A Phase I Study to Assess the Safety and Tolerability of Pembrolizumab in Combination With Fixed Rate Gemcitabine Chemotherapy in Patients With Leiomyosarcoma and Undifferentiated Pleomorphic Sarcoma
Phase: PHASE1
Conditions: Sarcoma
Sponsor: Royal Marsden NHS Foundation Trust

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IN ORDER TO AVOID ERRORS, PLEASE DISCARD OUTDATED VERSIONS OF THE PROTOCOL BUT RETAIN ONE COPY 
FOR INVESTIGATOR SITE FILE 
CONFIDENTIAL 
 
 
 
 
 
 
A phase I study to assess the safety and tolerability of pembrolizumab in 
combination with fixed rate gemcitabine chemotherapy in patients with 
leiomyosarcoma and undifferentiated pleomorphic sarcoma 
Short title: 
GEMMK study 
Sponsor: 
Royal Marsden NHS Foundation Trust 
Sponsor protocol number: 
CCR 4541 
EudraCT: 
2016-004092-45 
ClinicalTrials.gov ID: 
NCT03123276 
Protocol version and date: 
V5.1, 16 May 2022 
REC Reference: 
17/LO/0767 

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Signature Page: 
 
 
The undersigned confirm that the following protocol has been agreed and accepted and that the Chief investigator 
agrees to conduct the trial in compliance with the approved protocol and will adhere to the principles outlined in the 
Medicines for Human Use (Clinical Trials) Regulations 2004 (SI 2004/1031) amended regulations (SI 2006/1928) and 
any subsequent amendments of the clinical trials regulations, GCP guidelines, the Sponsor’s SOPs and other regulatory 
requirements as amended. 
I agree to ensure that the confidential information contained in this document will not be used for any other purpose 
other than the evaluation or conduct of the clinical investigation without the prior written consent of the sponsor. 
I also confirm that I will make the findings of the study publically available through publication or other dissemination 
tools without any unnecessary delay and that an honest accurate and transparent account of the study will be given 
and that any discrepancies from the study as planned in this protocol will be explained.  
Chief Investigator / Principle Investigator 
Name (Please print) 
 
 
Signature 
 
 
Date
 
Statistician  
Name (Please print) 
 
 
Signature
 
Date 
 
 
 
 
 
 

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Contents 
KEY TRIAL CONTACTS 
11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
15 
1.TRIAL SUMMARY 
28 
2.BACKGROUND & RATIONALE 
30 
2.1 BACKGROUND 
30 
2.1.1. PHARMACEUTICAL AND THERAPEUTIC BACKGROUND 
30 
2.1.2. PRECLINICAL AND CLINICAL TRIAL DATA 
30 
2.2 RATIONALE 
31 
2.2.1. RATIONALE FOR THE TRIAL AND SELECTED SUBJECT POPULATION 
31 
2.2.2. RATIONALE FOR DOSE SELECTION/REGIMEN/MODIFICATION 
32 
3.OBJECTIVES & ENDPOINTS 
34 
3.1PRIMARY OBJECTIVE & ENDPOINT 
34 
3.2SECONDARY OBJECTIVE & ENDPOINT 
34 
3.3EXPLORATORY OBJECTIVE (BIOMARKER RESEARCH) 
34 
4.TRIAL DESIGN 
35 
4.1TRIAL DESIGN 
35 
4.2STUDY FLOW CHART 
37 
5.SELECTION OF PATIENTS 
38 
5.1ENTRY CRITERIA 
38 

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5.2SUBJECT INCLUSION CRITERIA 
38 
5.3SUBJECT EXCLUSION CRITERIA 
40 
5.4SCREENING AND ENROLMENT 
41 
5.5REGISTRATION 
41 
6.STUDY PLAN AND PROCEDURES 
43 
6.1VISIT SCHEDULE 
43 
6.2ADMINISTRATIVE PROCEDURES 
45 
6.2.1. INFORMED CONSENT 
45 
6.2.2. INCLUSION/EXCLUSION CRITERIA 
45 
6.2.3. MEDICAL HISTORY 
45 
6.2.4. PRIOR AND CONCOMITANT MEDICATIONS REVIEW 
45 
6.2.5. DISEASE DETAILS AND TREATMENT 
46 
6.2.6. ASSIGNING SCREENING/TREATMENT ALLOCATION NUMBERS 
46 
6.2.7. ASSIGNING A SUBJECT IDENTIFICATION CARD 
46 
6.3. CLINICAL PROCEDURES/ASSESSMENTS 
46 
6.3.1. AE MONITORING AND SAFETY ASSESSMENTS 
46 
6.3.2. FULL PHYSICAL EXAM 
47 
6.3.3. VITAL SIGNS 
47 
6.3.4. ECOG PERFORMANCE SCALE 
47 
6.3.5. TUMOUR IMAGING AND ASSESSMENT OF DISEASE 
47 

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6.3.6. TUMOUR TISSUE COLLECTION (MANDATORY) AND CORRELATIVE STUDIES BLOOD 
SAMPLE 
47 
6.4. LABORATORY PROCEDURES/ASSESSMENTS 
48 
6.5. OTHER PROCEDURES 
52 
6.6. VISIT REQUIREMENTS 
52 
6.6.1. SCREENING VISIT 
52 
6.6.2. TREATMENT PERIOD 
53 
6.6.3. SAFETY FOLLOW UP VISITS 
56 
6.6.4. FOLLOW UP VISITS 
56 
6.6.5. SURVIVAL FOLLOW UP 
56 
6.6.6. SECOND COURSE PHASE (RETREATMENT PERIOD) 
56 
7. 
TRIAL TREATMENTS
 
58 
7.1. DOSE SELECTION/MODIFICATION 
58 
7.1.1. DOSE SELECTION 
58 
7.1.2. DOSE MODIFICATION (ESCALATION/TITRATION/OTHER) 
59 
7.2. TIMING OF DOSE ADMINISTRATION 
66 
7.3. TRIAL BLINDING/MASKING 
66 
7.4. TREATMENT ALLOCATION 
66 
7.5. CONCOMITANT MEDICATIONS/VACCINATIONS (ALLOWED & PROHIBITED) 
67 
7.5.1. ACCEPTABLE CONCOMITANT MEDICATIONS 
67 

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7.5.2. PROHIBITED CONCOMITANT MEDICATIONS 
67 
7.6. RESCUE MEDICATIONS & SUPPORTIVE CARE 
68 
7.6.1. SUPPORTIVE CARE GUIDELINES 
68 
7.7. DIET/ACTIVITY/OTHER CONSIDERATIONS 
73 
7.7.1. DIET 
73 
7.7.2. CONTRACEPTION 
73 
7.7.3. USE IN PREGNANCY 
73 
7.7.4. USE IN NURSING WOMEN 
73 
7.8. SUBJECT WITHDRAWAL/DISCONTINUATION CRITERIA 
74 
7.8.1. DISCONTINUATION OF STUDY THERAPY AFTER CR 
74 
7.9. SUBJECT REPLACEMENT STRATEGY 
75 
7.10. CLINICAL CRITERIA FOR EARLY TRIAL TERMINATION 
75 
8. PHARMACOVIGILANCE 
75 
8.1. ADVERSE EVENTS 
75 
8.1.1. ADVERSE EVENT DEFINITION 
75 
8.1.2. ADVERSE REACTION DEFINITION 
76 
8.1.3. DISEASE PROGRESSION 
76 
8.1.4. NEW CANCERS 
76 
8.1.5. ABNORMAL LABORATORY TEST RESULTS 
76 
8.1.6. PREGNANCY AND LACTATION 
76 

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8.2. ASSESSING AND RECORDING ADVERSE EVENTS 
76 
8.3. EVALUATING ADVERSE EVENTS 
77 
8.4. SERIOUS ADVERSE EVENTS (SAES) 
78 
8.4.1. REPORTING SAES 
79 
8.4.2. EVENTS EXEMPT FROM BEING REPORTED AS SAES. 
79 
8.5. EVENTS OF CLINICAL INTEREST (ECI) 
80 
8.5.1. DEFINITION OF ECIS 
80 
8.5.2. REPORTING OF ECIS 
82 
8.6. DEFINITION OF AN OVERDOSE FOR THIS PROTOCOL AND REPORTING OF AN OVERDOSE 82 
8.7. REPORTING OF PREGNANCY AND LACTATION 
83 
8.8. DEFINITION OF SERIOUS ADVERSE REACTION (SAR) 
83 
8.9. DEFINITION OF SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION (SUSARS) 
83 
8.10. REPORTING OF SUSARS 
83 
8.11. ANNUAL REPORTING OF SERIOUS ADVERSE EVENTS 
84 
8.12. URGENT SAFETY MEASURES 
84 
9. STATISTICAL AND DATA ANALYSIS PLAN 
84 
9.1. SAMPLE SIZE 
84 
9.2. STATISTICAL ANALYSIS 
84 
9.2.1. PRIMARY ENDPOINT 
84 
9.2.2. SECONDARY ENDPOINTS 
84 

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9.2.3. EXPLORATORY ENDPOINTS 
85 
10. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
85 
10.1. INVESTIGATIONAL PRODUCT 
85 
10.2. PACKAGING AND LABELING INFORMATION 
86 
10.3. CLINICAL SUPPLIES DISCLOSURE 
86 
10.4. STORAGE AND HANDLING REQUIREMENTS 
86 
10.5. RETURNS AND RECONCILIATION 
86 
11. REGULATORY, ETHICAL AND LEGAL ISSUES 
86 
11.1. GOOD CLINICAL PRACTICE 
86 
11.2. RESEARCH ETHICS COMMITTEE-REC/ REGULATORY AUTHORITY – RA 
86 
11.2.1. INITIAL APPROVAL 
86 
11.2.2. APPROVAL OF AMENDMENTS 
87 
11.2.3. ANNUAL SAFETY REPORTS AND END OF TRIAL NOTIFICATION 
87 
11.3. REGULATORY AUTHORITY APPROVAL 
87 
11.4. NOTIFICATIONS OF SERIOUS BREACHES TO GCP AND / OR THE PROTOCOL 
87 
11.5. INSURANCE AND LIABILITY 
87 
11.6. CONTACTS WITH GENERAL PRACTITIONER (GP) 
88 
11.7. PATIENT CONFIDENTIALITY 
88 
11.7.1. PATIENT CONFIDENTIALITY AND DATA SHARING 
88 
11.7.2. PHARMACOGENETIC CONFIDENTIALITY 
88 

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11.8. DATA COLLECTION AND DOCUMENTATION 
88 
11.9. END OF TRIAL 
89 
12. DATA AND STUDY MANAGEMENT 
89 
12.1. SOURCE DATA 
89 
12.2. LANGUAGE 
89 
12.3. DATA COLLECTION 
89 
12.4. ELECTRONIC RECORDING OF DATA 
89 
12.5. DATA MANAGEMENT 
90 
12.6. STUDY MANAGEMENT STRUCTURE 
90 
12.6.1. DELEGATION OF RESPONSIBILITIES 
90 
12.6.1.1. RM-CTU 
90 
12.6.1.2. MERCK SHARP & DOHME (MSD) CORP. 
90 
12.6.1.3. SARCOMA RESEARCH FUND 
90 
12.7. PROTOCOL COMPLIANCE AND AMENDMENTS 
90 
12.8. TRIAL MANAGEMENT 
90 
12.8.1. TRIAL MANAGEMENT GROUP 
91 
12.8.2. SAFETY REVIEW COMMITTEE (SRC) 
91 
12.9. MONITORING 
91 
12.10. QUALITY CONTROL AND QUALITY ASSURANCE 
91 
12.11. CLINICAL STUDY REPORT 
92 

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12.12. RECORD RETENTION 
92 
12.13. REPORTING AND PUBLICATION 
92 
12.14. ETHICAL CONSIDERATIONS 
92 
13. LIST OF REFERENCES 
93 
14. APPENDICES 
96 
14.1. APPENDIX 1 – ECOG PERFORMANCE STATUS 
96 
14.2. COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS V4.0 (CTCAE) 
96 
14.3. RESPONSE EVALUATION CRITERIA IN SOLID TUMOURS (RECIST) 1.1 CRITERIA FOR 
EVALUATING RESPONSE IN SOLID TUMOURS 
96 
 
 
Table 1- Adequate Organ Function Laboratory Values 
Table 2-Labortory Tests 
Table 3-Trial Treatment 
Table 4 –Dose Modification Guidelines for Drug-Related Adverse Events 
Table 5- Infusion Reaction Treatment Guidelines 
Table 6 – Determining AE Causality 
Table 7-Immune Related AEs considering ECIs 
Table 8 – Product Descriptions 
 
 
 
 
 
 

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KEY TRIAL CONTACTS  
 
Chief Investigator 
Dr Robin L Jones 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 0207 808 2457 
Email: Robin.jones@rmh.nhs.uk 
Co-Investigator 
Dr Charlotte Benson 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Email: Charlotte.Benson@rmh.nhs.uk 
Research Fellow 

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Andrea Napolitano 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust Fulham 
Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email:  Andrea.Napolitano@rmh.nhs.uk 
 
Catriona Goggin 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust Fulham 
Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: caitriona.goggin@rmh.nhs.uk 
 
Anna Stansfeld 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust Fulham 
Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: anna.stansfeld@rmh.nhs.uk 
 
Preethika Mahalingham 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust Fulham 
Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: preethika.mahalingam@rmh.nhs.uk 
 
 
 
 
 
 
 
 
 
 
 
Sponsor 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Email: GCPcomplianceteam@rmh.nhs.uk or research.development@rmh.nhs.uk 
Funder 

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Merck Sharp & Dohme (MSD) Limited
         Hertford Road,  
         Hoddesdon Hertfordshire EN11 9BU 
Trial Manager 
 Luke WebsterTrial Manager 
Royal Marsden Clinical Trials Unit 
Downs Rd, Sutton SM2 5PT 
Tel: 02088642 6011 Ext: 6767 
Fax: 0208 915 6762 
Email: gemmk.trial@rmh.nhs.uk 
Study Statistician 
Bernice Asare 
Research Data Management and Statistics Unit Royal 
Marsden Hospital 
Downs Rd, Sutton SM2 5PT 
Email: Bernice.Asare@rmh.nhs.uk 
 
PROTOCOL CONTRIBUTORS  
Chief Investigator 
Dr Robin L Jones 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 0207 808 2457 
Email: Robin.jones@rmh.nhs.uk 
Co-Investigator 
Dr Charlotte Benson 
Consultant Medical Oncologist 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Email: Charlotte.Benson@rmh.nhs.uk 
Research Fellow 
Jonathan Noujaim 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust  
Fulham Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: undefined [john.c.njm@gmail.com] 
Sponsor 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Email: GCPcomplianceteam@rmh.nhs.uk or research.development@rmh.nhs.uk
Funder 

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Merck Sharp & Dohme Limited 
Hertford Road, Hoddesdon 
Hertfordshire EN11 9BU 
Senior Trial Manager 
Yash Patel 
Snr. Trial Manager 
Royal Marsden Clinical Trials Unit 
Downs Rd, Sutton SM2 5PT 
Tel: 02088642 6011 Ext: 4297 
Fax: 0208 915 6762 
Email: gemmk.trial@rmh.nhs.uk 
Study Statistician 
Komel Khabra 
Research Data Management and Statistics Unit Royal 
Marsden Hospital 
Downs Rd, Sutton SM2 5PT 
Email: Komel.Khabra@rmh.nhs.uk 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ABPI
Association of the British Pharmaceutical Industry
ADC 
apparent diffusion coefficient 
AE
adverse event
alk phos/ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AML 
acute myeloid leukaemia 
ANC 
absolute neutrophil count 
APTT
Activated partial thromboplastin time
AST
aspartate aminotransferase 
ATM  
Ataxia telangectasia mutated 
ATR 
Ataxia telangectasia and Rad3-related 
AUC 
area under the curve 
BP
blood pressure
Cmax 
maximum observed plasma concentration 
CPT
Cell Preparation Tube 
CR 
complete response 
CRF 
case report form 
CR-UK 
Cancer Research UK 
CT 
computed tomography 
CTA
clinical trial authorisation
Day 
calendar day 
DDR
DNA damage response
DLT 
dose limiting toxicity 
DMR  
Dose modification ratio 
DNA-PK 
DNA-dependent protein kinase 
ECOG 
Eastern Cooperative Oncology Group 
EDTA 
Ethylenediaminetetra-acetic acid
ELISA 
Enzyme-linked immunosorbent assay 
ESMO 
European Society for Medical Oncology 
FDR  
Fixed Dose Rate 
GGT  
Gamma-glutamyl transpeptidase 
GCLP  
Good Clinical Laboratory Practice 
GCP 
Good Clinical Practice 
gdL  
gram(s) per decilitre  
GFR  
Glomerular Filtration Rate 
GI50
Concentration for half-maximal growth inhibition
GMP 
Good Manufacturing Practice 
GSK3b
Glycogen synthase kinase 3 beta
Gy
Gray
Hb 
Haemoglobin
HNSTD 
Highest non-severely toxic dose 
IC50 
Half maximal inhibitory concentration 
ICMJE 
International Committee of Medical Journal Editors

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IMP 
Investigational medicinal product 
INR 
International normalised ratio 
IR
Ionising radiation
ITF 
Investigator Trial File 
L/h 
litres per hour 
LDH
Lactate Dehydrogenase
MTD 
Maximum tolerated dose 
mg 
Milligram 
mg/m2
milligram per square metre
MHRA 
Medicines and Healthcare products Regulations Agency 
mmHg 
Millimetres of mercury 
MRI
magnetic resonance imaging
NTD 
non-tolerated dose 
PBMC 
Peripheral blood mononuclear cells 
PDc
pharmacodynamics
PD 
progressive disease 
P-gp 
P-glycoprotein 
PET
positron emission tomography
PFS 
Progression free survival 
PK 
Pharmacokinetic 
PR 
partial response 
PT 
Prothrombin time 
QC
quality control
QP 
Qualified Person  
QTc 
Corrected Q-T interval 
REC
Research Ethics Committee

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RECIST 
Response Evaluation Criteria in Solid Tumours 
RPA 
Replication protein A 
SAE
serious adverse event
SD 
stable disease 
SDV 
source data verification 
SJS
Stevens Johnson syndrome
SOP 
standard operating procedure 
SPC 
Summary of marketed Product Characteristics 
SRC 
safety review committee
STD10 
Severely toxic dose for 10% of animals 
STS  
Soft Tissue Sarcomas 
SUSAR
suspected unexpected serious adverse (drug) reaction
T1/2 
terminal elimination half-life 
TEN 
toxic epidermal necrolysis 
TSC
Trial Steering Committee 
Tmax 
Time to reach Cmax 
TGI 
Tumour growth inhibition 
ULN
upper limit of normal
UPS 
Undifferentiated pleomorphic sarcoma  
USM 
urgent safety measure 
WBC 
white blood cell 
 
 
 
 
 
 

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TABLE OF REVISIONS MADE TO THE PROTOCOL 
Protocol v2.0 
 
 
 
Page/ 
Section 
Previous Wording 
New Wording 
Comments/Explanation/Ratio
nale for Amendment 
Page 7 
N/A 
N/A 
Updates to key trial contacts 
Section 1 
Subjects will receive treatment in repeated 3-
week cycles. Subjects may remain on 
treatment until they experience disease 
progression or unacceptable toxicity, until they 
meet any of the withdrawal criteria or until the 
study is terminated by the sponsor 
Subjects will receive treatment in 
repeated 3-week cycles. Subjects may 
remain on treatment until they 
experience disease progression or 
unacceptable toxicity, until they meet 
any of the withdrawal criteria or until the 
study is terminated by the sponsor.  
Note: A subject may be granted an 
exception to continue on treatment with 
confirmed radiographic progression if 
clinically stable or clinically improved. 
Clarification of exception to 
withdrawal criteria which 
appears later in the protocol 
Section 3 
Primary Endpoint:  To establish the maximum 
tolerated dose (MTD) of pembrolizumab that 
can be safely combined with Gemcitabine in 
the absence of dose limiting toxicities (DLTs). 
 
 
 
 
 
 
 
Exploratory Endpoint 
Immunophenotyping of pre- and post-
treatment (9 weeks) biopsies (FFPE samples, 
density and phenotype of tumour infiltrating 
lymphocytes; CD3+, CD8+, CD45, FoxP3 and 
PD1, 
Endpoint: To establish the maximum 
tolerated dose (MTD) of gemcitabine 
that can be safely combined with 
pembrolizumab in the absence of dose 
limiting toxicities (DLTs). 
 
Exploratory objective: 
“To explore the relationship between, T 
cell and myeloid compartments, immune 
checkpoints and response to 
Pembrolizumab and Gemcitabine in 
leiomyosarcoma and undifferentiated 
pleomorphic sarcoma” 
 
Exploratory Endpoint 
Immunophenotyping of pre- and post-
treatment (9 weeks) biopsies (FFPE 
samples, density and phenotype of 
tumour infiltrating lymphocytes; CD3+, 
CD8+, CD45, FoxP3 and PD1 fresh biopsy 
samples  for immunology studies to 
perform detailed phenotypic and 
functional analysis of T cell and myeloid 
compartments) .
Clarification of primary 
endpoint 
 
Additional tissue collection & 
analysis details for exploratory 
endpoint 
Section 4 
A mandatory tumour biopsy will be collected 
prior to the start of treatment for pre-
treatment testing for PD-L1 expression, 
Immunophenotyping and extent and 
localization of tumour infiltrating lymphocytes 
and following 3 cycles of therapy for analysis of 
potential markers of tumour response on post-
treatment tissue. Additional mandatory bloods 
will be collected for analysis of potential 
circulating immune markers. Patient genetic 
material will also be collected for analysis of 
potential markers of tumour response and 
future pharmacogenetic analyses. Provision of 
genetic material is not mandatory for 
Up to four mandatory paired tumour 
biopsies will be collected prior to the 
start of treatment for genomic and 
proteomic analyses, pre-treatment 
testing PD-L1 expression, 
Immunophenotyping and extent and 
localization of tumour infiltrating 
lymphocytes, and following 3 cycles of 
therapy for analysis of potential markers 
of tumour response on post-treatment 
tissue. Immunogenicity of sarcomas 
including PD-L1 expression can change 
with previous treatment (Ref: Patel et al 
(39).  It is essential that biopsies reflect 
Clarification of the rationale 
for obtaining biopsies 
 
Treatment period time frame 
for first patient in a cohort 
removed-this was an error in 
the original protocol. 
 

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participation in the main study.
The first patient entered in a cohort will be 
treated over 72 hours and observed for 11 days 
(Day 14 of the treatment cycle). 
the immunophenotype at the timepoint 
of starting the trial, and after treatment 
has been received. Archival tumour 
tissue can therefore not be used in this 
part of the study. Additional mandatory 
bloods will be collected for analysis of 
potential circulating immune markers.  
 
Section 5.2 
2. Be  able  to  provide  archival  tissue  for  
pathology  review  and   confirmation  of a  
diagnosis  of leiomyosarcoma or 
undifferentiated pleomorphic sarcoma 
9. Demonstrate adequate organ function as 
defined in Table-1 (all screening labs should be 
performed within 10 days of treatment 
initiation). 
 
1. Have a histologically confirmed case of 
undifferentiated pleomorphic sarcoma 
or leiomyosarcoma and be willing to 
consent for archival tumour material to 
be requested for transfer to The Royal 
Marsden for future review.  
2. Have biopsiable disease and be willing 
to agree to a biopsy in order to permit 
acquisition of mandatory paired tumour 
biopsies done during screening and 
following 9 weeks of treatment for 
analysis of immunomodulation. 
8. Demonstrate adequate organ function 
as defined in Table-1 (all screening labs 
should be performed within 28 days of 
treatment initiation). 
 
Inclusion criteria number 1 
amended and number 2 
reworded 
 
 
Inclusion criteria-Timeframe 
for screening labs amended 
Section 6.1 
Visit Schedule 
See protocol v1.3 (20 May 2017) 
See protocol v2.0 for updated Visit 
Schedule and corresponding updates to 
text in Section 6.
Visit Schedule updated in 
order to support text 
Table 2 
Laboratory 
Tests 
Blood Urea Nitrogen 
Urea 
Confirmation that Urea not 
blood urea nitrogen should be 
tested as part of biochemistry 
Labs. 
Section 7.1.2 
Dose 
Modification 
Table 
See protocol v1.3 (20 May 2017) 
See protocol v2.0 
New Dose Modification Table 
from Funder 
Section 4 & 
7.1.2 
Neutropenia <0.5 x 109/L for >5 days or with 
fever. 
Thrombocytopenia <25 x 109/L. 
Any non-haematological CTCAE Grade 3 or 4 
toxicity that is, in the opinion of the 
investigator, clinically significant. 
Where, in the investigator’s opinion, it is likely 
that administration of gemcitabine is causally 
linked with the toxicity or observed effect. 
 
A dose limiting toxicity is defined as: 
• 
Neutropenia <0.5 x 109/L for 
>5 days. This must be 
confirmed with repeat blood 
tests at the Royal Marsden 
Hospital within 6 days of the 
diagnosis of neutropenia.              
• 
Febrile neutropaenia as per 
definition by ESMO (>38.3°C or 
two consecutive readings of 
>38.0°C for 2 hours and an 
absolute neutrophil count 
(ANC) of <0.5 x 109/L or 
expected to fall below <0.5 x 
109/L) 
• 
Thrombocytopenia <25 x 
109/L.  
• 
Any non-haematological CTCAE 
Grade 3 or 4 toxicity that is, in 
the opinion of the investigator, 
clinically significant.  
The toxicities listed above must be, in 
the investigator’s opinion, likely to be 
causally linked with the administration of 
Reworded DLT definition 
agreed at Safety Review 
Committee Meeting. 
 
 
 
 

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Gemcitabine.
 
Section 6 
 
Correlative blood studies will be collected on 
Day 1 of cycle 1 and repeated every 2 cycles 
until cycle 6. Bloods will be performed 
according to local procedures, usually under 
ultrasound guidance, and handled in 
accordance with the procedures described in 
the Appendix. 
30-40ml blood will be collected for 
correlative research studies at the 
timepoints specified in the Visit Schedule 
in Section 6.1.  18 mls of blood (2xEDTA 
tubes) will be collected at the time of 
pre-treatment biopsy and post-
treatment biopsy following 3 cycles of 
treatment. In addition, 3 mls of blood 
will be collected in Tempus tubes to 
extract RNA. 
 
Clarification of volume of 
blood to be collected for 
research purposes. 
Section 7.1.1  
See Table 3 in protocol v1.3 (20 May 2017)  
See protocol v2.0 - Table 3  
 
Cycles will be repeated every 21 days for 
6-8 cycles depending on tolerability and 
response. Further cycles of Gemcitabine 
can be administered if clinically 
indicated. 
 
 
Clarification of Gemcitabine 
Dosing 
Section 7.1.1  
N/A 
The pembrolizumab infusion will be 
administered on day 1 and repeated 
every 21 days until disease progression 
or withdrawal criteria are met; for up to 
24 months of uninterrupted treatment 
or 35 administrations, whatever is later.
Clarification of Pembrolizumab 
dosing 
Section 7.1.2  
N/A 
Toxicities which are, in the Investigator’s 
opinion, a consequence of treatment 
with Gemcitabine will be managed 
according the Royal Marsden Sarcoma 
Unit’s standard procedures for managing 
Gemcitabine-related toxicity. Patients 
will be clinically assessed prior to the 
administration of every dose of 
Gemcitabine. 
Clarification of the process for 
the management of 
Gemcitabine –related toxicity 
Section 5.2 
(Inclusion 
Criteria) & 
7.7.2 
Patients should start using birth control from 
study Visit 1 throughout the study period up to 
120 days after the last dose of study therapy. 
Patients should start using birth control 
from study Visit 1 throughout the study 
period up to 6 months after the last dose 
of study therapy. 
Time frame for use of birth 
control increased from 120 
days to 6 months after the last 
dose of study therapy as per 
Gemcitabine SmPC.
Section 8.2 
N/A 
In case of grade 3 and grade 4 toxicity,  
blood  and samples from  affected tissue 
can be used  for  immune analysis, 
genomic and proteomic studies.  Tissue 
will only be collected if it can be 
obtained as part of a clinically indicated 
investigation or a therapeutic procedure 
to treat the toxicity.  This is optional.
Clarification that optional 
additional research samples 
pose no additional risk. 
Section 10.1  
See Table 8 in Protocol v1.3 (20 May 2017) 
See protocol v2.0 – Table 8 
Details of IMP-Gemcitabine 
supply added
Section 
12.8.2 
Trial Steering Committee (TSC) 
A trial steering committee (TSC) will be 
established at the start of the trial.  The TSC 
will be chaired by  an independent chair and 
include the chief investigators (Dr Jones). Other 
Safety Review Committee (SRC) 
The SRC will include the Chief 
investigator for the trial (Dr Robin Jones), 
a Representative from RM-Clinical Trials 
Unit, a Statistician and be chaired by a 
Safety Review Meetings are 
conducted by the SRC not TSC. 

GEMMK Protocol v5.1 IRAS 209543      
 
                   21 
 
independent members (1-2 including a 
sarcoma expert and statistician) will be 
appointed prior to the start of the study. The 
TSC  will also take on the role of IDMC as part 
of a closed session without Dr Jones. 
 
The role of the TSC is to monitor trial progress 
and to ensure the protocol and GCP principles 
are adhered to. The TSC’s terms of reference, 
roles and responsibilities will be defined in a 
charter. Further internal or external experts 
may be consulted by the TSC as necessary. 
 
clinician independent of study 
investigators. The SRC will meet at every 
dose escalation point. The role of the 
SRC is:  
• 
Review relevant safety data 
and make dose escalation 
decisions  
• 
Reviews all SAEs and emerging 
safety data both from RM 
Sponsored studies and external 
SUSARS received from MSD  
• 
Monitor progress of the trials 
and ensure emerging safety 
information is evaluated and 
protocol and GCP principles are 
adhered to.  
The SRC terms of reference, roles and 
responsibilities will be defined in a 
charter. Further internal or external 
experts may be consulted as necessary. 
Section 12 
12.6.1.3 Participating Sites 
Responsibilities are defined in an agreement 
between an individual participating sites and 
the sponsor, which must be signed and in place 
prior to recruitment commencement.  Also 
(but not limited to);-putting and keeping in 
place arrangements to adhere to the principles 
of GCP keeping a copy of all ‘essential 
documents’ (as defined under the principles of 
GCP) in an Investigator Site and Pharmacy File 
and ensuring appropriate archiving of all 
essential documentation once the trial has 
ended 
-taking appropriate urgent safety measures 
-Sites wishing to participate in this study will be 
required to provide evidence that they can are 
equipped to deliver the protocol treatment for 
the duration of the study. 
12.6.1.3.Sarcoma Research Fund 
 
A grant from the Sarcoma Research Fund 
will fund the translational research. 
 
This is a single centre study 
therefore ‘participating sites’ 
section not required. 
 
Confirmation of source of 
funding for translational 
research. 
Section 4.2  
Trial Diagram  
(Flowchart) 
 
Flowchart removed as no 
longer required. Details 
included in amended Visit 
Schedule in Section 6. 
Protocol v3.0 
 
 
Page/ 
Section 
Previous Wording 
New Wording
Comments/Explanation/Ratio
nale for Amendment 
Section 4.1 
Part A: Dose 
escalation 
cohort 
N/A 
Three patients must complete 
one full cycle of treatment (to 
day 21 of cycle 1) without the 
need for a dose reduction, for a 
dose-escalation decision to be 
made. Treatment delays of up to 
14 days within the first cycle are 
acceptable. 
Patients 
who 
undergo treatment delays will 
still be considered evaluable. 
Clarification regarding the 
definition of an evaluable 
patient added to the protocol 
on the recommendation of the 
Safety Review Committee. 
 
Clarification regarding the 
maximum delay to treatment 
permitted during cycle 1, 
defined in days. 

GEMMK Protocol v5.1 IRAS 209543      
 
                   22 
 
Section 6.1 
Visit Schedule 
Please see Visit Schedule (Protocol v2.0, dated 
27.03.2019) 
Please 
see 
Visit 
Schedule 
(Protocol v3.0) 
Visit Schedule updated in 
order to support text 
Section 6.4 
Laboratory 
Procedures/A
ssessments  
Please see Table 2 (Protocol v2.0, dated 
27.03.2019) 
See Protocol v3.0 – Table 2
Additional blood test results can be 
collected 
at 
the 
clinician’s 
discretion.…but blood tests can be 
performed at additional time-points if 
deemed necessary by a clinician. 
Amylase, bicarbonate and GGT 
added as routine chemistry 
test. 
Clarification that additional 
blood test results may be 
collected if considered 
necessary by a clinician.
Section 7  
Please see Table 3 (Protocol v2.0, dated 
27.03.2019)   
See Protocol v3.0 – Table 3
The table has been updated to 
provide clarification of the 
treatment period and dosing 
for both Pembrolizumab and 
Gemcitabine at study visits. 
Section 7.1.2 
Dose 
Modification 
N/A 
Patients requiring dose reductions during 
the first cycle of treatment will be 
considered non-evaluable. 
Clarification of the definition 
of an evaluable patient as per 
recommendations from the 
trial’s Safety Review 
Committee. 
Section 8.4.1 
Assessment of expectedness will be made by 
the Chief Investigator (CI) against the current 
version 
of 
the 
Investigator 
Brochure 
(Pembrolizumab IB, Section 7.3) or Summary of 
Product Characteristics (Gemcitabine SmPC, 
Section 4.8).  If updated versions of the 
investigator brochure are released during the 
course of the trial then assessment of 
expectedness will be made against the current 
regulatory approved version. 
The 
Investigator 
Brochure 
for 
Pembrolizumab and Summary of Product 
Characteristics for Gemcitabine as last 
amended and approved by the national 
competent 
authority 
serve 
as 
the 
reference safety information for the 
assessment of the expectedness of any 
adverse reaction that might occur during 
the clinical trial. 
Specific location of RSI 
removed from Protocol. 
Key Trial 
Contacts 
Bodil Engelmann 
 Bodil.engelmann@rmh.nhs.uk 
Victoria Pittordou 
Tel: 02088642 6011 Ext: 4297 
 
Alannah Smrke 
Alannah.Smrke@rmh.nhs.uk 
Marta Vergnano 
Tel: 02088642 6011 Ext: 6767 
Update to the key trial 
contacts 
Section 1 
Trial 
Summary 
Subjects may remain on treatment until they 
experience disease progression or unacceptable 
toxicity, until they meet any of the withdrawal 
criteria or until the study is terminated by the 
sponsor.   
Subjects may remain on treatment until 
they experience disease progression or 
unacceptable toxicity, until they meet any 
of the withdrawal criteria or until the 
study is terminated by the sponsor, for up 
to 24 months of uninterrupted treatment 
or 35 administrations whichever is later.   
Clarification of Pembrolizumab 
period and dosing. 

GEMMK Protocol v5.1 IRAS 209543      
 
                   23 
 
Section 7.7.2. 
Contraceptio
n 
Non-pregnant, non-breast- feeding women may 
be enrolled if they are willing to use 2 methods 
of birth control or are considered highly unlikely 
to conceive.   
Non-pregnant, 
non-breast-
feeding 
women may be enrolled if they are willing 
to use 2 methods of birth control (1 
effective form of contraception from the 
list provided below and a condom) or are 
considered highly unlikely to conceive.   
Accepted methods of 
contraception to be used have 
been clarified. 
Protocol v4.0 
 
 
 
Page/ 
Section 
Previous Wording
New Wording 
Comments/Explanation/Ratio
nale for Amendment 
Key Trial 
Contacts and 
Protocol 
Contributors 
Yevette McGovern
Yevette.McGovern@rmh.nhs.uk 
 
Clinical Research Fellow 
Emine Hatipoglu 
Quezada/Peggs Laboratory  
Immune 
Regulation 
and 
Tumour 
Immunotherapy Group 
 UCL Cancer Institute Paul O’Gorman Building 
 72 Huntley Street London WC1E 6DD 
Email: E.Hatipoglu@ucl.ac.uk 
Alex Ostler
Sarcoma Unit 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email:  Alex.Ostler@rmh.nhs.uk 
  
Andrea Napolitano 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email:  Andrea.Napolitano@rmh.nhs.uk 
 
Jonathan Noujaim  
undefined [john.c.njm@gmail.com]
Key trial contacts and to 
original protocol contributors 
have been updated and 
corrected. 
Section 5.5 
Registration 
When the patient signs the consent form, they 
will be allocated a trial ID that will be used to 
identify the patient for all future assessments.  
 
If eligible, the patient will begin on the trial and 
keep the same trial ID assigned at consent.  
 
Treatment will begin within 3 days from the 
date of registration. 
When the patient signs the consent form, 
they will be registered onto the study and 
allocated a trial ID that will be used to 
identify the patient for all future 
assessments, before entering screening.  
 
If eligible, the patient will be enrolled and 
begin on the trial, keeping the same trial 
ID assigned at consent. 
 
Treatment will begin within 7 days from 
the date eligibility is confirmed by a 
member of RM-CTU. 
The stepwise process of trial id 
assignment and registration, 
screening assessment, 
eligibility confirmation and 
patient enrolment, and finally 
treatment start, has been 
clarified. The time between 
eligibility confirmation and 
treatment start has been 
updated, to account for public 
holidays and patient 
commitments. 
Section 6 
Study Plan 
and 
procedures 
See visit schedule in protocol v3.0 (10 
September 2020) 
See protocol v4.0 for updated Visit 
Schedule and keys, and corresponding 
updates to text in Section 6.6.2, 6.6.3 and 
6.6.4 
The possibility of telephone 
consultations has been 
introduced to account for the 
impact of a pandemic on the 
study. 
Visit Schedule has been 
updated in order to support 
text. 
Section 13 
List of 
References 
38.
Tawbi 
HA, 
Burgess 
MA, 
Crowley J, van Tine BA, Hu J, Schuetze S, et al. 
Safety an defficacy of PD- 1 blockade using 
pembrolizumab in patienst with advanced soft 
issue and bone sarcomas: Results of SARC028, a 
multicentre Phase II study. Presented at the 
American Society of Clinical Oncology (ASCO) 
Annual Meeting 2016. 
38.
Tawbi HA, Burgess M, Bolejack 
V, Van Tine BA, Schuetze SM, Hu J, et al. 
Pembrolizumab in advanced soft-tissue 
sarcoma and bone sarcoma (SARC028): a 
multicentre, 
two-cohort, 
single-arm, 
open-label, phase 2 trial. Lancet Oncol. 
2017; 18(11): 1493-1501. 
Reference 38 has been 
updated from a conference 
presentation to the 
correspondent journal article, 
published in the following 
year. 

GEMMK Protocol v5.1 IRAS 209543      
 
                   24 
 
Protocol v5.0
Page/ 
Section 
Previous Wording
New Wording
Comments/Explanation/Ratio
nale for Amendment 
Key Trial 
Contacts and 
Protocol 
Contributors 
Alannah Smrke
Sarcoma Unit 
Royal Marsden NHS Foundation Trust Fulham 
Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4633 
Email:  Alannah.Smrke@rmh.nhs.uk 
 
Marta Vergnano  
Senior Trial Manager 
Catriona Goggin 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: caitriona.goggin@rmh.nhs.uk 
 
Anna Stansfeld 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: anna.stansfeld@rmh.nhs.uk 
 
Preethika Mahalingham 
Sarcoma Unit 
Royal Marsden NHS Foundation Trust 
Fulham Rd, London SW3 6JJ 
Tel: 02088642 6011 Ext: 4630 
Email: 
preethika.mahalingam@rmh.nhs.uk 
 
Luke Webster 
Trial Manager 
Key trial contacts have been 
updated. 
Multiple 
instances 
neutropaenia
neutropenia
Spelling update
Multiple 
instances 
Laboratory Manual
Study Sample Manual
Wording update to reflect 
reference document. 
5.3 Subject 
Exclusion 
Criteria 
10. 
Has 
a 
history 
of 
(non-infectious) 
pneumonitis that required steroids or current 
pneumonitis. 
 
 
18. Has received a live vaccine within 30 days of 
planned start of study therapy.  
10. Has a history of (non-infectious) 
pneumonitis/interstitial lung disease that 
required steroids or current pneumonitis 
/interstitial lung disease. 
 
18. Has received a live vaccine or live-
attenuated vaccine within 30 days of 
planned 
start 
of 
study 
therapy. 
Administration of killed vaccines is 
allowed 
Wording update in line with 
new IB. 

GEMMK Protocol v5.1 IRAS 209543      
 
                   25 
 
6.1 Visit 
Schedule 
n/a
Table updated, AD-HOC column added. 
 
Key point m added: Optional bloods for 
germline sequencing can be taken at any 
point in the trial. These bloods should 
only be collected once. Consent must be 
given for the bloods to be taken. 
Amendments made to include 
new optional blood collection. 
6.3.6
n/a
Mandatory tumour biopsies will be 
examined by a pathologist to identify 
parts of the specimen needed for routine 
histopathological examination. Any 
remaining material will be used to 
generate FFPE tissue, fresh frozen 
samples (snap frozen); and cellular 
material will be transferred on ice or 
viably frozen for xenograft implantation 
into mice. 
Added summary of how 
mandatory biopsies are 
processed. 
6.3.6
In addition, 3mls of blood will be collected in 
Tempus tubes to extract RNA. 
In addition, 2.5mls of blood will be 
collected in PAXgene tubes to extract 
RNA. 
Update to type of tubes 
available to the trial 
6.3.7
n/a
Optional blood and tissue collection at 
significant toxicity 
When a patient suffers a significant 
toxicity blood and tissue samples may be 
collected; if considered safe and the 
patient has consented to do so. Tissue will 
only be collected if it can be obtained as 
part of a clinically indicated investigation 
or a therapeutic procedure to treat the 
toxicity (i.e. colonoscopy for colitis).  
Added new section 6.3.7 to 
clarify optional blood and 
tissue collection at significant 
toxicity. 
 
6.3.8
n/a
6.3.8. Optional research blood 
collection 
Optional research bloods for germline 
analysis can be taken at any point in the 
trial and should be taken at the most 
appropriate timepoint/visit to allow for 
the collection. Five tubes of bloods will 
be taken; EDTA 3ml, two EDTA 9ml 
vacutainer blood and two PAXgene® 
2.5mL Blood RNA tubes. Optional 
research bloods will be collected once. 
Consent must be given prior to sample 
collection. 
Sample collection will be performed 
according to local procedures and 
handled in accordance with the 
procedures described in the Study 
Sample Manual. The results of the 
Added new section 6.3.7 to for 
new optional research blood 
collection. 
 

GEMMK Protocol v5.1 IRAS 209543      
 
                   26 
 
germline analysis will not be distributed 
to trial participants. 
7.1.2 Dose 
Modification 
(escalation/ti
tration/other
) 
n/a
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If an SAE is thought to be related to 
pembrolizumab (see the investigator’s 
brochure 
for 
more 
details), 
pembrolizumab will be withheld for 
drug-related Grade 4 hematologic 
toxicities, non-hematological toxicity 
≥ Grade 3 including laboratory 
abnormalities, and severe or life-
threatening AEs as per Table 3 below. 
Adverse events (both non-serious and 
serious) 
associated 
with 
pembrolizumab 
exposure 
may 
represent an immunologic etiology. 
These adverse events may occur 
shortly after the first dose or several 
months after the last dose of 
treatment. See Section 7.6.1 for 
supportive care guidelines, including 
use of corticosteroids. 
 
 
 
 
 
n/a 
Interventions 
administered 
in 
combination can be difficult to attribute 
of an adverse event to a single 
component.  The investigator may 
attribute 
a 
toxicity 
event 
to 
the 
combination, to gemcitabine alone or to 
pembrolizumab alone, for adverse events 
listed in [Table 4]. Both interventions 
must be held according to the criteria in 
Table 6 Dose Modification and Toxicity 
Management Guidelines for Immune-
Related Adverse Events Associated with 
Pembrolizumab. If the AE is considered 
immune-related, 
both 
interventions 
should 
be 
held 
according 
to 
recommended dose modifications. 
 
If an SAE is thought to be 
related to pembrolizumab (see 
the investigator’s brochure for 
more details), pembrolizumab 
will be withheld for drug-
related Grade 4 hematologic 
toxicities, non-haematological 
toxicity ≥ Grade 3 including 
laboratory abnormalities, and 
severe or life-threatening AEs as 
per Table 4 below. Adverse 
events (both non-serious and 
serious) 
associated 
with 
pembrolizumab 
exposure, 
including coadministration with 
additional 
compounds 
may 
represent 
an 
immunologic 
etiology. These adverse events 
may occur shortly after the first 
dose or several months after 
the last dose of treatment. See 
Section 7.6.1 for supportive 
care guidelines, including use of 
corticosteroids. 
 
Participants may not have any 
dose modifications (no change 
in dose or schedule, as 
described in Table 4) of 
pembrolizumab in this study. If 
the toxicity does not resolve or 
the criteria for resuming 
treatment are not met, the 
participant must be 
Wording update in line with 
new IB. 

GEMMK Protocol v5.1 IRAS 209543      
 
                   27 
 
discontinued from all study 
interventions. If the toxicities 
do resolve and conditions are 
aligned with what is defined in 
Table 4, the combination of 
gemcitabine and 
pembrolizumab may be 
restarted at the discretion of 
the investigator. In these cases 
where the toxicity is attributed 
to the combination or to 
gemcitabine alone, re-initiation 
of pembrolizumab as a 
monotherapy may be 
considered at the investigator’s 
discretion. 
 
Table 4
Table 4 Dose Modification and Toxicity 
Management Guidelines for Immune-related 
AEs Associated with Pembrolizumab 
 
 
 
New Table 
Table 4 Dose Modification and Toxicity 
Management Guidelines for Immune-
related 
AEs 
Associated 
with 
Pembrolizumab monotherapy and IO 
Combinations 
 
New Table 
Table update in line with new 
IB. 
 
 
 

GEMMK Protocol v5.1 IRAS 209543      
 
                   28 
 
1. TRIAL SUMMARY 
Title 
Phase I trial gemcitabine + pembrolizumab in leiomyosarcoma and 
undifferentiated pleomorphic sarcoma (GEMMK study) 
Trial Phase
Phase 1
Clinical Indication 
Metastatic or inoperable leiomyosarcoma and undifferentiated 
pleomorphic sarcoma 
Trial Type 
Open-label 
Type of Control 
None 
Route of Administration
Intravenous
Trial Blinding 
None 
Treatment Groups 
Part A: Dose-escalation cohort  
Part B: Expansion cohort 
Number of trial subjects 
Up to a total of 30 patients. 
Part A (Dose-escalation cohort): Max of 18 patients Part B (Expansion 
cohort): Total of 12 patients 
Estimated enrolment period 24 months 
Estimated duration of trial 
36 months 
Duration of participation
Subjects will receive treatment in repeated 3-week cycles. Subjects 
may remain on treatment until they experience disease progression 
or unacceptable toxicity, until they meet any of the withdrawal 
criteria or until the study is terminated by the sponsor, for up to 24 
months of uninterrupted treatment or 35 administrations whichever 
is later.  Note: A subject may be granted an exception to continue on 
treatment with confirmed radiographic progression if clinically stable 
or clinically improved.
Objectives 
 
 
 
 
 
 
Primary 
• 
To evaluate the safety and tolerability of a fixed dose rate 
of gemcitabine when administered in combination with 
pembrolizumab. 
  
Secondary 
• 
To establish the appropriate dose of gemcitabine for 
use in combination with pembrolizumab the 
expansion cohort 
 
• 
To obtain efficacy evidences of the anti-tumour activity of 
gemcitabine in combination with pembrolizumab in 
patients with advanced leiomyosarcoma and 
undifferentiated pleomorphic sarcoma, according to RECIST 

GEMMK Protocol v5.1 IRAS 209543      
 
                   29 
 
 
 
 
 
 
 
 
 
 
Exploratory 
• 
To explore the relationship between PD-L1 tumour 
expression and immune response 
 
• 
To explore the relationship between, T cell and 
myeloid compartments, immune checkpoints and 
response to Pembrolizumab and Gemcitabine in 
leiomyosarcoma and undifferentiated pleomorphic 
sarcoma. 
 
• 
To complement other work aimed at generating a sarcoma 
“immunoscore” created from Immunophenotyping samples 
from the Royal Marsden Sarcoma Unit tissue bank 
correlated with progression-free and overall survival 
 
• 
To explore other predictive biomarkers of immune response 
to PD-L1 inhibition in leiomyosarcoma and undifferentiated 
pleomorphic sarcoma.
Endpoints 
Primary
• 
To establish the maximum tolerated dose (MTD) of 
gemcitabine that can be safely combined with 
pembrolizumab in the absence of dose limiting toxicities 
(DLTs) 
Secondary 
• 
To make a preliminary evaluation of response by using 
RECIST v1.1 to document best response rate, best 
reduction in tumour size and progression free survival, 
assessed 9 weeks after start of therapy 
Exploratory 
• 
Immunophenotyping of pre- and post-treatment (9 weeks) 
biopsies (FFPE samples, density and phenotype of tumour 
infiltrating lymphocytes; CD3+, CD8+, CD45, FoxP3 and PD1 
fresh biopsy samples for immunology studies to perform 
detailed phenotypic and functional analysis of T cell and 
myeloid compartments). 
• 
to perform detailed phenotypic and functional analysis of T 
cell and myeloid compartments.  
• 
Location of tumour infiltrating lymphocytes (proximity to 
tumour cells and location relative to the microvasculature; 
Prototype analysis software at ICR) 
• 
Response stratification according to tumour PD-L1 
expression 
• 
Exploratory analyses to research other potential immune 
response biomarkers in collected tissue and potential 
circulating immune markers in additional collected 
bloods. 
 
 
 

GEMMK Protocol v5.1 IRAS 209543      
 
                   30 
 
2. BACKGROUND & RATIONALE 
2.1 Background 
Refer to the Summary of Product Characteristics (SPC) for detailed background information on pembrolizumab. 
 2.1.1. Pharmaceutical and Therapeutic Background 
The importance of intact immune surveillance in controlling outgrowth of neoplastic transformation has been 
known for decades(1). Accumulating evidence shows a correlation between tumour- infiltrating lymphocytes 
(TILs) in cancer tissue and favorable prognosis in various malignancies (2-6). In particular, the presence of CD8+ 
T-cells and the ratio of CD8+ effector T-cells / FoxP3+ regulatory T-cells seems to correlate with improved 
prognosis and long-term survival in many solid tumours. 
 
The PD-1 receptor-ligand interaction is a major pathway hijacked by tumours to suppress immune control. The 
normal function of PD-1, expressed on the cell surface of activated T-cells under healthy conditions, is to down-
modulate unwanted or excessive immune responses, including autoimmune reactions. PD-1 (encoded by the 
gene Pdcd1) is an Ig superfamily member related to CD28 and CTLA-4 which has been shown to negatively 
regulate antigen receptor signaling upon engagement of its ligands (PD-L1 and/or PD-L2) (7, 8). The structure 
of murine PD-1 has been resolved (9). PD-1 and family members are type I transmembrane glycoproteins 
containing an Ig Variable-type (V-type) domain responsible for ligand binding and a cytoplasmic tail which is 
responsible for the binding of signaling molecules. The cytoplasmic tail of PD-1 contains 2 tyrosine-based 
signaling motifs, an immunoreceptor tyrosine-based inhibition motif (ITIM) and an immunoreceptor tyrosine-
based switch motif (ITSM). Following T-cell stimulation, PD-1 recruits the tyrosine phosphatases SHP-1 and SHP-
2 to the ITSM motif within its cytoplasmic tail, leading to the dephosphorylation of effector molecules such as 
CD3ζ, PKCθ and ZAP70 which are involved in the CD3 T-cell signaling cascade (10-12). The mechanism by which 
PD- 1 down modulates T-cell responses is similar to, but distinct from that of CTLA-4 as both molecules regulate 
an overlapping set of signaling proteins (13, 14). PD-1 was shown to be expressed on activated lymphocytes 
including peripheral CD4+ and CD8+ T-cells, B-cells, T regs and Natural Killer cells (15, 16). Expression has also 
been shown during thymic development on CD4-CD8- (double negative) T-cells as well as subsets of 
macrophages and dendritic cells (17). The ligands for PD-1 (PD-L1 and PD-L2) are constitutively expressed or 
can be induced in a variety of cell types, including non-hematopoietic tissues as well as in various tumours (18-
20). Both ligands are type I transmembrane receptors containing both IgV- and  IgC-like  domains in  the 
extracellular  region  and contain  short cytoplasmic regions with no known signaling motifs. Binding of either 
PD-1 ligand to PD-1 inhibits T-cell activation triggered through the T-cell receptor. PD-L1 is expressed at low 
levels on various non-hematopoietic tissues, most notably on vascular endothelium, whereas PD-L2 protein is 
only detectably expressed on antigen-presenting cells found in lymphoid tissue or chronic inflammatory 
environments. PD-L2 is thought to control immune T-cell activation in lymphoid organs, whereas PD-L1 serves 
to dampen unwarranted T-cell function in peripheral tissues. Although healthy organs express little (if any) PD-
L1, a variety of cancers were demonstrated to express abundant levels of this T-cell inhibitor. PD-1 has been 
suggested to regulate tumour-specific T-cell expansion in subjects with melanoma (MEL)(21). This suggests that 
the PD-1/PD-L1 pathway plays a critical role in tumour immune evasion and should be considered as an 
attractive target for therapeutic intervention. 
 
Pembrolizumab is a potent and highly selective humanized 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. KeytrudaTM 
(pembrolizumab) has recently been approved in the United Stated for the treatment of patients with 
unresectable or metastatic melanoma and disease progression following ipilumumab and, if BRAF V600 
mutation positive, a BRAF inhibitor. 
 
2.1.2. Preclinical and Clinical Trial Data 

GEMMK Protocol v5.1 IRAS 209543      
 
                   31 
 
 
Refer to the Summary of Product Characteristics for the data. 
 
2.2 Rationale 
2.2.1. Rationale for the Trial and Selected Subject Population 
 
Soft tissue sarcomas (STS) are a group of rare mesenchymal neoplasms affecting all ages. STS most commonly 
present as localised disease but despite surgery and adjuvant treatment more than half of patients will 
develop recurrent or metastatic disease. Leiomyosarcoma (LMS), a malignancy of smooth muscle, is one of 
the most common STS and when advanced is typically treated with chemotherapy. Undifferentiated 
pleomorphic sarcoma (UPS) is also a common sarcoma subtype with an aggressive behavior. Recent studies 
have demonstrated reasonable sensitivity of LMS and UPS to gemcitabine monotherapy with an objective 
response rate of 8-19% (22, 23). In addition, the SARC 28 trial demonstrated that pembrolizumab has single 
agent activity in UPS with a response rate of 44% (4 out of 9 patients) (38). However, the overall survival is 
still only about 12 months which illustrates the critical clinical need for improved therapies for advanced UPS 
and LMS as well as sarcomas in general. 
 
Immunotherapy has shown great promise for advanced solid tumour malignancies including sarcoma. Immune 
checkpoint blockade with the antibodies ipilimumab and nivolumab, targeting CTLA4 and programmed cell 
death 1 (PD-1), has led to rapid, deep and durable objective responses in 53% of patients with advanced 
melanoma (24). Some sarcoma subtypes (synovial and myxoid/ round cell liposarcoma) express high levels of 
NY-ESO-1, one of the most immunogenic cancer testis antigens (CTA), and by augmenting the natural immune 
response, significant anti-tumour response would be anticipated. Studies of adoptive T cell therapy have shown 
some activity in synovial sarcoma.(25) However, in a pilot study of a CTLA4 inhibitor in synovial sarcoma, no 
clinical responses were seen in 6 synovial sarcoma patients despite high CTA expression (26). 
 
The inhibitory interaction between PD1 on T lymphocytes and PD-L1 or PD-L2 on tumour cell surface attenuates 
the immune response by decreasing cytokine production and inducing T-lymphocyte anergy and apotosis. 
Expression of PD-L1 on sarcoma cells is prognostic (27) and, at least in NSCLC, pretreatment tumour PD-L1 
expression was a significant predictor of response to pembrolizumab (RECIST  response  rate  according  to  PD-
L1  above/below  significant  expression  =  57%  vs     9%)(28 
 
Leiomyosarcoma patient samples express PD-L1 protein in approximately 70% of cases indicating that anti-PD-
L1 is a rationale strategy for this histological subgroup of sarcoma (27). 
 
Gemcitabine becomes di and tri phosphorylated in cells and has a number of actions including inhibition of 
ribonucleotide reductase and, because of false incorporation into DNA, causing chain termination during DNA 
replication, resulting in impaired cell replication and apoptosis (29). In addition, gemcitabine is suggested to 
augment the anti-tumour T-cell response in at least 4 different ways. 1) The gemcitabine related apoptosis 
causes increased dendritic cell dependent antigen presentation to T-cells (30).  2) In BALB-C mice bearing 
mesothelioma, gemcitabine leads to depletion   of B-cells causing a relative increase in the T-cells (31). 3) 
Patients with NSCLC treated with a 30min infusion of gemcitabine have increased tumour necrosis factor (TNF), 
increased interleukin (IL)-2 production, and significant decreases in total white blood cell and lymphocyte 
counts (CD3+, CD8+, and CD16+ lymphocytes) (32). 4) Partial restoration of immune-visibility of tumour cells 
to T cells by an upregulation of HLA1 expression (33). The anticancer activity of gemcitabine, previously thought 
to be purely cytotoxic, may in fact be due, in part, to an altered immune tumour microenvironment. In addition 
to the immune modulation of gemcitabine monotherapy, gemcitabine combinations may have even more 
pronounced immune effects. Gemcitabine treatments been shown to augment  cellular  CD40 monoclonal 
antibody induced CD8 T-cell anti-tumour activity in a mouse model (34), and in patients with pre-treated renal 

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cancer, gemcitabine enhances the activity of TNF-α (29). 
 
In this study we propose to combine the immune synapse checkpoint inhibitor with the cytotoxic and immune 
modulating agent, gemcitabine. It is hoped that this dual immunomodulatory approach will enhance the effect 
of pembrolizumab on PD-L1 expressing undifferentiated pleomorphic sarcoma and leiomyosarcomas, leading 
to a safe treatment with improved patient outcomes. 
 
2.2.2. Rationale for Dose Selection/Regimen/Modification 
 
Pembrolizumab Dose Selection 
An open-label Phase I trial (Protocol 001) is being 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 mg/kg, administered every 2 weeks (Q2W) in subjects with advanced solid tumours. 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 (1 
mg/kg, 3 mg/kg and 10 mg/kg Q2W). No MTD has been identified to date. 10.0 mg/kg Q2W, the highest dose 
tested in PN001, will be the dose and schedule utilized in Cohorts A, B, C and D of this protocol to test for initial 
tumour activity. Recent data from other clinical studies within the pembrolizumab program has shown that a 
lower dose of pembrolizumab and a less frequent schedule may be sufficient for target engagement and clinical 
activity. 
 
PK data analysis of pembrolizumab administered Q2W and Q3W showed slow systemic clearance, limited 
volume of distribution, and a long half-life (refer to IB). Pharmacodynamic data (IL-2 release assay) suggested 
that peripheral target engagement is durable (>21 days). This early PK and pharmacodynamic data provides 
scientific rationale for testing a Q2W and Q3W dosing schedule. 
 
A population pharmacokinetic analysis has been performed using serum concentration time data from 
476 patients. Within the resulting population PK model, clearance and volume parameters of pembrolizumab 
were found to be dependent on body weight. The relationship between clearance and body weight, with an 
allometric exponent of 0.59, is within the range observed for other antibodies and would support both body 
weight normalized dosing or a fixed dose across all body weights. Pembrolizumab has been found to have a 
wide therapeutic range based on the melanoma indication. 
 
The differences in exposure for a 200 mg fixed dose regimen relative to a 2 mg/kg Q3W body weight based 
regimen are anticipated to remain well within the established exposure margins of 0.5 – 5.0 for pembrolizumab 
in the melanoma indication. The exposure margins are based on the notion of similar efficacy and safety in 
melanoma at 10 mg/kg Q3W vs. the proposed dose regimen of 2 mg/kg Q3W (i.e. 5-fold higher dose and 
exposure). The population PK evaluation revealed that there was no significant impact of tumour burden on 
exposure. In addition, exposure was similar between the NSCLC and melanoma indications. Therefore, there 
are no anticipated changes in exposure between different indication settings. 
 
The rationale for further exploration of 2 mg/kg and comparable doses of pembrolizumab in solid tumours is 
based on: 1) similar efficacy and safety of pembrolizumab when dosed at either 2 mg/kg or 10 mg/kg Q3W in 
melanoma patients, 2) the flat exposure-response relationships of pembrolizumab for both efficacy and safety 
in the dose ranges of 2 mg/kg Q3W to 10 mg/kg Q3W, 3) the lack of effect of tumour burden or indication on 
distribution behavior of pembrolizumab (as assessed by the population PK model) and 4) the assumption that 
the dynamics of pembrolizumab target engagement will not vary meaningfully with tumour type. 
 
The choice of the 200 mg Q3W as an appropriate dose for the switch to fixed dosing is based on simulations 
performed using the population PK model of pembrolizumab showing that the fixed dose of 200 mg every 3 

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weeks will provide exposures that 1) are optimally consistent with those obtained with the 2 mg/kg dose every 
3 weeks, 2) will maintain individual patient exposures in the exposure range established in melanoma as 
associated with maximal efficacy response and 3) will maintain individual patients exposure in the exposure 
range established in melanoma that are well tolerated and safe. 
 
A fixed dose regimen will simplify the dosing regimen to be more convenient for physicians and to reduce 
potential for dosing errors. A fixed dosing scheme will also reduce complexity in the logistical chain at treatment 
facilities and reduce wastage. 
 
Gemcitabine Dose Selection 
 
Fixed Dose Rate Infusion 
Initial pharmacokinetic data from pancreatic adenocarcinoma studies documented an increase in intracellular 
gemcitabine triphosphate concentration when gemcitabine was administered at a fixed dosed rate.(35) 
Subsequently, a phase II trial in soft tissue sarcoma compared single agent gemcitabine administered as a fixed 
dose rate (FDR) of 10 mg/m2/min during a 120-minute intravenous infusion, at 1,200 mg/m2 days 1 and 8, 
every 21 days to a combination therapy where gemcitabine dose was administered at a fixed dose rate 900 
mg/m2 intravenous infusion during 90 minutes on days 1 and 8, with docetaxel 100 mg/m2 intravenously during 
60 minutes day 8, every 21 days. In the 9 LMS patients treated with single agent gemcitabine, there was 1 PR 
and 7 SD over a period of 6 months. One dose reduction was necessary in 26% of STS patients treated with 
single agent gemcitabine with 94% overall dose intensity. 
 
A second phase II trial randomly assigned LMS (uterine and non- uterine) patients to single agent gemcitabine 
(1,000 mg/m2 administered at a fixed-dose rate of 10 mg/m2 per minute via a 100-minute 
i.v. infusion on days 1, 8, and 15 every 28 days) compared to gemcitabine plus docetaxel arm (gemcitabine was 
administered at a fixed-dose rate of 900 mg/m2 in a 90-minute infusion on days 1 and 8, with docetaxel at 100 
mg/m2 in a 60-minute infusion on day 8 after gemcitabine, every 21 days).(23) In the single agent arm, among 
43 LMS patients, there was 1 CR, 6 PR and 21 SD. Dose intensity was 85% and 96% respectively for the non- 
uterine and uterine subgroups. 
 
Immunomodulatory Role of Gemcitabine 
The immunomodulatory role of FDR gemcitabine was explored in a prospective study in patients with advanced 
refractory renal cell carcinoma.(36) Twelve patients received 800 mg/m2  FDR gemcitabine (i.v. infusion of 10 
mg/m2/min) on days 1 and 8 every 3 weeks, combined with 3.0 x106 U s.c. IFN-α on days 1, 3, and 5 of each week. A 
disease control rate (PR+SD) of 64% and time to progression of 7.1 months was significantly better than historical 
controls. A dose reduction of gemcitabine was necessary in 25% of patients. 
Treatment Sequencing in Mouse Models 
Treatment protocols were initiated 9 days after tumour inoculation in BALB/c mice. 120ug/g gemcitabine 
i.p. D1, 4, 7, 10 & 13 and 100ug FGK45 (anti-CD40 antibody) 3x over 6 days were administered. The 
combination and sequence of gemcitabine followed by FGK45 led to the greatest tumour kill.(37) 
 
Dose Selection  
With the previous described pre-clinical and clinical data, a starting dose of single agent gemcitabine 
administered as a fixed dose rate (FDR) of 10 mg/m2/min during a 120-minute intravenous infusion, at 800 
mg/m2 days 1 and 8, every 21 days was selected with subsequent incremental doses to 1000 mg/m2 and 1200 
mg/m2 depending on dose limiting toxicity. 
 
 

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3. OBJECTIVES & ENDPOINTS 
3.1 Primary Objective & Endpoint 
Objective: 
To evaluate the safety and tolerability of a fixed dose rate of gemcitabine when administered in combination with 
pembrolizumab 
Hypothesis: 
Administration of gemcitabine with pembrolizumab is safe. 
Endpoint: 
To establish the maximum tolerated dose (MTD) of gemcitabine that can be safely combined with pembrolizumab in 
the absence of dose limiting toxicities (DLTs). 
3.2 Secondary Objective & Endpoint 
Objective: 
1. To establish the appropriate dose of gemcitabine for use in combination with pembrolizumab the expansion 
cohort 
2. To obtain evidence of the anti-tumour activity of gemcitabine in combination with pembrolizumab in patients with 
advanced leiomyosarcoma and undifferentiated pleomorphic sarcoma, according to RECIST 
Hypothesis: 
Gemcitabine acts in synergy with PD-L1 inhibition as an anti-cancer strategy 
Endpoint: 
To make a preliminary evaluation of response by using RECIST v1.1 to document best response rate, best 
reduction in tumour size and progression free survival, assessed 9 weeks after start of therapy 
 
3.3 Exploratory Objective (Biomarker research) 
Objective: 
1. To explore the relationship between PD-L1 tumour expression and immune response 
2. To explore the relationship between T cell and myeloid compartments, immune checkpoints and response 
to Pembrolizumab and Gemcitabine in leiomyosarcoma and undifferentiated pleomorphic sarcoma. 
3. To complement other work aimed at generating a sarcoma “immunoscore” created from 
Immunophenotyping samples from the Royal Marsden Sarcoma Unit tissue bank correlated with progression-
free and overall survival 
4. To explore other predictive biomarkers of immune response to PD-L1 inhibition in leiomyosarcoma and 
undifferentiated pleomorphic sarcoma. 
Endpoints: 

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1. Immunophenotyping of pre- and post-treatment (9 weeks) biopsies (FFPE samples, density and phenotype 
of tumour infiltrating lymphocytes; CD3+, CD8+, CD45, FoxP3 and PD1 fresh biopsy samples for immunology 
studies to perform detailed phenotypic and functional analysis of T cell and myeloid compartments). 
2. Location of tumour infiltrating lymphocytes (proximity to tumour cells and location relative to the 
microvasculature; Prototype analysis software at ICR)  
3. Response stratification according to tumour PD-L1 expression 
4. Exploratory analyses to research other potential immune response biomarkers in collected tissue and 
potential circulating immune markers in additional collected bloods 
 
4. TRIAL DESIGN  
4.1 Trial Design 
This is a two part, phase I, single centre dose escalation and dose expansion study to establish the safety, 
tolerability and pharmacokinetics of pembrolizumab in combination with different dose levels of fixed dose 
rate gemcitabine in patients with newly diagnosed metastatic or inoperable leiomyosarcoma and 
undifferentiated pleomorphic sarcoma (UPS), for whom gemcitabine monotherapy is deemed appropriate, or 
in patients with previously treated leiomyosarcoma and undifferentiated pleomorphic sarcoma, not including 
gemcitabine, with disease progression documented in the 12 weeks prior to enrolment. 
 
There will be a maximum of 18 patients in the dose-escalation cohort (part A) and the starting dose will be a 
fixed dose rate (FDR) gemcitabine of 800 mg/m2 on day 1 and 8 of 21 days cycles in combination of 200 mg of 
pembrolizumab given as an infusion on day 1 every 3 weeks. There will be a minimum of three and a maximum 
of six evaluable patients entered per dose cohort and each patient will continue to receive treatment cycles of 
gemcitabine in combination with pembrolizumab for as long as he/she is, in the opinion of the investigator, 
deriving clinical benefit and continues to meet re-treatment criteria. Treatment will continue until disease 
progression or is stopped because of toxicity. There will be an option to continue pembrolizumab alone in 
patients with SD or response who stop gemcitabine for toxicity before completing 6 cycles of combination 
therapy. During the dose-escalation phase, safety, tolerability, biological and clinical activity will be assessed 
and the maximum tolerated dose (MTD) will be established. 
 
The MTD cohort (part B) will then be expanded to a total of 12 patients in order to further evaluate the safety 
and tolerability of that dose as well as to preliminarily assess response to therapy 
 
Up to four mandatory tumour biopsies will be collected prior to the start of treatment for genomic and 
proteomic analyses, pre-treatment testing PD-L1 expression, Immunophenotyping and extent and localization 
of tumour infiltrating lymphocytes and following 3 cycles of therapy for analysis of potential markers of tumour 
response on post-treatment tissue. Immunogenicity of sarcomas including PD-L1 expression can change with 
previous treatment (39).  It is essential that biopsies reflect the immunophenotype at the timepoint of starting 
the trial, and after treatment has been received. Archival tumour tissue can therefore not be used in this part 
of the study. Additional mandatory bloods will be collected for analysis of potential circulating immune 
markers. 
 
Part A: Dose escalation cohort 
Part A will be the dose escalation phase. Gemcitabine doses will be escalated (or de-escalated) until the non-
tolerated dose (NTD) is attained and a maximum tolerated dose (MTD) is defined. A maximum of 18 patients 
will be recruited in cohorts of 3 to 6 patients as part of a toxicity rule-based 3+3 design. The total number of 
patients will depend upon the number of dose escalations and toxicities observed. 
 
The starting dose (dose level 1) will be 800 mg/m2 of FDR gemcitabine given by 120 min IV infusion on Day 1 
and Day 8 of each 3 week cycle (see Rationale for choice of starting doses). Pembrolizumab will be administered 
as a 200 mg IV infusion on Day 1 following the infusion of FDR gemcitabine. Pembrolizumab infusions will be 

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repeated every 3 weeks. Each dose escalation cohort will consist of a minimum of three and a maximum of six 
patients. 
 
A dose limiting toxicity is defined as: 
• 
Neutropenia <0.5 x 109/L for >5 days. This must be confirmed with repeat blood tests at the Royal Marsden 
Hospital within 6 days of the diagnosis of neutropenia. 
• 
Febrile neutropenia as per definition by ESMO (>38.3°C or two consecutive readings of >38.0°C for 2 hours 
and an absolute neutrophil count (ANC) of <0.5 x 109/L or expected to fall below <0.5 x 109/L) 
• 
Thrombocytopenia <25 x 109/L.  
• 
Any non-haematological CTCAE Grade 3 or 4 toxicity that is, in the opinion of the investigator, clinically 
significant.  
 
The toxicities listed above must be, in the investigator’s opinion, likely to be causally linked with the administration 
of Gemcitabine. 
 
In the unlikely event that dose-limiting toxicity (DLT) occurs at the proposed starting dose and that dose is 
deemed intolerable, a second cohort of patients will be recruited and a dose of 600 mg/m2 (dose level –1). If 
no dose limiting toxicity (DLT) is documented, the FDR gemcitabine dose will be escalated to 1000 mg/m2 and 
subsequently to 1200 mg/m2 unless 2 or more patients in a single cohort have experienced DLT. 
 
If the first patient does not experience dose-limiting toxicity by Day 14 of the first treatment cycle, two 
additional patients may be entered. Three patients must complete one full cycle of treatment (to day 21 of 
cycle 1) without the need for a dose reduction, for a dose-escalation decision to be made. Treatment delays of 
up to 14 days within the first cycle are acceptable. Patients who undergo treatment delays will still be 
considered evaluable. 
 
If one of the first three patients in a cohort experiences a DLT during the first cycle, the cohort will be expanded 
to six patients. If 2/3 or 2/6 patients in a cohort experience DLT during the first cycle, that dose will be 
considered intolerable, no further dose-escalations will occur and cohort expansion of the next lowest dose 
(the presumed maximum tolerated dose – MTD) will commence. Only toxicities occurring during the first 
treatment cycle will be taken into account for dose escalation decisions. 
 
If a patient withdraws or is withdrawn for reasons other than DLT prior to completing Cycle 1, the patient will 
be replaced. 
 
Part B: Maximum tolerated dose cohort 
A total of 12 additional patients will be recruited and dosed at the MTD identified in Part A in order to ensure 
the tolerability and biological activity of gemcitabine in combination with pembrolizumab as well to 
preliminarily assess response to therapy. 
 
Evaluation of tumour response will be according to RECIST v1.1 (Response Evaluation Criteria in Solid Tumours) 
criteria. The RECIST v1.1 guidelines for measurable, non-measurable, target and non-target lesions and the 
objective tumour response criteria (complete response, partial response, stable disease or progression of 
disease) are presented in the Appendix. 
 
All patients will have imaging performed at the end of the 3rd and the 6th cycle. After cycle 6, RECIST evaluation 
will be performed at the end of every third cycle for the duration of the entire study, or more frequently if it 
deemed necessary by the Investigator. 

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4.2 Study flow chart 
 
 
 
 
 
 
 
 
 
 

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5. SELECTION OF PATIENTS 
5.1 Entry Criteria 
Patients with newly diagnosed metastatic or inoperable leiomyosarcoma, for whom gemcitabine 
monotherapy is deemed appropriate or previously treated leiomyosarcoma, not including 
gemcitabine, with disease progression documented in the 12 weeks prior to enrolment. 
5.2 Subject Inclusion Criteria 
In order to be eligible for participation in this trial, the subject must: 
1. Have a histologically confirmed case of undifferentiated pleomorphic sarcoma or leiomyosarcoma 
and be willing to consent for archival tumour material to be requested for transfer to The Royal 
Marsden for future review. 
2. Have biopsiable disease and be willing to agree to a biopsy in order to permit acquisition of 
mandatory paired tumour biopsies done during screening and following 9 weeks of treatment for 
analysis of immunomodulation. 
3. Be willing and able to provide written informed consent/assent for the trial 
4. Be ≥ 18 years of age on day of signing informed consent 
5. Have a performance status of 0 or 1 on the ECOG Performance Scale. 
6. Have measurable disease based on RECIST 1.1. 
7. Have a life expectancy of >12 weeks (investigator to record this in patient’s medical notes) 
8. Demonstrate adequate organ function as defined in Table-1 (all screening labs should be 
performed within 28 days of treatment initiation). 
 
 
 
 
 
 
 
 
 
 

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Table 1- Adequate Organ Function Laboratory Values 
 
Hepatic 
 
Serum total bilirubin 
≤ 1.5 X ULN OR 
Direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 
ULN
AST (SGOT) and ALT (SGPT) 
≤ 2.5 X ULN OR 
≤ 5 X ULN for subjects with liver metastases 
Albumin 
>25 g/L 
Coagulation
International 
Normalized Ratio 
(INR) or Prothrombin Time (PT) 
 
Activated Partial Thromboplastin 
Time (aPTT) 
≤1.5  X  ULN  unless  subject  is  receiving  anticoagulant  therapy     as 
long as PT or PTT is within therapeutic range of intended use of 
anticoagulants 
≤1.5 X ULN unless subject is receiving anticoagulant therapy 
as long as PT or PTT is within therapeutic range of intended use of 
anticoagulants
aCreatinine clearance should be calculated per institutional standard. 
 
9. Female subject of childbearing potential should have a negative urine or serum pregnancy 
within 72 hours prior to receiving the first dose of study medication. If the urine test is 
positive or cannot be confirmed as negative, a serum pregnancy test will be required. 
10. Female subjects of childbearing potential (Section 7.7.2) must be willing to use an adequate 
method of contraception as outlined in Section 7.7.2 – Contraception, for the course of the 
study through 6 months after the last dose of study medication. 
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
11. Male subjects of childbearing potential (Section 7.7.2) must agree to use an adequate 
method of contraception as outlined in Section 7.7.2 - Contraception, starting with the first 
dose of study therapy through 6 months after the last dose of study therapy. 
System 
Laboratory Value 
Hematological
Absolute neutrophil count (ANC) 
≥1.5 and 109/L 
Platelets 
≥100 x 109/L 
Hemoglobin 
≥9 g/dL without transfusion or EPO dependency (within 7 days of 
assessment) 
Renal
Serum creatinine OR 
Measured 
or 
calculateda 
creatinine clearance 
(GFR can also be used in place of 
creatinine or CrCl)
≤1.5 X upper limit of normal (ULN) OR 
 
≥60 mL/min for subject with creatinine levels > 1.5 X institutional 
ULN 

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Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject. 
5.3 Subject Exclusion Criteria 
The subject must be excluded from participating in the trial if the subject: 
1. Is currently participating and receiving study therapy or has participated in a study of an 
investigational agent and received study therapy or used an investigational device within 4 
weeks of the first dose of treatment. 
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of trial treatment. 
 
3. Has a known history of active TB  (Bacillus Tuberculosis) 
4. Hypersensitivity to either Pembrolizumab or Gemcitabine or any of their excipients. 
5. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 
or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events due to agents 
administered more than 4 weeks earlier. 
6. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 
weeks prior to study Day 1 or who has not recovered (i.e., ≤ Grade 1 or at baseline) from 
adverse events due to a previously administered agent. 
Note: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and may qualify 
for the study if considered appropriate after undergoing a baseline neurological examination. 
Note: If subject received major surgery, they must have recovered adequately from the toxicity 
and/or complications from the intervention prior to starting therapy. 
7. Has a known additional malignancy that is progressing or requires active treatment. 
Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma of the skin that 
has undergone potentially curative therapy or in situ cervical cancer. 
8. Has known active central nervous system (CNS) metastases and/or carcinomatous 
meningitis. Subjects with previously treated brain metastases may participate provided they 
are stable (without evidence of progression by imaging for at least four weeks prior to the first 
dose of trial treatment and any neurologic symptoms have returned to baseline), have no 
evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days 
prior to trial treatment. This exception does not include carcinomatous meningitis which is 
excluded regardless of clinical stability. 
9. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. 
with use of disease modifying agents, corticosteroids or immunosuppressive drugs). 
Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement 
therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic 
treatment. 

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10. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids 
or current pneumonitis/interstitial lung disease. 
11. Has an active infection requiring systemic therapy. 
12. Has a history or current evidence of any condition, therapy, or laboratory abnormality that 
might confound the results of the trial, interfere with the subject’s participation for the full 
duration of the trial, or is not in the best interest of the subject to participate, in the opinion of 
the treating investigator. 
13. Has known psychiatric or substance abuse disorders that would interfere with cooperation 
with the requirements of the trial. 
14. Is pregnant or breastfeeding, or expecting to conceive or father children within the 
projected duration of the trial, starting with the pre-screening or screening visit through 6 
months after the last dose of trial treatment. 
15. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent. 
16. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies). 
17. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA 
[qualitative] is detected). 
18. Has received a live vaccine or live-attenuated vaccine within 30 days of planned start of 
study therapy. Administration of killed vaccines is allowed 
Note: Seasonal influenza vaccines for injection are generally inactivated flu vaccines and are 
allowed; however intranasal influenza vaccines (e.g., Flu-Mist®) are live attenuated vaccines, 
and are not allowed. 
5.4 Screening and enrolment 
 
The Investigator at site should keep a record of all patients screened for entry into this study. 
Copies of the screening logs should be filed in the Site File. For each patient the primary reason 
for exclusion should be recorded. Diagnostic data obtained as part of the patient’s standard 
care can be used to determine eligibility provided they fall within the protocol defined 
timelines. Written informed consent must be obtained prior to the patient undergoing any 
study specific procedures. 
 
5.5 Registration  
 
When the patient signs the consent form, they will be registered onto the study and allocated 
a trial ID that will be used to identify the patient for all future assessments, before entering 
screening. Once all the screening assessments have been completed and the data entered in 
the CRFs, the patient will be assessed for eligibility. This eligibility assessment will also be 
confirmed by a member of RM-CTU. If eligible, the patient will be enrolled and begin on the 
trial, keeping the same trial ID assigned at consent. If the patient is not eligible then the local 
investigator will make alternative arrangements for the treatment of the patient. 
 
The trial ID will be a unique number that once assigned will become the permanent study 
identifier for that patient. In the event a patient is registered onto the study but does not begin 

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treatment, then that patient’s trial ID will not be reassigned. Treatment will begin within 7 days 
from the date eligibility is confirmed by a member of RM-CTU. To ensure patient 
confidentiality, patients will only be identified on CRFs, other trial specific forms and all 
communication to RM-CTU using their assigned trial ID. It is the PI’s responsibility to maintain 
a confidential record of the identity i.e. full name, date of birth and hospital number for the 
patients enrolled in this study and their assigned trial ID. At the end of the study this record 
should be archived along with the Site File. 
 
 
 
 
 
 
 
 

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6. STUDY PLAN AND PROCEDURES 
6.1 Visit Schedule 
 

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Visit Schedule Key: 
a: Prior to any study specific assessments or procedures 
b: Within 72 hours prior to study drug administration on D1 and D8 
c: Imaging to be repeated at the end cycle 3 and cycle 6 and after every 3 additional cycles until discontinuation 
d:  During week 3 of cycle 3 
e:  Pregnancy test to be performed up to 72hrs prior to starting treatment and on a monthly basis during the trial period. 
f: Within 7 days prior to starting treatment 
g: Every 6-8 weeks for 1 year, and every 12 weeks thereafter 
h: To be performed on D1 & D8 for as long as patient is receiving Gemcitabine on day 8 
i:  To be performed at cycle 3, 5 and 7 and every 3 cycles thereafter 
j: These visits are only for patients who discontinue study treatment for a reason other than disease progression. 
k: in the event of a pandemic, follow-up visits of patients who have discontinued GEMMK can be conducted through telephone consultations and blood 
tests should be arranged by local GP if deemed appropriate by the study team. This is a preventative measure for infections that pose serious risk to human 
health. 
l: In the event of a pandemic state, telemedicine-based consultations may be used to assess patients after C3 in place of in-person visits if deemed safe and 
appropriate by the investigator or sub-investigator. Patients are required to attend in person to the Royal Marsden Hospital for observations, blood tests 
and treatment. This would be a preventative and patient protective measure for infections that pose a significant risk to human health. 
m: Optional bloods for germline sequencing can be taken at any point in the trial. These bloods should only be collected once. Consent must be given for 
the bloods to be taken. 
 
 

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6.2 Administrative Procedures 
The Visit Schedule summarizes the trial procedures to be performed at each visit. Individual 
trial procedures are described in detail below. It may be necessary to perform these procedures 
at unscheduled time points if deemed clinically necessary by the investigator. 
 
 
6.2.1. Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. Consent must be documented by the subject’s dated signature 
or by the subject’s legally acceptable representative’s dated signature on a consent form along 
with the dated signature of the person conducting the consent discussion. 
 
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the HRA/REC approval/favorable 
opinion in advance of use. The subject or his/her legally acceptable representative should be 
informed in a timely manner if new information becomes available that may be relevant to the 
subject’s willingness to continue participation in the trial. The communication of this 
information will be provided and documented via a revised consent form or addendum to the 
original consent form that captures the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature. 
 
Specifics about a trial and the trial population will be added to the consent form template at 
the protocol level. 
 
The informed consent will adhere to HRA/REC requirements, applicable laws and regulations. 
 
6.2.2. Inclusion/exclusion criteria 
All inclusion and exclusion criteria will be reviewed by the investigator or qualified designee to 
ensure that the subject qualifies for the trial. 
 
6.2.3. Medical History 
A medical history will be obtained by the investigator or qualified designee. Medical history 
will include all active conditions, and any condition diagnosed within the prior 10 years that 
are considered to be clinically significant by the Investigator. Details regarding the disease for 
which the subject has enrolled in this study will be recorded separately and not listed as 
medical history. 
 
6.2.4. Prior and concomitant medications review 
 
Prior Medications 
The investigator or qualified designee will review prior medication use, including any protocol- 
specified washout requirement, and record prior medication taken by the subject within 28 
days before starting the trial. Treatment for the disease for which the subject has enrolled in 
this study will be recorded separately and not listed as a prior medication. 
 
Concomitant Medications 
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial. All medications related to reportable SAEs and ECIs should be recorded as defined in 

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sections 8.4 & 8.5 
 
6.2.5. Disease details and treatment 
Disease Details 
The investigator or qualified designee will obtain prior and current details regarding disease status. 
Prior Treatment Details 
The investigator or qualified designee will review all prior cancer treatments including systemic 
treatments, radiation and surgeries. 
 
Subsequent Anti-Cancer Therapy Status 
The investigator or qualified designee will review all new anti-neoplastic therapy initiated after 
the last dose of trial treatment. If a subject initiates a new anti-cancer therapy within 30 days 
after the last dose of trial treatment, the 30 day Safety Follow-up visit must occur before the 
first dose of the new therapy. Once new anti-cancer therapy has been initiated the subject will 
move into survival follow-up. 
 
6.2.6. Assigning screening/treatment allocation numbers 
During the screening phase, patients will be allocated a Trial ID number that will be used to 
identify the patient for all future assessments. Upon entering the study, patients will be 
enrolled with same trial ID which will become their Trial Enrolment ID. This will consist of the 
Investigator site number followed by the next sequential patient number. The order of entry 
into the study will determine a patient’s cohort and corresponding dose level. The investigator 
for designated staff will be responsible for allocating and recording patient numbers. 
 
6.2.7. Assigning a Subject Identification Card 
All subjects will be given a Subject Identification Card identifying them as participants in a 
research trial. The card will contain trial site contact information (including direct telephone 
numbers) to be utilized in the event of an emergency. The investigator or qualified designee 
will provide the subject with a Subject Identification Card after the subject provides written 
informed consent. 
 
6.3. Clinical Procedures/Assessments 
 
6.3.1. AE Monitoring and safety assessments 
The primary endpoint for safety analysis is treatment emergent adverse events. 
 
The following events will be recorded in the CRF as adverse events, from the time of 
administration of the first dose of study drug: 
• CTCAEs all grades (including new events post dose and changes from baseline). All non-
clinically significant out of range clinical chemistry, haematology and urinalysis results (in 
the opinion of the Investigator) will not be reported as adverse events. 
 
• Abnormal findings during clinical assessments, including physical examination, BP and HR. 
 
• Clinical chemistry, haematology, urinalysis results out of range and considered clinically 
significant in the opinion of the Investigator. 
 
• Spontaneous patient reports. 
 
The investigator or qualified designee will assess each subject to evaluate for potential new or 

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worsening AEs as specified in the Trial Flow Chart and more frequently if clinically indicated.  
Adverse experiences will be graded and recorded throughout the study and during the follow-
up period according to NCI CTCAE Version 4.0 (see Section 14.2). Toxicities will be characterized 
in terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment. 
 
Please refer to section 8.3 for detailed information regarding the assessment and recording of 
AEs. 
 
6.3.2. Full physical exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period. Clinically significant abnormal findings should be recorded as medical history. 
A full physical exam should be performed during screening. 
 
For cycles that do not require a full physical exam per the Trial Flow Chart, the investigator or 
qualified designee will perform a directed physical exam as clinically indicated prior to trial 
treatment administration. 
 
6.3.3. Vital Signs 
The investigator or qualified designee will take vital signs at screening, prior to the 
administration of each dose of trial treatment and at treatment discontinuation as specified in 
the Trial Visit Schedule (Section 6.1). Vital signs should include temperature, pulse, respiratory 
rate, and blood pressure.  Height will be measured at screening only. 
 
6.3.4. ECOG Performance Scale 
The investigator or qualified designee will assess ECOG status (see Appendix) at screening, prior 
to the administration of each dose of trial treatment (Day 1 of each cycle and at day 8 while 
patient is receiving Gemcitabine), discontinuation of trial treatment and at the safety follow-
up visits as specified in the Trial Visit Schedule 
 
6.3.5. Tumour Imaging and assessment of disease 
Anti-tumour activity will be assessed according to RECIST v1.1 criteria – please refer to the 
Appendix for details. CT scans will be performed as appropriate for the RECIST evaluation. 
 
RECIST evaluation will be performed at baseline and at the end of cycle 3 and cycle 6. 
 
Thereafter RECIST evaluation will be performed at the end of every 3 additional cycles for the 
duration of the study, or more frequently if deemed necessary by the Investigator. 
 
6.3.6. Tumour tissue collection (mandatory) and correlative studies Blood sample  
Mandatory tumour biopsies will be collected before the start of therapy and following 3 cycles 
of therapy. Biopsies will be performed according to local procedures, usually under ultrasound 
guidance, and handled in accordance with the procedures described in theStudy Sample 
Manual for the Trial. Mandatory tumour biopsies will be examined by a pathologist to identify 
parts of the specimen needed for routine histopathological examination. Any remaining 
material will be used to generate FFPE tissue, fresh frozen samples (snap frozen); and cellular 
material will be transferred on ice or viably frozen for xenograft implantation into mice. 
 
Bloods will be performed according to local procedures, and handled in accordance with the 
procedures described in the Study Sample Manual. 
 

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30-40ml blood will be collected for correlative research studies at the time-points specified in the 
Visit Schedule in Section 6.1.  18 mls of blood (2xEDTA tubes) will be collected at the time of pre-
treatment biopsy and post-treatment biopsy following 3 cycles of treatment. In addition, 2.5ls of 
blood will be collected in PAXgene tubes to extract RNA. 
6.3.7 Optional blood and tissue collection at significant toxicity 
When a patient suffers a significant toxicity blood and tissue samples may be collected; if considered 
safe and the patient has consented to do so. Tissue will only be collected if it can be obtained as part 
of a clinically indicated investigation or a therapeutic procedure to treat the toxicity (i.e. colonoscopy 
for colitis).   
6.3.8. Optional research blood collection 
Optional research bloods for germline analysis can be taken at any point in the trial and should be 
taken at the most appropriate timepoint/visit to allow for the collection. Five tubes of bloods will be 
taken; EDTA 3ml, two EDTA 9ml vacutainer blood and two PAXgene® 2.5mL Blood RNA tubes. 
Optional research bloods will be collected once. Consent must be given prior to sample collection. 
Sample collection will be performed according to local procedures and handled in accordance with 
the procedures described in the Study Sample Manual. The results of the germline analysis will not 
be distributed to trial participants. 
6.4. Laboratory Procedures/Assessments 
Laboratory tests for hematology, chemistry, urinalysis and others are specified in Table 2. 
Additional blood test results can be collected at the clinician’s discretion. The total amount of 
blood/tissue to be drawn/collected over the course of the trial (from pre-trial to post-trial 
visits), including approximate blood/tissue volumes drawn/collected by visit and by sample 
type per subject can be found in the Study Sample Manual. 
 
Bloods for determination of clinical chemistry and haematology will be taken at the times given 
in the Study Visit Schedule but blood tests can be performed at additional time-points if 
deemed necessary by a clinician. The date and time of collection will be recorded on the 
appropriate CRF. 
 
Laboratory tests for screening should be performed within 28 days prior to the first dose of 
treatment. During treatment, pre-dose laboratory procedures can be conducted up to 72 hours 
prior to dosing at each cycle. Results must be reviewed by the investigator or qualified designee 
and found to be acceptable prior to each dose of trial treatment. 
 
The clinical chemistry and haematology analysis will be performed at the local laboratory of 
the Department of Haematology and Clinical Biochemistry at the Royal Marsden Hospital. 
 
 
 
 
 
 
 
 
 

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Table 2 – Laboratory Tests 
Haematology 
Chemistry 
Urinalysis 
Other 
Hematocrit 
Albumin 
Blood 
Serum β-human chorionic 
gonadotropin† 
Hemoglobin 
Amylase 
Glucose 
 PT (INR) 
Platelet count 
Alkaline phosphatase 
Protein 
aPTT 
WBC (total and differential)  
Alanine aminotransferase (ALT) 
Specific gravity 
Total thriiodothyronine (T3) 
Red Blood Cell Count 
Aspartate aminotransferase (AST) 
Microscopic exam (If abnormal) Free tyroxine (T4) 
Absolute Neutrophil Count 
Lactate dehydrogenase (LDH) 
Urine pregnancy test † 
 
Thyroid stimulating hormone (TSH) 
Absolute Lymphocyte Count 
Uric Acid 
 
Blood for correlative studies 
 
Calcium 
 
 
 
Chloride 
 
 
 
Glucose 
 
 
 
 Phosphate 
 
 
 
Potassium 
 
 
 
Sodium 
 
 
 
Magnesium 
 
 
 
Total Bilirubin 
 
 
 
Direct Bilirubin (If total bilirubin is elevated 
above the upper limit of normal) 
 
 
 
Total protein 
 
 
 
Creatinine 
 
 
 
Creatinine clearance 
 
 

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Urea  
 
 
 
Bicarbonate 
 
 
 
GGT (Gamma glutamyl transferase) 
 
 
 
† Perform on women of childbearing potenaal only. If urine pregnancy results cannot be conﬁrmed as negaave, a serum pregnancy test will be required. 
Additional blood test results can be collected at the clinician’s discretion. 
 

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6.5. Other Procedures 
When a subject discontinues/withdraws prior to trial completion, all applicable activities 
scheduled for the final trial visit should be performed at the time of discontinuation. Any 
adverse events which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 8.2 - Assessing and 
Recording Adverse Events. Subjects who a) attain a CR or b) complete 24 months of treatment 
with pembrolizumab may discontinue treatment with the option of restarting treatment if they 
meet the criteria specified in Section Second Course Phase (Retreatment Period). After 
discontinuing treatment following assessment of CR, these subjects should return to the site 
for Safety Follow-up Visits and then proceed to the Follow-Up Period of the study (both 
described in Section 6.6). 
 
6.6. Visit Requirements 
Visit requirements are outlined in Section 6.1 – Visit schedule. Specific procedure-related 
details are provided above in Section 6 – Study Plan and Procedures. 
 
6.6.1. Screening Visit 
The screening visit will be conducted prior to the start of gemcitabine and pembrolizumab. 
(Please refer to Visit Schedule for specific timeframes for screening assessments). 
 
The following procedures will be carried out at screening: 
• Written informed consent obtained from patient. 
• Demographic data, including date of birth, sex, height, and race. 
• Medical and surgical history, including all previous, now resolved, significant medical 
conditions, date of diagnosis, extent of disease, disease staging, radiation and oncology 
surgical history. 
• Prior and Concomitant medication review 
• A Full Physical examination 
• Vital signs including height and weight 
• ECOG performance status 
• Collection of blood sample for haematology and biochemistry profile as per 
Haematology and Chemistry laboratory tests in Table 2. Thyroid function tests (T3, FT4 
& TSH) and PT/INR and aPTT will also be measured. 
• A pregnancy test, where appropriate 
• Urinalysis 
• Confirmation patient meets the study selection criteria (Note: documented evidence 
of histological confirmation of disease and, if applicable, post-menopausal/sterile status 
is required for monitoring purposes). 
• Tumour Biopsies & correlative studies blood collection  
• Tumour Imaging with RECIST evaluation 
• Request made for consent for archival tumour material to be requested for transfer to The 
Royal Marsden for future review. 

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If a procedure is performed as part of a patient’s routine care prior to consent and screening, 
data from these procedures may be used as part of the screening data, provided they are 
performed within 72 hours of the screening assessments, thereby not subjecting the patients 
to repeat assessments. 
 
6.6.2. Treatment Period 
Treatment cycles can occur within a scheduling window of +/- 3 days, apart from cycle 1 day 1. 
Please refer to the Visit Schedule. 
 
Cycle 1 
• In addition to the assessments below, adverse events will be recorded on every day 
that the patient attends the clinic. 
 
Pre-dose (Cycle Day 1) 
• A Full Physical examination, including weight. 
 
• Collection of blood sample for haematology and biochemistry profile (as listed in 
Table 2), thyroid function tests, PT/INR and aPTT and pregnancy test where indicated. 
 
Please Note: Pre-dose bloods must demonstrate Adequate Organ Function Laboratory Values as 
per Table 1. in order to commence treatment.  
If bloods are out of range, cycle 1 day 1 will be delayed until blood results are within ranges 
stipulated in Table 1.  
If cycle 1 day 1 is delayed, please check screening assessment are all still valid on first day of 
treatment, i.e all assessment completed within 28 days of cycle 1 day 1. 
• Vital signs 
 
• Urinalysis 
 
• ECOG performance  
 
• RECIST evaluation when indicated (Note: in Cycle 1, the screening assessment will be 
used as the pre- dose disease status). 
 
• Review of Adverse Events 
 
• Concomitant medication review  
 
• Recheck eligibility criteria 
 
Administration of study medication (Cycle Day 1) 
• Gemcitabine and pembrolizumab should be administered as an intravenous infusion 
via peripheral or central venous access. The appropriate doses and treatment regime is 
detailed in section   7. 

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• Vital signs on Cycle Day 1 are measured every 4 hours +/- 1 hour or as clinically 
indicated, if the patient is an in-patient during the infusion. (If the patient is an out-
patient for the infusion, vital signs on Cycle Days 1 are measured as clinically indicated). 
 
• Recording of concomitant medication 
 
Pre-dose (Cycle Day 8) 
 
• Physical examination 
• 
Collection of blood sample for haematology and biochemistry profile as per Haematology 
and Chemistry laboratory tests in Table 2. 
• 
ECOG Performance Status 
• 
Vital signs 
• 
Adverse Events review 
 
Cycle 2 
• Physical examination on D1 and D8 (D8 assessment needed if patient is receiving 
Gemcitabine on day 8), including weight on Day 1. 
 
• ECOG performance on Day 1 and day 8 (D8 assessment needed if patient is receiving 
Gemcitabine on day 8). 
 
• Recheck eligibility criteria. 
• Vital signs on Day 1 and Day 8 (D8 assessment needed if patient is receiving Gemcitabine on 
day 8). 
 
• Recording of concomitant medications on Day 1 
 
• Collection of blood sample for haematology and biochemistry profile as per 
Haematology and Chemistry laboratory tests in Table 2  (within 72 hours of D1 and D8 
while patient is receiving gemcitabine) 
 
• Pregnancy test 
 
Cycles 3, 4 and subsequent cycles 
 
• In addition to the assessments below, adverse events will be recorded on every day 
that the patient attends the clinic. 
 
• Physical examination, including weight on Day 1 
 
• ECOG performance on Day 1 (and Day 8 while patient is receiving Gemcitabine). 
 
• Vital signs on Day 1 (and day 8 while patient is receiving Gemcitabine). 
 
• Recording of concomitant medications on Day 1 

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• Collection of blood sample for haematology and biochemistry profile as per 
Haematology and Chemistry laboratory tests in Table 2 (within 72 hours of D1 and D8 
while patient is receiving gemcitabine) and pregnancy test. 
 
• At the end of cycle 3, an additional tumour biopsy will be done. Blood samples for correlative 
studies will be collected at the same time (See GEMMK Trial Study Sample Manual). 
 
• In the event of a pandemic state, telemedicine-based consultations may be used to assess 
patients after C3 in place of in-person visits if deemed safe and appropriate by the 
investigator or sub-investigator. Patients are required to attend in person to the Royal 
Marsden Hospital for observations, blood tests and treatment. This would be a preventative 
and patient protective measure for infections, such as covid-19, that pose a significant risk to 
human health.    
 
RECIST evaluation for subsequent cycles 
• RECIST evaluation will be performed at the end of cycle 3 and cycle 6. 
 
• After cycle 6, RECIST evaluation will be performed at the end of every 3 additional 
cycles for the duration of the study, or more frequently if deemed necessary by the 
Investigator. 
 
Final Assessment or study withdrawal 
The following assessments will be carried out within 30 days of the start of the last dose of 
study medication or at study withdrawal: 
 
• 
Collection of blood sample for haematology and biochemistry profile as per Haematology and 
Chemistry laboratory test in Table 2, including Thyroid function tests.  
 
• Recording of adverse events. 
 
• Pregnancy test (where applicable) 
 
• Concomitant medications. 
 
• A Full Physical examination. 
 
• Vital signs. 
 
• ECOG performance status. 
 
• Tumour Imaging & RECIST evaluation 
 
• Collection of blood samples for correlative studies 
 
• 
In the case of grade 3 and 4 toxicity at discontinuation, blood and samples from 
affected tissue can be collected if the patient has given consent for this.  Tissue should 
only be collected if it can be obtained as part of a clinically indicated investigation or 
therapeutic procedure to treat toxicity. 

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• 
In the event of a pandemic, follow-up visits of patients who have discontinued GEMMK 
may be conducted through telephone consultations and blood tests should be 
arranged by local GP if deemed appropriate by the study team. This is a preventative 
measure for infections that pose serious risk to human health. 
 
 
6.6.3. Safety Follow up visits 
The mandatory Safety Follow-Up Visits should be conducted approximately 30 and 135 days 
after the last dose of trial treatment or before the initiation of a new anti-cancer treatment, 
whichever comes first.  All AEs that occur prior to the Safety Follow-Up Visit should be 
recorded. Subjects with an AE of Grade > 1 will be followed until the resolution of the AE to 
Grade 0-1 or until the beginning of a new anti- neoplastic therapy, whichever occurs first. SAEs 
that occur prior to the safety follow-up visit or before initiation of a new anti-cancer treatment 
should also be followed and recorded. Subjects who are eligible for retreatment with 
pembrolizumab (as described in Section 6.6.6) may have up to three safety follow-up visits, two 
after the Treatment Period and one after the Second Course Phase. In the event of a pandemic, 
follow-up visits may be conducted through telephone consultations. 
 
6.6.4. Follow up visits 
Subjects who discontinue trial treatment for a reason other than disease progression will move 
into the Follow-Up Phase and should be assessed every 6-8 weeks by radiologic imaging to 
monitor disease status. After 1 year, the imaging time point will occur every 12 weeks (± 7 
days). Every effort should be made to collect information regarding disease status until the 
start of new anti-neoplastic therapy, disease progression, death, end of the study or if the 
subject begins retreatment with pembrolizumab as detailed in Section 6.6.6. Information 
regarding post-study anti-neoplastic treatment will be collected if new treatment is initiated. 
In the event of a pandemic, follow-up visits may be conducted through telephone consultations 
 
Subjects who are eligible to receive retreatment with pembrolizumab according to the criteria 
in Section 6.6.6 will move from the follow-up phase to the Second Course Phase when they 
experience disease progression. 
 
6.6.5. Survival Follow up 
Once a subject experiences confirmed disease progression or starts a new anti-cancer therapy, the 
subject moves into the survival follow-up phase and should be contacted by telephone every 12 
weeks to assess for survival status until death, withdrawal of consent, or the end of the study, 
whichever occurs first. 
6.6.6. Second Course Phase (Retreatment Period) 
Subjects who stop pembrolizumab with SD or better may be eligible for up to one year of 
additional pembrolizumab therapy if they progress after stopping study treatment.  This 
retreatment is termed the Second Course Phase of this study and is only available if the study 
remains open and the subject meets the following conditions: 
Either 
o Stopped initial treatment with pembrolizumab after attaining an 
investigator-determined confirmed CR according to RECIST 1.1, and 
 

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 
Was treated for at least 24 weeks with pembrolizumab before discontinuing 
therapy 
 
 
Received at least two treatments with pembrolizumab beyond the 
date when the initial CR was declared 
 
 
OR 
o Had SD, PR or CR and stopped pembrolizumab treatment after 24 months 
of study therapy for reasons other than disease progression or intolerability 
AND 
• 
Experienced an investigator-determined confirmed radiographic disease 
progression after stopping their initial treatment with pembrolizumab 
 
• 
Did not receive any anti-cancer treatment since the last dose of pembrolizumab 
 
• 
Has a performance status of 0 or 1 on the ECOG Performance Scale 
• 
Demonstrates adequate organ function as detailed in Table – 1 
• 
Female subject of childbearing potential should have a negative serum or urine 
pregnancy test within 72 hours prior to receiving retreatment with study 
medication. 
 
• 
Female subject of childbearing potential should be willing to use 2 methods of 
birth control or be surgically sterile, or abstain from heterosexual activity for the 
course of the study through 6 months after the last dose of study medication 
(Reference Section 7.7.2). Subjects of child bearing potential are those who have 
not been surgically sterilized or have been free from menses for > 1 year. 
 
 
• 
Male subject should agree to use an adequate method of contraception starting 
with the first dose of study therapy through 6 months after the last dose of study 
therapy. 
 
 
• 
Does not have a history or current evidence of any condition, therapy, or 
laboratory abnormality that might interfere with the subject’s participation for 
the full duration of the trial or is not in the best interest of the subject to 
participate, in the opinion of the treating investigator. 
 
Subjects who restart treatment will be retreated at the same dose and dose interval as when 
they last received pembrolizumab.  Treatment will be administered for up to one additional 
year. 
 
 
 
 
 

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7. TRIAL TREATMENTS 
The treatment to be used in this trial is outlined below in Table 3 – Trial Treatment 
Drug 
Dose/Potency 
Dose 
frequency 
Route of 
Administrati
on
Regimen/Treat
ment Period 
Use 
pembrolizumab 
200 mg 
Day 1 
Every 3 
weeks 
IV infusion 
over 30 min. 
Until disease 
progression or 
withdrawal 
criteria are 
met; for up to 
24 months of 
uninterrupted 
treatment or 35 
administrations 
whichever is 
later.  
 
 
Experiment
al 
The pembrolizumab dosing interval may be increased due to toxicity as described in Section 7. 
Pembrolizumab may be continued alone if gemcitabine was stopped because of cumulative toxicity 
and the patient continues to demonstrate SD or ongoing response 
Drug 
Dose/Potency 
Dose 
Frequency 
Route of 
Administrati
on 
Regimen/Treat
ment period  
Use 
Gemcitabine
Fixed dose 
rate 
Incremental 
doses of 
800mg/m2 
1000mg/m2 
1200mg/m2 
Day 1, day 
8 every 3 
weeks 
IV infusion 
over 120 
min. 
For 6-8 cycles 
depending on 
tolerability and 
response.  
Further cycles 
of Gemcitabine 
(up to 35 in 
total) can be 
administered if 
clinically 
indicated. 
 
 
o
r withdrawal 
criteria are met 
Experiment
al 
Gemcitabine can be dose band as per standard of care (in line with NHS England guideline)
 
Trial treatment should begin on the day of registration or as close as possible to the date on 
which treatment is allocated/assigned. 
 
7.1. Dose Selection/Modification 
7.1.1. Dose Selection 

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The rationale for selection of doses to be used in this trial is provided in Section 4.0 – 
Background and Rationale. 
 
Pembrolizumab 
The dose amount required to prepare the pembrolizumab infusion solution will be a fixed 200 
mg IV dose. Details on preparation and administration are provided in the Pharmacy Manual. 
The pembrolizumab infusion will be administered on day 1 and repeated every 21 days until 
disease progression or withdrawal criteria are met; for up to 24 months of uninterrupted 
treatment or 35 administrations whichever is later. 
 
Gemcitabine 
A starting dose of 800 mg/m2 of single agent gemcitabine administered as a fixed dose rate 
(FDR) of 10 mg/m2/min during a 120-minute intravenous infusion, on days 1 and 8, every 21 
days was selected with subsequent incremental doses to 1000 mg/m2 and 1200 mg/m2 
depending on dose limiting toxicity (see rationale of dose selection in section 4.0). Cycles will 
be repeated every 21 days for 6-8 cycles depending on tolerability and response. Further cycles 
of Gemcitabine can be administered if clinically indicated for up to 24 months of uninterrupted 
treatment or 35 cycles whichever is later.  
 
Single agent gemcitabine is considered a low risk agent for emesis. Steroids should be avoided 
for premedication prior to gemcitabine infusion. Premedication will consist of metoclopramide 
10 mg IV infusion 30 min prior to gemcitabine infusion. Acute and delayed emesis can be 
managed with dopamine receptor antagonists (metoclopramide and domperidone), 5-HT3 
antagonists (ondansetron), and neurokinin-1 receptor antagonists (aprepitant) in refractory 
cases. Steroids should be avoided. 
 
7.1.2. Dose Modification (escalation/titration/other) 
The investigator will assess the causality of reported SAEs to either single agent gemcitabine or 
pembrolizumab. 
 
Interventions administered in combination can be difficult to attribute of an adverse event to a 
single component.  The investigator may attribute a toxicity event to the combination, to 
gemcitabine alone or to pembrolizumab alone, for adverse events listed in [Table 4]. Both 
interventions must be held according to the criteria in Table 6 Dose Modification and Toxicity 
Management Guidelines for Immune-Related Adverse Events Associated with Pembrolizumab. If the 
AE is considered immune-related, both interventions should be held according to recommended 
dose modifications. 
 
If an SAE is thought to be related to pembrolizumab (see the investigator’s brochure for more 
details), pembrolizumab will be withheld for drug-related Grade 4 hematologic toxicities, non-
haematological toxicity ≥ Grade 3 including laboratory abnormalities, and severe or life-
threatening AEs as per Table 4 below. Adverse events (both non-serious and serious) 
associated with pembrolizumab exposure, including coadministration with additional 
compounds may represent an immunologic etiology. These adverse events may occur shortly 
after the first dose or several months after the last dose of treatment. See Section 7.6.1 for 
supportive care guidelines, including use of corticosteroids. 
 
Participants may not have any dose modifications (no change in dose or schedule, as 
described in Table 4) of pembrolizumab in this study. If the toxicity does not resolve or the 
criteria for resuming treatment are not met, the participant must be discontinued from all 
study interventions. If the toxicities do resolve and conditions are aligned with what is 

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defined in Table 4, the combination of gemcitabine and pembrolizumab may be restarted at 
the discretion of the investigator. In these cases where the toxicity is attributed to the 
combination or to gemcitabine alone, re-initiation of pembrolizumab as a monotherapy may 
be considered at the investigator’s discretion. 
 
 
 
 
 
 

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Table 4 Dose Modification and Toxicity Management Guidelines for Immune-related AEs Associated with Pembrolizumab monotherapy and IO 
CombinationsGeneral instructions: 
1. Severe and life-threatening irAEs should be treated with IV corticosteroids followed by oral steroids. Other immunosuppressive treatment should 
begin if the irAEs are not controlled by corticosteroids. 
2. Study intervention must be permanently discontinued if the irAE does not resolve or the corticosteroid dose is not ≤10 mg/day within 12 weeks 
of the last study intervention treatment.  
3. The corticosteroid taper should begin when the irAE is ≤ Grade 1 and continue at least 4 weeks. 
4. If study intervention has been withheld, study intervention may resume after the irAE decreased to ≤ Grade 1 after corticosteroid taper. 
 
 
irAEs 
Toxicity Grade 
(CTCAE v4.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other Therapies 
Monitoring and Follow-up 
Pneumonitis  
Grade 2 
Withhold  
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
•  Add prophylactic antibiotics for 
opportunistic infections 
•  Monitor participants for signs and symptoms of 
pneumonitis 
•  Evaluate participants with suspected 
pneumonitis with radiographic imaging and 
initiate corticosteroid treatment 
Recurrent 
Grade 2,  
Grade 3 or 4  
Permanently 
discontinue 
Diarrhea/Colitis  
Grade 2 or 3 
Withhold 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
 
•  Monitor participants for signs and symptoms of 
enterocolitis (ie, diarrhea, abdominal pain, 
blood or mucus in stool with or without fever) 
and of bowel perforation (ie, peritoneal signs 
and ileus) 
•  Participants with ≥Grade 2 diarrhea suspecting 
colitis should consider GI consultation and 
performing endoscopy to rule out colitis 
Recurrent 
Grade 3 or 
Grade 4 
Permanently 
discontinue 

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irAEs 
Toxicity Grade 
(CTCAE v4.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other Therapies 
Monitoring and Follow-up 
•  Participants with diarrhea/colitis should be 
advised to drink liberal quantities of clear 
fluids. If sufficient oral fluid intake is not 
feasible, fluid and electrolytes should be 
substituted via IV infusion 
AST or ALT 
Elevation or 
Increased 
Bilirubin 
Grade 2 a 
Withhold 
•  Administer corticosteroids (initial dose of 
0.5 to 1 mg/kg prednisone or equivalent) 
followed by taper 
•  Monitor with liver function tests (consider 
weekly or more frequently until liver enzyme 
value returned to baseline or is stable) 
Grade 3 b or 4 c 
Permanently 
discontinue 
•  Administer corticosteroids (initial dose of 
1 to 2 mg/kg prednisone or equivalent) 
followed by taper 
T1DM or 
Hyperglycemia 
New onset 
T1DM or  
Grade 3 or 4 
hyperglycemia 
associated with 
evidence of 
β-cell failure 
Withhold d 
•  Initiate insulin replacement therapy for 
participants with T1DM 
•  Administer antihyperglycemic in 
participants with hyperglycemia 
•  Monitor participants for hyperglycemia or other 
signs and symptoms of diabetes 
Hypophysitis 
Grade 2 
Withhold 
•  Administer corticosteroids and initiate 
hormonal replacements as clinically 
indicated 
•  Monitor for signs and symptoms of hypophysitis 
(including hypopituitarism and adrenal 
insufficiency) 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
Hyperthyroidism 
Grade 2 
Continue 

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irAEs 
Toxicity Grade 
(CTCAE v4.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other Therapies 
Monitoring and Follow-up 
Grade 3 or 4 
Withhold or 
permanently 
discontinue d 
•  Treat with nonselective beta-blockers 
(eg, propranolol) or thionamides as 
appropriate 
•  Monitor for signs and symptoms of thyroid 
disorders 
Hypothyroidism 
Grade 2, 3 or 4 
Continue 
•  Initiate thyroid replacement hormones 
(eg, levothyroxine or liothyronine) per 
standard of care 
•  Monitor for signs and symptoms of thyroid 
disorders 
Nephritis: 
grading 
according to 
increased 
creatinine or 
acute kidney 
injury 
Grade 2 
Withhold 
•  Administer corticosteroids (prednisone 1 
to 2 mg/kg or equivalent) followed by 
taper 
•  Monitor changes of renal function 
Grade 3 or 4 
Permanently 
discontinue 
Neurological 
Toxicities 
Grade 2 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 3 or 4 
Permanently 
discontinue 
Myocarditis 
Grade 1 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
and/or exclude other causes 
Grade 2, 3 or 4 
Permanently 
discontinue 
Exfoliative 
Dermatologic 
Conditions 
Suspected SJS, 
TEN, or 
DRESS 
Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Confirmed SJS, 
TEN, or 
DRESS 
Permanently 
discontinue 

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irAEs 
Toxicity Grade 
(CTCAE v4.0) 
Action With 
Pembrolizumab 
Corticosteroid and/or Other Therapies 
Monitoring and Follow-up 
All Other irAEs 
Persistent Grade 2 Withhold 
•  Based on severity of AE administer 
corticosteroids 
•  Ensure adequate evaluation to confirm etiology 
or exclude other causes 
Grade 3 
Withhold or 
discontinue based 
on the event e  
Recurrent 
Grade 3 or 
Grade 4  
Permanently 
discontinue 
AE(s)=adverse event(s); ALT= alanine aminotransferase; AST=aspartate aminotransferase; CTCAE=Common Terminology Criteria for Adverse Events; DRESS=Drug 
Rash with Eosinophilia and Systemic Symptom; GI=gastrointestinal; IO=immuno-oncology; ir=immune related; IV=intravenous; SJS=Stevens-Johnson Syndrome; 
T1DM=type 1 diabetes mellitus; TEN=Toxic Epidermal Necrolysis; ULN=upper limit of normal. 
Note: Non-irAE will be managed as appropriate, following clinical practice recommendations. 
a AST/ALT: >3.0 to5.0 x ULN if baseline normal; >3.0 to 5.0 x baseline, if baseline abnormal;  
bilirubin:>1.5 to 3.0 x ULN if baseline normal; >1.5 to 3.0 x baseline if baseline abnormal 
b AST/ALT: >5.0 to 20.0 x ULN, if baseline normal; >5.0 to 20.0 x baseline, if baseline abnormal; bilirubin:>3.0 to 10.0 x ULN if baseline normal; >3.0 to 10.0 x baseline 
if baseline abnormal 
c AST/ALT: >20.0 x ULN, if baseline normal; >20.0 x baseline, if baseline abnormal;  
bilirubin: >10.0 x ULN if baseline normal; >10.0 x baseline if baseline abnormal 
d The decision to withhold or permanently discontinue pembrolizumab is at the discretion of the investigator or treating physician. If control achieved or ≤ Grade 2, 
pembrolizumab may be resumed. 
e Events that require discontinuation include, but are not limited to: encephalitis and other clinically important irAEs (eg, vasculitis and sclerosing cholangitis). 
 
 

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Dosing interruptions are permitted in the case of medical / surgical events or logistical reasons 
not related to study therapy (e.g., elective surgery, unrelated medical events, patient 
vacation, and/or holidays). Subjects should be placed back on study therapy within 3 weeks 
of the scheduled interruption, unless otherwise discussed with the Sponsor. The reason for 
interruption should be documented in the patient's study record. 
 
Dose modification for Gemcitabine 
A dose-limiting toxicity is defined as: 
 
• 
Neutropenia <0.5 x 109/L for >5 days.  This must be confirmed with repeat blood tests at the 
Royal Marsden Hospital within 6 days of the diagnosis of neutropenia.                                                                      
• 
Febrile neutropenia as per definition by ESMO (>38.3°C or two consecutive readings of 
>38.0°C for 2 hours and an absolute neutrophil count (ANC) of <0.5 x 109/L or expected to 
fall below <0.5 x 109/L) 
• 
Thrombocytopenia <25 x 109/L.  
• 
Any non-haematological CTCAE Grade 3 or 4 toxicity that is, in the opinion of the 
investigator, clinically significant.  
The toxicities listed above must be, in the investigator’s opinion, likely to be causally linked 
with the administration of Gemcitabine 
 
If a patient experiences dose-limiting toxicity, treatment will be stopped (including 
pembrolizumab infusions) and supportive therapy administered as required. A delay of up to 
14 days is permitted to allow for resolution of toxicity. 
 
If the toxicity resolves or reverts to CTCAE Grade 0 or 1 or the Baseline (pre-study) level within 
14 days of onset of the DLT and the patient is showing clinical benefit, treatment with 
gemcitabine and pembrolizumab may be restarted at the preceding dose level (at the 
investigators discretion) 
 
If after a 14-day delay the toxicity has not resolved to CTCAE Grade 0 or 1 or baseline, the 
patient must be withdrawn from the study or continue with pembrolizumab alone if 
considered safe. 
 
If unacceptable toxicity occurs after 14 days of therapy, doses may be reduced after 
consultation with the responsible project physician. Patients requiring dose reductions during 
the first cycle of treatment will be considered non-evaluable. The dose can be de-escalated by 
1 dose level in an individual patient. Thereafter if a patient experiences drug-related CTCAE 
Grade 3 or greater then no further gemcitabine therapy may be administered and the patient 
must be withdrawn from the study or continue with pembrolizumab alone if considered safe. 
 
Toxicities which are, in the Investigator’s opinion, a consequence of treatment with 
Gemcitabine will be managed according to the Royal Marsden Sarcoma Unit’s standard 
procedures for managing Gemcitabine-related toxicity. Patients will be clinically assessed prior 
to the administration of every dose of Gemcitabine. 
 
Following 6 cycles of chemotherapy, if the patient has ongoing response to therapy (stable 
disease or tumour regression) and gemcitabine had to be stopped because of cumulative 
toxicity or patient choice, pembrolizumab infusions can be continued every 3 weeks until 
discontinuation criteria are met. 
 
Re-treatment with Gemcitabine 

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Before a patient can start a second or subsequent cycle of treatment, the following blood count 
parameter criteria must be met: 
 
• Absolute neutrophil count ≥1.5 x 109/L. 
• Platelet count ≥100 x 109/L. 
• No non-haematological, drug-related toxicity > CTCAE grade 1 or greater than pre-
existing baseline level. 
 
If the patient does not meet the criteria, then a subsequent cycle of treatment may be delayed 
for a maximum period of 14 days. If after 14 days the criteria remain unmet the patient must 
be withdrawn from the study and the toxicity or haematological finding must be captured on 
the CRF as an adverse event. 
 
The re-treatment criteria apply to the start of a second or subsequent cycle only and are not 
applicable to the entire cycle, i.e. it is acceptable to have grade 2 or above toxicity following 
treatment however, this must have recovered or improved prior to re-treatment. 
 
7.2. 
Timing of Dose Administration 
 
Trial treatment should be administered on Day 1 of each cycle after all procedures/assessments 
have been completed as detailed on the visit schedule (Section 6.1). Trial treatment may be 
administered up to 3 days before or after the scheduled Day 1 of each cycle due to 
administrative reasons. 
 
All trial treatments will be administered on an outpatient basis, other than the first patient in 
the study, who will be monitored as an in-patient for 72 hours. 
 
Gemcitabine 
Gemcitabine will be administered first (before pembrolizumab) at a fixed dose rate (FDR) of 10 
mg/m2/min during a 120-minute intravenous infusion, on day 1. It will be subsequently re-
administered on day 8 and the cycle repeated every 3 weeks. 
Pembrolizumab 
Pembrolizumab 200 mg will be administered as a 30 minute IV infusion every 3 weeks. The site 
should make every effort to target infusion timing to be as close to 30 minutes as possible. 
However, given the variability of infusion pumps from site to site, a window of -5 minutes and 
+10 minutes is permitted (i.e., infusion time is 30 minutes: -5 min/+10 min). 
 
The Pharmacy Manual contains specific instructions for the preparation of the pembrolizumab 
infusion fluid and administration of infusion solution. 
 
7.3. 
Trial Blinding/Masking 
This is an open-label trial; therefore the investigator and subject will know the treatment 
administered. 
 
7.4. 
Treatment Allocation 
The first 12 recruited patients fulfilling the inclusion criteria will be allocated to the dose 

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escalation cohort. Once the maximum tolerated dose is determined, a further 12 patients will 
be allocated to the maximum tolerated dose cohort. 
 
7.5. 
Concomitant Medications/Vaccinations (allowed & prohibited) 
Medications or vaccinations specifically prohibited in the exclusion criteria are not allowed 
during the ongoing trial. If there is a clinical indication for one of these or other 
medications or vaccinations specifically prohibited during the trial, discontinuation from 
trial therapy or vaccination may be required. The investigator should discuss any questions 
regarding this with the MSD Clinical team. The final decision on any supportive therapy or 
vaccination rests with the investigator and/or the subject's primary physician. 
 
7.5.1. Acceptable Concomitant Medications 
All treatments that the investigator considers necessary for a subject’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded on the case report form (CRF) 
including all prescription, over- the-counter (OTC), herbal supplements, and IV medications and 
fluids. If changes occur during the trial period, documentation of drug dosage, frequency, 
route, and date may also be included on the CRF. 
 
All concomitant medications received within 28 days before the first dose of trial treatment 
and 30 days after the last dose of trial treatment should be recorded. Concomitant medications 
administered after 30 days after the last dose of trial treatment should be recorded for SAEs 
and ECIs as defined in sections 8.2 & 8.5. 
 
7.5.2. Prohibited Concomitant Medications 
Subjects are prohibited from receiving the following therapies during the Screening and 
Treatment Phase (including retreatment for post-complete response relapse) of this trial: 
• 
Antineoplastic systemic chemotherapy or biological therapy 
• 
Immunotherapy not specified in this protocol 
• 
Chemotherapy not specified in this protocol 
• 
Investigational agents other than pembrolizumab and Gemcitabine 
• 
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 trial treatment and while 
participating in the trial. Examples of live vaccines include, but are not limited to, 
the following: measles, mumps, rubella, varicella/zoster, yellow fever, rabies, 
BCG, and typhoid vaccine. 
• 
Systemic glucocorticoids 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 
investigator. 
Subjects who, in the assessment by the investigator, require the use of any of the 
aforementioned treatments for clinical management should be removed from the trial. 
Subjects may receive other medications that the investigator deems to be medically necessary. 

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The Exclusion Criteria describes other medications which are prohibited in this trial. There are 
no prohibited therapies during the Post-Treatment Follow-up Phase 
 
7.6. 
Rescue Medications & Supportive Care 
7.6.1. Supportive Care Guidelines 
Subjects should receive appropriate supportive care measures as deemed necessary by the 
treating investigator. Suggested supportive care measures for the management of adverse 
events with potential immunologic etiology are outlined below. 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 as metastatic disease or bacterial or viral infection, which might 
require additional supportive care. The treatment guidelines are intended to be applied when 
the investigator determines the events to be related to pembrolizumab. 
 
Note: if after the evaluation the event is determined not to be related, the investigator does 
not need to follow the treatment guidance (as outlined below). For events which are 
considered to be related to Gemcitabine, the Royal Marsden Sarcoma Unit’s standard 
procedures for Gemcitabine-related toxicity management will be followed. Refer to Section 
7.1.2 for dose modification guidance. 
 
It may be necessary to perform conditional procedures such as bronchoscopy, endoscopy, or 
skin photography as part of evaluation of the event. 
 
• Pneumonitis 
In clinical trials, dyspnea, unrelated to underlying disease, has been reported in association 
with gemcitabine therapy. Dyspnea was occasionally accompanied by bronchospasm. 
Pulmonary toxicity and pneumonitis has been reported with the use of gemcitabine. The 
etiology of these effects is unknown. If such effects develop, gemcitabine should be 
discontinued. Early use of supportive care measures may help ameliorate these conditions. 
Pneumonitis induced by gemcitabine or pembrolizumab cannot be distinguished on clinical 
grounds. Any suspicion of therapy-related pneumonitis should be treated as follow: 
• For Grade 2 events, treat with systemic corticosteroids. When symptoms improve to 
Grade 1 or less, steroid taper should be started and continued over no less than 4 weeks. 
• For Grade 3-4 events, immediately treat with intravenous steroids. Administer 
additional anti-inflammatory measures, as needed. 
• Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration. 
• Diarrhoea/Colitis 
Subjects should be carefully monitored for signs and symptoms of enterocolitis (such as 
diarrhea, abdominal pain, blood or mucus in stool, with or without fever) and of bowel 
perforation (such as peritoneal signs and ileus). 
• All subjects who experience diarrhea/colitis should be advised to drink liberal quantities 
of clear fluids. If sufficient oral fluid intake is not feasible, fluid and electrolytes should 
be substituted via IV infusion. For Grade 2 or higher diarrhoea, consider GI consultation 
and endoscopy to confirm or rule out colitis. 

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• For Grade 2 diarrhoea/colitis, administer oral corticosteroids. 
• For Grade 3 or 4 diarrhoea/colitis, treat with intravenous steroids followed by high dose 
oral steroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be started and 
continued over no less than 4 weeks. 
• 
Type 1 diabetes mellitus (if new onset, including diabetic ketoacidosis [DKA]) or ≥ Grade 3 
Hyperglycemia, if associated with ketosis (ketonuria) or metabolic acidosis (DKA) 
o For T1DM or Grade 3-4 Hyperglycemia 
 
Insulin replacement therapy is recommended for Type I diabetes mellitus 
and for Grade 3-4 hyperglycemia associated with metabolic acidosis or 
ketonuria. 
 
Evaluate patients with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 
• Hypophysitis: 
o For Grade 2 events, treat with corticosteroids. When symptoms improve to Grade 1 
or less, steroid taper should be started and continued over no less than 4 weeks. 
Replacement of appropriate hormones may be required as the steroid dose is 
tapered. 
o For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered. 
 
• Hyperthyroidism or Hypothyroidism: 
o Thyroid disorders can occur at any time during treatment. Monitor patients for 
changes in thyroid function (at the start of treatment, periodically during treatment, 
and as indicated based on clinical evaluation) and for clinical signs and symptoms of 
thyroid disorders. 
 
o Grade 2 hyperthyroidism events (and Grade 2-4 hypothyroidism): 
 
In 
hyperthyroidism, 
non-selective 
beta-blockers 
(e.g. 
propranolol) are suggested as initial therapy. 
 
In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyroinine, is indicated per standard of care. 
o Grade 3-4 hyperthyroidism 
 
Treat with an initial dose of IV corticosteroid followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, 
steroid taper should be started and continued over no less than 
4 weeks. Replacement of appropriate hormones may be 
required as the steroid dose is tapered. 
• Hepatic: 
o For Grade 2 events, monitor liver function tests more frequently until 
returned to baseline values (consider weekly). 
 
Treat with IV or oral corticosteroids 
o For Grade 3-4 events, treat with intravenous corticosteroids for 24 to 48 
hours. 
o When symptoms improve to Grade 1 or less, a steroid taper should be 
started and continued over no less than 4 weeks. 

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• Renal Failure or Nephritis: 
o For Grade 2 events, treat with corticosteroids. 
o For Grade 3-4 events, treat with systemic corticosteroids. 
o When symptoms improve to Grade 1 or less, steroid taper should be 
started and continued over no less than 4 weeks. 
• 
Management of Infusion Reactions: Signs and symptoms usually develop during or 
shortly after drug infusion and generally resolve completely within 24 hours of 
completion of infusion. 
Table 5 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 5 Infusion Reaction Treatment Guidelines 
NCI CTCAE Grade 
Treatment 
Premedication at subsequent 
dosing 
Grade 1 
Mild reaction; infusion interruption not 
indicated; intervention not indicated 
Increase monitoring of vital signs as medically indicated until the subject is 
deemed medically stable in the opinion of the investigator. 
None 
Grade 2 
Requires infusion interruption but responds 
promptly to symptomatic treatment (e.g., 
antihistamines, NSAIDS, narcotics, IV fluids); 
prophylactic medications indicated for < =24 hrs 
Stop Infusion and monitor symptoms. Additional appropriate medical 
therapy may include but is not limited to: 
IV fluids Antihistamines NSAIDS 
Acetaminophen Narcotics 
Increase monitoring of vital signs as medically indicated until the subject is 
deemed medically stable in the opinion of the investigator. 
If symptoms resolve within one 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 subject should be 
premedicated for the next scheduled dose. 
Subjects who develop Grade 2 toxicity despite adequate premedication 
should be permanently discontinued from further trial treatment 
administration. 
Subject may be premedicated 
1.5h (± 30 minutes) prior to 
infusion of pembrolizumab (MK- 
3475) with: 
 
Diphenhydramine 50 mg po 
(or equivalent dose of 
antihistamine). 
 
Acetaminophen 500- 1000 
mg po (or equivalent dose of 
antipyretic). 

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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: IV fluids Antihistamines NSAIDS Acetaminophen Narcotics Oxygen 
Pressors Corticosteroids Epinephrine 
 
Increase monitoring of vital signs as medically indicated until the subject is 
deemed medically stable in the opinion of the investigator. 
Hospitalization may be indicated. 
Subject is permanently discontinued from further trial treatment 
administration. 
No subsequent dosing 
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period of drug administration. 

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7.7. Diet/Activity/Other Considerations 
7.7.1. Diet 
Subjects should maintain a normal diet unless modifications are required to manage an AE such as diarrhoea, 
nausea or vomiting. 
 
7.7.2. Contraception 
Pembrolizumab may have adverse effects on a foetus in utero. Furthermore, it is not known if pembrolizumab 
has transient adverse effects on the composition of sperm. Non-pregnant, non-breast- feeding women may be 
enrolled if they are willing to use 2 methods of birth control (1 effective form of contraception from the list 
provided below and a condom) or are considered highly unlikely to conceive.  Highly unlikely to conceive is 
defined as one of those: 
1. Surgically sterilized 
2. Postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year 
will be considered postmenopausal) 
3. Not heterosexually active for the duration of the study 
 
Patients should start using birth control from study Visit 1 throughout the study period up to 6 months after 
the last dose of study therapy. The following are considered as effective birth control methods: 
1. Combined oral/intravaginal/transdermal contraceptive agent associated with inhibition of ovulation 
(which contains estrogen and progestogen both) 
2. Progestogen-only oral/injectable/implantable hormonal contraception associated with inhibition of 
ovulation 
3. Copper intrauterine device (IUD) 
4. Intrauterine hormone-releasing system (IUS) 
5. Bilateral tubal occlusion 
6. Vasectomised partner 
7. Sexual abstinence 
 
Patients should be informed that taking the study medication may involve unknown risks to the foetus (unborn 
baby) if pregnancy were to occur during the study. In order to participate in the study they must adhere to the 
contraception requirement (described above) for the duration of the study and during the safety follow-up 
period. If there is any question that a patient will not reliably comply with the requirements for contraception, 
that patient should not be entered into the study. 
 
7.7.3. Use in Pregnancy 
If a patient inadvertently becomes pregnant while on treatment with pembrolizumab, the patient will 
immediately be removed from the study. The site will contact the patient at least monthly and document the 
patient’s status until the pregnancy has been completed or terminated. The outcome of the pregnancy will be 
reported to the Sponsor and to MSD without delay and within 24 hours if the outcome is a serious adverse 
event (e.g., death, abortion, congenital anomaly, or other disabling or life- threatening complication to the 
mother or newborn). The study investigator will make every effort to obtain permission to follow the outcome 
of the pregnancy and report the condition of the foetus or newborn to the RM-CTU. 
 
7.7.4. Use in Nursing Women 
It is unknown whether pembrolizumab is excreted in human milk. Since many drugs are excreted in human 
milk, and because of the potential for serious adverse reactions in the nursing infant, subjects who are breast-
feeding are not eligible for enrollment. 
 

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7.8. Subject Withdrawal/Discontinuation Criteria 
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial at the discretion of the 
investigator should any untoward effect occur. In addition, a subject may be withdrawn by the investigator or 
the Sponsor if enrollment into the trial is inappropriate, the trial plan is violated, or for administrative and/or 
other safety reasons. Specific details regarding discontinuation or withdrawal are provided in Section 6.5 – 
Other Procedures. 
 
A subject must be discontinued from the trial for any of the following reasons: 
 
• 
The subject or legal representative (such as a parent or legal guardian) withdraws consent 
• 
Confirmed radiographic disease progression 
Note: For unconfirmed radiographic disease progression please see Section 6.3.5. 
Note: A subject may be granted an exception to continue on treatment with confirmed radiographic 
progression if clinically stable or clinically improved.  
• 
Unacceptable adverse experiences as described in Sections 7 & 8. 
• 
Intercurrent illness that prevents further administration of treatment 
• 
Investigator’s decision to withdraw the subject 
• 
The subject has a confirmed positive serum pregnancy test 
• 
Noncompliance with trial treatment or procedure requirements 
• 
The subject is lost to follow-up 
• 
Completed 24 months of uninterrupted treatment with pembrolizumab or 35 administrations of study 
medication, whichever is later 
 
Note: 24 months of study medication is calculated from the date of first dose. Subjects who stop 
pembrolizumab after 24 months may be eligible for up to one year of additional study treatment if they 
progress after stopping study treatment provided they meet the requirements detailed in Section 6.6.6. 
 
• 
Administrative reasons 
The End of Treatment and Follow-up visit procedures are listed in Section 6.1 (Visit schedule) and Section 6.6 
(Visit Requirements). After the end of treatment, each subject will be followed for 30 days for adverse event 
monitoring (serious adverse events will be collected for 90 days after the end of treatment as described in 
Section 8.4). Subjects who discontinue for reasons other than progressive disease will have post-treatment 
follow-up for disease status until disease progression, initiating a non- study cancer treatment, withdrawing 
consent or becoming lost to follow-up. After documented disease progression each subject will be followed by 
telephone for overall survival until death, withdrawal of consent, or the end of the study, whichever occurs 
first. 
 
7.8.1. Discontinuation of Study Therapy after CR 
Discontinuation of treatment may be considered for subjects who have attained a confirmed CR that have been 
treated for at least 24 weeks with pembrolizumab and had at least two treatments with pembrolizumab beyond 
the date when the initial CR was declared. Subjects who then experience radiographic disease progression may 
be eligible for up to one year of additional treatment with pembrolizumab via the Second Course Phase at the 
discretion of the investigator if no cancer treatment was administered since the last dose of pembrolizumab, 
the subject meets the safety parameters listed in the Inclusion/Exclusion criteria, and the trial is open. Subjects 
will resume therapy at the same dose and schedule at the time of initial discontinuation.  Additional details are 
provided in Section 6.6.6. 
 
 
 

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7.9. Subject Replacement Strategy 
 
If a patient is withdrawn from the study for reasons other than DLT before the end of the first treatment cycle, 
the patient must be replaced. This will be done for both parts A and B. 
 
If a patient withdraws from the study prior to completion of their current cycle of treatment, and for reasons 
other than progression or non-tolerability, the reason for withdrawal should be sought and recorded on the 
case report form. AEs should be followed up until resolution. 
 
When patients are withdrawn from the study, they can ask for their sample to be destroyed. In the event 
that testing has already been performed, requests to destroy test results will not be possible as the 
associated data may be required for audit purposes by a regulatory authority. 
 
Patients that withdraw from the study or discontinue treatment after completion of the first treatment cycle 
will not be replaced. 
 
7.10. Clinical Criteria for Early Trial Termination 
 
Early trial termination will be the result of the criteria specified below: 
 
1. Quality or quantity of data recording is inaccurate or incomplete. 
2. Poor adherence to protocol and regulatory requirements 
3. Incidence or severity of adverse drug reaction in this or other studies indicates a potential health hazard to 
subjects 
4. Plans to modify or discontinue the development of the study drug 
In the event of MSD decision to no longer supply study drug, ample notification will be provided so that 
appropriate adjustments to subject treatment can be made. 
 
8. PHARMACOVIGILANCE 
8.1. Adverse events 
8.1.1. Adverse Event Definition 
An AE is defined as any untoward, undesired or unplanned occurrence (including deterioration of a pre-existing 
medical condition) in a patient administered a pharmaceutical product or undertaking a protocol-specified 
procedure. 
An AE can be an unfavourable and unintended sign, symptom, disease, and/or laboratory or physiological 
observation associated with the use of a medicinal product of protocol-specified procedure but does not 
necessarily have to have a causal relationship to this treatment or procedure. 
 
Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a pre- existing 
condition (present at baseline) that is temporally associated with the use of the pembrolizumab or 
Gemcitabine, is also an adverse event. 
 
Changes resulting from normal growth and development that do not vary significantly in frequency or severity 
from expected levels are not to be considered adverse events. Examples of this may include, but are not limited 

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to, onset of menses or menopause occurring at a physiologically appropriate time. 
 
Adverse events may also occur in screened patients during any pre-allocation baseline period as a result of a 
protocol-specified intervention, including washout or discontinuation of usual therapy, diet, or a procedure. 
 
8.1.2. Adverse Reaction Definition 
An AE assessed by the Principal Investigator and / or Chief Investigator as reasonably likely to be related to the 
administration of a medicinal product or protocol-specified procedure. 
 
8.1.3. Disease Progression 
Disease progression of the cancer under study is not considered an adverse event unless it results in 
hospitalisation. 
 
8.1.4. New Cancers 
The development of a new cancer should be regarded as an SAE and reported accordingly. 
 
8.1.5. Abnormal Laboratory Test Results 
All clinically important abnormal laboratory test results occurring during the study will be recorded as AEs. The 
clinically important abnormal laboratory tests will be repeated at appropriate intervals until they return either 
to baseline or to a level deemed acceptable by the investigator, or until a diagnosis that explains them is made. 
 
8.1.6. Pregnancy and Lactation 
Pregnancy and lactation are not considered adverse events, however these events should be reported to the 
RM-CTU following guidance in section 8.7. 
 
8.2. Assessing and Recording Adverse Events 
 
All adverse events will be recorded from the time of consent until 135 days after the date of the administration 
of the last dose of Pembrolizumab. They will be followed up according to local practice until the event has 
stabilised or resolved, or the follow-up visit has taken place, whichever is the sooner. Serious Adverse Events 
(SAEs) will also be recorded throughout the study. The reporting timeframe for adverse events meeting any 
serious criteria is described in section 8.4. 
 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events resolve, 
stabilise or the patient completes the trial. Any unresolved AEs at the patient’s last visit should be followed up 
for as long as medically indicated, but without further recording in the eCRF. 
 
If an Investigator learns of any AE that he/she consider serious, including death, at any time after a patient has 
completed the study and he/she considers there is a reasonable possibility that the event is related to 
pembrolizumab or Gemcitabine, the Investigator should notify the RM-CTU. 
 
The following details will be collected in the eCRF for each AE: 
• 
AE description / diagnosis 
• 
Date of onset and date of resolution 
• 
NCI-CTCAE grade maximum intensity 
• 
Seriousness 
• 
Investigator causality rating against the study medication (yes/no) 
• 
Action taken with regard to study medication 
• 
Outcome 
 
For the pre-registration period adverse events will not be collected in patients that have not undergone any 

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protocol-specified procedure or intervention. If the patient requires a blood draw, fresh tumour biopsy etc. for 
the study then the patient will be required to consent to the main study and AEs will be captured as described 
above. In the case of grade 3 and 4 toxicity, blood and samples from the affected tissue can be used for immune 
analysis, genomic and proteomic studies.  Tissue will only be collected if it can be obtained as part of a clinically 
indicated investigation or therapeutic procedure to treat toxicity. This is not mandatory. 
 
8.3. Evaluating Adverse Events 
 
AEs will be evaluated by an investigator who is a qualified physician. 
 
Determining AE Severity and Grade 
 
AE severity and grade will be evaluated according to the NCI Common Terminology for Adverse Events (CTCAE), 
version 4.0. Any adverse event which changes CTCAE grades which change indicating an improvement in 
toxicity are not reported as AEs. 
 
Grade 1
Mild; asymptomatic or mid symptoms; clinical or diagnostic observations only;
intervention not indicated. 
Grade 2 
Moderate; minimal, local or non-invasive intervention indicated; limiting age 
appropriate instrumental ADL. 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalisation or prolongation or hospitalisation indicated; disabling; limiting 
self-care ADL. 
Grade 4
Life threatening consequences; urgent intervention indicated.
Grade 5 
Death related to AE 
 
Determining AE Causality 
The Principal Investigator must endeavor to obtain sufficient information to assess the causality of the AE and 
must provide his/her opinion whether the event has any relationship to the administered study treatment / 
procedure. This may require instituting supplementary investigations of significant AEs based on their clinical 
judgment of the likely causative factors and/or include seeking a further opinion from a specialist in the field 
of the AE. 
 
Causality is the relationship of an AE to the IMP and it will be determined by criteria that are given in Table 6 
Determining AE Causality. 
 
 
 
 
 
 
 
 
 

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Definite: 
• There is clear evidence to suggest a causal relationship. 
• Starts within a time related to the IMP administration and 
• No obvious alternative medical explanation. 
Probable: 
• There is evidence to suggest a causal relationship 
• Starts within a time related to the IMP administration and 
• Cannot be reasonably explained by known characteristics of the patient’s 
clinical state. 
Possible:
• A causal relationship between the IMP and the AE is at least a reasonable 
possibility. 
• Starts within a time related to the IMP administration 
• However, the influence of other factors may have contributed to the event 
(e.g.the patient’s clinical condition, other concomitant treatments). 
Unlikely: 
• There is little evidence to suggest there is a causal relationship. 
• There is another reasonable explanation for the event (e.g. the patient’s 
clinical condition, other concomitant treatment). 
• The time association is such that the trial drug is not likely to have had an 
association with the observed effect. 
Not related: 
• The AE is definitely not associated with the IMP administered. 
 
8.4. Serious Adverse Events (SAEs) 
 
A ‘serious adverse event’ is defined as follows: 
 
Any untoward medical occurrence or effect that at any dose that: 
• 
results in death; 
• 
is life-threatening or places the patient, in the view of the investigator, at immediate risk of death 
from the event as it occurred1; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation2 
• 
results in persistent or significant incapacity or disability; 

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• 
is a congenital anomaly or birth defect; 
• 
is associated with an overdose (whether accidental or intentional). Any adverse event associated 
with an overdose is considered a serious adverse event. 
• 
is any other medically important event.3 
 
1This does not include an AE which hypothetically might have caused death if had it occurred in a more severe 
form. 
2Hospitalisation is defined as an unexpected inpatient admission, regardless of length of stay, even if the hospitalisation 
is a precautionary measure for continued observation. It does not usually apply to scheduled admissions that were 
planned before study inclusion or visits to casualty (without admission). 
3 A  medically  important  event  may  not  result  in  death,  not  be  life  threatening,  or  not require hospitalisation but 
may be considered a serious adverse event when, based upon appropriate medical judgment, the event that may 
jeopardise the patient and require medical or surgical intervention to prevent one of the outcomes listed above. 
 
8.4.1. Reporting SAEs 
All SAEs regardless of causality, pregnancy or overdose that occur from the time of the first dose of 
pembrolizumab until the safety follow-up or the initiation of a new anticancer therapy, whichever is earlier, 
must be reported on the SAE report form within 24 hours of the investigator / designee becoming aware of the 
event. The SAE form should be sent to the RM-CTU by Fax 02089156762 who will in turn notify the sponsor and 
MSD of the event. 
 
Assessment of causality for all SAEs will be made by the PI/designee or delegate. Assessment of expectedness 
will be made by the Chief Investigator (CI).  The Investigator Brochure for Pembrolizumab and Summary of 
Product Characteristics for Gemcitabine as last amended and approved by the national competent authority 
serve as the reference safety information for the assessment of the expectedness of any adverse reaction that 
might occur during the clinical trial.  The report will then be reviewed by the Chief Investigator (or a nominated 
representative) to confirm relatedness and expectedness. The NCI CTCAE Version 4 must be used to grade each 
SAE, and the worst grade recorded. If new or amended information on a previously reported SAE becomes 
available, the Investigator should report this to the RM-CTU on a new SAE report form. If the SAE has not been 
reported within the specified timeframes, a reason for lateness must be included when sending the SAE report 
form. The RM-CTU will in turn submit the updated report to the sponsor and MSD. Please refer to the SAE 
completion guidelines for further information. 
 
Additionally, any SAE, considered by an investigator who is a qualified physician to be related to the IMP or 
protocol-specified procedure that is brought to the attention of the investigator at any time outside of the time 
period specified in the previous paragraph also must be reported immediately to the RM-CTU who will inform 
the Sponsor and MSD. 
 
8.4.2. Events exempt from being reported as SAEs. 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is prolonged 
for any reason and then an SAE form must be completed. The events must still be recorded in the appropriate 
section of the eCRF. 
 
1. Elective admissions to hospital for procedures which were planned and documented in the medical 
records at the time of consent are not SAEs, and do not require SAE reporting. 
2. Hospitalisation for administration of the IMP, or to facilitate study procedures such as pharmacokinetic 
sampling according to the trial protocol, is also exempt from being reported as an SAE. 

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3. Progressive disease and death due to disease are not considered SAE’s but should be reported in 
the eCRFs 
8.5. Events of Clinical Interest (ECI) 
 
8.5.1. Definition of ECIs  
Selected non-serious and serious adverse events can also be classified as Events of Clinical Interest (ECI) and 
must be reported as described below. 
Events of clinical interest for this trial include: 
1. an overdose of MSD product, as defined in Section 8.6 - Definition of an Overdose for This Protocol and 
Reporting of Overdose to the Sponsor, that is not associated with clinical symptoms or abnormal laboratory 
results. 
2. an elevated AST or ALT lab value that is greater than or equal to 3X the upper limit of normal and an 
elevated total bilirubin lab value that is greater than or equal to 2X the upper limit of normal and, at the 
same time, an alkaline phosphatase lab value that is less than 2X the upper limit of normal, as determined 
by way of protocol-specified laboratory testing or unscheduled laboratory testing.* 
*Note: These criteria are based upon available regulatory guidance documents. The purpose of the criteria is 
to specify a threshold of abnormal hepatic tests that may require an additional evaluation for an underlying 
etiology. 
 
 
3.  Any AEs identified in the below table 7 can be classified as immune-related events of clinical interest. All 
irECIs should be reported as described in section 8.5.2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table 7-Immune related AEs considering ECIs 
Pneumonitis  - (classified as ECI if ≥ Grade 2) 
Acute interstitial Pneumonitis 
Interstitial Lung Disease 
Pneumonitis 
Colitis - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Intestinal Obstruction
Colitis
Colitis microscopic
Enterocolitis 
Enterocolitis hemorrhagic 
Gastrointestinal perforation 
Necrotising colitis 
Diarrhoea 
 
Endocrine - (classified as ECI if ≥ Grade 3 or ≥ Grade 2 and resulting in dose modification or use of 
systemic steroids to treat the AE) 
Adrenal Insufficiency
Hyperthyroidism
Hypophysitis
Hypopituitarism 
Hypothyroidism 
Thyroid disorder 
Thyroiditis 
Hyperglycemia, if ≥Grade 3 and associated with ketosis or 
metabolic acidosis (DKA) 
Endocrine (classified as ECI) 
Type 1 diabetes mellitus (if new onset)
Hematologic - (classified as ECI if ≥ Grade 3 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Autoimmune 
haemolytic 
anaemia 
Aplastic anaemia 
Thrombotic thrombocytopenic 
purpura 
Idiopathic thrombocytopenia 
purpura 
Disseminated
intravascular 
coagulation 
Haemolytic uraemic syndrome
Hepatic - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of 
systemic steroids to treat the AE) 
Hepatitis
Autoimmune hepatitis
Transaminase elevations 
(ALTand/or AST) 
Infusion reactions - (classified as ECI for any grade)
Allergic reaction 
Anaphylaxis 
Cytokine release syndrome 
Serum sickness 
Infusion reactions 
Infusion-like reactions 
Neurologic - (classified as ECI for any grade)

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Autoimmune neuropathy 
Guillain-Barre syndrome 
Demyelinating polyneuropathy 
Myasthenic syndrome
Ocular - (classified as ECI if ≥ Grade 2 or any grade resulting in dose modification or use of systemic 
steroids to treat the AE) 
Uveitis 
Iritis 
 
Renal - (classified as ECI for ≥ Grade 2) 
Nephritis
Nephritis autoimmune
Renal Failure
Renal failure acute 
Creatinine elevations - (classify as ECI if ≥ Grade 3 or any grade 
resulting in dose modification or use of systemic steroids to treat 
the AE) 
Skin - (classified as ECI for any grade) 
Dermatitis exfoliate 
Erythema multiforme 
Stevens-Johnson Syndrome 
Toxic epidermal necrolysis 
 
 
Skin - (classified as ECI for ≥ Grade 3)
Pruritus 
Rash 
Rash generalised 
Rash maculo-papular 
Any rash clinical significant in the physicians judgement. 
Other - (classified as ECI for any grade)
Myocarditis 
Pancreatitis 
Percarditis 
Any other grade 3 event which is considered immune-related by the physician. 
Patients should be assessed for possible ECIs prior to each dose. Lab results should be evaluated and patients 
should be asked for signs and symptoms suggestive of an immune-related event. Patients who develop an ECI 
thought to be immune-related should have additional testing to rule out other etiologic causes. If lab results or 
symptoms indicate a possible immune-related ECI, then additional testing should be performed to rule out 
other etiologic causes. If no other cause is found, then it is assumed to be immune-related. 
 
8.5.2. Reporting of ECIs 
For the time period beginning at treatment allocation through 90 days following cessation of treatment, or 30 
days following cessation of treatment if the subject initiates new anticancer therapy, whichever is earlier, any 
ECI, or follow up to an ECI, whether or not related to MSD product, must be reported using the SAE/ECI report 
form within 24 hours of the PI/designee becoming aware of the event to the RM-CTU by fax 02089156762 who 
will in turn notify who will inform the Sponsor and MSD. 
 
8.6. Definition of an Overdose for this Protocol and Reporting of an Overdose 
 
For purposes of this trial, an overdose of pembrolizumab will be defined as any dose of 1,000 mg or greater (≥5 
times the indicated dose). No specific information is available on the treatment of overdose of pembrolizumab. 

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Appropriate supportive treatment should be provided if clinically indicated. In the event of overdose, the 
subject should be observed closely for signs of toxicity. Appropriate supportive treatment should be provided 
if clinically indicated. 
 
If an adverse event(s) is associated with (“results from”) the overdose of a MSD product, the adverse event(s) 
is reported as a serious adverse event, even if no other seriousness criteria are met. 
 
If a dose of MSD’s product meeting the protocol definition of overdose is taken without any associated clinical 
symptoms or abnormal laboratory results, the overdose is reported as a non-serious Event of Clinical Interest 
(ECI), using the terminology “accidental or intentional overdose without adverse effect.” 
 
All reports of overdose either SAE or ECI must be reported within 24 hours of the PI or designee becoming 
aware of the event to the RM-CTU by Fax 0208 915 6762 who will inform MSD. 
 
8.7. Reporting of Pregnancy and Lactation 
 
It is the responsibility of investigators or their designees to report any pregnancy or lactation in a patient 
(spontaneously reported to them), that occurs during the trial or within 120 days of completing the trial, or 12 
weeks following cessation of treatment if the patient initiates new anticancer therapy, whichever is earlier. All 
patients who become pregnant must be followed to the completion/termination of the pregnancy. Pregnancy 
outcomes of spontaneous abortion, missed abortion, benign hydatidiform mole, blighted ovum, fetal death, 
intrauterine death, miscarriage and stillbirth must be reported as serious adverse events (Important Medical 
Events). If the pregnancy continues to term, the outcome (health of infant) must also be reported with the 
parents’ consent. Such events must be reported within 24 hours to RM-CTU by Fax 0208 915 6762 who will 
inform MSD. 
 
8.8. Definition of Serious Adverse Reaction (SAR) 
 
A SAR is defined as an SAE that is judged to be related to any dose of study drug administered to the patient. 
 
8.9. Definition of Suspected Unexpected Serious Adverse Reaction (SUSARS) 
 
A SUSAR is a serious adverse reaction, the nature or severity of which is not consistent with the applicable 
product information (e.g. investigator’s brochure for an unauthorised investigational product or summary of 
product characteristics for an authorised product). 
 
8.10. Reporting of SUSARs 
 
All SUSARs must be reported using the SAE report form within 24 hours of the PI/designee becoming aware of 
the event to the RM-CTU by fax 02089156762. The RM-CTU will in turn notify the Sponsor, MSD, relevant 
Independent Ethics Committee (IEC) / Institutional review, appropriate regulatory authorities and the 
participating Principal Investigators in accordance with regulatory requirements and within the timelines as 
defined below: 
 
• 
For fatal and life-threatening SUSARs the sponsor should report at least the minimum information as 
soon as possible and in any case no later than seven days after being made aware of the case. In 
addition, follow-up reports for fatal and life-threatening SUSARs will be provided within 8 days of the 
date of the initial report. 
• 
SUSARs which are not fatal and not life-threatening are to be reported within 15 days 
 

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Follow up of patients who have experienced a SUSAR should continue until recovery is complete or the condition has 
stabilised. 
8.11. Annual Reporting of Serious Adverse Events 
 
The Development Safety Update Report (DSUR) will be submitted annually on the anniversary of regulatory 
approval for the trial. This report will be submitted to regulatory authorities and Independent Ethics 
Committees (IEC) in accordance with all applicable global laws and regulations. Copies will be forwarded to the 
Sponsor and Investigators. 
 
8.12. Urgent Safety Measures 
 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect the 
patient of a clinical trial against any immediate hazard to their health or safety. This includes procedures taken 
to protect patients from pandemics or infections that pose serious risk to human health. 
 
USMs may be taken without prior notification from the competent authority. However the CI/DI must notify 
the Medicines and Healthcare Products Regulations (MHRA) the Research Ethics Committee (REC) and the 
Sponsor of the new events and the measures taken and the plan for further action immediately via telephone, 
and in writing within 3 days of the measure being implemented. Should the site initiate a USM, the Investigator 
must inform the RM-CTU immediately by: 
• 
Email: GEMMK.Trial@rmh.nhs.uk 
• 
Telephone: 020 88642 6011 Ext: 6766 
• 
Fax: 020 8915 6762 
 
The notification must include: 
• 
The date of the USM 
• 
Who took the decision; and 
• 
Why the action was taken 
 
RM-CTU will then inform the Sponsor, the MHRA and the REC immediately via telephone, and in writing within 
three days of USM initiation. RM-CTU will distribute the response and any subsequent amendments to the trial 
site. 
 
9. STATISTICAL AND DATA ANALYSIS PLAN 
 
9.1. Sample Size 
 
There will be a maximum of 18 patients in part A. The trial will continue to recruit a further 12 patients in part 
B at the MTD determined in part A. We expect to recruit all patients in part A (3+3 design) within the first 12 
months of the study recruitment period. Since the part B (expansion phase) will be descriptive 12 patients will 
be sufficient as it is expected to recruit a further 12 patients in the last 12 months of the study recruitment 
period. 
 
9.2. Statistical Analysis 
 
9.2.1. Primary Endpoint 
Toxicities will be tabulated as frequencies and proportions. 
 
9.2.2. Secondary Endpoints 

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All patients in part A and part B will be included in the secondary endpoint analysis regardless of which dose 
level they are treated. 
 
Overall best response rate will be presented as a proportion of patients with a response of CR or PR at 9 weeks 
of starting treatment according to the RECIST criteria. This will be presented with the appropriate 95% CI. 
 
Best reduction in tumour size will be presented as waterfall plots. 
 
Progression free survival will be calculated using Kaplan Meier methods. This will be defined from starting 
treatment to date of progression or death where any progression free surviving patients will be censored at 
last follow up. The median and 9 week PFS will be presented with the 95% CI. 
 
9.2.3. Exploratory Endpoints 
All patients in part A and part B will be included in the exploratory endpoint analysis. 
 
Immunophenotype of pre and post treatment (9 weeks), location of tumour infiltrating lymphocytes and 
response stratification according to tumour PD-L1 expression will be presented as descriptive statistics where 
any qualitative data will be presented as frequencies, proportions and 95% CIs and any quantitative data will 
be presented with mean, SD, median, IQR  and ranges. 
 
To identify predictive biomarkers of immune response to PD-L1, univariate binary logistic regression analyses 
will be conducted. Any biomarkers with a p value<0.1 will be entered into a forward stepwise multivariate 
model with known prognostic factors. 
To identify predictive biomarkers of immune response to PD-L1, univariate binary logistic regression analyses 
will be conducted. Any biomarkers with a p value<0.1 will be entered into a forward stepwise multivariate 
model with known prognostic factors. 
 
10. LABELING, PACKAGING, STORAGE AND RETURN OF CLINICAL SUPPLIES 
 
 
10.1. Investigational Product 
 
The investigator shall take responsibility for and shall take all steps to maintain appropriate records and ensure 
appropriate supply, storage, handling, distribution and usage of investigational product in accordance with the 
protocol and any applicable laws and regulations. 
 
Clinical Supplies for Pembrolizumab will be provided by MSD as summarized in Table 8. Clinical supplies for 
Gemcitabine as summarised in table 8 below will be obtained from hospital stock. 
 
Table 8 – Product Descriptions 
 
 
Product Name & Potency 
 
Dosage Form 
Pembrolizumab 100 mg/ 4mL 
 
Solution for Infusion 
 

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Product Name & Potency 
 
Dosage Form 
Gemcitabine 38mg/ml  
Concentrate for solution for Infusion  
 
10.2. Packaging and Labeling Information  
 
Clinical supplies will be affixed with a clinical label in accordance with regulatory requirements. 
 
10.3. Clinical Supplies Disclosure 
 
This trial is open-label; therefore, the subject, the trial site personnel, the investigator are not blinded to 
treatment. Drug identity (name, strength) is included in the label text; random code/disclosure envelopes or 
lists are not provided. 
 
10.4. Storage and Handling Requirements 
 
Clinical supplies must be stored in a secure, limited-access location under the storage conditions specified on 
the label. 
 
Receipt and dispensing of trial medication must be recorded by an authorized person at the trial site. 
 
Clinical supplies may not be used for any purpose other than that stated in the protocol. 
 
10.5. Returns and Reconciliation 
 
The investigator is responsible for keeping accurate records of the clinical supplies received from MSD or 
designee, the amount dispensed to and returned by the subjects and the amount remaining at the conclusion 
of the trial. 
 
Upon completion or termination of the study, all unused and/or partially used investigational product will be 
destroyed at the site per institutional policy. It is the Investigator’s responsibility to arrange for disposal of 
all empty containers, provided that procedures for proper disposal have been established according to 
applicable federal, state, local and institutional guidelines and procedures, and provided that appropriate 
records of disposal are kept. 
 
11. REGULATORY, ETHICAL AND LEGAL ISSUES 
 
11.1. Good Clinical Practice 
 
The study will be conducted in accordance with the conditions and principles of GCP as defined in the clinical 
trials regulations. 
 
11.2. Research Ethics Committee-REC/ Regulatory Authority – RA 
 
11.2.1. Initial Approval 
Before starting the trial, the protocol, patient information sheet, consent form, any other written information 
that will be provided to the patients and any advertisements that will be used and details of any patient 

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compensation must be approved by the Royal Marsden/Institute of Cancer Research  joint Committee for 
Clinical Research. Once approved, the study will then be submitted to the relevant Ethics Committee for their 
review and approval. 
 
Prior to the shipment of IMP and the enrolling any patients the Investigator at each site is responsible for any 
site specific assessments and obtaining local R&D approval for the study. The participating site will be required 
to sign an agreement with RM-CTU which includes requirement to sign and adhere to the trial protocol. 
 
11.2.2. Approval of Amendments 
Any protocol amendment should be agreed with the trial management group (TMG) and be approved by the 
sponsor prior to submission and review by the relevant Ethics Committee. Once favourable opinion from IEC 
has been obtained the amendment can be distributed to site and implemented. It is the responsibility of the 
Principal Investigator to submit amendment to their R&D department for R&D approval Amendments requiring 
REC approval may be implemented only after a copy of the REC/RA’s approval letter has been obtained. 
Amendments that are intended to eliminate an apparent immediate hazard to patients may be implemented 
prior to receiving Sponsor or REC/RA approval. However, in this case, approval must be obtained as soon as 
possible after implementation. 
 
11.2.3. Annual Safety Reports and End of Trial Notification 
It is the responsibility of the sponsor to submit the Development Safety Update Report annually to the MHRA/ 
REC on the anniversary of the studies MHRA/REC approval. This will facilitate the authorities continuing review 
of the study. These authorities will also be informed of the end of the study by the sponsor within 90 days of 
the trial completion.  Copies of these reports will also be held within the main trial master file. 
 
11.3.  
Regulatory Authority Approval 
 
The study will be performed in compliance with UK regulatory requirements. Clinical Trial Authorisation (CTA) 
from the Medicines and Healthcare products Regulatory Authority (MHRA) will be obtained prior to the start 
of the study. In addition, the MHRA must approve amendments (as instructed by the Sponsor), receive SUSAR 
reports and annual safety updates, and be notified of the end of the trial. 
  
11.4. Notifications of Serious Breaches to GCP and / or the Protocol 
 
The Sponsor will notify the MHRA and REC in writing of any serious breaches of: 
 
a. The condition and principles of GCP in connection with the trial 
b. The protocol 
This will be done within 7 days if becoming aware of that breach, in accordance with the applicable UK 
regulations as amended from time to time. 
 
For the Purpose of the regulations a “serious breach” is a breach which is likely to effect to a significant degree 
 
a. The safety or physical integrity of the subjects of the trial; or 
b. The scientific integrity of the trial. 
Systematic or persistent non-compliance by the site with GCP and/or the study protocol, including failure to 
report SAEs occurring on trial within the specified timeframes, may be deemed a serious breach. 
 
11.5. Insurance and Liability 

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The Sponsors have secured indemnity from the manufacturer of pembrolizumab for patients in relation to adverse 
side effects for medicine-induced injury. Indemnity for participating hospitals is provided by the usual NHS indemnity 
arrangements for clinical negligence. A copy of the relevant insurance policy/indemnity scheme or summary shall be 
provided on request. 
11.6. Contacts with General Practitioner (GP) 
It is the Investigator’s responsibility to inform the patient’s GP by letter that the patient is taking part in the 
study provided the patient agrees to this, and information to this effect is included in the PIS and ICF. A copy of 
the letter should be filed in the Site File. A template letter approved by the REC/RA will be provided by the 
Sponsor to the participating site. 
 
11.7. Patient Confidentiality 
11.7.1. Patient Confidentiality and Data Sharing 
The Principal investigator must ensure that the patient’s confidentiality is maintained in compliance with the UK 
Data Protection Acts of 1998 & 2018. In all study correspondence submitted to the RM-CTU all participants will be 
identified by their initials and unique Trial Reference study number only which will be used in all e-CRFs or other 
documents submitted to the RM-CTU. In compliance with GCP guidelines, it is required that the investigator and 
institution permit authorised representatives of the sponsor and of the regulatory agency(s) direct access to review 
the patient’s original medical records for verification of study-related procedures and data. Direct access includes 
examining, analysing, verifying, and reproducing any records and reports that are important to the evaluation of the 
study. The investigator is obligated to inform and obtain the consent of the patient to permit named representatives 
to have access to his/her study-related records without violating the confidentiality of the patient. 
11.7.2. Pharmacogenetic Confidentiality 
All pharmacogenetic samples and the information associated with the samples will be coded and stored 
appropriately to ensure confidentiality of the patient’s information and to enable destruction of the samples if 
requested.   Since the evaluations are not expected to benefit the patient directly or to alter the treatment course, 
the results will not be placed in the patient’s medical record and will not be made available to members of the 
family, the personal physician, or other third parties, except as specified in the informed consent. 
11.8. Data Collection and Documentation 
It is the Investigator’s responsibility to ensure that all relevant data is clearly recorded in the medical records. The 
Investigator must allow the Trial Monitors direct access to relevant source documentation for verification of data 
entered into the e-CRF, taking into account data protection regulations. The clinical data should be recorded in the 
e-CRF and the must be verifiable by the source data. 
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the sponsor appointed to audit the trial, or by REC. Details will remain confidential 
and patients’ names will not be recorded outside the hospital. 
 
 
The Principal Investigators at each centre are confirming agreement with his/her local NHS Trust to ensure that: 
• 
sufficient data is recorded for all participating patients to enable accurate linkage between hospital 
records and e-CRFs 
• 
source data and all trial related documentation are accurate, complete, maintained and accessible for 
monitoring and audit visits 
• 
original consent forms are dated and signed by both patient and investigator and are kept together in 
a central log together with a copy of the specific patient information sheet(s) given at the time of 
consent 

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• 
all essential documents must be retained after the trial ends to comply with current legislation 
• 
No study document will be destroyed without prior written agreement between the Sponsor and the PI. 
Should the PI wish to assign the study records to another party or move them to another location, written 
agreement must be obtained from the Sponsor. 
 
11.9. End of Trial 
 
The end of the trial is defined as the last patient’s last visit. 
 
12. DATA AND STUDY MANAGEMENT 
12.1. Source Data 
 
All information in original records and certified copies of original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the trial are classified as 
source data. Source data are contained in source documents; these are defined as original documents, data, 
and records e.g., hospital records, clinical and office charts, laboratory notes, memoranda, patients' diaries or 
evaluation checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate copies, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, patient files, and records kept at the pharmacy, at the laboratories and at 
medico-technical departments involved in the clinical trial. 
12.2. Language 
 
All e-CRFs will be in English. Generic names for concomitant medications should be recorded in the CRF 
wherever possible. All written material to be used by patients must use vocabulary that is clearly understood, 
and be in the language appropriate for the study site. 
 
12.3. Data Collection 
 
The medical records/medical notes should be clearly marked and to allow for easy identification of a patient’s 
participation in the clinical trial. The Investigator (or delegated member of the site study  team) must record all 
data relating to protocol procedures, IMP administration, laboratory data, safety data and efficacy data into 
the e-CRF. 
 
12.4. Electronic Recording of Data 
 
Patients’ data will be documented on a trial specific e-CRF designed by RM-CTU. Should the eCRF not be 
available before the study is ready to begin paper CRFs will be used until the switch can be made. 
 
The Investigator is responsible for ensuring the accuracy, completeness, clarity and timeliness of the data 
reported in the e-CRFs. Only the Investigator, and those personnel who have completed the Study Team 
Responsibilities Signature Log/Delegation Log as authorised by the PI, should enter or change data in the e-
CRFs. All protocol required investigations must be reported in the e-CRF.  The Investigators must retain all 
original reports, traces and images from these investigations for future reference.  The data will be entered in 
a clinical trials database (Macro).  If a patient withdraws from the study, the reason must be noted on the e-
CRF. 
 
Authorised site personnel must not enter study-specific data directly into e-CRFs and ensure all results are 
appropriately documented in the patients’ medical records. The e-CRF will be signed electronically by the 
Investigator or by an authorised staff member. Study specific information will be entered into an e-CRF visit by 

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visit. Data that are derived should be consistent with the source documents or the discrepancies should be 
explained. All e-CRF data should be anonymous, i.e. identified by study patient trial enrolment ID number only. 
 
12.5. Data Management 
 
Data management will be carried out by RM-CTU using an electronic database and in accordance with the data 
management plan agreed by the RM-CTU and RDSU. Data entry will be carried out by appropriately trained 
personnel at participating centres. Queries will be raised centrally by the trial manager / trial monitor and sent 
to the participating centre for resolution. 
 
12.6. Study Management Structure 
 
12.6.1. Delegation of Responsibilities 
This trial is sponsored by the Royal Marsden. This trial will be conducted in accordance with the professional 
regulatory standards required for non-commercial research in the NHS under the research governance 
framework for health and social care and good clinical practice. The following responsibilities have been 
delegated to: 
 
12.6.1.1. RM-CTU 
RM-CTU has overall responsibility for facilitating and coordinating the conduct of the trial and is also responsible for 
collating data obtained, and undertaking and reporting all analyses. The responsibilities of RM-CTU for the day-to-
day management of the trial will include the following; 
• 
ensuring an appropriate ethics opinion has been sought, and any amendments have been approved 
• 
giving notice of amendments to protocol, make representations about amendments to the Main REC, 
HRA and MHRA as applicable 
• 
notifying site and Sponsor that the trial has ended 
• 
registering patients 
• 
raising and resolving queries with local investigators 
• 
keeping records of all serious adverse events (SAEs), overdose incidents, pregnancies and ECI’s 
reported by investigators (as outlined in section 8 above) 
• 
notifying the Main REC, MHRA and Investigators of related Serious Adverse Events 
 
12.6.1.2. Merck Sharp & Dohme (MSD) Corp. 
MSD will be providing study funding and an investigational medicinal drug - pembrolizumab. 
12.6.1.3. Sarcoma Research Fund 
A grant from the Sarcoma Research Fund will fund the translational research. 
 
12.7. Protocol Compliance and amendments 
The participating site will be required to sign an agreement with RM-CTU which includes requirement to sign 
and adhere to the trial protocol. 
Any protocol amendment should be agreed with the trial management group (TMG) and be approved by the 
sponsor prior to submission and review by the relevant Ethics Committee and the MHRA where required. Once 
favourable Opinion from REC and if applicable the MHRA has been obtained the amendment may be 
disseminated to site and implemented. It is the responsibility of the Principal Investigator to submit 
amendment to their R&D department for R&D approval. 
 
12.8. Trial Management 

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The RM-CTU will be responsible for the day-to-day coordination and management of the trial. This includes all 
duties relating to safety reporting. A trial agreement will be signed between the site and RM-CTU. Once all 
relevant trial approvals are in place an initiation (visit or teleconference) will be conducted. In addition, training 
and ongoing advice will be provided by trial training workshop(s), site initiation and ongoing site support to 
each participating site by Trial Management Group (TMG). 
 
12.8.1. Trial Management Group  
A Trial Management Group (TMG) will be set up and membership will include Chief Investigator, Chief Co 
Investigator, Trial Statistician and Trial Manager. Principal Investigators and other key study personnel will be 
invited to join the TMG as appropriate. The TMG have operational responsibility for the conduct of the trial. 
 
At the beginning of the study the TMG will meet every 2 weeks until the first 6 patients registered to receive 
gemcitabine and pembrolizumab have completed 12 weeks of treatment. 
 
Once all 6 patients have completed 12 weeks of treatment a safety assessment will be conducted reviewing all 
AE’s, SAE’s and radiation toxicities occurring in this population. 
 
12.8.2. Safety Review Committee (SRC) 
The SRC will include the Chief investigator for the trial (Dr Robin Jones), a Representative from RM-Clinical Trials 
Unit, a Statistician and be chaired by a clinician, independent of study investigators. The SRC will meet at every dose 
escalation point. The role of the SRC is to:  
• 
Review relevant safety data and make dose escalation decisions for all studies  
• 
Reviews all SAEs and emerging safety data both from RM Sponsored studies and external SUSARS received 
from MSD  
• 
Monitor progress of the trials and ensure emerging safety information is evaluated and protocol and GCP 
principles are adhered to.  
 
The SRC terms of reference, roles and responsibilities will be defined in a charter. Further internal or external 
experts may be consulted as necessary. 
 
12.9. Monitoring  
During the trial the Royal Marsden Monitoring Team is responsible for monitoring data quality in accordance 
with relevant standard operating procedures (SOPs). Incoming data will be monitored for protocol compliance 
and if any inconsistent or missing data is identified queries will be sent to the site for resolution. Any systematic 
inconsistencies may trigger an onsite monitoring visit. 
The trial statistician will periodically examine the data for anomalies and outliers, such as too few or too many 
events. Queries will be raised by the trial coordinators in such situations and communication with the clinical 
teams will take place. In addition, statistical monitoring of unusual dates and inconsistent data will take place. 
Again, these will raise queries via the trial coordinators. 
If an on-site monitoring visit is required, RM-CTU will contact the site to agree convenient date.  The site must 
ensure that relevant site file and patient notes are available for review.  Royal Marsden Monitoring Team staff 
conducting onsite monitoring will review the investigator site file and carry out source data verification to 
confirm compliance with the protocol, trial agreement. 
12.10. Quality Control and Quality Assurance 

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Quality Control (QC) will be performed according to RM-CTU internal procedures. The study may be audited by 
a Quality Assurance (QA) representative of the Sponsor. All necessary data and documents will be made 
available for inspection. 
12.11. Clinical Study report 
 
Clinical data will be presented at the end of the trial based on final data listings. The CI/designee together with 
the trial statistician will prepare a brief clinical study report / publication based on the final data listings. A 
summary of the report must be provided to the Research Ethics Committee and the MHRA within 1 year from 
the submission of the end of trial notification. 
 
12.12. Record Retention 
 
Essential documents are documents that individually and collectively permit evaluation of the conduct of the 
trial and substantiate the quality of the data collected. During the clinical trial and after trial closure the 
Investigator must maintain adequate and accurate records to enable both the conduct of a clinical trial and the 
quality of the data produced to be evaluated and verified in accordance with current legislation. 
 
RM-CTU will maintain essential documents to facilitate the management of the trial, audit and inspection in 
accordance with RM G-SOPs and in compliance with the clinical trial regulatory requirements. The medical files of 
trial subjects shall be retained in accordance with national legislation and in accordance with the maximum period of 
time permitted by the hospital, institution or private practice. All medical records and TMF documentation will be 
retained for a minimum of 5 years after the study has concluded. 
12.13. Reporting and Publication 
The trial results will be submitted for publication in a relevant medical journal with authorship according to the 
criteria defined by the ICMJE (http://www.icmje.org). These state that: Authorship credit should be based 1) 
substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; 
2) drafting the article or revising it critically for important intellectual content; and 3) final approval of the 
version to be published. Authors should meet conditions 1, 2, and 3. 
 
Draft publications (manuscripts, abstracts, slides and posters) should be submitted to the RM-CTU for 
circulation to the relevant parties to allow sufficient time for review prior to submission. There will be a 15 day 
period to review abstracts, posters or slides and a 40 day period to review manuscripts and respond to the 
author with any revisions. 
12.14. Ethical considerations 
 
Before starting the trial, the protocol, patient information sheet and consent form must be approved by the 
RM/ICR joint Committee for Clinical Research. Once approved, the study may then be submitted to the relevant 
regulatory authorities. 
 
It is the Chief and Principal Investigator’s responsibility to update patients (or their authorised representatives, 
if applicable) whenever new information (in nature or severity) becomes available that might affect the 
patient’s willingness to continue in the trial.  The Chief and Principal Investigator must ensure this is 
documented in the patient’s medical records and the patient is re-consented, where appropriate. 
 
The Sponsor and Chief and Principal Investigator must ensure that the trial is carried out in accordance with 
the GCP principles and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 2006/1928 as 
amended) and The Declaration of Helsinki (http://www.wma.net/en/30publications/10policies/b3/). 
 

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tolerizing host tumor-specific CD8 T cells. J Immunol. 2003;170(10):4905-13. 
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14. APPENDICES 
14.1. Appendix 1 – ECOG Performance Status 
 
Grade
 
Description
0
Normal activity. Fully active, able to carry on all pre-disease performance 
without restriction. 
1
Symptoms, but ambulatory. Restricted in physically strenuous activity, 
but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., 
light housework, office work). 
2
In bed <50% of the time. Ambulatory and capable of all self-care, but
unable to carry out any work activities. Up and about more than 50% of 
waking hours. 
3
In bed >50% of the time. Capable of only limited self-care, confined to 
bed 
or chair more than 50% of waking hours. 
4
100% bedridden. Completely disabled. Cannot carry on any self-care.
Totally confined to bed or chair. 
5
Dead.
* As published in Am. J. Clin. Oncol.: Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis,T.E., 
McFadden, E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 5:649-655, 1982. The Eastern Cooperative 
Oncology Group, Robert Comis M.D., Group Chair. 
 
14.2. Common Terminology Criteria for Adverse Events V4.0 (CTCAE) 
 
The descriptions and grading scales found in the revised NCI Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0 will be utilized for adverse event reporting. 
(http://ctep.cancer.gov/reporting/ctc.html) 
 
14.3. Response Evaluation Criteria in Solid Tumours (RECIST) 1.1 Criteria for 
Evaluating Response in Solid Tumours 
 
RECIST version 1.1* will be used in this study for assessment of tumour response. While 

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either CT or MRI may be utilized, as per RECIST 1.1, CT is the preferred imaging technique in 
this study. 
* As published in the European Journal of Cancer: 
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. 
Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. 
Verweij. New response evaluation criteria in solid tumours: Revised RECIST guideline (version 
1.1). Eur J Cancer. 2009 Jan;45(2):228-47. 
 
In addition, volumetric analysis will be explored by central review for response assessment.