mg - day 2 
 Cycle 2: 
o Rituximab 375mg/m2 - day 1  
o Pembrolizumab 200mg - day 1 
 After cycle 2:  
o Rituximab 375mg/m2 - 12 weekly on day 1 (cycles 6, 10, 14 & 18) 
o Pembrolizumab 200mg - day 1 of every cycle  
 
Treatment will continue until cycle 18 unless disease progression or discontinuation due 
to toxicity or any other cause (whichever occurs sooner). Patients who experience 
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disease progression at any point during the trial will have the study therapy ceased and 
be managed as per standard of care at their institution. 
 
Where both rituximab and pembrolizumab are delivered on the same day, rituximab 
should be administered first. 
 
See diagram below for visual representation. 
 
Cycle 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
Day 
1 
2 
8 
15 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
1 
Rituximab  
(375 mg/m2 IV) 
X 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
Pembrolizumab 
(200mg IV) 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
8.3. 
Trial Treatment Details  
8.3.1. 
Criteria to receive treatment 
Full blood count (FBC) and tests of renal and hepatic function should be assessed prior 
to every cycle (within 3 days prior to treatment) to ensure the following criteria are met: 
 
 Neutrophils ≥ 0.5 x 109/L 
 Platelets ≥ 25 x 109/L 
 AST or ALT ≤ 2.5 x ULN 
 Bilirubin ≤ 1.5 x ULN 
 
If the above criteria are not met (for reasons other than disease bone marrow infiltration 
– see below) prior to treatment, the cycle should be delayed until the blood counts have 
recovered (see section 8.4 and 8.5 for information on dose delays and treatment 
discontinuation due to adverse events). 
 
8.3.1.1. Patients with high levels of WM bone marrow infiltration at registration 
Patients registered on to the trial with a high level of WM infiltration in the bone marrow, 
and neutrophils and platelets lower than 0.5 x 109/L and 25 x 109/L respectively, are 
permitted to receive treatment providing these blood counts are no lower than the level 
at registration. If either blood count taken prior to a treatment cycle is lower than the level 
at registration, the cycle should be delayed until the blood counts have recovered to the 
registration level.  If in subsequent cycles the neutrophils and platelet counts have 
improved to above 0.5 x 109/L and 25 x 109/L respectively, these levels should be met 
for all future cycles of treatment, if not, treatment should be delayed.     
 
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8.3.2. 
Re-scheduling treatment for logistical reasons 
If for logistical reasons (e.g. bank holiday), treatment cannot take place on the scheduled 
day, treatment days can be re-scheduled as follows: 
 Doses can be brought forward a maximum of 2 days.  
 Doses can be delayed for a maximum of 7 days, however, if treatment is delayed 
for longer than 2 days, all subsequent doses for the remainder of trial treatment 
should be rescheduled in line with the delayed dose. For example, if C3D1 is 
delayed by 3 days, C4D1 should take place 3 weeks after the delayed C3D1 date. 
 
For dose delays as a result of adverse events please refer to section 8.4. 
8.3.3. 
Administration for IgM flare 
Prior to the first cycle, if the total IgM is >40, pre-emptive plasmapheresis is 
recommended to get total IgM <40 and prevent IgM flare – defined as a >25% increase 
in total IgM. This phenomenon has been associated with single agent rituximab therapy 
in this setting, and can be associated with symptomatic hyperviscosity and/or escalation 
of WM related symptoms (e.g. neuropathy). 
 
See section 8.4.6 for further details on IgM flare management. 
8.3.4. 
Pembrolizumab administration 
Pembrolizumab is a potent and highly selective humanised monoclonal antibody (mAb) 
of the IgG4/kappa isotype designed to directly block the interaction between PD-1 and 
its ligands, PD-L1 and PD-L2.  
The PembroWM Summary of Drug Arrangements document (SoDA) must be 
referred to for detailed information regarding the handling, storage, preparation 
and administration of pembrolizumab. A summary is outlined below: 
Supply and Storage: 
Pembrolizumab will be supplied in a kit containing 2 x 4mL solution for infusion vials 
(100mg/4ml). It should be stored in its original carton at refrigerated conditions 2 – 8 °C 
and protected from light. 
Preparation: 
Pembrolizumab infusion solutions should be prepared in 0.9% Sodium Chloride Injection 
or 5% Dextrose Injection and the final concentration should be between 1 mg/mL and 10 
mg/mL. Please note, the preferred diluent is 0.9% Sodium Chloride and 5% dextrose is 
only permissible if normal saline is not available. Once diluted the product should be used 
as soon as possible, however storage allowances for IV bags are permitted (see SoDA 
for detailed information).  
Administration: 
Pembrolizumab should be given intravenously over 30 minutes, with a window of -5 and 
+10 minutes, every 3 weeks at a dose of 200mg using an infusion pump.  A sterile, non-
pyrogenic, low-protein binding 0.2 to 5 µm in-line filter made of polyethersulfone (PES) 
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or 0.2 to 5 µm add-on filter should be used when administering the product. Refer to the 
SoDA for the infusion materials that are compatible with pembrolizumab. 
 
Important Information: 
 Do not use pembrolizumab if discolouration is observed. 
 Do not shake or freeze the vial(s) or infusion solution. 
 Do not administer the product as an intravenous push or bolus.  
 Unused infusion solution for injection should not be used for another infusion of 
the same subject or different subject.  
 Do not combine, dilute of administer it as an infusion with other medicinal products 
or co-administer other drugs through the same infusion line. 
 Contact UCL CTC immediately if there is any departure from the guidance listed 
in the PembroWM Summary of Drug Arrangements document. 
8.3.5. 
Rituximab administration 
Rituximab (or biosimilar equivalent) should be given intravenously at a dose of 375 
mg/m2 for a maximum of 1 year as indicated in the tables above.  Rituximab should be 
administered as per local policy. 
Dose banding of rituximab is allowed as per local policy.  If a patient’s weight changes, 
local policy for dose recalculation should be followed. Rapid infusion of rituximab is 
permitted as per local policy.  For further details on the administration please refer to 
the SPC for details. 
Patients should receive pre-medication prior to rituximab infusion as per standard local 
policy.  Below serves as suggested guidance to the Investigator in the absence of 
standard local policies: 
  
Guidance on pre-medication prior to rituximab infusion (to be given within 30 mins to 2 
hours prior to treatment): 
 
Analgesic: Paracetamol 
or equivalent 
Antihistamine: 
chlorpheniramine or 
cetirizine equivalent 
Glucocorticoid: 
dexamethasone, or 
equivalent  
1000 mg orally (PO) 
10 mg 
IV (chlorphenamine) 
or 10 mg PO 
(cetirizine) 
8 mg 
(hydrocortisone 200 
mg IV; prednisolone 
50 mg) 
 
Supportive care (e.g. G-CSF/transfusions) may be given at the discretion of the local 
investigator as per local practice. 
 
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8.4. 
Management of Adverse Events 
8.4.1. 
General considerations 
Dose reductions for pembrolizumab and rituximab are not permitted. 
The doses of pembrolizumab and rituximab should be delayed as required according to 
sections below when experiencing a treatment related adverse event. In case of a 
treatment delay, both drugs should be withheld. This includes AEs related to only one 
IMP (e.g. a rituximab related AE results in both rituximab and pembrolizumab being 
withheld).  
Treatment cycles should be delayed, and not be omitted as a result of adverse events, 
and upon resolution treatment should resume at the scheduled cycle. 
If any immune-related AE does not resolve within 12 weeks of the last dose of an IMP, 
or if corticosteroids cannot be reduced to ≤10 mg prednisolone or equivalent per day 
within 12 weeks then treatment should be permanently discontinued.  See section 8.5 for 
full treatment discontinuation details. 
Treatment should also be delayed or discontinued if any adverse event, laboratory 
abnormality, or intercurrent illness which, in the judgment of the Investigator, presents a 
substantial clinical risk to the subject with pembrolizumab or rituximab dosing. 
 
 
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8.4.2. 
Pembrolizumab related adverse events 
Immune related adverse events 
If a patient experiences a pembrolizumab immune-related event, trial treatment should 
be withheld or discontinued as per the table below.   
Where treatment is withheld, treatment should resume once the adverse event has 
reduced to grade 1 or 0 (as per table below). Corticosteroid taper should be initiated 
upon the adverse event improving to grade 1 or less and continue to taper over at least 
4 weeks.  Tapering should be performed as per local clinical practice.  
For severe and life-threatening immune related adverse events, IV corticosteroid should 
be initiated first followed by oral steroid. Other immunosuppressive treatment should be 
initiated if immune related adverse events cannot be controlled by corticosteroids. 
 
Toxicity Management Guidelines for Immune-related AEs associated with Pembrolizumab  
Immune-
related 
AEs 
 
Severity 
grade    
CTCAE v5.0 
Action 
taken  
irAE management  
Monitor and follow-up  
Pneumonitis  
Grade 2 
Withhold 
treatment 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisolone 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 
treatment 
Diarrhoea / 
Colitis  
Grade 2 or 3 
Withhold 
treatment 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisolone or equivalent) 
followed by taper 
 
 Monitor participants for signs and 
symptoms of enterocolitis (i.e., 
diarrhoea, 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 
diarrhoea suspecting colitis should 
consider GI referral and 
performing endoscopy to rule out 
colitis.  
 Participants with diarrhoea/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. 
Grade 4 or 
recurrent Grade 
3 
Permanently 
discontinue 
treatment 
AST / ALT 
elevation or 
Increased 
bilirubin 
Grade 2 
Withhold 
treatment 
 Administer corticosteroids 
(initial dose of 0.5- 1 mg/kg 
prednisolone 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) 
Grade 3 or 4  
Permanently 
discontinue 
treatment 
 Administer corticosteroids 
(initial dose of 1-2 mg/kg 
prednisolone or equivalent) 
followed by taper 
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Immune-
related 
AEs 
 
Severity 
grade    
CTCAE v5.0 
Action 
taken  
irAE management  
Monitor and follow-up  
Type 1 diabetes 
mellitus (T1DM) 
or 
Hyperglycaemia 
 
Newly onset 
T1DM or  
Grade 3 or 4 
hyperglycaemia 
associated with 
evidence of -
cell failure 
Withhold 
treatment 1  
 Initiate insulin replacement 
therapy for participants with 
T1DM  
 Administer anti-
hyperglycaemic in 
participants with 
hyperglycaemia  
 
 Monitor participants for 
hyperglycaemia or other signs and 
symptoms of diabetes. 
Hypophysitis 
Grade 2 
Withhold 
treatment 
 
 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 
discontinue 
treatment 1  
 
Hyperthyroidism  
Grade 2 
Continue 
treatment 
 
 Treat with nonselective 
beta-blockers (e.g., 
propranolol) or thionamides 
as appropriate  
 Monitor for signs and symptoms 
of thyroid disorders.  
 
Grade 3 or 4  
Withhold or  
permanently 
discontinue 
treatment 1 
 
Hypothyroidism 
Grade 2-4 
Continue 
treatment 
 Initiate thyroid replacement 
hormones (e.g., 
levothyroxine or 
liothyroinine) per standard 
of care 
 Monitor for signs and symptoms 
of thyroid disorders.  
 
Nephritis 
associated with 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
treatment 
 
 Administer corticosteroids 
(prednisolone 1-2 mg/kg or 
equivalent) followed by 
taper. 
 Monitor changes of renal function 
 
Grade 3 or 4  
Permanently 
discontinue 
treatment 
 
Neurological 
Toxicities 
Grade 2 
Withhold 
treatment 
 Based on severity of AE 
administer corticosteroids 
 Ensure adequate evaluation to 
confirm aetiology and/or exclude 
other causes 
Grade 3 or 4 
Permanently 
discontinue 
treatment 
Myocarditis 
Grade 1 
Withhold 
treatment 
 
 Based on severity of AE 
administer corticosteroids 
 Ensure adequate evaluation to 
confirm aetiology and/or exclude 
other causes 
 
Grade 2-4 
Permanently 
discontinue 
treatment 
 
Exfoliative 
Dermatologic 
Conditions 
Suspected 
Steven-Johnson 
syndrome (SJS), 
Toxic epidermal 
necrolysis (TEN) 
or Drug rash 
with eosinophilia 
and systemic 
symptom 
(DRESS)  
Withhold 
treatment 
 Based on severity of AE 
administer corticosteroids 
 Ensure adequate evaluation to 
confirm aetiology and/or exclude 
other causes 
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Immune-
related 
AEs 
 
Severity 
grade    
CTCAE v5.0 
Action 
taken  
irAE management  
Monitor and follow-up  
Confirmed SJS, 
TEN or DRESS 
Permanently 
discontinue 
treatment 
 
All other 
immune-related 
AEs 
Persistent Grade 
2 
Withhold 
treatment 
 Based on type and severity 
of AE administer 
corticosteroids  
 Ensure adequate evaluation to 
confirm aetiology and/or exclude 
other causes 
 
Grade 3 
Withhold or 
discontinue 
treatment 
based on 
type of 
event.  
Events that 
require 
discontinuatio
n include and 
not limited to:  
encephalitis 
and other 
clinically 
important 
irAEs (e.g. 
vasculitis and 
sclerosing 
cholangitis)  
 
Grade 4 or 
recurrent Grade 
3  
Permanently 
discontinue 
treatment 
 
1. 
‘Withhold or permanently discontinue treatment’ is at the discretion of the investigator or treating physician.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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8.4.3. 
Pembrolizumab Infusion-related reactions 
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 below: 
Infusion Related 
Reaction Grade 
CTCAE v5.0 
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, opiates, 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 
Paracetamol 
Opiates 
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: 
Chlorphenamine 50 mg po (or 
equivalent dose of antihistamine). 
Paracetamol 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: 
Adrenaline** 
IV fluids 
Antihistamines 
NSAIDs 
Paracetamol 
Opiates 
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, adrenaline 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.  
 
 
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8.4.4. 
Other pembrolizumab related adverse events 
Any pembrolizumab related adverse events not included in the tables above should be 
managed as follows: 
 
Adverse 
Event 
Severity 
grade  
CTCAE v5.0 
Action taken   
AE management 
Resume treatment  
Any other 
pembrolizumab 
related AE 
 
Grade 31 
Withhold treatment 
Treat AE as per local 
policy 
When event resolves to 
grade 1 or 0 
 
Grade 42 
Permanently discontinue 
treatment 
Treat AE as per local 
policy 
 
 
1. 
Excluding fatigue, alopecia, and electrolyte disturbances that can be corrected and are unlikely to cause clinical 
safety concerns. 
2. 
Excluding neutropenia <7 days, lymphopenia, amylase abnormalities that are not associated with clinical 
symptoms, grade 4 drug-related endocrinopathy AEs which are adequately controlled with physiologic hormone 
replacement, and electrolyte abnormalities that can be corrected and are not felt to be a cause for clinical safety 
concern. 
 
8.4.5. 
Rituximab related adverse events and Infusion related reactions 
Dose reductions for rituximab are not permitted. 
 
Refer to the appropriate rituximab SPC for rituximab related adverse event and infusion 
related reaction dose and AE management.  If rituximab treatment is withheld on a cycle 
where pembrolizumab is administered, pembrolizumab should also be withheld and the 
cycle delayed until rituximab treatment can be continued.   
 
All patients should also be monitored for toxicity including infusion related reactions 
(IRR), tumour lysis syndrome (TLS), progressive multifocal leukoencephalopathy (PML); 
infections; Stevens-Johnson syndrome (SJS); hyperglycaemia; renal and hepatic 
impairment; cardiac toxicity. Special precautions for use relating to these conditions and 
guidance for appropriate action are provided in the SPC.  
8.4.6. 
IgM flare 
If there are any clinical or laboratory concerns about IgM flare in the first 2 cycles, 
plasmapheresis/other supportive care may be instituted and the subject may remain on 
trial treatment.  
 
If at any timepoint after the end of cycle 2 plasmapheresis is required for symptomatic 
relief of IgM flare (or for any other reason), then the patient will have to cease study 
therapy and be managed as per standard of care at their institution. 
 
 
 
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8.5. 
Treatment discontinuation 
Trial treatment should be permanently discontinued if a patient experiences any of the 
following:  
 disease progression whilst on trial  
 an immune-related AE that does not resolve within 12 weeks of last dose of IMP 
 treatment with corticosteroids cannot be reduced to ≤10 mg prednisolone or 
equivalent per day within 12 weeks 
 Any grade 4 IMP related AE or laboratory abnormality apart from the following:  
o Grade 4 neutropenia <7 days (G-CSF may be instituted, and continued until 
neutrophils exceed 1.5x109/L, as per institutional policy)  
o Grade 4 lymphopenia 
o Grade 4 amylase abnormalities that are not associated with clinical 
symptoms 
o Grade 4 drug-related endocrinopathy AEs which are adequately controlled 
with physiologic hormone replacement 
o Electrolyte abnormalities that can be corrected and are not felt to be a cause 
for clinical safety concern. 
 Grade 2 infusion related reaction (pembrolizumab related) for a second time 
despite receiving premedication  
 Any grade 3 or 4 infusion related reaction (pembrolizumab related)  
In instances where patients discontinue treatment, both pembrolizumab and rituximab 
should be discontinued.  Patients will continue to be followed up in line with the protocol 
(see section 8.11).  
8.6. 
Management 
of 
Overdoses, 
Trial 
treatment 
error, 
or 
Occupational Exposure 
8.6.1. 
Overdose 
Overdose is administration of a quantity of a trial treatment, either per administration or 
cumulatively, which is in excess of the protocol specified dose. The dose can either be 
evaluated as overdose by the trial team at site or by the Sponsor upon review. 
There is no or little information on overdose with pembrolizumab or rituximab. In case of 
overdose, patients must be closely monitored for signs or symptoms of adverse reactions 
and appropriate symptomatic treatment instituted. 
Overdoses should be reported on an incident report (see section 13.1). Any adverse 
events resulting from an overdose should be reported as a SAE (see section 12.2.2 for 
reporting procedures).  Overdoses of pembrolizumab that are in excess of 5 x the 
protocol specified dose (i.e. >1000mg), with or without adverse events resulting from an 
overdose, should be reported as an adverse event of special interest (AESI) (see section 
12.1 and 12.4, Adverse event of special interest, for reporting procedures). 
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8.6.2. 
Medication error  
A medication error is any unintentional error in prescribing, dispensing, or administration 
of an IMP or an investigational treatment while in the control of a healthcare professional 
or consumer. The error can be identified either by the trial team at site or by the Sponsor 
upon review.  
If the medication error is an overdose, refer to the section above. Otherwise, medication 
errors should be reported on an incident report (see section 13.1). Any adverse events 
resulting from a medication error/investigational treatment error should be reported as 
an SAE (see section 12.2.2 for reporting procedures). 
8.6.3. 
Occupational exposure 
Exposure to an IMP as a result of one’s professional or non-professional occupation. 
Occupational exposure should be reported on an incident report form (see section 13.1). 
8.7. 
Supportive Care  
Supportive Treatment 
 
Patients should receive appropriate supportive care as deemed necessary by the treating 
investigator. The following supportive treatments are recommended: 
 
 Tumour lysis syndrome medication (e.g. allopurinol*) daily for 7 days starting 24-
48 hours prior to trial treatment (first cycle only)  
* rasburicase can be used as per local policy 
 Antiviral prophylaxis (e.g. aciclovir) for the duration of treatment and for 3 months 
after completion  
 PCP prophylaxis: Local PCP prophylaxis policy should be followed 
 Moderate anti-emetic risk: Local anti-emetic policy should be followed 
 
Suggested supportive care measures for the management of adverse events with 
potential immunologic aetiology are outlined above (section 8.4). Where appropriate, 
these guidelines include the use of oral or intravenous treatment with corticosteroids as 
well as additional anti-inflammatory agents if symptoms do not improve with 
administration of corticosteroids.  Note that several courses of steroid tapering may be 
necessary as symptoms may worsen when the steroid dose is decreased. For each 
disorder, attempts should be made to rule out other causes such infection, which might 
require additional supportive care. The use of corticosteroids as supportive care for any 
other indication, such as anti-emetic therapy, during study is not permitted (see section 
8.8 below).  
 
G-CSF/transfusions may be given prior to treatment (including during screening) at the 
discretion of the local investigator as per local practice. 
 
Concomitant Medication 
 
Concomitant medication may be given as medically indicated at the local investigator’s 
discretion. 
 
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Viral Hepatitis   
 
Serious or life-threatening reactivation of viral hepatitis may occur in subjects treated with 
rituximab. Therefore, subjects who are anti-HB core positive, or have a known history of 
HBV infection, should receive prophylaxis as per local policy. 
 
Vaccines 
 
Even though no interaction studies have been performed, patients are permitted to 
receive COVID-19 vaccinations that are not live vaccines during treatment. The timing of 
COVID-19 vaccine administration and trial treatment should be determined by the 
Principal Investigator or a Co-investigator at site in the best interests of the patient, 
however it is recommended patients should not receive pembrolizumab within 24 hours 
of having a COVID-19 vaccine. Details of vaccine administration should be added to the 
Rolling Concomitant Medication CRF and medical records. 
 
Administration of inactivated (killed antigen) vaccines is permitted. 
8.8. 
Contraindications 
The use of topical or systemic corticosteroids or immunosuppressants should be avoided 
during the trial (except in the case of immune-related toxicity - see sections 8.4) because 
of their potential interference with the pharmacodynamic activity and efficacy of 
pembrolizumab. If possible, patients should stop any steroid treatment prior to study 
entry.  If, however, this is not possible, patients will be permitted to enter the trial if the 
dose of steroids is at a low dose (≤ 10 mg/day prednisolone or equivalent corticosteroid) 
which has been stable for at least 3 months. Unless due to immune-related toxicity, the 
initiation of steroid treatment during the study, or the necessity to increase the dose of 
any ongoing steroid treatment, should lead to withdrawal of the patient from the study. 
 
Participants are prohibited from receiving the following therapies during treatment: 
 Antineoplastic systemic chemotherapy or biological therapy  
 Immunotherapy not specified in this protocol 
 Chemotherapy not specified in this protocol 
 Investigational agents other than pembrolizumab 
 Radiation therapy  
o Note:  Radiation therapy to a symptomatic solitary lesion or to the brain 
may be allowed at the investigator’s discretion.   
 Live vaccines within 30 days prior to the first dose of study treatment, while 
participating in the study, and for 4 months after stopping treatment.  Examples of 
live vaccines include, but are not limited to, the following: measles, mumps, 
rubella, varicella/zoster, yellow fever, rabies, BCG, and typhoid vaccine. Seasonal 
influenza vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (e.g. FluMist®) are live attenuated 
vaccines and are not allowed.  
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 Systemic corticosteroids for any purpose other than to modulate symptoms from 
an event of clinical interest of suspected immunologic etiology.  The use of 
physiologic doses of corticosteroids may be approved after consultation with the 
Sponsor. 
Participants who, in the assessment by the Investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the study.  
All treatments that the Investigator considers necessary for a participant’s welfare may 
be administered at the discretion of the Investigator in keeping with the community 
standards of medical care.   
Medications or vaccinations specifically prohibited in the exclusion criteria are not 
allowed during the ongoing study.  If there is a clinical indication for any medication or 
vaccination specifically prohibited during the study, discontinuation from study therapy or 
vaccination may be required.  The final decision on any supportive therapy or vaccination 
rests with the Investigator.  However, the decision to continue the participant on study 
treatment requires the mutual agreement of the Investigator, the Sponsor and the 
participant. 
8.9. 
Pharmacy Responsibilities 
All pharmacy aspects of the trial at participating sites are the responsibility of the PI, who 
may delegate this responsibility to the local pharmacist or other appropriately qualified 
personnel, who will be the Pharmacy Lead. The delegation of duties must be recorded 
on the site staff delegation log. 
Pembrolizumab supplied for the PembroWM trial are for PembroWM trial patients only 
and must not be used outside the context of this protocol. 
Pharmacists should refer to the Summary of Drug Arrangements document for further 
details on suppliers, ordering, labelling, storage, preparation and handling and 
destruction. 
8.9.1.  Temperature Excursions 
All temperature excursions outside the storage conditions specified in the IB/Summary 
of Drug Arrangements document must be reported to UCL CTC as per the ‘Pharmacy 
Procedure for Reporting Temperature Excursions’ (see Pharmacy Site File).  
Upon identifying an excursion: 
• all affected trial stock must be quarantined IMMEDIATELY  
• the ‘Notification of Temperature Excursion’ form must be completed and e-mailed 
to ctc.excursions@ucl.ac.uk or faxed to +44 (0)20 7679 9861.  
Please note that UCL CTC must be informed immediately if a patient has been 
administered drug affected by a temperature excursion. 
 
 
 
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8.9.2. IMP accountability 
The Pharmacy Lead must ensure that appropriate records are maintained. 
These records must include accountability for each drug including: receipt (where 
applicable), dispensing, reconciliation and destruction of unused medication (on sponsor 
authorisation). Accountability forms will be supplied, and must be used, unless there is a 
prior agreement from UCL CTC to use alternative in-house records.  
Copies of completed drug accountability logs must be submitted to UCL CTC for all trial 
patients upon request. Also refer to section 14.2 (Centralised Monitoring). 
8.10. 24 Hour/Out-of-Office Hours Emergency Drug-Specific Advice 
Pembrolizumab Office hours 
09:00 to 17:00 Monday to 
Friday, 
excluding 
Bank 
Holidays 
 
All other times 
Outside office hours 
 
Contact UCL CTC 
02076799860 
Merck Sharp & Dohme Ltd  
Switchboard: 0208 154 8000 
8.11. Clinical Management after Treatment Discontinuation 
After treatment discontinuation, further therapy will be at the discretion of the treating 
clinician.  Subsequent treatment will not be considered part of the trial. 
If a patient discontinues trial treatment early, they will remain on trial for follow up 
purposes unless they explicitly withdraw consent. Also refer to sections 9 (Assessments) 
and 15 (Withdrawal of Patients) for further details regarding treatment discontinuation, 
patient withdrawal from trial treatment and withdrawal of consent to data collection. 
For all patients, disease status, late toxicity and survival will be followed up yearly until 
the last patient completes 2 years of follow up and the end of trial is declared.    
8.12. Drug Provision after the End of the Trial 
 
Patients will receive pembrolizumab for a maximum of 1 year or until disease progression, 
treatment discontinuation due to unacceptable toxicity, or any other reason (whichever 
occurs sooner).  There are no arrangements in place for supply following progression or 
beyond a year of treatment.  
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9. 
ASSESSMENTS 
Please also see Schedule of Events table in Appendix 2. 
9.1. 
Registration Assessments 
Patients must give written informed consent before any trial specific screening 
investigations may be carried out. The following assessments or procedures are required 
to evaluate the suitability of patients for the trial and should be performed within 28 days 
prior to full registration unless otherwise stated: 
 Complete medical history including demographics (including age and sex) 
and prior treatments 
o Medical history should include disease diagnosis, β2-microglobulin 
levels at diagnosis, MYD88/CXCR4 status (if available), documenting 
relevant medical conditions 
 Clinical examination: physical examination (including assessment of lymph 
node, liver and spleen size) 
 Concurrent medication assessment 
 Baseline adverse event assessment 
 Observations: pulse, temperature, blood pressure, oxygen saturations 
 Height and Weight 
 Assessment of ECOG performance status (see appendix 3) 
 Quality of life questionnaire – EORTC QLQ-C30 (to be completed before 
starting treatment) 
 Full blood count (including red blood cell (RBC), haemoglobin (Hb), white 
blood cell (WBC) absolute neutrophil count (ANC), absolute lymphocyte 
count (ALC), haematocrit and platelets) 
 Biochemistry (including bicarbonate, uric acid, albumin, alkaline phosphatase 
(ALP), alanine/aspartate transaminase (ALT/AST), total bilirubin, calcium, 
creatinine, potassium, sodium, glucose, urea, and estimated glomerular 
filtration rate (eGFR), U&E, liver function tests (LFT), LDH and amylase) 
 Hepatitis B & C serology (HBsAg, HBsAb, HBcAb and HCV antibody) and HIV 
serology (note if HBcAb is positive HBV DNA testing will need to be performed) 
 Electrocardiogram (ECG) 
 Serum IgM, IgG and IgA 
 Serum paraprotein 
 Serum free light chain (SFLC)  
 Direct antiglobulin test 
 β2 microglobulin 
 TSH, glucose and ACTH tests 
 Highly sensitive urine or serum pregnancy test in women of childbearing 
potential (WOCBP) 
 CT scan of neck, chest, abdomen and pelvis (NCAP) (within 28 days prior to 
starting trial treatment)  
 Bone marrow aspirate and trephine (within 28 days prior to starting treatment).  
 
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Research samples (see section 10 for further details) – all samples below 
are optional and therefore should only be obtained from patients who 
have given consent, been pre-registered and assigned a trial number 
 Bone marrow aspirate and trephine  
 Peripheral blood  
 Lymph node biopsy (if nodal disease) to be obtained within 28 days prior to 
the start of treatment  
o If it is not possible to obtain a biopsy within 28 days prior to start of 
treatment, then historical biopsy tissue may be retrieved and sent to 
HMDS.   
9.2. 
Assessments during Treatment 
Patients should be seen prior to and during each cycle of trial treatment.  Investigations 
should be performed in line with the Schedule of Events table in appendix 2. 
9.2.1. Assessments prior to each cycle of treatment 
 
The following assessments should be performed within 3 days prior to each cycle: 
 
 Clinical examination: physical examination (including assessment of lymph 
node, liver and spleen size) 
 Concurrent medication assessment 
 Adverse event assessment 
 Observations: pulse, temperature, blood pressure, oxygen saturations 
 Weight 
 Assessment of ECOG performance status (see appendix 3) 
 Full blood count (including red blood cell (RBC), haemoglobin (Hb), white 
blood cell (WBC) absolute neutrophil count (ANC), absolute lymphocyte 
count (ALC), haematocrit and platelets) 
 Biochemistry (including bicarbonate, uric acid, albumin, alkaline phosphatase 
(ALP), alanine/aspartate transaminase (ALT/AST), total bilirubin, calcium, 
creatinine, potassium, sodium, glucose, urea, and estimated glomerular 
filtration rate (eGFR), U&E, liver function tests (LFT), and amylase) 
 Electrocardiogram (ECG) 
 Serum IgM, IgG and IgA 
 Serum paraprotein 
 Serum immunofixation (only to be performed if paraprotein not detectable) 
 TSH, glucose and ACTH tests 
 Highly sensitive urine or serum pregnancy test in women of childbearing 
potential (WOCBP) 
 
 
 
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9.2.2. Disease response assessments 
In addition to the assessments before each treatment cycle (section 9.2.1), disease 
response is to be assessed at 12 weeks (+/- 3 days), 24 weeks (+/- 3 days) and 1 year 
(+/- 2 weeks) after commencing treatment.  The following assessments should be 
performed at these time points: 
 
 Concurrent medication assessment 
 Adverse event assessment 
 Full blood count (including red blood cell (RBC), haemoglobin (Hb), white 
blood cell (WBC) absolute neutrophil count (ANC), absolute lymphocyte 
count (ALC), haematocrit and platelets) 
 Biochemistry (including bicarbonate, uric acid, albumin, alkaline phosphatase 
(ALP), alanine/aspartate transaminase (ALT/AST), total bilirubin, calcium, 
creatinine, potassium, sodium, glucose, urea, and estimated glomerular 
filtration rate (eGFR), U&E, liver function tests (LFT)) 
 Quality of life questionnaire – EORTC QLQ-C30 (only performed at week 24) 
 Serum IgM, IgG and IgA 
 Serum paraprotein 
 Serum free light chain (SFLC)  
 Serum immunofixation (only to be performed if paraprotein not detectable) 
 CT scan of neck, chest, abdomen and pelvis (NCAP) (CT scans to be 
performed at week 24 and 1 year after commencing treatment in patients with 
evidence of measurable/nodal disease on baseline scan)  
 Bone marrow aspirate and trephine (only to be performed at week 24 and year 
1 after commencing treatment).   
 
Research samples – week 24 and 1 year only (see section 10 for further 
details) – all samples below are optional and therefore should only be 
obtained from patients who have given consent 
 Bone marrow aspirate  
 Peripheral blood 
 
Response at these time points should be assessed using the International Working 
Group for WM response criteria (see appendix 4). 
Patients will remain on treatment for a maximum of 1 year or until disease progression, 
discontinuation due to unacceptable toxicity or any other reason (whichever occurs 
sooner).  
9.3. 
Assessments after Disease Progression 
Following disease progression patients will be assessed at 5 months (+4 weeks) after 
the date of treatment discontinuation, over the phone or at a standard hospital visit for 
the purposes of: 
 
Adverse event assessment 
Patients are then followed up for the trial annually from the date of progression for the 
following: 
 
Remission status assessment (investigations as per local protocols) 
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9.4. 
Assessments after treatment discontinuation (for reasons 
other than disease progression) 
If patients complete treatment or are withdrawn from trial treatment early, for reasons 
other than disease progression the following assessments are to be performed on day 60 
(+/- 3 days) following treatment discontinuation: 
 Clinical examination: physical examination (including assessment of lymph 
node, liver and spleen size) 
 Concurrent medication assessment 
 Adverse event assessment 
 Blood pressure  
 Weight 
 Assessment of ECOG performance status (see appendix 3) 
 Full blood count (including red blood cell (RBC), haemoglobin (Hb), white 
blood cell (WBC) absolute neutrophil count (ANC), absolute lymphocyte 
count (ALC), haematocrit and platelets) 
 Biochemistry (including bicarbonate, uric acid, albumin, alkaline phosphatase 
(ALP), alanine/aspartate transaminase (ALT/AST), total bilirubin, calcium, 
creatinine, potassium, sodium, glucose, urea, and estimated glomerular 
filtration rate (eGFR), U&E, liver function tests (LFT), LDH, and amylase) 
 TSH, glucose and ACTH tests 
 
Patients will then be assessed at 5 months (+4 weeks) after the date of treatment 
discontinuation, over the phone or at a standard hospital visit for the purposes of: 
 
Adverse event assessment 
 
Patients are then followed up for the trial annually from the date of treatment 
discontinuation for the following: 
 
Remission status assessment (investigations as per local protocols) 
 
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10. 
EXPLORATORY BIOLOGICAL STUDIES 
Biological studies are an important, but optional part of the trial. We will be collecting two 
types of sample: formalin fixed paraffin embedded tissue (bone marrow and lymph 
nodes) and blood.  
The objective for the translational studies is to identify biomarkers of immunological 
response to the combination of pembrolizumab and rituximab in patients with 
relapsed/refractory WM. The translational research aims to inform our understanding of 
which patients respond to therapy and the underlying mechanisms of response to study 
treatment.  
The following exploratory endpoints will be assessed: 
 Assessment of 
PD-1 
and PD-L1/ 
PD-L2 
expression 
by 
FISH and 
immunohistochemistry (IHC).  A positive correlation between high PD-L1 
expression levels and responses to PD-1 inhibitors has been seen in advanced 
stage Hodgkin lymphoma patients); this would allow assessment of whether 
response to PD-1 inhibitors in WM is mediated by a similar mechanism. 
Assessment of the distribution of expression of PD-1 and PD-L1/ PD-L2 by IHC 
would further explore the hypothesis that signalling through this pathway 
contributes to the facilitative effect of the tumour microenvironment, and whether 
PD-1 inhibitors abrogate this interaction 
 IHC to assess baseline and on-treatment changes to distribution and composition 
of immune response cells in the microenvironment 
 Analysis of baseline biopsies (where available) to elucidate potential mechanisms 
of action of tumour response 
 Assessment of treatment outcome according to tumour genotype, as determined 
by a Next Generation Sequencing (NGS) panel to include mutations in MYD88, 
CXCR4, TP53, BTK and PLCvgamma. 
 Correlation of bone marrow response with reduction in serum IgM level. Previous 
studies have shown that there can be a discrepant response between the IgM and 
bone marrow 
 Quantification of bone marrow involvement by morphologic assessment of 
trephine and flow cytometric assessment of aspirate for MRD with correlative 
assessment of MRD on peripheral blood at the same timepoints 
Procedures to determine disease response assessment are mandatory in the trial as 
outlined in the Assessments section 9, however providing samples for the biological 
studies is optional to the patient. Additional samples should only be obtained from 
consenting patients. Patients who do not give their consent to donate the optional 
samples can still take part in the trial.  
 
The Haematological Malignancy Diagnostic Service (HMDS) in Leeds will be responsible 
for analysis of the optional samples.   
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UCL CTC will inform HMDS if a patient has given consent for samples to be analysed as 
part of the trial and whether they have consented for surplus samples to be stored for 
future ethically approved research. Laboratory processing of any samples will not occur 
until patient consent has been confirmed. Please refer to the laboratory manual for details 
of how to send and log samples. Patients must be pre-registered and assigned a trial 
number before any samples are sent to HMDS. 
 
We will be collecting four types of sample: lymph node biopsy (in FFPE), bone marrow 
aspirates trephine (in FFPE), bone marrow aspirate and peripheral blood.  
 
Sites must keep a record of all samples sent to HMDS. See the Laboratory Manual for 
more details of how to track samples. 
10.1. 
Lymph node and bone marrow trephine formalin fixed paraffin embedded 
blocks – optional to patient 
In all patients, a bone marrow trephine sample should be obtained at pre-registration 
within 28 days prior to starting treatment.   
 
In patients with nodal disease, a lymph node biopsy sample at pre-registration should 
also be taken. Preferably the nodal biopsy should be obtained within 28 days prior to 
C1D1. If not possible, then historical lymph node biopsy tissue may be sent.   
 
Formalin fixed paraffin embedded (FFPE) tissue from the bone marrow trephine and 
lymph node should be sent to HMDS, Leeds.  Please see the laboratory manual for 
further details of how to send 
 
3µm sections of the tissue block will be taken and immunohistochemistry performed. At 
least ten markers will be assessed for each case including: CD5, CD10, CD79a, CD56, 
CD20, CD38, PD1, PD-L1, PD-L2. For PD-L1 and PD-L2, the percentage of malignant 
and non-malignant cells with positive staining will be reported and a central pathological 
report provided. 
 
GEP will be performed using the HTG Immunopanel and the Affymetrix Human 
Transcriptome Array, which is a whole transcriptome array. These are two gene 
expression platforms currently being used in HMDS with bioinformatic support from 
within HMDS and in collaboration with the University of Leeds. The panel will include 
mutations in MYD88, CXCR4, TP53, BTK and PLCvgamma  
 
Once analysis is complete, blocks can be returned to sites at their request. 
10.2. 
Bone marrow samples – optional to patient 
Research bone marrow aspirate samples will be obtained at the following time points: 
 
Time point 
Sample required 
Pre-registration (up to 28 days prior to starting treatment) 
5 ml bone marrow aspirate in EDTA 
Week 24 post commencing treatment 
5 ml bone marrow aspirate in EDTA 
1 year post commencing treatment 
5 ml bone marrow aspirate in EDTA 
 
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Multicolour flow panels will be performed on the marrow to identify the flow cytometry 
phenotype, with further samples taken halfway and at the end of therapy to assess 
minimum residual disease in bone marrow. 
 
Bone marrow samples, or any products produced from these, will not be returned to sites.  
10.3. 
Peripheral blood samples – optional to patient 
Research peripheral blood samples will be obtained at the following time points: 
 
Time point 
Sample required 
Pre-registration (up to 28 days prior to starting treatment) 
20 (4 x 5) ml peripheral blood in EDTA 
Week 24 post commencing treatment 
20 (4 x 5) ml peripheral blood in EDTA 
1 year post commencing treatment 
20 (4 x 5) ml peripheral blood in EDTA 
 
Multicolour flow panels will be performed on blood on the baseline sample to identify the 
flow cytometry phenotype, with further samples taken halfway through and at the end of 
therapy to assess minimal residual disease in peripheral blood. 
 
Blood samples, or any products produced from these, will not be returned to sites.  
 
 
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11. 
DATA MANAGEMENT AND DATA HANDLING 
GUIDELINES 
Data will be collected from sites on version controlled case report forms (CRFs) designed 
for the trial and supplied by UCL CTC. Data must be accurately transcribed onto trial 
CRFs and must be verifiable from source data at site. Examples of source documents 
are hospital records which include patient’s medical notes, laboratory and other clinical 
reports etc. 
Where copies of supporting source documentation (e.g. autopsy reports, pathology 
reports, CT scan images etc.) are being submitted to UCL CTC, the patient’s trial number 
must be clearly indicated on all material and any patient identifiers removed/blacked out 
prior to sending to maintain confidentiality. 
Please note that, for this trial, patients must consent to their NHS/CHI number being 
supplied to UCL CTC. This is required in order to allow for follow up via national registries 
where needed. 
11.1. Completing Case Report Forms 
All CRFs must be completed and signed by staff who are listed on the site staff delegation 
log and authorised by the PI to perform this duty. The PI is responsible for the accuracy 
of all data reported in the CRF. 
All entries must be clear, legible and written in ballpoint pen. Any corrections made to a 
CRF at site must be made by drawing a single line through the incorrect item ensuring 
that the previous entry is not obscured. Each correction must be dated and initialed. 
Correction fluid must not be used. 
The use of abbreviations and acronyms should be avoided. 
11.2. Missing Data 
To avoid the need for unnecessary data queries CRFs must be checked at site to ensure 
there are no blank fields before sending to UCL CTC (unless it is specifically stated that 
a field may be left blank). When data are unavailable because a measure has not been 
taken or test not performed, enter “ND” for not done. If an item was not required at the 
particular time the form relates to, enter “NA” for not applicable. When data are unknown 
enter the value “NK” (only use if every effort has been made to obtain the data). 
11.3. Timelines for Data Return 
CRFs must be completed at site and returned to UCL CTC as soon as possible after the 
relevant visit and within 4 weeks of the patient being seen. Registration forms should be 
faxed/emailed to UCL CTC. Death forms and SAE reports should be returned within 24 
hours by fax/email.  
 
Sites that persistently do not return data within the required timelines may be suspended 
from recruiting further patients into the trial by UCL CTC and subjected to a ‘triggered’ 
monitoring visit. See section 14.3 (‘Triggered’ On-Site/Remote Monitoring) for details. 
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11.4. Data Queries 
Data arriving at UCL CTC will be checked for legibility, completeness, accuracy and 
consistency, including checks for missing or unusual values. Data Clarification Requests 
will be sent to the data contact at site. Further guidance on how data contacts should 
respond to data queries can be found on the Data Clarification Request forms. 
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12. 
PHARMACOVIGILANCE  
12.1. Definitions 
The following definitions have been adapted from Directive 2001/20/EC, ICH E2A “Clinical 
Safety Data Management: Definitions and Standards for Expedited Reporting” and ICH 
GCP E6.  
Adverse Event (AE) 
Any untoward medical occurrence in a patient treated on a trial protocol, which does not 
necessarily have a causal relationship with an IMP. An AE can therefore be any 
unfavourable and unintended sign (including an abnormal laboratory finding), symptom 
or disease temporally associated with the use of an IMP, whether or not related to that 
IMP. See section 12.2.1 for AE reporting procedures. 
Adverse Reaction (AR) 
All untoward and unintended responses to an IMP related to any dose administered. A 
causal relationship between an IMP and an adverse event is at least a reasonable 
possibility, i.e. the relationship cannot be ruled out. 
Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
An adverse event or adverse reaction that at any dose:  
• Results in death 
• Is life threatening (the term “life-threatening” refers to an event in which the patient 
was at risk of death at the time of the event. It does not refer to an event that 
hypothetically might have caused death if it were more severe) 
• Requires in-patient hospitalisation or prolongs existing hospitalisation 
• Results in persistent or significant disability/incapacity 
• Is a congenital anomaly or birth defect 
• Is otherwise medically significant (e.g. important medical events that may not be 
immediately life-threatening or result in death or hospitalisation but may 
jeopardise the patient or may require intervention to prevent one of the other 
outcomes listed above) 
See section 12.2.2 for SAE reporting procedures. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
A serious adverse reaction, the nature or severity of which is not consistent with the 
applicable reference safety information. 
i.e. an adverse event that meets all the following criteria: 
 Serious – meets one or more of the serious criteria, listed under the definition of 
SAE above 
 Related – assessed by the local PI or designee, or Sponsor as causally related to 
one or more elements of the trial treatment 
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 Unexpected – the event is not consistent with the applicable reference safety 
information  
See section 12.3 for reporting procedures for these events. 
Adverse event of special interest (AESI) 
An AE that is of scientific and medical concern to the Trial Management Group and MSD 
for which rapid communication is required. The AESI may not meet the standard criteria 
for seriousness and it may occur outside the standard AE reporting timeframes for the 
trial.  
See section 12.4 for the list of AESI for the trial and their reporting procedures for these 
events. 
Urgent event  
An AE that is protocol-related and requires completion of a trial specific Case Report 
Form.  
See section 12.5 for a list of and reporting procedures for these events. 
Overdose, Trial treatment error, or Occupational exposure 
Refer to section 8.6 for details on reporting of these events. 
12.2. Reporting Procedures 
Adverse Event Term 
An adverse event term must be provided for each adverse event. Wherever possible a 
valid term listed in the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
should be used. This is available online at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_
Quick_Reference_8.5x11.pdf  
Severity grade of each adverse event must be determined by using CTCAE v5. 
Causality 
The relationship between the treatment and an adverse event will be assessed. 
For AEs (including SAEs), the local PI or designee will assess whether the event is 
causally related to each IMP. 
For SAEs, a review will also be carried out by the Sponsor’s delegate. 
Causal relationship to each trial treatment must be determined as follows: 
• Related (reasonable possibility) to an IMP 
• Not related (no reasonable possibility) to an IMP 
UCL CTC will consider events evaluated as related to be adverse reactions. 
 
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12.2.1. Reporting of Adverse Events (AEs) 
All adverse events that occur between informed consent and 5 months post last IMP 
administration must be recorded in the patient medical notes and the trial CRFs.  
An AE cover sheet should be completed and a photocopy submitted to UCL CTC at each 
trial visit. The Adverse Event form should be submitted when there are new AEs or 
changes to existing AEs on the form. Any updates or changes to previously reported AEs 
must be initialed and dated. Report the worst grade observed for the AE on the form. 
Those meeting the definition of a Serious Adverse Event (SAE) or Adverse Event of 
Special Interest (AESI) must also be reported to UCL CTC using the trial specific SAE 
Report. Also refer to section 12.2.2 (Reporting of Serious Adverse Events (SAEs)) and 
section 12.4 (Adverse Events of Special Interest)). Adverse events meeting the definition 
of an Urgent Event must be reported on an Urgent Event form (see section 12.5 Urgent 
Events). 
Pre-existing conditions (i.e. conditions present at registration) do not qualify as adverse 
events unless they worsen or recur (i.e. improves/resolves and then worsens/reappears 
again). 
E.g. an AE could be an exacerbation of a chronic or intermittent pre-existing condition 
including either an increase in frequency and/or intensity of the condition (worsening of 
the event). Another example of an AE is when a pre-existing condition improves during 
the trial (e.g. from grade 3 to grade 1) and then it worsens again (e.g. from grade 1 to 
grade 2), even if the event is of severity equal or lower to the original condition 
(improvement and recurrence of the event).  
NB the disease(s) under study and its anticipated day-to-day fluctuations would not be 
an AE. 
12.2.2. Reporting of Serious Adverse Events (SAEs) 
All SAEs that occur between the signing of informed consent and 5 months post last IMP 
administration (or after this date if the site investigator feels the event is related to 
an IMP) must be submitted to UCL CTC by email within 24 hours of observing or learning 
of the event, using the trial specific SAE Report. All sections on the SAE Report must be 
completed. If the event is not being reported within 24 hours to UCL CTC, the 
circumstances that led to this must be detailed in the SAE Report to avoid unnecessary 
queries. 
Exemptions from SAE Report submission 
For this trial, the following events are exempt from requiring submission on an SAE 
Report unless considered to be related to an IMP (rituximab and/or 
pembrolizumab). Exempt events must be recorded in the relevant section(s) of the trial 
CRFs: 
• events that occur more than 5 months post last IMP administration. Note: this does 
not include pregnancy related events (see section 12.7) 
• disease progression  
• rituximab infusion reactions, unless life-threatening or fatal 
Please note that hospitalisation for elective treatment, palliative care, logistical or socio-
economic reasons does not qualify as an SAE. 
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Completed SAE Reports must be emailed to UCL CTC within 24 hours 
of becoming aware of the event  
Email: ctc.pembroWM@ucl.ac.uk  
 
 
SAE Follow-Up Reports 
UCL CTC will follow up all SAE/SARs until resolution and until there are no further 
queries. 
Sites must ensure any new and relevant information is provided to UCL CTC promptly. 
If an event term changes or a new event is added, the causality must be re-assessed by 
an Investigator. If the event is not being reported to UCL CTC within 24 hours, the 
circumstances that led to the delay must be detailed in the SAE/SAR Report to avoid 
unnecessary queries. 
 
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Adverse Event Reporting Flowchart 
 
 
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SAE Processing at UCL CTC 
On receipt of the SAE Report, UCL CTC will check for legibility, completeness, accuracy 
and consistency. Expectedness will be evaluated, to determine whether or not the case 
qualifies for expedited reporting, using the approved RSI (the list of expected adverse 
events in the IB for pembrolizumab and SPC for rituximab). 
The CI, or their delegate (e.g. a clinical member of the TMG), will review the SAEs to 
perform an evaluation of causality on behalf of the sponsor. If UCL CTC has considered 
expectedness difficult to determine, the CI, or their delegate, will be consulted for their 
opinion at this time. 
UCL CTC will submit all SAE Reports concerning patients who have received 
pembrolizumab to MSD Ltd according to the timelines outlined in the agreement between 
UCL and MSD Ltd. 
12.3. SUSARs  
If the event is evaluated as a Suspected Unexpected Serious Adverse Reaction 
(SUSAR), UCL CTC will submit a report to the MHRA and REC within the required 
timelines. 
Wherever possible, evaluations of causal relationship by both the site and the Sponsor’s 
clinical reviewer will be reported. 
Informing Sites of SUSARs 
UCL CTC will inform all UK PIs of any SUSARs that occur on the trial. PIs will receive a 
quarterly line listing which must be processed according to local requirements. 
UCL CTC will forward reports received from MSD Ltd regarding SUSARs that have 
occurred on other trials using pembrolizumab to all PIs. These must be processed 
according to local requirements and filed with the IB. 
12.4. Adverse events of special interest 
The following adverse events of special interest for pembrolizumab must be collected 
between start of treatment and 5 months post last IMP administration. They must be 
reported on an SAE report regardless of their seriousness within 24 hours of becoming 
aware of the event. All sections on the SAE Report must be completed. In terms of 
causality and expectedness, these reports will be processed as other SAE reports. The 
AESIs are: 
 An overdose of pembrolizumab that is in excess of 5 x the protocol specified dose 
(i.e. >1000mg), with or without adverse events 
 The following conditions met at the same time, at any time during the trial 
o An elevated AST or ALT lab value >3x the upper limit of normal (ULN) and 
o An elevated total bilirubin lab value that is >2x ULN and 
o An alkaline phosphatase lab value that is <2x ULN 
 
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All AEs of special interest must be reported by emailing a completed 
SAE report to UCL CTC within 24 hours of becoming aware of the 
event  
Email: ctc.pembroWM@ucl.ac.uk  
 
UCL CTC will submit all SAE Reports relating to AESIs in patients who have received 
pembrolizumab to MSD according to the timelines outlined in the agreement between 
UCL and MSD. 
12.5. Urgent events 
The following events must be collected and reported as urgent events between start of 
treatment and the end of the trial. They must be reported on the relevant CRF and e-
mailed to UCL CTC within the timelines stated. If the event meets a definition of an SAE, 
an SAE report must also be submitted as per Section 12.2.2.   
 
Event 
Description 
Form 
required 
Timeframe  
Death 
Death 
from 
any 
cause 
(reportable at any point while the 
patient is enrolled onto the trial).   
Death form 
Within 24 hours of 
becoming aware 
of the death 
Disease 
progression 
Progression of WM, confirmed by 
standard local investigations (if 
local 
investigations 
are 
inconclusive, UCL CTC should 
be contacted for advice) 
Disease 
progression 
form 
Within 72 hours of 
becoming aware 
of 
confirmed 
progression 
 
All Urgent Events must be reported by emailing a completed Urgent 
Event Form to UCL CTC within the timeframes specified above of 
becoming aware of the event 
Email: ctc.pembroWM@ucl.ac.uk  
 
12.6. Safety Monitoring 
UCL CTC will provide safety information to the Trial Management Group (TMG) and the 
Independent Data Monitoring Committee (IDMC) on a periodic basis for review.   
Trial safety data will be monitored to identify: 
• whether disease-related events (exempt from SAE reporting as per section 12.2.2) 
appear to be enhanced by the IMPs  
• new adverse reactions to the combination therapy 
• a higher incidence in rare adverse events than is stated in the IB/SPC for an IMP 
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• trial related events that are not considered related to the IMP treatment, but may 
lead to changes to the trial documents. These would include events related to 
NIMPs. 
• Review of incidence of AESIs as outlined in section 12.4 
In addition to periodic reviews, an IDMC meeting can be triggered as a result of trial-
treatment related deaths (see also section 17.3) 
If UCL CTC identifies or suspects any issues concerning patient safety at any point during 
the trial, the CI or TMG will be consulted for their opinion, and if necessary the issue will 
be referred to the IDMC. 
12.7. Pregnancy 
Reporting Period 
For any pregnancy exposure to trial treatment, the site must submit a trial specific 
Pregnancy Report to UCL CTC by email within 24 hours of learning of its occurrence. 
A pregnancy exposure to trial treatment includes: 
 Pregnancy in a trial patient  
 Pregnancy in a partner of a male trial patient  
 Exposure to treatment in a partner of a male trial patient who was pregnant at the 
start of the trial 
occurring between the start of trial treatment and 12 months after last IMP administration 
for female patients and between the start of trial treatment and 4 months after last IMP 
administration for female partners. 
The site must request consent from the pregnant trial patient or pregnant female partner 
of a male patient to report information regarding a pregnancy using: 
 For female patients: the trial-specific Pregnancy Monitoring Information Sheet and 
Informed Consent Form for trial patients 
 For female partners of male patients: the trial specific Pregnancy Monitoring 
Information Sheet and Informed Consent Form for partners of trial patients 
If consent is not given, the notification that a pregnancy has occurred will be retained by 
UCL CTC, however no further action will be taken on the information detailed in the 
report. 
 
 
All pregnancies must be reported by emailing a completed 
Pregnancy Report to UCL CTC within 24 hours of becoming aware of 
the pregnancy 
Email: ctc.pembroWM@ucl.ac.uk  
 
Pregnancy Follow-Up Reports 
For pregnant patients or partners who consent, their pregnancies must be followed-up at 
least monthly for up to 8 weeks after the end of the pregnancy (or later if there are 
ongoing issues) to collect information on any ante- and post-natal problems for both 
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mother and child. If significant new information is received, follow-up Pregnancy Reports 
must be submitted to UCL CTC by email within 24 hours of learning of the new 
information. In case of adverse outcome to the pregnancy reports must include an 
evaluation of the possible relationship of each trial treatment to the pregnancy outcome. 
SAEs during pregnancy 
Any SAE occurring in a pregnant patient must be reported using the trial specific SAE 
Report, according to SAE reporting procedures. Refer to section 12.2.2 (Reporting of 
Serious Adverse Events (SAEs)) for details. 
Pregnancy Report processing at UCL CTC 
UCL CTC will submit a report to the MHRA and the REC if the pregnancy outcome meets 
the definition of a SUSAR. Refer to section 12.3 (SUSARs) for details. 
UCL CTC will submit all Pregnancy Reports concerning exposure to pembrolizumab to 
MSD Ltd according to the timelines outlined in the agreement between UCL and MSD 
Ltd. 
12.8. Development Safety Update Reports (DSURs) 
Safety data obtained from the trial will be included in DSURs that UCL CTC will submit 
to the MHRA and the REC. 
UCL CTC will provide MSD Ltd with DSURs that include information regarding 
pembrolizumab. 
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13. 
INCIDENT REPORTING AND SERIOUS BREACHES 
13.1. Incident Reporting 
Organisations must notify UCL CTC of all deviations from the protocol or GCP 
immediately. An incident report may be requested and will be provided, but an equivalent 
document (e.g. Trust Incident form) is acceptable where already completed. 
If site staff are unsure whether a certain occurrence constitutes a deviation from the 
protocol or GCP, the UCL CTC trial team can be contacted immediately to discuss. 
UCL CTC will use an organisation’s history of non-compliance to make decisions on 
future collaborations. 
UCL CTC will assess all incidents to see if they meet the definition of a serious breach. 
13.2. Serious Breaches 
A “serious breach” is defined as a breach of the protocol or of the conditions or principles 
of Good Clinical Practice (or equivalent standards for conduct of non-CTIMPs) which is 
likely to affect to a significant degree the safety or physical or mental integrity of the trial 
subjects, or the scientific value of the research. 
Systematic or persistent non-compliance by a site with GCP and/or the protocol, 
including failure to report SAEs occurring on trial within the specified timeframe, may be 
deemed a serious breach. 
In cases where a serious breach has been identified, UCL CTC will inform the MHRA 
and REC within 7 calendar days of becoming aware of the breach. 
Sites must have written procedures for notifying the sponsor of serious breaches (MHRA 
Guidance on the Notification of Serious Breaches). 
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14. 
TRIAL MONITORING AND OVERSIGHT 
Participating sites and PIs must agree to allow trial-related on-site monitoring, Sponsor 
audits and regulatory inspections by providing direct access to source data/documents 
as required. Where permitted by site policy, remote access to source data/documentation 
may also be provided by participating sites for remote monitoring by UCL CTC or its 
representatives. 
Patients are informed of this in the patient information sheet and are asked to consent to 
their medical notes being reviewed by appropriate individuals on the consent form. UCL 
CTC staff or its representatives will conduct all monitoring in compliance with the 
participant consent, site policy and data protection requirements. 
UCL CTC will determine the appropriate level and nature of monitoring required for the 
based on the objective, purpose, phase, design, size, complexity, endpoints and risks 
associated with the trial. Risk will be assessed on an ongoing basis and adjustments 
made accordingly. 
Details of monitoring activities will be included in the trial monitoring plan and conveyed 
to sites during initiation. The trial monitoring plan will be kept under review during the trial 
and updated information provided to sites as necessary. 
14.1. On-Site and Remote Monitoring 
On-Site Monitoring 
Sites will be sent an email in advance of any on-site monitoring visits, confirming when a 
visit is scheduled to take place. The email will include a list of the documents to be 
reviewed, interviews that will be conducted, planned inspections of the facilities and who 
will be performing the visit. 
Remote Monitoring 
UCL CTC defines remote monitoring as activities conducted at a location remote from 
the research site which replicate some on-site activities e.g. source data review. Remote 
monitoring may be conducted in response to exceptional circumstances preventing 
access to participating sites (e.g. global pandemic) or conducted routinely. Details of 
remote monitoring will be agreed with participating sites, conducted in accordance with 
site policy and documented in the monitoring plan. 
Sites will be sent an email in advance, confirming when remote monitoring is scheduled 
to take place and how the source documents will be remotely accessed. The email will 
include a list of the documents to be reviewed, interviews that will be conducted and who 
will be performing the remote monitoring.  
Remote monitoring will be conducted by UCL CTC or its representatives via a device 
with adequate security. Patient confidentiality will be maintained at all times, and 
monitoring activities will be conducted in an appropriate environment where no 
unauthorised viewing or overhearing of conversations is possible by third parties. Refer 
to section 11 Data Management and Data Handling Guidelines for details of how secure 
documentation may be submitted to UCL CTC. 
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Monitoring Follow Up 
Following on-site/remote monitoring, the Trial Monitor/Trial Coordinator will provide a 
follow up email to the site, which will summarise the documents reviewed and a 
statement of findings, incidents, deficiencies, conclusions, actions taken and/or actions 
required. The PI at each site will be responsible for ensuring that monitoring findings are 
addressed in a timely manner, and by the deadline specified. 
14.2. Centralised Monitoring 
UCL CTC performs centralised monitoring, which requires the submission of documents 
by sites to UCL CTC for review. The documents requested include but are not limited to: 
delegation log, preliminary registration and full registration forms, PI CV & GCP, drug 
accountability logs (patient and stock balance), screening log, sample inventory logs and 
ISF & PSF checklists. Expectations for document submission will be explained during 
site initiation and UCL CTC will send emails to sites requesting the documents when 
required. 
Sites will be requested to conduct quality control checks of documentation held within 
the Investigator Site File and Pharmacy Site File at the frequency required for the trial. 
Checklists detailing the current version/date of version controlled documents will be 
provided by UCL CTC for this purpose. 
14.3. ‘Triggered’ On-Site/Remote Monitoring 
Additional on-site/remote monitoring visits may be scheduled where there is evidence or 
suspicion of non-compliance at a site with important aspect(s) of the trial protocol/GCP 
requirements. 
On-Site Monitoring 
Sites will be sent an email in advance outlining the reason(s) for the visit and confirming 
when it will take place. The email will include a list of the documents that are to be 
reviewed, interviews that will be conducted, planned inspections of the facilities and who 
will be performing the visit. 
Remote Monitoring 
Sites will be sent an email in advance, confirming when remote monitoring is scheduled 
to take place and how the source documents will be remotely accessed. The email will 
include a list of the documents to be reviewed, interviews that will be conducted via 
telephone/videoconference and who will be performing remote monitoring. 
14.4. Escalation of Monitoring Issues 
Where monitoring indicates that a patient may have been placed at risk (e.g. evidence 
of an overdose having been administered or indication that dose modification rules for 
an IMP were not observed following an adverse event), the matter will be raised urgently 
with site staff and escalated as appropriate. 
UCL CTC will assess whether it is appropriate for the site to continue participation in the 
trial and whether the incident(s) constitute a serious breach. Refer to section 13 (Incident 
Reporting and Serious Breaches 
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14.5. Oversight Committees 
14.5.1. Trial Management Group (TMG) 
The TMG will include the Chief Investigator, clinicians and experts from relevant 
specialties and PembroWM trial staff from UCL CTC (see page 4). The TMG will be 
responsible for overseeing the trial. The group will meet regularly (at least bi-annually) 
and will send updates to PIs (via newsletters or at Investigator meetings) and to the NCRI 
lymphoma Clinical Studies Group. 
The TMG will review substantial amendments to the protocol prior to submission to the 
REC and MHRA. All PIs will be kept informed of substantial amendments through their 
nominated responsible individual and are responsible for their prompt implementation. 
TMG members will be required to sign a TMG charter, which describes the committee’s 
responsibilities in relation to the trial and requires any potential conflicts of interest to be 
declared.   
14.5.2. Trial Steering Committee (TSC) 
The role of the TSC is to provide overall supervision of the trial. The TSC will review the 
recommendations of the Independent Data Monitoring Committee and, on consideration 
of this information, recommend any appropriate amendments/actions for the trial as 
necessary. The TSC acts on behalf of the funder and the Sponsor. 
TSC members will be required to sign a TSC charter, which describes the committee’s 
responsibilities and requires any potential conflicts of interest to be declared. 
14.5.3. Independent Data Monitoring Committee (IDMC) 
The role of the IDMC is to provide independent advice on data and safety aspects of the 
trial. Meetings of the Committee will be held at least annually, or as necessary to address 
any issues.  Although no formal interim analysis is planned, an IDMC meeting will be 
triggered in the event of significant toxicity (see section 17.3 for further details). The IDMC 
is advisory to the TSC and can recommend premature closure of the trial to the TSC. 
IDMC members will be required to sign an IDMC charter, which describes the 
committee’s responsibilities and requires any potential conflicts of interest to be declared. 
14.5.4. Role of UCL CTC 
UCL CTC will be responsible for the day to day coordination and management of the trial 
and will act as custodian of the data generated in the trial (on behalf of UCL). UCL CTC 
is responsible for all duties relating to pharmacovigilance which are conducted in 
accordance with section 12 (Pharmacovigilance ).  
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15. 
WITHDRAWAL OF PATIENTS 
In consenting to the trial, patients are consenting to trial treatment, assessments, 
collection of biological samples, follow-up and data collection. 
15.1. Patients who do not start Trial Treatment 
If a patient does not start treatment, the reasons for this must be recorded in the patient’s 
medical notes and on the relevant Case Report Form(s). Reasons that a patient may not 
start treatment include: 
 Deterioration in health 
 Patient decision 
 No longer eligible 
If a patient does not start treatment, then the patient should be withdrawn from the trial. 
Data collected will be used in the trial analysis, where appropriate. Biological samples 
collected may still be used unless the patient explicitly withdraws consent to this. 
15.2. Discontinuation of Trial Treatment 
A patient may be withdrawn from trial treatment whenever such treatment is no longer in 
the patient’s best interests, but the reasons for doing so must be recorded in the patient’s 
medical notes and on the relevant Case Report Form(s). Reasons for discontinuing 
treatment may include: 
• Disease progression whilst on therapy 
• Unacceptable toxicity (see section 8.5 for full details) 
• Intercurrent illness which prevents further treatment 
• Patient decision not to continue with trial treatment 
• Any alterations in the patient’s condition which justifies the discontinuation of 
treatment in the site investigator’s opinion 
• Non-compliance with the trial treatment and/or procedures 
• If a female patient becomes pregnant or male/female fails to use adequate birth 
control (for patients of childbearing potential) 
In these cases patients will remain within the trial for the purposes of follow-up and data 
analysis unless they explicitly withdraw consent.  See section 9 for details. 
If a patient expresses their wish to withdraw from trial treatment, sites should explain the 
importance of remaining on trial follow-up, or failing this of allowing routine follow-up data 
to be used for trial purposes and for allowing existing collected data to be used. If the 
patient gives a reason for wishing to discontinue treatment, this should be recorded. 
The following CRFs should be submitted if a patient discontinues trial treatment early: 
 Treatment summary form 
 Treatment forms for all cycles of treatment received 
 Rolling AE form for all cycles of treatment received 
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Thereafter, unless the patient has withdrawn consent, the site should report 
AEs/SAEs and submit relevant follow up forms.  
15.3. Withdrawal of Consent 
If a patient withdraws consent for any aspect of the study, the ‘Change of Status Form’ 
should be completed and submitted to UCL CTC.  
15.3.1. Withdrawal of consent for follow up 
If a patient withdraws consent for trial follow up, but is happy to continue with future data 
collection from hospital medical notes: 
 They will remain on trial for follow up 
 The patient will no longer have trial-specific visits and assessments. Follow up 
forms should be completed based on the routine visit nearest the due date for the 
follow up form   
 The following CRFs must be submitted at time of withdrawal: 
o Change of status form 
o All CRFs up to and including the date of withdrawal of consent 
 Thereafter, the site should report AEs/SAEs as per section 12.2 and follow up 
forms, including notifications of progression and death. 
15.3.2. Withdrawal of consent for data collection 
If a patient explicitly states they do not wish to contribute further data to the trial their 
decision must be respected: 
 The following CRFs must be submitted at the time of withdrawal: 
o Change of status form 
o All CRFs up to and including the date of withdrawal of consent 
 Thereafter no further data should be submitted, with the exception of SAE reports 
as per section 12.2 (due to the regulatory requirement for oversight of IMP safety) 
15.3.3. Withdrawal of consent for use of samples 
If a patient withdraws consent for the use of some or all of their samples in the trial or for 
future research, this should be reported on the Change of Status form. Unless the patient 
has also withdrawn consent for treatment/follow up, management and data collection 
should continue as per protocol.  
 
 
 
 
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15.4. Losses to Follow-Up 
If a patient moves from the area, every effort should be made for the patient to be followed 
up at another participating trial site and for this new site to take over the responsibility for 
the patient, or for follow-up via GP. Details of participating trial sites can be obtained from 
the UCL CTC trial team, who must be informed of the transfer of care and follow up 
arrangements. If it is not possible to transfer to a participating site, the registering site 
remains responsible for submission of forms. 
If a patient is lost to follow-up at a site every effort should be made to contact the patient’s 
GP to obtain information on the patient’s status. 
At the time of loss to follow up, the following CRFs should be submitted: 
 Change of status form 
 All CRFs due up to and including the date of loss to follow up 
If contact is re-established with the patient, further follow up forms should be sent, 
including notifications of progression. A death form should also be submitted if the site 
becomes aware the patient has died. 
Prior to primary analysis and presentation/publication of the primary endpoint data, UCL 
CTC will ask sites to attempt to re-establish contact with patients who were lost to follow 
up and/or check hospital records for evidence of when the patient was last known to be 
alive and evidence of disease progression and death.  
 
 
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16. 
TRIAL CLOSURE 
16.1. End of Trial 
For regulatory purposes the end of the trial will be when the final data item for the final 
patient is received by the UCL CTC (i.e. it is anticipated that this will be when the final 
patient completes their 2 year follow-up visit). At this point the ‘declaration of end of trial’ 
form will be submitted to the MHRA and Ethics Committee, as required. 
Following this, UCL CTC will advise sites on the procedure for closing the trial at the site. 
Once the end of trial has been declared, no more prospective patient data will be collected 
but sites must co-operate with any data queries regarding existing data to allow for 
analysis and publication of results. 
16.2. Archiving of Trial Documentation 
At the end of the trial, UCL CTC will archive securely all centrally held trial related 
documentation for a minimum of 5 years. Arrangements for confidential destruction will 
then be made. It is the responsibility of PIs to ensure data and all essential documents 
relating to the trial held at site are retained securely for a minimum of 5 years after the 
end of the trial, and in accordance with national legislation. 
Essential documents are those which enable both the conduct of the trial and the quality 
of the data produced to be evaluated and show whether the site complied with the 
principles of GCP and all applicable regulatory requirements. 
UCL CTC will notify sites when trial documentation held at sites may be archived. All 
archived documents must continue to be available for inspection by appropriate 
authorities upon request. 
16.3. Early Discontinuation of Trial 
The trial may be stopped before completion as an Urgent Safety Measure on the 
recommendation of the TSC or IDMC (see section 14.5.2 Trial Steering Committee (TSC) 
and 14.5.3 Independent Data Monitoring Committee (IDMC)). Sites will be informed in 
writing by UCL CTC of reasons for early closure and the actions to be taken with regards 
the treatment and follow up of patients. 
16.4. Withdrawal from Trial Participation by a Site 
Should a site choose to close to recruitment the PI must inform UCL CTC in writing. 
Follow up as per protocol must continue for any patients recruited into the trial at that site 
and other responsibilities continue as per the mNCA. 
 
 
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17. 
STATISTICS 
17.1. Sample Size Calculation 
The primary endpoint is the overall response rate (defined as complete response (CR), 
very good partial response (VGPR), partial response (PR) or minor response (MR) i.e. a 
greater than 25% reduction in the serum IgM level) by 24 weeks post commencing 
treatment. 
 
It is thought the response rate could be around 60% but a rate of more than 40% is 
needed for this combination to be taken forward into a larger study. Using an A’Hern 
phase II trial design with a 1-sided alpha of 0.05 and power of 80% we will require 42 
patients. The primary endpoint will be met if we see 23 or more responses.  
17.2. Statistical analysis 
17.2.1. Analysis of primary endpoint 
The primary endpoint is the overall response rate (defined as complete response (CR), 
very good partial response (VGPR), partial response (PR) or minor response (MR) i.e. a 
greater than 25% reduction in the serum IgM level) by week 24 post commencing 
treatment. This will be presented as a percentage with 90% confidence interval. We do 
not expect missing response data at this time point (in this patient population) to be a 
problem, however, if it occurs it will be treated in the following way: 
 
Response data before 
24 weeks 
24 week 
response 
Clinical status at 
week 24 
Response 
Response reported at 
an earlier time point 
Missing 
Alive with no 
progression reported 
Responder 
No response at earlier 
time points 
Missing 
Any 
Non responder 
Any 
Missing 
Progressed or died 
Non responder 
 
Any patient who does not start trial treatment will be excluded and replaced.  
17.2.2. Analysis of secondary endpoints and secondary analyses 
 
Safety and tolerability of pembrolizumab in combination with rituximab 
 
As this is continuous treatment, care will be taken to assess the burden of adverse events 
over time rather than just the worst grades seen. 
 
Rates of adverse events (as assessed by CTCAE version 5.0) will be presented in four 
ways: 
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1. Worst grade seen of each event, i.e. the number of patients who experience a 
grade 1-2 or 3+ event at any time point. 
2. Worst grade seen of each event per cycle, i.e. the number of patients who 
experience a grade 1-2 or 3+ event during each cycle. 
3. Proportion of cycles where patients experience a grade1-2 or grade 3-4 AE. 
This may also be presented by the number of cycles depending on the numbers 
of patients stopping treatment. 
4. Median number of grade 1-2 or 3+ AEs (of any type) experienced at each cycle.  
 
Analyses 3-4 may focus on clinical events only i.e. excluding lower level biochemical and 
haematological events which may not have an impact on the patient’s quality of life.  
 
Depending on the frequency of adverse events, we may also look at duration of some 
events, possibly as a proportion of the time on treatment.  
 
AEs of special interest will be reported in more detail, with events of any grade presented.  
 
All adverse event analysis will be descriptive.  
 
Best response and time to best response. 
The best response is the best response seen from the start of treatment; all response 
time points will be included.  
Time to maximal response to treatment will be calculated as the time from the date of 
registration until the date of the best response. This will be presented as the median and 
range and will be reported for responding patients only. 
 
Time to next treatment  
Time to next treatment will be analysed using Kaplan-Meier survival analyses, with the 
time calculated from the date of registration to the date of the start of the next line of 
therapy. Patients who do not start a further line of treatment will be censored at the date 
last seen/date of death. The median (if applicable) and rates at 1 and 2 years will be 
presented.  
 
Progression free survival 
Progression free survival will be analysed using Kaplan-Meier survival analyses, with the 
time calculated from the date of registration to the date of progression/death. Patients 
who are alive and progression free will be censored at the date last seen. The median (if 
applicable), rates at 1 and 2 years and a Kaplan-Meier curve will be presented. 
 
Overall survival 
Overall survival will be analysed using Kaplan-Meier survival analyses, with the time 
calculated from the date of registration to the date of death. Patients who are alive will be 
censored at the date last seen. The median (if applicable), rates at 1 and 2 years and a 
Kaplan-Meier curve will be presented. 
 
Quality of life 
Quality of life is assessed using the QLQ-30 questionnaire at baseline and at week 24. 
Differences between baseline and week 24 will be compared using paired t-tests and 
changes between baseline and week 24 may also be compared to historical data from 
the R2W trial.  
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17.3. Interim analyses 
There will be no formal interim analyses however toxicities will be monitored closely 
throughout the trial (see section 12.6). In addition to periodic reviews, an IDMC meeting 
will be triggered as a result of trial-treatment related deaths as outlined below.   
An IDMC review will be triggered if the number of treatment related deaths exceeds 
10% of the number of patients recruited. 
Number of Patients 
(N) 
Number of treatment related 
deaths needed for IDMC 
trigger 
(more than 10% of N) 
10 
2 
15 
2 
20 
3 
25 
3 
30 
4 
35 
4 
 
 
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18. 
ETHICAL AND REGULATORY CONSIDERATIONS 
This trial will adhere to the conditions and principles of GCP as outlined in the Medicines 
for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031), as amended. 
In conducting the trial, the Sponsor, UCL CTC and sites shall comply with the protocol 
and with all relevant guidance, laws and statutes, as amended from time to time, 
applicable to the performance of clinical trials and research including, but not limited to: 
• The UK Policy Framework for Health and Social Care Research, issued by the 
Health Research Authority 
• Human Rights Act 1998 
• Data Protection Act 2018 
• General Data Protection Regulation (EU)2016/679 (GDPR) 
• Freedom of Information Act 2000 
• Human Tissue Act 2004 
• Medicines for Human Use (Clinical Trials) Regulations (SI 2004/1031), and 
subsequent amendments  
• Medicines Act 1968  
• Good Manufacturing Practice  
18.1. Ethical Approval 
The trial will be conducted in accordance with the World Medical Association Declaration 
of Helsinki entitled ‘Ethical Principles for Medical Research Involving Human Subjects’ 
(1996 version) and in accordance with the terms and conditions of the ethical approval 
given to the trial. 
The trial has received a favourable opinion from the London – London West Research 
Ethics Committee (REC) and Health Research Authority (HRA) approval for conduct in 
the UK. 
UCL CTC will submit Annual Progress Reports to the REC, commencing one year from 
the date of ethical approval for the trial. 
Favourable opinion will also be obtained in all participating countries outside the UK in 
compliance with all local laws, statutes and requirements. 
18.2. Regulatory Approval 
A Clinical Trial Authorisation (CTA) has been granted for the trial. 
The trial will be conducted at approved trial sites in accordance with the trial protocol and 
the terms of the CTA granted by the MHRA.  
18.3. Site Approvals 
Evidence of assessment of capability and capacity by the Trust/Health Board R&D for a 
trial site must be provided to UCL CTC. Sites will only be activated when all necessary 
local approvals for the trial have been obtained. 
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18.4. Protocol Amendments 
UCL CTC will be responsible for gaining ethical and regulatory approval, as appropriate, 
for amendments made to the protocol and other trial-related documents. Once approved, 
UCL CTC will ensure that all amended documents are distributed to sites as appropriate. 
Site staff will be responsible for acknowledging receipt of documents and for 
implementing all amendments promptly. 
18.5. Patient Confidentiality & Data Protection 
Patient identifiable data, including initials and date of birth will be required for the 
registration process and will be provided to UCL CTC. UCL CTC will preserve patient 
confidentiality and will not disclose or reproduce any information by which patients could 
be identified. Data will be stored in a secure manner and UCL CTC trials are registered 
in accordance with the Data Protection Act 2018 and GDPR with the Data Protection 
Officer at UCL. 
Patient identifiable data, including initials and date of birth will be provided to the HMDS 
in order to process the sample. HMDS will preserve patient confidentiality and will not 
disclose or reproduce any information by which patients could be identified. 
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19. 
SPONSORSHIP AND INDEMNITY 
19.1. Sponsor Details 
 
Sponsor Name: University College London 
 
Address: 
Joint Research Office 
Gower Street 
London 
WC1E 6BT 
 
Contact: 
Managing Director, UCLH/UCL Research 
 
 
 
Tel:  
020 3447 9995/2178 (unit admin)  
Fax: 
020 3447 9937 
19.2. Indemnity 
University College London holds insurance against claims from participants for injury 
caused by their participation in the clinical trial. Participants may be able to claim 
compensation if they can prove that UCL has been negligent. However, as this clinical 
trial is being carried out in a hospital, the hospital continues to have a duty of care to the 
participant of the clinical trial. University College London does not accept liability for any 
breach in the hospital’s duty of care, or any negligence on the part of hospital employees. 
This applies whether the hospital is an NHS Trust or otherwise. 
Participants may also be able to claim compensation for injury caused by participation in 
this clinical trial without the need to prove negligence on the part of University College 
London or another party. Participants who sustain injury and wish to make a claim for 
compensation should be advised to do so in writing in the first instance to the Chief 
Investigator, who will pass the claim to the Sponsor’s Insurers, via the Sponsor’s office.  
Hospitals selected to participate in this clinical trial shall provide clinical negligence 
insurance cover for harm caused by their employees and a copy of the relevant insurance 
policy or summary shall be provided to University College London, upon request. 
 
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20. 
FUNDING 
MSD Ltd are supporting the central coordination of the trial through UCL CTC, 
translational research at HMDS, and supplying pembrolizumab free of charge for use in 
the trial.   
Research A costs will be reimbursed to sites as per the finance section of the mNCA. 
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Protocol Template version 11/Mar/2021 
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21. 
PUBLICATION POLICY 
The results of the PemboWM trial will be presented at relevant conferences and published 
in a peer reviewed journal. The primary publication from the trial will be written by the 
TMG. Authors will include the CI, TMG members, representatives of UCL CTC including 
the trial coordinator and trial statistician, and PIs at sites that make a significant 
contribution to patient recruitment.  
Abstracts and papers will be reviewed by MSD Ltd prior to submission in accordance with 
the requirements of the Trial Drug Supply Agreement. 
The ISRCTN/Clinicaltrials.gov number of the trial and the funder reference number will 
be quoted in all publications. 
Sites may not publish any data pertaining to PembroWM patients without prior written 
permission from the TMG. 
Data generated from the PembroWM trial will be the property of UCL as Trial Sponsor. 
 
 
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22. 
REFERENCES 
Ansell SM. PD-1 Is Expressed on B-Cells in Waldenstrom Macroglobulinemia and 
Promotes Malignant Cell Viability and Proliferation. Blood 2014 124:3015; 
Bröckelmann PJ, Engert A. Checkpoint Inhibition in Hodgkin Lymphoma - a Review. 
Oncol Res Treat. 2017 ;40(11):654-660 
Brookmeyer, B et al. A confidence interval for the median survival time, Biometrics 1982; 
38(1): 29-41. 
Cockcroft DW, et al. Nephron 1976; 16(1):31-41. 
Common Toxicity Criteria Version 4.03. Cancer Therapy Evaluation Program. 14 June 
2010. 
Davids, M.S., et al., Phase I First-in-Human Study of Venetoclax in Patients With 
Relapsed or Refractory Non-Hodgkin Lymphoma. J Clin Oncol, 2017. 35(8): p. 826-833. 
Ding W, Laplant B, Witzig T el al. PD-1 Blockade with Pembrolizumab in Relapsed Low 
Grade Non-Hodgkin Lymphoma. ASH annual meeting abstracts, 2017  
Gavriatopoulou M, García-Sanz R, Kastritis E et al. BDR in newly diagnosed patients 
with WM: final analysis of a phase 2 study after a minimum follow-up of 6 years. Blood. 
2017 Jan 26; 129(4):456-459.  
Ghobrial IM, Redd R, Armand P et al. Phase I/II trial of everolimus in combination with 
bortezomib and rituximab (RVR) in relapsed/refractory Waldenstrom macroglobulinemia. 
Leukemia. 2015 Dec;29(12):2338-46 
Gertz MA, Fonseca R, Rajkumar SV. Waldenström’s Macroglobulinemia. Oncologist 
2000; 5:63-67 
Gertz MA. Waldenström macroglobulinemia: 2015 update on diagnosis, risk stratification, 
and management. Am. J. Hematol. 2015; 90:347–354. 
Gustine J, Meid K, Dubeau T et al. Ibrutinib Discontinuation in Waldenström 
Macroglobulinemia: Etiologies, Outcomes, and IgM Rebound. Blood 2017 – ASH annual 
meeting abstracts 
Greenwood, M. The natural duration of cancer. Reports of Public Health and Related 
Subjects, HMSO, London, 1926; 33:1-26. 
Hodge LS, Ziesmer SC, Yang ZZ, et al. IL-21 in the bone marrow microenvironment 
contributes to IgM secretion and proliferation of malignant cells in Waldenstrom 
macroglobulinemia. Blood. 2012 Nov 1; 120(18):3774-82 
Jacobson CA, Freedman AS. First-line treatment of indolent lymphoma: axing CHOP? 
Lancet 2013; 381:1163. 
Jalali S, Price-Troska T, Villasboas Bisneto J et al. Soluble PD-1 Ligands Regulate T-
Cell Function in Waldenstrom’s Macroglobulinemia. ASH Annual meeting abstracts 
2017.  
Kastritis E, Gavriatopoulou M, Kyrtsonis M et al. Dexamethasone, rituximab, and 
cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final 
analysis of a phase 2 study. Blood. 2015 Sep 10; 126(11):1392-4. 
DocuSign Envelope ID: 426F4AEA-7A6C-41BC-AFD4-40D6FE5A342B


Pembro WM 
 
Pembro WM protocol version v2.0 27/07/2021 
Protocol Template version 11/Mar/2021 
page 86 of 94 
Kuhne, M.R., et al., BMS-936564/MDX-1338: a fully human anti-CXCR4 antibody 
induces apoptosis in vitro and shows antitumor activity in vivo in hematologic 
malignancies. Clin Cancer Res, 2013. 19(2): p. 357-66. 
Leblond V, Kastritis E, Advani R, et al. Treatment recommendations from the Eighth 
International Workshop on Waldenström's Macroglobulinemia. Blood. 2016 Sep 
8;128(10):1321-8 
Morel P, Duhamel A, Gobbi P, et al. International prognostic scoring system for 
Waldenström macroglobulinemia. Blood. 2009 Apr 30; 113(18):4163-70. 
Nastoupil L, Westin J, Fowler N et al. PD-1 Blockade with Pembrolizumab in Relapsed 
Low Grade Non-Hodgkin Lymphoma. ASH Annual meeting abstracts, 2017. 
Oken MM, et al. Toxicity and Response Criteria of the Eastern Cooperative Oncology 
Group. Am J Clin Oncol 1982; 5:649-655. 
Owen RG et al. Response assessment in Waldenström macroglobulinaemia: update 
from the VIth International Workshop. Br J of Haematol, 2013; 160:171-176. 
Patnaik A, Kang SP, Rasco D, et al.. Phase I Study of Pembrolizumab (MK-3475; Anti-
PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors. Clin Cancer Res 
2015 Oct 1;21(19):4286-93 
Rummel MJ, Niederle N, Maschmeyer G, 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; 381:1203–10. 
Santos-Lozano, A., et al., Response rate to the treatment of Waldenstrom 
macroglobulinemia: A meta-analysis of the results of clinical trials. Crit Rev Oncol 
Hematol, 2016. 105: p. 118-26. 
Treon, S.P., How I treat Waldenstrom macroglobulinemia. Blood, 2015. 126(6): p. 721-
32. 
Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in Previously Treated Waldenström’s 
Macroglobulinemia. N Engl J Med 2015; 372:1430-40. 
Treon SP, Xu L, Hunter Z. MYD88 Mutations and Response to Ibrutinib in Waldenström’s 
Macroglobulinemia. N Engl J Med 2015; 373: 584-85.Treon SP, Xu L, Yang G, et al. 
MYD88 MUT Somatic Mutation in Waldenström’s Macroglobulinemia. N En 
Treon SP, Tripsas CK, Meid K, et al. Carfilzomib, rituximab, and dexamethasone (CaRD) 
treatment 
offers 
a 
neuropathy-sparing 
approach 
for 
treating Waldenström's 
macroglobulinemia. Blood. 2014 Jul 24;124(4):503-10.  
Treon SP, Meid P, Gustine J et al. Long-Term Follow-up of Previously Treated Patients 
Who Received Ibrutinib for Symptomatic Waldenstrom’s Macroglobulinemia: Update of 
Pivotal Clinical Trial. Blood 2017 – ASH annual meeting abstracts 
Yang J, Hatcher J, Wang J et al. A Novel, Highly Selective IRAK1 Inhibitor Jh-X-119-01 
Shows Synergistic Tumor Cell Killing with Ibrutinib in MYD88 Mutated B-Cell Lymphoma 
Cells. ASH Annual Meeting Abstacts, 2017. 
 
 
 
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Protocol Template version 7 25/Jul/2016 (updated in line with version 8 19/Jun/2018 
page 87 of 94 
 
APPENDIX 1: QUICK REFERENCE GUIDE TO PATIENT VISITS 
 
Pre-
registration  
(within 28 days of 
full registration 
unless otherwise 
stated) 
D1 of 
each 
cycle  
(- 3days) a  
Response 
at 12 
weeks  
(+/- 3days) 
Response 
at 24 weeks  
(+/- 3days) 
Response 
at 1 year 
(+/- 2weeks) 
D+60 post 
treatment 
discontinuation 
(+/- 3days) b 
5 months post 
treatment 
discontinuation 
(+4weeks) 
Annual FU 
until EoT 
declared  
(pt who complete 
treatment/ 
discontinue for 
reasons other 
than progression) 
Annual 
FU until 
EoT 
declared 
(following 
disease 
progression) 
Eligibility checklist 
X 
 
 
 
 
 
 
 
 
Demographics and 
Medical History (see 
9.1) 
X 
 
 
 
 
 
 
 
 
Physical 
examination 
including 
performance status 
and observations(see 
9.1 & 9.2) 
X 
X 
 
 
 
X 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
X 
 
 
 
Quality of Life 
Questionnaire 
X 
 
 
X 
 
 
 
 
 
Lymph node biopsyc 
X 
 
 
 
 
 
 
 
 
Adverse Event 
reportingd 
X 
Concomitant 
Medications 
X 
ECGe 
X 
X 
 
 
 
 
 
 
 
Hepatitis B and C 
serology 
X 
 
 
 
 
 
 
 
 
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HIV serology 
X 
 
 
 
 
 
 
 
 
FBC 
X 
X 
X 
X 
X 
X 
 
 
 
U+E  
X 
X 
X 
X 
X 
X 
 
 
 
LFT 
X 
X 
X 
X 
X 
X 
 
 
 
LDH 
X 
 
 
 
 
X 
 
 
 
Β2 microglobulin 
X 
 
 
 
 
 
 
 
 
Serum IgM, IgG, IgA 
X 
X 
X 
X 
X 
 
 
 
 
Serum paraprotein 
X 
X 
X 
X 
X 
 
 
 
 
Serum 
immunofixationf 
 
X 
X 
X 
X 
 
 
 
 
Direct antiglobulin 
test 
X 
 
 
 
 
 
 
 
 
TSH, glucose, 
ACTH 
X 
X 
 
 
 
X 
 
 
 
Pregnancy test  
(serum or urine) 
X 
X 
 
 
 
 
 
 
 
Amylase  
X 
X 
 
 
 
X 
 
 
 
CT scang 
X 
 
 
X 
X 
 
 
 
 
Serum SFLC 
X 
 
X 
X 
X 
 
 
 
 
Bone marrow 
aspirate and 
trephineh 
X 
 
 
X 
X 
 
 
 
 
MyD88 and CXCR4 
mutation status by 
NGSi 
X 
 
 
 
 
 
 
 
 
Flow for B-cell and 
plasma cell 
phenotypej 
X 
 
 
X 
X 
 
 
 
 
Remission status 
and assessment of 
late toxicityk 
 
 
 
 
 
 
 
X 
X 
 
 
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 a: patients will remain on treatment for a maximum of 1 year or until disease progression, discontinuation due to unacceptable toxicity or any other reason 
(whichever occurs sooner). 
b: patients who complete treatment or discontinue treatment early for reasons other than progression should be followed at day 60 post treatment discontinuation 
(+/-3 days).  They will then be followed up at 5 months and annually thereafter until the last patient completes 2 years of follow up. 
c: Lymph node biopsy if nodal disease. Biopsy within 28 days prior to C1D1 preferred. If not possible, then historical biopsy tissue will be obtained and sent for 
exploratory analysis at HMDS (see section 10 for further details). Note: this only applies to patients who have given consent to optional samples being sent to 
HMDS. 
d: Adverse events are to be recorded between informed consent and 5 months after the last IMP administration.  AESI and SAES are to be reported to UCL CTC 
within 24 hours of awareness (see section 12 for details), 
e: A 12 lead ECG should be performed for all patients pre-registration and prior to commencing each cycle of pembrolizumab.  Further ECGs should be performed 
as clinically indicated.  
f: Serum immunofixation to be performed only if paraprotein no longer detectable.  
g: CT scan of neck, chest, abdomen and pelvis (NCAP) to be performed pre-registration (within 28 days prior to starting treatment).  CT scan (NCAP) to be 
repeated at 24 weeks and 1 year post commencing treatment only if nodal disease on baseline assessment. Thereafter, only to be done if clinical concerns of 
nodal progression.  If no measurable disease was documented at baseline, then a CT NCAP should be performed as clinically indicated. 
h: Bone marrow aspirate and trephine to be performed pre-registration (within 28 days prior to starting treatment) and at week 24 and 1 year to determine 
response.  Samples to be analysed locally.  Additionally, for consenting patients bone marrow samples to be sent to HMDS for exploratory analysis (see section 10 
for further details). 
i: Peripheral blood sample for MyD88 and CXCR4 analysis will be sent at screening to HMDS for exploratory analysis from consenting patients (see section 10 for 
further details).  
j: Peripheral blood sample for flow cytometry for B-cell/plasma cell phenotypes will be sent to HMDS for exploratory analysis from consenting patients (see section 
10 for further details). 
k: Remission status as per local policy. 
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Protocol Template version 7 25/Jul/2016 (updated in line with version 8 19/Jun/2018 
page 90 of 94 
 
APPENDIX 2: ECOG PERFORMANCE STATUS  
*Oken et al, 1982 
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Protocol Template version 11/Mar/2021 
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APPENDIX 3: RESPONSE ASSESSMENT*  
Response category  
 
Definition  
Complete response (CR)  
 
Absence of serum monoclonal IgM protein by 
immunofixation  
 
Normal serum IgM levela 
 
Complete resolution of lymphadenopathy and 
splenomegaly if present at baseline  
 
Morphologically normal bone marrow 
aspirate and trephine biopsy  
 
Very Good Partial Response (VGPR)  
 
Detectable monoclonal IgM protein 
 
≥90% reduction in serum IgM level from 
baselineb 
 
Complete resolution of extramedullary 
disease, i.e. lymphadenopathy/splenomegaly 
if present at baseline 
 
No new signs or symptoms of active disease  
 
Partial response (PR)  
 
Detectable monoclonal IgM protein  
 
≥50% but <90% reduction in serum IgM level 
from baselineb  
 
Reduction in extramedullary disease, i.e. 
lymphadenopathy/splenomegaly if present at 
baseline  
 
No new signs or symptoms of active disease  
 
Minor response (MR)  
 
Detectable monoclonal IgM protein 
 
≥25% but <50% reduction in serum IgM level 
from baselineb  
 
No new signs or symptoms of active disease  
 
Stable disease (SD)  
 
Detectable monoclonal IgM protein 
 
<25% reduction and <25% increase in serum 
IgM level from baselineb 
 
No progression in extramedullary disease, 
i.e.  lymphadenopathy/splenomegaly  
 
No new signs or symptoms of active disease  
 
Progressive disease (PD)  
 
≥25% increase in serum IgM levela,b from 
lowest nadirc and/or 
 
Progression in clinical features attributable to 
the disease  
 
*Owen et al, 2013 
aIgM responses/progression should be confirmed by a second measurement (ideally taken within the 
same cycle as the initial measurement) 
bSequential changes in IgM levels may be determined either by IgM protein quantitation by densitometry 
or total serum IgM quantitation by nephelometry 
cThe effects of any plasmapheresis should be considered when determining the lowest nadir 
Note: where local investigations are inconclusive in determining progression, or the Site are uncertain that 
the progression in clinical features is attributable to the disease, the TMG should be contacted for advice. 
In these circumstances please email ctc.PembroWM@ucl.ac.uk. 
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APPENDIX 4: PROTOCOL VERSION HISTORY 
Protocol: 
Amendments: 
 
Version 
no. 
Date 
Amendment no.  
Protocol 
Section 
(no./title) 
Summary of main changes from previous 
version. 
1 
12/10/18 
Initial submission 
n/a 
n/a 
1.1 
19/12/18 
Response to 
MHRA grounds of 
non-acceptance 
6.2.1 
 
6.3.3 and 
throughout  
 
6.3.5 
-Clarifying the Bilirubin levels required for 
trial inclusion 
-Clarifying that the urine pregnancy test 
should be highly sensitive test (minimum 
sensitivity 25 IU/I) 
-Amending information to state that patients 
that become pregnant prior to initiating 
treatment will be withdrawn from the trial 
1.2 
12/02/19 
Response to REC 
provisional 
opinion 
14.4.3 
 
17.3 
-Addition of trigger points for IDMC review 
of safety data  
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2.0 
010/05/21 
Amendment 08 
TMG 
 
1.1 
 
 
6.2.1 
 
 
 
 
 
 
 
6.2.2 
 
 
 
 
 
 
 
 
 
 
 
 
7.1, 7.2 
and 
throughout 
 
 
8.3 
 
 
 
 
8.4.2 
 
8.7 
 
 
 
8.10 
 
 
14 
 
 
15 
 
 
 
16.1 
 
16.2 
 
 
18 
 
 
19 
-Update to members 
 
-Update to duration of recruitment and total 
sites  
 
- Clarifying the description of measurable 
disease 
-Allowing more severe cytopenias, with no 
lower limit if cytopenia is due to bone 
marrow involvement and growth 
factor/transfusion support permitted prior to 
C1D1. 
 
-BTK inhibitors allowed up until 48 hours 
prior to C1D1 
-Addition of live-attenuated vaccines 
-Clarifying the exclusion of Hep C positive 
patients 
-Allowing a short course of oral 
prednisolone within 7 days of C1D1 
following BTK inhibitor discontinuation            
-Allowing a subset of patients with a history 
of colitis 
-Removal of current participation in any 
other CTIMP when C1D1 commences 
 
-Addition of pre-registration process to 
assign a trial number prior to full registration 
to enable translational samples to be sent 
to central laboratory 
 
-Allowing patients with cytopenias Grade 4 
(as per CTCAE v5.0) to receive treatment  
-Allowing treatment to be moved due to 
logistical reasons 
 
-Updated management of irAEs table 
 
-Guidance added for the use of vaccines 
-Guidance added for the use of growth 
factor/transfusions 
 
-Updated MSD out of hours telephone 
number 
 
-Addition of remote monitoring and the 
escalation process for monitoring issues 
 
-Addition of the withdrawal of consent 
process and clarifications made for losses 
to follow-up 
 
-Clarification of the End of Trial 
 
-Archiving duration updated to 5 years 
 
 
-Updated ethical and regulatory 
considerations 
 
-Updated sponsor contact 
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Appendix 3 
 
 
 
Throughout 
-Clarification on determining the nadir 
-Addition of repeat testing to confirm 
remission and progression 
 
-Removal of faxing process 
-Minor clarifications and corrections of 
typographical errors 
 
 
 
 
 
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