A Feasibility Window Study of Pembrolizumab Prior to Second Evacuation for Post-molar Gestational Trophoblastic Neoplasia
Phase: PHASE2
Conditions: Gestational Trophoblastic Disease, Gestational Trophoblastic Neoplasia, Gestational Trophoblastic Tumor, Recurrent
Sponsor: Imperial College London

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CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
 
Full Study Title: 
A 
feasibility 
window 
study 
of 
pembrolizumab prior to second evacuation 
for post-molar gestational trophoblastic 
neoplasia. 
 
 
 
Short Study title / Acronym: 
 
RESOLVE 
 
Product:   
 
 
 
 
Pembrolizumab 
 
Development Phase:   
 
 
Phase II 
 
 
Sponsor: 
 
 
 
 
Imperial College London 
 
ClinicalTrials.gov ID: 
                   NCT05635344 
 
 
Version no:                      
 
2.0            
 
 
 
 
 
Protocol Date:  
 
 
 
10th July 2023 
 
 
 
 
 
Property of Cancer Research UK Imperial Centre: Cancer Clinical Trials Section 
(CCTS) 
May not be used, divulged or published without the consent of CCTS 
 
This protocol has regard for the HRA guidance 
 

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RESEARCH REFERENCE NUMBERS 
 
 
 
 
Include all relevant reference numbers in the table below, delete/amend any that are 
not applicable.  
 
 
IRAS ID: 
1006984 
REC Reference Number: 
23/LO/0260 
EudraCT Number: 
2022-002986-14 
ISRCTN Number / Clinical trials.gov 
Number: 
NCT05635344 
Sponsor ID: 
22CX7947 
Protocol Number: 
C/43/2022 
 
 
 
Keywords: 
 
Cancer immunology, immune failure, immune rejection, immunotherapy, gestational 
trophoblastic neoplasia 
 
 
 
 

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CONTACT LIST 
 
Chief Investigator  
Dr. Ehsan Ghorani 
CRUK Clinician Scientist 
1st Floor, Imperial Centre for Translational and Experimental Medicine 
Department of Surgery and Cancer 
Imperial College London 
Hammersmith Campus 
Du Cane Road 
London W12 0NN 
UNITED KINGDOM 
 
Tel: +44 (0)20 3311 1421 
Email: e.ghorani@imperial.ac.uk 
 
Sponsor 
Research Governance and Integrity Team Imperial College London 
Room 221, Level 2, Medical School Building 
St Mary’s Campus 
Norfolk Place  
London W2 1PG 
UNITED KINGDOM 
 
Contact: Rinat Ezra 
Head of Research Governance and Integrity 
Email: rrgit.ctimp.team@imperial.ac.uk 
Tel: +44 (0)20 7594 1862 
 
Funder 
Clinical trial funding is through the Imperial BRC and the Cancer Treatment and 
Research Trust Charity.  
Translational funding is from CRUK. 
 
ICTU Trial Coordinator  
Aaron Clarke 
Clinical Trial Coordinator 
Cancer Research UK Imperial Centre: Clinical Trials Section (CCTS) 
Cancer Research UK Convergence Science Centre 
Department of Surgery and Cancer 
Imperial College London 
5th Floor Roderick Hill Building, South Kensington Campus 
Prince Consort Road, London, SW7 2AZ  

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Tel: 02033117740 
Email: Aaron.Clarke@Imperial.ac.uk 
 
Study Statistician 
Dr Jingky Pamesa Lozano-Kuehne  
Email: j.lozano-kuehne@academicians.eu 
 
Laboratories (delete if not applicable) 
Experimental Cancer Medicine (ECMC) /ICBRC Laboratory 
2nd Floor, B Block North 
Department of Surgery and Cancer 
Imperial College London 
Hammersmith Campus 
Du Cane Road 
London W12 0NN 
UNITED KINGDOM 
 
Email: ecmcbiobank@imperial.ac.uk   
Tel: +44 (0)20 3313 2349 
 
Protocol development group  
Ehsan Ghorani 
CRUK Clinician Scientist 
Imperial 
College 
London 
Michael Seckl 
Professor of Molecular Cancer Medicine 
Imperial 
College 
London 
Naveed Sarwar 
Consultant Medical Oncologist 
Imperial 
College 
Healthcare NHS Trust 
Xianne Aguiar 
Lead Gestational Trophoblastic Disease Nurse 
Imperial 
College 
Healthcare NHS Trust 
Matthew Winter 
Consultant Medical Oncologist and Honorary Reader 
in Medical Oncology 
Sheffield University 
Tom Bourne 
Professor of Gynaecology 
Imperial 
College 
London 
Philip Badman 
CRUK Centre Cancer Clinical Trials Operations 
Manager 
Imperial 
College 
London 
Aaron Clarke 
CRUK Centre Cancer Clinical Trials Coordinator 
Imperial 
College 
London 
 
 

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Clinical queries 
Clinical queries should be directed to the Chief Investigator or ICTU Study Manager 
who will direct the query to the appropriate person. 
 
This protocol describes the RESOLVE trial and provides information about 
procedures for enrolling participants to the trial. The protocol should not be used as 
a guide for the treatment of other participants; every care was taken in its drafting, 
but corrections or amendments may be necessary. These will be circulated to 
investigators in the study, but centres enrolling participants for the first time are 
advised to contact the Trial Coordination centre to confirm they have the most recent 
version. Problems relating to this trial should be referred, in the first instance, to the 
Trial Coordination centre. 
This trial 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 the International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) guidelines. It will be conducted in compliance with the protocol, 
the Data Protection Act 2018 and other regulatory requirements as appropriate.

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ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
Adverse Event 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
AST 
Aspartate transaminase 
BMI 
Body mass index 
CCTS 
Cancer Clinical Trials Section 
CEAC 
Cost Effectiveness Curve 
CXH 
Charing Cross Hospital 
CI 
Chief Investigator 
CNS 
Central Nervous System 
CR 
Complete response 
CRF 
Case Report Form 
CRUK 
Cancer Research UK 
CTA 
Clinical Trial Authorisation 
CTCAE 
Common Terminology Criteria for Adverse Events 
DoR 
Duration of response 
DSUR 
Development Safety Update Report 
EC 
Database hosted by the Experimental Cancer Medicine Centre 
ECMC 
Experimental Cancer Medicine Centre 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EORTC 
European Organisation for Research and Treatment of Cancer 
FDG-PET Fluorodeoxyglucose-Positron Emission Tomography 
GMP 
Good Manufacturing Practice 
Hct 
Haematocrit 
Hgb 
Haemoglobin 
HRA 
Health Research Authority 
ICBRC 
Imperial Cancer Biomarker Resource Centre 
ICER 
Incremental cost effectiveness ratio 

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ICHNT 
Imperial College Healthcare NHS Trust 
ICMJE 
International Committee of Medical Journal Editors 
ICTU 
Imperial Clinical Trials Unit 
IDMC 
Independent Data Monitoring Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
ITT 
Intention to Treat 
IUD 
Intrauterine device 
IV 
Intravenous 
LDH 
Lactate dehydrogenase 
LFT 
Lung function test 
NETSCC 
NIHR Evaluation, Trials and Studies Coordinating Centre 
NIHR 
HTA 
National Institute for Health Research: Health Technology Assessment 
Programme 
NIMP 
Non- Investigational Medicinal Product 
NMB 
Net monetary benefit 
NSCLC 
Non-small cell lung cancer 
ORR 
Overall response rate 
OS 
Overall survival 
PD 
Progressive Disease 
PFS  
Progression free survival 
PPIE 
Patient and Public Involvement and Engagement 
PR 
Partial response 
QA 
Quality Assurance 
QALY 
Quality adjusted life year 
QC 
Quality Control  
QoL 
Quality of life 
REC 
Research Ethics Committee 
RECIST 
Response Evaluation Criteria in Solid Tumours 
RGIT 
Research Governance and Integrity Team 
RSI 
Reference Safety Information 

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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Stable disease 
SmPC 
Summary of Product Characteristics 
SOP 
Standard Operating Procedure 
SSAR 
Suspected Serious Adverse Reaction 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T3 
Triiodothyronine 
T4 
Thyroxine 
TMG 
Trial Management Group  
TST 
Thyroid function test 
TSC 
Trial Steering Committee 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper Limit of Normal 
WBC 
White blood cell 
 
 
 

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Table of Contents 
RESEARCH REFERENCE NUMBERS 
2 
CONTACT LIST 
3 
1. 
BACKGROUND 
16 
1.1 
Introduction: ....................................................................................................... 16 
1.2 
Clinical Rationale: Reducing exposure to chemotherapy amongst patients with low-
risk disease ....................................................................................................... 17 
1.2.1 Chemotherapy ................................................................................................... 17 
1.2.2 Second evacuation ............................................................................................ 18 
1.2.3 Immunotherapy before second evacuation may greatly enhance cure rates ...... 18 
1.3 
Scientific Rationale ............................................................................................ 19 
1.3.1 GTN as an extreme model of immune suppression: how do cancers escape 
immune control? ................................................................................................ 19 
1.3.2 GTN as an extreme model of tumour rejection triggered by pembrolizumab: how 
does immunotherapy work? ............................................................................... 20 
1.4 
Safety Considerations ........................................................................................ 20 
1.4.1 Pembrolizumab for GTN .................................................................................... 20 
1.4.2 Pembrolizumab delivery with respect to second evacuation ............................... 21 
1.4.3 Second evacuation ............................................................................................ 21 
2. 
OBJECTIVES AND ENDPOINTS 
22 
2.1 
Primary Objectives and Endpoints ..................................................................... 22 
2.2 
Secondary Objective and Endpoint .................................................................... 22 
3. 
STUDY DESIGN 
23 
3.1 
Design ............................................................................................................... 23 
3.2 
Treatment regimens ........................................................................................... 23 
4. 
PARTICIPANT ENTRY 
24 
4.1 
Study setting and population .............................................................................. 24 
5. 
PROCEDURES AND MEASUREMENTS 
27 
5.1 
Identification and recruitment of participants ...................................................... 27 
5.2 
Pre-screening .................................................................................................... 27 
5.3 
On Study Screening (pre-randomisation) ........................................................... 27 
5.4 
Randomisation ................................................................................................... 28 
5.5 
Visit Schedule .................................................................................................... 30 
5.6 
Study Schedules ................................................................................................ 34 
5.7 
Follow-up ........................................................................................................... 34 
5.8 
Procedures, Assessments and Laboratory Evaluations ...................................... 34 
5.9 
Incidental Findings ............................................................................................. 37 
6. 
TREATMENTS 
39 
6.1 
Investigational Medicinal Product Details ........................................................... 39 
6.2 
Labelling and Packaging .................................................................................... 39 
6.3 
Storage and Dispensing ..................................................................................... 39 
6.4 
Dosage, Duration and Compliance .................................................................... 39 
6.5 
Accountability ..................................................................................................... 39 
6.6 
Drug interactions / Precautions / Contraindications ............................................ 39 
6.7 
Overdose of IMP ................................................................................................ 40 
6.8 
Dose Modifications for Toxicity ........................................................................... 40 
6.9 
Study drug administration .................................................................................. 40 
6.10 Pre-medications / Non-IMP details ..................................................................... 40 

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6.11 Withdrawal from Study ....................................................................................... 40 
6.12 Lost To Follow Up .............................................................................................. 41 
In the event that a patient has been lost to follow up, this should be recorded on the 
eCRF with their last known contact date and survival status at the time. Lost to 
follow up status and steps taken to try to contact patient should also be noted in 
the patient’s medical notes. ............................................................................... 41 
6.13 Trial Closure ...................................................................................................... 41 
7. 
PHARMACOVIGILANCE 
42 
7.1 
Definitions .......................................................................................................... 42 
7.2 
Causality ............................................................................................................ 43 
7.3 
Severity of Adverse Events ................................................................................ 44 
7.4 
Reporting Procedures ........................................................................................ 44 
7.5 
Developmental Safety Update Reports / Annual Safety Reports ........................ 46 
7.6 
Pregnancy .......................................................................................................... 46 
7.7 
Reporting urgent safety measures ..................................................................... 46 
8. 
STATISTICAL ANALYSES 
46 
8.1 
Sample Size and power considerations ............................................................. 46 
8.1.1 Feasibility of the treatment strategy.................................................................... 46 
8.1.2 Feasibility of recruitment .................................................................................... 46 
8.1.3 Detection of a clinical meaningful result ............................................................. 47 
8.1.4 Translation aims................................................................................................. 47 
8.2 
Planned recruitment rate .................................................................................... 47 
8.3 
Statistical analysis .............................................................................................. 48 
8.3.1 Analysis populations .......................................................................................... 48 
8.3.2 Primary Endpoint Analysis ................................................................................. 48 
8.3.3 Secondary Endpoint Analysis ............................................................................. 48 
8.3.4 Safety Analysis .................................................................................................. 49 
9. 
REGULATORY, ETHICAL AND LEGAL ISSUES 
50 
9.1 
Declaration of Helsinki ....................................................................................... 50 
9.2 
Good Clinical Practice ........................................................................................ 50 
9.3 
Research Ethics Committee (REC) Approval ..................................................... 50 
9.4 
Regulatory Authority Approval ............................................................................ 51 
9.5 
HRA approval .................................................................................................... 51 
9.6 
Other Required Approvals .................................................................................. 51 
9.7 
Non-Compliance and Serious Breaches ............................................................ 51 
9.8 
Insurance and Indemnity and Sponsor ............................................................... 52 
9.9 
Funding .............................................................................................................. 52 
9.10 Trial Registration ................................................................................................ 52 
9.11 Informed Consent .............................................................................................. 52 
9.12 Contact with General Practitioner ....................................................................... 53 
9.13 Participant Confidentiality ................................................................................... 53 
9.14 Data Protection and Participant Confidentiality .................................................. 53 
9.15 End of Trial ........................................................................................................ 53 
9.16 Study Documentation and Data Storage ............................................................ 53 
10. 
DATA MANAGEMENT 
55 
10.1 Source Data ....................................................................................................... 55 
10.2 Language ........................................................................................................... 55 
10.3 Database ........................................................................................................... 55 

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10.4 Data Collection .................................................................................................. 55 
10.5 Archiving ............................................................................................................ 55 
11. 
STUDY MANAGEMENT STRUCTURE 
56 
11.1 Trial Steering Committee ................................................................................... 56 
11.2 Trial Management Group ................................................................................... 56 
11.3 Data Monitoring Committee ............................................................................... 56 
11.4 Early Discontinuation of the Study ..................................................................... 56 
11.5 Risk Assessment ............................................................................................... 56 
11.6 Monitoring .......................................................................................................... 56 
11.7 Quality Control and Quality Assurance ............................................................... 57 
11.8 Peer review ........................................................................................................ 57 
11.9 Public Involvement ............................................................................................. 57 
11.10 Publication and Dissemination policy ................................................................. 57 
12. 
REFERENCES 
59 
13. 
REVISION HISTORY 
62 
SIGNATURE PAGE 2 (SPONSOR) 
64 
SIGNATURE PAGE 3 (STATISTICIAN) 
65 
SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
66 
 
 
 

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TRIAL SUMMARY 
TITLE 
 
RESOLVE: A feasibility window study of pembrolizumab prior to 
second evacuation for post-molar gestational trophoblastic 
neoplasia. 
PRIMARY 
OBJECTIVE  
1. 
To determine the feasibility of conducting a definitive study 
of neoadjuvant pembrolizumab prior to second evacuation 
of low risk postmolar gestational trophoblastic neoplasia 
(GTN).  
2. 
To collect tissue at the point of second evacuation and blood 
to support translational research into the mechanisms of 
immune evasion and immunotherapy sensitivity in this 
disease 
SECONDARY 
OBJECTIVES 
To assess the rate of surgical cure with and without 
pembrolizumab. 
To assess the safety of a single dose of pembrolizumab prior to 
second evacuation versus second evacuation alone. 
PHASE 
II 
DESIGN 
Single-centre randomised open-label study of neoadjuvant 
pembrolizumab vs standard of care (SOC) 
SAMPLE SIZE 
20 patients; randomised 1:1 to standard of care control or single 
dose of neoadjuvant pembrolizumab. 
STUDY 
POPULATION 
Adults 
(≥18yrs) 
with 
pathologically 
confirmed 
complete 
hydatidiform mole (CHM) who have developed low risk postmolar 
GTN after primary evacuation. 
INCLUSION 
CRITERIA 
SUMMARY 
1. Written informed consent prior to initiation of any study 
procedures and willingness and ability to comply with the 
study schedule. 
2. Age ≥18yrs 
3. Postmolar GTN defined as recurrence or persistence of 
histologically confirmed CHM after primary surgical 
evacuation with no intervening treatment. 
4. Postmolar GTN defined as plateau or rising human 
chorionic gonadotropin (hCG). Plateaued hCG is defined 
as four or more equivalent values of hCG over at least 3 

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weeks. Rising hCG is defined as two consecutive rises in 
hCG of 10% or greater over at least 2 weeks. 
5. hCG under 20,000 IU/L 
6. Low risk disease as defined by the Federation of 
Obstetrics and Gynecology (FIGO) 2000 risk scoring 
criteria (score of 6 or less) 
7. No metastatic disease on chest X-ray  
8. Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
performance status of 0-1 
9. Disease present within the uterine cavity and not within 
5mm of the serosal surface. 
 
Adequate organ function as defined in the following: 
10. Adequate bone marrow function measured within 28 days 
prior to administration of study treatment as defined below: 
Absolute granulocyte count ≥ 1.5 x 109/L ; Platelet count ≥ 
100 x 109/L ; Haemoglobin ≥ 9.0 g/dL (may have been 
blood transfused) 
11. Adequate renal function: Calculated creatinine clearance 
≥ 30 ml/min according to the Cockcroft-Gault formula. 
12. Adequate hepatic function: Serum bilirubin ≤ 1.5 x Upper 
normal limit (ULN) and AST/ALT ≤ 2.5 X ULN 
EXCLUSION 
CRITERIA 
SUMMARY 
1. Patients with other invasive malignancies, with the 
exception of non-melanoma skin cancer, patients who 
have had any evidence of the other cancer present within 
the last 2 years or patients whose previous cancer 
treatment contraindicates this protocol therapy 
2. Patients with histologically confirmed choriocarcinoma, 
placental site trophoblastic tumour (PSTT) or epithelioid 
trophoblastic tumour (ETT) on the first curettage 
3. Pregnant Women 
4. Uncontrolled vaginal bleeding 
5. Administration of live vaccine within 30 days prior to the 
first dose of study drug.  
6. History of immunodeficiency or receiving chronic systemic 
steroid therapy (in dosing exceeding 10 mg daily of 
prednisone 
equivalent) 
or 
any 
other 
form 
of 

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immunosuppressive therapy within 7 days prior to the first 
dose of study drug.  
7. Active autoimmune disease that has required systemic 
treatment in the past 2 years (i.e. with use of disease 
modifying agents, corticosteroids or immunosuppressive 
drugs). Replacement therapy (e.g., thyroxine, insulin, or 
physiologic corticosteroid replacement therapy for adrenal 
or pituitary insufficiency, etc.) is not considered a form of 
systemic treatment and is allowed.  
8. History of (non-infectious) pneumonitis that required 
steroids or has current pneumonitis.  
9. History of Human Immunodeficiency Virus (HIV) infection.  
10. Has a known history of Hepatitis B (defined as Hepatitis B 
surface antigen [HBsAg] reactive) or known active 
Hepatitis C virus (defined as HCV RNA [qualitative] is 
detected) infection.  
11. History of active Bacillus Tuberculosis (TB).  
12. History or current evidence of any condition, therapy, or 
laboratory abnormality that might confound the results of 
the study, interfere with the subject's participation for the 
full duration of the study, or is not in the best interest of the 
subject to participate, in the opinion of the treating 
investigator.  
13. History of allogenic tissue/solid organ transplant. 
TREATMENT, 
FOLLOW 
UP 
AND 
MAIN 
STUDY 
PROCEDURES 
Patients who undergo primary evacuation for CHM, followed up 
at the Charing Cross Hospital (CXH) national GTD registration 
centre will be approached with information about the study. Post 
primary evacuation, hCG levels are routinely monitored. Those 
diagnosed with postmolar GTN based on rising or plateaued hCG 
are routinely invited to CXH for further treatment. Patients will 
undergo screening procedures and if eligible be recruited into the 
study at this point. 
 
Randomisation will be 1:1 to one of two arms: 
1. Standard of care (SOC): second evacuation by ultrasound 
guided suction evacuation and curettage (n=10) 
2. Neoadjuvant 
pembrolizumab 
followed 
by 
second 
evacuation (n=10) 

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Pembrolizumab will be given as a single 200 mg IV dose with 
second evacuation 14 days later. In the SOC arm, patients will 
undergo second evacuation on day 10 post randomisation. 
Between pembrolizumab administration and second evacuation, 
patients will have 2 clinical reviews to determine whether any new 
indication for urgent chemotherapy has arisen and commence 
this immediately if so. 
Cancer tissue for research will be collected at the point of second 
evacuation and patients will subsequently enter a standard of 
care surveillance protocol. 
PRIMARY 
ENDPOINT 
Feasibility of the approach, defined as the proportion of eligible 
patients who consent to randomisation and the proportion of 
patients randomised to the intervention arm who complete 
protocol treatments.  
SECONDARY 
ENDPOINTS 
Proportion of patients who achieve a sustained complete 
response following second evacuation and no further anti-cancer 
therapy, defined as normalisation of hCG and no rise by 1 year 
post procedure. 
Incidence of adverse effects of second evacuation and 
pembrolizumab within 30 days and 12 weeks respectively, 
assessed by Common Terminology Criteria for Adverse Events 
(CTCAE v5.0, 27 Nov 2017). 
ESTIMATED 
RECRUITMENT 
PERIOD 
12 months 
END OF TRIAL 
DEFINITION 
The end of the trial is defined as collection of the last data point 
for the last patient 
IMP 
Name:  Pembrolizumab 
Formulation: Concentrate for solution for infusion 
Dose: Single 200 mg single dose in the intervention arm.  
Route of administration: Intravenous (IV) 
 
 

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1. BACKGROUND 
 
1.1 
Introduction: 
Gestational trophoblastic diseases (GTD) are a variety of rare, pregnancy-related 
proliferative disorders of placental trophoblasts. GTD ranges from premalignant 
conditions of partial and complete hydatidiform mole (CHM) to malignant gestational 
trophoblastic neoplasias (GTN) including invasive mole, choriocarcinoma and the 
rare placental-site trophoblastic and epithelioid trophoblastic tumours1. 
Patients with GTD are registered at one of three UK centres, of which the largest is 
Charing Cross Hospital (CXH), London. The CXH Trophoblastic Disease Centre is 
furthermore the largest of its kind globally with over 1200 registrations per year. 
Most patients with GTD are radiologically diagnosed with premalignant hydatidiform 
mole during early pregnancy and subsequently undergo surgical evacuation of the 
uterus. Amongst patients with CHM, approximately 15% are not cured by primary 
evacuation. This is diagnosed usually with rising or plateaued human chorionic 
gondadotrophin (hCG) levels (a sensitive marker of disease burden)2. Patients 
usually have intrauterine and sometimes extrauterine disease. Postmolar disease at 
this point is considered to be malignant GTN and requires further therapy, usually 
with chemotherapy or second evacuation. Chemotherapy carries a number of short 
and long term toxicities that negatively impact quality of life. Our patient 
representatives indicate that our predominantly young cohort of women are keen to 
avoid these toxicities. Approximately one third of patients are cured with second 
evacuation alone3. 
Immunotherapy with pembolizumab that targets the T cell inhibitory receptor PD1 are 
highly effective in GTN (~75% cure rate)4. In other cancer types that are less 
sensitive, pembrolizumab delivered prior to disease resection has proven to be highly 
effective, resulting in high pathological complete response rates (elimination of all 
viable cancer cells)5,6.  These observations motivates us to ask whether treatment 
with pembrolizumab prior to second evacuation of postmolar GTN could enhance the 
surgical cure rate and represent a powerful approach to cure this disease without 
requiring chemotherapy. 
From a translational research perspective, the unique immune biology of GTN offers 
an ideal opportunity to deepen our understanding of immune regulation in cancer. 
GTN arises from placental trophoblasts and as such is a semi- or fully allogeneic 
transplant with both maternal and paternal genomic contribution7. Conventionally, 
such HLA mismatched transplants are expected to be rapidly rejected by the host 
immune system that recognises paternal antigens as foreign, yet GTN can be widely 
metastatic and fatal without therapy. In parallel, the exceptionally high response rate 
of this disease to immunotherapy offers an opportunity to study the biology of an 
optimally activated anti-cancer immune response. Thus, GTN represents a model to 

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study both mechanisms of extreme immune evasion in a highly antigenic environment 
and the basis of immunotherapy sensitivity. 
Here, we propose a feasibility window study of neoadjuvant pembrolizumab vs. no 
treatment prior to second evacuation of intrauterine postmolar GTN. The trial will 
enable us to determine whether pembrolizumab prior to second evacuation is 
acceptable to patients and feasible to deliver. This could directly set a new standard 
of care or motivate a larger, definitive study. Second evacuation tissues and blood 
samples will be used to support a CRUK funded study of immune regulation in cancer 
using GTN as a model, expected to yield novel insights into why the immune 
response is incapable of rejecting cancers in general and how pembrolizumab 
overcomes this. These insights will help develop new treatments and approaches to 
personalised care across cancer types.  
 
1.2 
Clinical Rationale: Reducing exposure to chemotherapy amongst 
patients with low-risk disease 
Two broad treatment options are considered for patients with postmolar GTN that has 
not spread beyond the uterus and who otherwise are considered low risk according 
to FIGO international criteria8. Firstly, further evacuation of intrauterine disease and 
secondly systemic treatment with chemotherapy. Whilst further treatments may be 
required, the overall cure rate approaches 100%, thus it is desirable to offer the least 
toxic approach upfront. 
A limitation of second evacuation is the relatively low cure rate of approximately 25-
35%3,9–11. Recently, immunotherapy with pembrolizumab has emerged as a highly 
active modality. In more common cancer types that are less immunotherapy 
responsive than GTN, immunotherapy given prior to surgery has yielded high 
response rates5,6. This hasn’t been tested in GTN. We hypothesise that 
immunotherapy given before second evacuation of recurrent GTN will significantly 
increase the cure rate resulting in a novel treatment approach that will reduce the 
need for exposure to toxic chemotherapy. 
 
1.2.1 Chemotherapy 
Although adopted as the usual first line choice, chemotherapy is toxic, inconvenient, 
adversely impacts quality of life and introduces additional financial and social 
morbidities12. Whilst GTN is highly chemotherapy sensitive, up to 40% of all low-risk 
patients develop resistance to 1st line methotrexate chemotherapy requiring a 
treatment change, usually to multiagent therapy13. These regimens come with 
considerable toxicities including short term alopecia, mucositis, fatigue and the risk 
of life threatening neutropenic sepsis14. Long term, there is an increased risk of 
second malignancy and early menopause15. Treatment requires overnight 
admissions away from home which many young patients find challenging. This view 

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is reiterated by our expert patient representative, who believes patients are generally 
strongly motivated to participate in trials that limit the need for chemotherapy. 
 
1.2.2 Second evacuation 
Second evacuation by suction curettage16 of recurrent intrauterine disease is an 
alternative approach for patients with no spread of disease beyond the uterus. 
Following early work suggesting that second evacuation alone may be a sufficient 
treatment for some patients17, this option has been explored in further retrospective 
studies3,10,11,18,19, two single arm prospective studies20,21 and one randomised phase 
II trial of evacuation vs. chemotherapy22. Collectively, these studies have established 
that second evacuation is a safe procedure that spares at least on quarter of patients 
the need for further treatment, depending on the hCG prior to evacuation. 
Globally, the largest study of second evacuation to date was carried out at CXH and 
reviewed the outcomes of 111 patients with disease recurrence following primary 
evacuation3. Amongst those with an hCG of 10,000 to 20,000 IU/L, the cure rate was 
25% (n=6 cured / 24 treated). Amongst all patients with an hCG less than 20 000 
IU/L, a cure rate of 35% was observed (n=20 cured / 57 treated). Since the overall 
cure rate remains close to 100%, it is arguable that minimisation of toxicity should be 
a key goal and some advocate second evacuation as a preferred, lower toxicity, 
option to chemotherapy particularly amongst those with lower hCG levels. In the era 
of immunotherapy agents that activate anti-tumour immune responses, it is possible 
that combining this modality with second resection may further reduce the need for 
chemotherapy. 
 
1.2.3 Immunotherapy before second evacuation may greatly enhance 
cure rates 
T cells of the immune system can recognise and control tumours, but their function is 
limited by inhibitory receptors (checkpoints). Monoclonal antibodies directed against 
these receptors (checkpoint blockade immunotherapy [CPI]) have proven to be 
effective across cancer types23–25. We have recently shown that GTN is profoundly 
CPI sensitive. Complete responses occur in ~70% of anti-PD1 treated patients4, the 
highest rate across all human cancers. 
Whilst CPI is mostly utilised in the setting of advanced, metastatic disease, it is 
increasingly studied in other settings. Several studies have now shown that 
neoadjuvant immunotherapy prior to cancer resection is a powerful approach, 
resulting in complete pathological responses amongst patients with melanoma6 and 
lung cancer5 amongst other cancer types. Given that the efficacy of anti-PD1 therapy 
is higher in GTN than these other tumour types that are conventionally considered to 
be most immunotherapy response, we hypothesise that neoadjuvant pembrolizumab 
prior to second evacuation could significantly enhance the cure rate over second 
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1.3 
 Scientific Rationale 
Tumour infiltrating T-cells (TILs) recognise cancer cells26–30, but untreated 
malignancies usually progress, indicating tumour microenvironmental (TME) immune 
dysfunction31. The mechanisms of immune suppression within the tumour 
environment are not well understood. 
In parallel, CPI has transformed the management of patients with multiple cancer 
types, but only a minority of patients benefit. The reasons for this are likewise 
unknown and underscore our limited understanding of the mechanisms governing TIL 
activity. 
In summary, we propose GTN to be a unique model of human cancer immune 
regulation. Comparative study of tissues obtained from the control and intervention 
arms of this trial will elucidate fundamental mechanisms of cancer immune 
suppression and how this is reversed by immunotherapy. This understanding will help 
develop new treatments and tools to better personalise treatment of patients with 
GTN and more common cancers. The translational aims are supported by a CRUK 
Clinician Scientist Fellowship awarded to the CI. Input from an expert patient 
representative suggests that this cohort are motivated to participate in research that 
will potentially result in treatment advances in GTN and other cancers. 
 
1.3.1 GTN as an extreme model of immune suppression: how do 
cancers escape immune control? 
T cells distinguish cancer from normal self by detecting differences in protein 
fragments (antigens) presented on MHC molecules. Cancers are antigenically 
different from self in that they overexpress certain non-mutated proteins and in most 
cases additionally present mutated or neo-antigens. The immune response is 
stronger against cancer cells that are antigenically more different to self32. GTN is a 
unique cancer type since it is genomically composed of both maternal and paternal 
contributions, and in many cases only from paternal DNA. Thus, GTN represents a 
semi- or fully-allogeneic transplant.  
Because of antigenic diversity particularly in MHC proteins, mismatched tissue 
transplants are usually rapidly rejected by the host immune system, yet GTN avoids 
this fate. Since it so strongly antigenic, this disease must employ very powerful 
mechanisms to suppress the immune response. Studying GTN as an extreme model 
of how a highly antigenic cancer type escapes immune destruction will thus shed light 
on mechanisms employed by other cancer types and drive research into new 
therapeutic approaches in this and other more common cancers. 
 

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1.3.2 GTN as an extreme model of tumour rejection triggered by 
pembrolizumab: how does immunotherapy work? 
Across cancer types, it remains unknown why some but not all patients respond to 
immunotherapy. An essential piece of missing information is precisely how agents 
such as pembrolizumab work, and in which immune cell population this drug acts on. 
T cells are broadly divided into CD4 T helper (Th) and CD8 T cytotoxic cells. These 
populations recognise antigens presented on MHC class I and class II respectively. 
Whilst relatively understudied, Th cells are central to the anti-tumour immune 
response. This population can adopt a variety of fates to play an important role in 
recruiting, activating and sustaining the activity of anti-cancer CD8 cytotoxic T cells. 
Th cells can additionally mediate tumour rejection both directly and indirectly. 
In parallel to employing strong mechanisms to prevent immune rejection, GTN is the 
most immunotherapy responsive cancer type described to date with a cure rate of 
~75%. This contrasts with 5 year survival rates of ~40% with the anti-PD1 directed 
agent nivolumab in advanced melanoma33 and ~30% with pembrolizumab in lung 
cancer respectively34. Notably, like many cancer types, GTN has suppressed or 
absent expression of MHC I required for CD8 T cell recognition, indicating a 
potentially important but unknown role of Th cells. This disease thus offers a unique 
opportunity to better understand the mechanisms of immune rejection triggered by 
anti-PD1 immunotherapy and in particular the CD4 T cell contribution to this. By 
studying the optimally activated intratumour immune response amongst patients with 
GTN treated with pembrolizumab in the intervention arm, we expect to greatly 
advance our understanding of how pembrolizumab acts, which are the effector 
populations and how they are regulated. 
 
1.4 
 Safety Considerations 
Individually, both pembrolizumab and second evacuation are characterised by a very 
low complication rate. 
 
1.4.1 Pembrolizumab for GTN 
Amongst patients with advanced GTN, pembrolizumab has proven to be a remarkably 
low toxicity agent. In CXH led global cohort of 58 patients treated over the past 7 
years, only one patient discontinued therapy because of toxicity and there have 
otherwise been no grade 3 or higher events. The single patient who stopped 
treatment had a renal transplant that unfortunately was rejected following 
pembrolizumab therapy. Patients with organ transplant are excluded from this study 
and with a single dose of pembrolizumab we anticipate no safety concerns. 
 

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1.4.2 Pembrolizumab delivery with respect to second evacuation 
As a standard of care, pembrolizumab is given at a flat dose of 200 mg IV once every 
3 weeks or 400 mg once every 6 weeks. Usually, patients are commenced on 200 
mg before switching to the higher dose once established. Although recent data 
suggest there is no difference in toxicity between the two regimens35, we propose to 
offer the lower dose as a precaution. 
In the intervention arm, we propose to carry out second evacuation 14 days following 
a single dose of pembrolizumab. We will allow a 2-day margin either side of the target 
to accommodate surgical theatre availability. To determine the number of doses and 
time to second evacuation, we have primarily aimed to balance two competing 
factors. Firstly, since patients have already been determined to require treatment for 
disease recurrence, the time between randomisation and evacuation should be 
minimised to reduce the risk of complications such as vaginal bleeding. Secondly, a 
period of time is required for maximal pembrolizumab effect in the tumour 
environment. In deciding on 14 days between pembrolizumab treatment and 
evacuation, we have considered data from patients with lung cancer treated with a 
single dose of pembrolizumab, which has shown a maximal effect on circulating T 
cell activation between 2-3 weeks post dose. In patients with advanced disease, 14 
days is considered the minimal time period before a tumour response is seen with 
hCG decline. Thus a 14 day window ensures sufficient time for pembrolizumab effect 
whilst minimising the risks associated with tumour progression if therapy is ineffective. 
 
1.4.3 Second evacuation 
Second evacuation by ultrasound guided suction curettage is considered to be a safe 
approach in suitably selected patients. In three contemporary prospective studies 
recruiting 134 patients with disease recurrence after primary evacuation21,22,36, a total 
of four grade 1 (3%) and one grade 3 (0.7%; requiring transfusion to support) cases 
of uterine haemorrhage were observed. In contrast, patients treated with 1st line 
methotrexate chemotherapy for low risk GTN have a reported rate of grade 3 
haemorrhage of approximately 2%37. Amongst patients undergoing second 
evacuation in the studies noted above, one case of grade 1 uterine perforation (0.7%) 
was managed conservatively. 
 
 

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2. OBJECTIVES AND ENDPOINTS 
2.1 Primary Objectives and Endpoints 
Objectives 
Endpoints 
To 
determine 
the 
feasibility 
of 
conducting 
a 
definitive 
study 
of 
neoadjuvant pembrolizumab prior to 
second 
evacuation 
of 
low 
risk 
postmolar 
gestational 
trophoblastic 
neoplasia (GTN) 
1. The proportion of eligible patients who consent 
to randomisation.  
 
2. The proportion of patients randomised to the 
intervention 
arm 
who 
complete 
protocol 
treatments. 
To collect tissues at the point of second 
evacuation and blood to support 
translational 
research 
into 
the 
mechanisms of immune evasion and 
immunotherapy 
sensitivity 
in 
this 
disease  
 
 
 
2.2 Secondary Objective and Endpoint 
Objectives 
Endpoints 
To assess the rate of surgical cure with 
and without pembrolizumab. 
Proportion of patients who achieve a sustained 
complete response following second evacuation 
and no further anti-cancer therapy, defined as 
normalisation of hCG and no rise by 1 year post 
procedure. 
 
To assess the safety of a single dose of 
pembrolizumab 
prior 
to 
second 
evacuation versus second evacuation 
alone. 
Incidence 
of 
adverse 
effects 
of 
second 
evacuation and pembrolizumab within 30 days 
and 12 weeks respectively, assessed by 
Common Terminology Criteria for Adverse 
Events (CTCAE v5.0, 27 Nov 2017). 
 
 
 
 
 

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3. STUDY DESIGN   
 
3.1 
 Design 
This is a single centre, randomised, open-label study of a single dose of 200 mg IV 
pembrolizumab followed by second evacuation 14 days later, or second evacuation 
alone for patients with low risk GTN who have failed primary surgical evacuation 
(Figure 1). 
 
3.2 
Treatment regimens  
 
Table 1: Summary of treatment groups 
Treatment arm 
Number of participants 
Second evacuation alone (control) 
10 
Pembrolizumab 
followed 
by 
second 
evacuation (Intervention) 
10 
Total number of participants 
20 
 
 
Figure 1: Study Flowchart 
 
 
Key: 
CHM – Complete Hydatidiform mole; 1ry – Primary; CPI – Checkpoint inhibitor; Pembro – 
Pembrolizumab; FU – Follow up Visit 
 

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4. PARTICIPANT ENTRY 
 
4.1 
Study setting and population 
The study will recruit patients aged 18 and above with untreated low risk GTN 
following primary uterine evacuation of CHM. Recruitment, treatment and follow-up 
will be at Charing Cross Hospital with the option of opening a second site if 
recruitment targets are not met.  
All potential patients recruited onto study must meet all the inclusion and none of the 
exclusion points listed below: 
 
(i) 
Inclusion criteria 
1. Written informed consent prior to initiation of any study procedures and 
willingness and ability to comply with the study schedule. 
 
2. Age ≥18yrs 
 
3. Postmolar GTN defined as recurrence or persistence of histologically 
confirmed CHM after primary surgical evacuation with no intervening 
treatment. 
 
4. Postmolar GTN defined as plateau or rising human chorionic gonadotropin 
(hCG). Plateaued hCG is defined as four or more equivalent values of hCG 
over at least 3 weeks. Rising hCG is defined as two consecutive rises in hCG 
of 10% or greater over at least 2 weeks. 
 
5. hCG under 20,000 IU/L 
 
6. Low risk disease as defined by the Federation of Obstetrics and Gynecology 
(FIGO) 2000 risk scoring criteria (score of 6 or less) 
 
7. No metastatic disease on chest X-ray. 
 
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 
 
9. Disease present within the uterine cavity not within 5mm of the serosal surface. 
 
10. Adequate bone marrow reserve or organ function as defined by any one of the 
following parameters: 
• Absolute neutrophil count ≥ 1.5 x 10^9 /L; 

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• Platelet count ≥ 100 x 10^9 /L; 
• Haemoglobin ≥ 9.0 g/dL (may have been blood transfused) 
• Creatinine clearance ≥ 30 ml/min (Cockcroft-Gault formula) 
• Serum bilirubin ≤ 1.5 x ULN 
• AST/ALT ≤ 2.5 X ULN 
 
11. All patients must agree to a highly effective method of contraception, or to 
complete abstinence* for 1 year following second evacuation. This is standard 
practice following second evacuation of GTN because hCG levels rise in 
pregnancy thus masking a potential cancer recurrence.  
 
*Complete abstinence (defined as refraining from heterosexual intercourse) must be 
in line with the preferred and usual lifestyle of the participant. Periodic abstinence 
(calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable 
methods of contraception. Female condom and male condom should not be used 
together. 
 
(ii) 
Exclusion criteria  
1. Patients with other invasive malignancies, with the exception of non-melanoma 
skin cancer, patients who have had any evidence of the other cancer present 
within the last 2 years or patients whose previous cancer treatment 
contraindicates this protocol therapy. 
 
2. Patients with histologically confirmed choriocarcinoma, placental site 
trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT) on the first 
curettage. 
 
3. Pregnant women.  
 
4. Uncontrolled vaginal bleeding. 
 
5. Administration of live vaccine within 30 days prior to the first dose of study 
drug. Examples of live vaccines include, but are not limited to, the following: 
measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, 
Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza 
vaccines for injection are generally killed virus vaccines and are allowed; 
however, intranasal influenza vaccines (eg, FluMist®) are live attenuated 
vaccines and are not allowed.  
 
6. History of immunodeficiency or receiving chronic systemic steroid therapy (in 
dosing exceeding 10 mg daily of prednisone equivalent) or any other form of 
immunosuppressive therapy within 7 days prior to the first dose of study drug.  

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7. 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 and is 
allowed.  
 
8. History of (non-infectious) pneumonitis that required steroids or has current 
pneumonitis.  
 
9. History of Human Immunodeficiency Virus (HIV) infection.  
 
10. Has a known history of Hepatitis B (defined as Hepatitis B surface antigen 
[HBsAg] reactive) or known active Hepatitis C virus (defined as HCV RNA 
[qualitative] is detected) infection. Note: no testing for Hepatitis B and Hepatitis 
C is required unless mandated by local health authority.  
 
11. History of active TB (Bacillus Tuberculosis).  
 
12. History or current evidence of any condition, therapy, or laboratory abnormality 
that might confound the results of the study, interfere with the subject's 
participation for the full duration of the study, or is not in the best interest of the 
subject to participate, in the opinion of the treating investigator.  
 
13. History of allogenic tissue/solid organ transplant. 
 
 

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5. PROCEDURES AND MEASUREMENTS  
 
5.1 
Identification and recruitment of participants  
Patients diagnosed with GTD are routinely registered at one of two centres covering 
England and Wales: Charing Cross Hospital, London (CXH) and Weston Park 
Hospital, Sheffield. Patients with a diagnosis of CHM following primary evacuation of 
intrauterine disease registered at CXH will be identified and sent information about 
the trial to provide time to consider participation. Following primary diagnosis, patients 
routinely undergo hCG monitoring (2-weekly urine and blood until hCG normalisation 
and then monthly urine hCG). In approximately 10-15% of cases a rise or plateau in 
hCG occurs, indicating failure of primary evacuation resulting in development of 
postmolar GTN and the need for further therapy. At this point, patients are routinely 
invited to CXH for further evaluation and can be enrolled into the study. 
 
5.2 
 Pre-screening 
As part of routine evaluation of suspected postmolar GTN, patients undergo 
assessments to determine whether the disease is low or high risk based on the FIGO 
2000 international guidelines. These tests include: 
• Thoracic x-ray, 
• Uterine ultrasound scan of the uterus 
• Blood tests to determine hCG level, organ function and viral status.  
Whilst low risk patients would be considered for single agent chemotherapy with 
methotrexate or second evacuation, high risk patients start multiagent chemotherapy. 
All patients in this cohort will have elevated hCG due to the nature of the disease and 
hCG is a marker that is also elevated during pregnancy. To rule pregnancy out, blood 
hCG testing will be paired with an uterine ultrasound scan to confirm presence of 
cancer and absence of a foetus.  
 
To reduce the number of patients we unnecessarily approach with further study 
information (which has the risk of increasing anxiety around the decision making 
process), we will offer the trial only to patients we have established to have low-risk 
disease amenable to second evacuation after the above standard of care 
investigations have been completed.  
 
5.3 
 On Study Screening (pre-randomisation)  
Pre-screening test results remain valid for 7 days prior to randomisation. Patients who 
are considered eligible based on pre-screening results will be invited to provide 
written informed consent before further study screening procedures.  
 

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We will obtain consent followed by on study screening procedures commencing on 
the day of attending CXH. These processes are expedited for the following reasons: 
firstly, to minimise the time between diagnosis and definitive therapy since delays 
introduce additional risks; secondly, as a national service, patients may travel long 
distances to attend CXH and we aim to reduce the inconvenience of additional 
attendances. 
 
Data obtained as standard of care prior to written informed consent may be used for 
the study provided they comply with the protocol specified timelines.  
 
Once written informed consent has been obtained, patients will be added to the study 
database, where a unique Screening ID will be allocated. This should be used in all 
correspondence during the screening period.  
 
Screening procedures and assessments are as follows: 
 
• Collection of demographic data 
• Review of medical history to include cancer history and treatment 
• Physical examination and performance status 
• Blood tests to confirm eligibility: thyroid function test, cortisol. 
• Record of vital signs (including height and weight) 
• Assessment of concomitant medications  
• Collection of research bloods 
• Recording of blood test results done as part of pre-screening: renal/liver 
function, full blood count, viral screen, coagulation screen, hCG 
• Recording of ultrasound scan and chest x-ray results done as part of pre-
screening 
 
A complete record of all patients who enter screening for the study, and those who 
go on to be enrolled, must be maintained at each site. The site investigators are 
responsible for ensuring that this record includes the allocated ID as well as the 
patient identifiable data including name, hospital number and date of birth.  
 
Eligible patients who take part in the study must meet all the listed inclusion criteria 
and none of the exclusion criteria (section 4.1).     
 
5.4 
 Randomisation  
After eligibility has been confirmed, patients will be randomised to the trial. 
Randomisation will be performed centrally by Imperial Cancer Clinical Trials Section 
(CCTS) using the study database.  There will be no option for manual randomisation. 
Upon randomisation each patient will be allocated a unique subject ID which should 
be used in all future correspondence. Please refer to the eCRF Completion Manual 
for further details on patient randomisation. 

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In this open-label study, randomisation will be on a 1:1 basis between second 
evacuation and pembrolizumab prior to second evacuation arms. Randomisation will 
be stratified according tp baseline hCG since this has been shown to strongly 
influence the probability of cure following second evacuation. Based on historical 
data, we have carried out simulations to show that randomising patients within pre-
defined hCG values corresponding to expected median or quartile limits results in 
balanced distribution of hCG values between the two arms in over 95% of simulated 
trials. The Trial Statistician will be responsible for holding the randomisation code 
securely until the final analysis of the study but also to enable the interim analysis. 
 
After eligibility has been confirmed, an archival tissue sample in the form of formalin 
fixed paraffin embedded (FFPE) tumour block and/or diagnostic tissue section will be 
collected from each patient. 
 
.

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5.5 
Visit Schedule  
 
Table 2: Schedule of Assessments: Second evacuation only 
 
Procedure 
Pre-
screening 
Baseline/ 
screening 
Day -3 to 0 
Day 71 
2 weeks post 
evacuation2 
6 weeks post 
evacuation2 
12 weeks post 
evacuation2 
Every 
2 
weeks 
post 
evacuation 
until 
normalisation of hCG 
Every month following 
normal hCG and until 1 
year post evacuation 
Informed Consent 
 
X 
 
 
 
 
 
 
Medical History & Demographics 
 
X 
 
 
 
 
 
 
Physical Exam 
 
X 
 
X 
X 
 
 
 
Performance Status 
 
X 
 
X 
X 
 
 
 
Vital Signs 
 
X 
 
 
 
 
 
 
Haematology 
X 
 
 
 
 
 
 
 
Biochemistry 
X 
 
 
 
 
 
 
 
Coagulation 
X 
 
 
 
 
 
 
 
Viral Screen (Hep B, Hep C, HIV) 
X 
 
 
 
 
 
 
 
Thyroid Function Tests and Cortisol 
 
X 
 
 
 
 
 
 
Tumour marker blood hCG 
X 
 
 
 
 
 
X 
 
Research Blood Sample  
 
X 
 
X 
X 
X 
 
 
Archival Tissue 
 
X 
 
 
 
 
 
 
Imaging - Chest X-ray 
X 
 
 
 
 
 
 
 
Imaging - Uterine ultrasound scan 
X 
 
X 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
Surgical evacuation 
 
 
X 
 
 
 
 
 
Urine hCG  
 
 
 
 
 
 
X 
X 
Adverse Events 
 
 
 
X 
X 
X 
 
 
Concomitant Medications 
 
X 
 
 
 
 
 
 

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1. Visit is permitted to be performed two days prior or after scheduled timepoint. 
2. Visit is permitted to be performed three days prior or after scheduled timepoint. 
 
 

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Table 3: Schedule of Assessments: Pembrolizumab arm 
 
Procedure 
Pre-
screening 
Baseline/ 
Screening 
 
Day -3 to 0 
Day 
0 
Day 
+71 
 
Day 
+111 
 
Day 
+141 
 
 
2 
weeks 
post 
evacuation
2 
6 
weeks 
post 
evacuation
2 
12 weeks 
post 
evacuation
2 
Every 2 weeks post 
evacuation 
until 
normalisation of hCG 
Every month following 
normal hCG and until 1 
year post evacuation 
Informed Consent 
 
X 
 
 
 
 
 
 
 
 
 
Medical History & Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
X 
 
 
X 
 
X 
X 
X 
 
 
Performance Status 
 
X 
 
 
X 
 
X 
X 
X 
 
 
Vital Signs 
 
X 
 
 
X 
 
 
 
 
 
 
Haematology 
X 
 
 
 
X 
 
 
X 
X 
 
 
Biochemistry 
X 
 
 
 
X 
 
 
X 
X 
 
 
Coagulation 
X 
 
 
 
X 
 
 
X 
X 
 
 
Viral screen (Hep B, Hep C, HIV) 
X 
 
 
 
 
 
 
 
 
 
 
Thyroid Function Tests and Cortisol 
 
X 
 
 
 
 
 
X 
X 
 
 
Tumour marker blood hCG 
X 
 
 
X 
X 
 
 
 
 
X 
 
Research Blood sample  
 
X 
 
 
 
X 
X 
X 
X 
 
 
Archival Tissue 
 
X 
 
 
 
 
 
 
 
 
 
Imaging – Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
Imaging – Uterine ultrasound scan 
X 
 
 
 
 
X 
 
 
 
 
 
Imaging 
– 
Optional 
Magnetic 
Resonance Imaging  
 
 
X3 
 
 
X4 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
 
 
Pembrolizumab  
 
 
X 
 
 
 
 
 
 
 
 

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1. 
Visit is permitted to be performed two days prior or after scheduled timepoint. 
2. 
Visit is permitted to be performed three days prior or after scheduled timepoint. 
3. 
Visit is permitted to be performed anytime from randomisation to before Pembro administration. 
4. 
Visit is permitted to be performed within two days prior to the second evacuation  
 
Surgical evacuation 
 
 
 
 
 
X 
 
 
 
 
 
Urine hCG  
 
 
 
 
 
 
 
 
 
X 
X 
Adverse Events 
 
 
 
 
X 
 
X 
X 
X 
 
 
Concomitant Medications 
 
X 
 
 
 
 
 
 
 
 
 

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5.6 
Study Schedules 
Scheduled visits, and their relevant assessments, will be conducted according to the 
randomised treatment arm – please refer to tables 2 and 3.  
 
5.7 
Follow-up 
Following second evacuation, patients in both arms will undergo standard of care 
urine and blood hCG monitoring every 2 weeks until hCG normalisation and then 
monthly urine hCG measurement for up to 1 year post evacuation. Failure of second 
evacuation to result in disease control is defined as per national guidelines (rise or 
plateau in hCG, hCG over 20,000 IU/L at 4 weeks, heavy vaginal bleeding). Patients 
will additionally have a clinical review and toxicity check at 2, 6 and 12 weeks post 
evacuation.   
 
 
5.8 
Procedures, Assessments and Laboratory Evaluations  
(i) 
Demographic data 
Patient month and year of birth will be collected at screening. For equality and 
diversity purposes, gender including gender reassignment; sexual orientation; marital 
status; disability; ethnicity, religion; geographical location and socioeconomic status 
and smoking status/history) will also be collected with all questions being optional to 
answer. 
 
(ii) 
Medical history to include cancer history and treatment 
A medical history will be taken. This history will detail the patient’s cancer, including 
details of prior anti-cancer therapies. Any other relevant medical history and 
treatments will also be recorded. Concurrent diseases, i.e., other medical conditions 
that are ongoing from the start of the study, will be documented as adverse events if 
they worsen. 
 
(iii) 
Vital signs 
Vital signs including height (screening only), weight, body temperature, pulse, blood 
pressure and BMI will be recorded as indicated in the schedule of assessment tables. 
Vital signs may be assessed at any time during the visit; however, pulse and blood 
pressure should be measured after at least 10 minutes rest.  
 
(iv) 
Physical exam 
A complete physical examination will be performed as indicated in the schedule of 
assessment tables.  The following examinations should be undertaken: general 

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appearance; skin; eyes, ears, nose, mouth and throat; head, neck and thyroid; chest; 
cardiovascular; abdomen; extremities; genitalia; spine; musculoskeletal; lymph 
nodes; neurological; other. The outcome of the examinations will be assessed to 
include whether normal, abnormal (clinically significant or not clinically significant) or 
not done. 
 
(v) 
ECOG performance status 
ECOG performance status will be performed as indicated in the schedule of 
assessments tables according to criteria as follows: 
 
Table 4: ECOG Performance status 
0 
Fully active, able to carry on all pre-disease activities without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature. For example, light housework, office work  
2 
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 
Capable of only limited self-care, confined to bed or chair 50% or more of 
waking hours  
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair  
5 
Death  
 
(vi) 
Laboratory evaluations: 
The following laboratory evaluations will be conducted as indicated in the schedule 
of assessments tables, with collection and analysis according to standard practice at 
the relevant site. 
• Haematology: White blood cell count (WBC) with differential, 
haemoglobin (Hgb), haematocrit (Hct) and platelet count. 
• Biochemistry: Chem 7 (sodium [Na], potassium [K], chloride [Cl], 
bicarbonate [CO2], creatinine [Cr], glucose), calcium, phosphate, 
magnesium, urea and electrolytes. Creatinine clearance calculated based 
on Cockcroft-Gault estimate. 
• Liver function tests (LFTs): ALT or AST (either or both as per local 
practice), alkaline phosphatase (ALP), albumin, lactate dehydrogenase 
(LDH) and total bilirubin. 
• Coagulation screen: APTT, PT 
• Thyroid function tests (TFTs): TSH, free T3, free T4. 
• Viral Screen: Hepatitis B, Hepatitis C and Human Immunodeficiency virus 
(HIV) 
• Human Chorionic Gonadotropin (hCG) blood or urine test 

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(vii) Tumour assessment 
Tumour assessment will be performed by serial hCG measurement. Complete 
response is defined as normalisation of hCG levels (<5 IU/L) post second evacuation. 
 
(viii)  Thoracic x-ray and uterine ultrasound Scan (USS) 
A thoracic x-ray and uterine ultrasound scan (USS) will be undertaken as part of pre-
screening to ascertain if disease is low or high risk. The USS will be transvaginal, 
unless adequate imaging to determine eligibility criteria can be obtained by a 
transabdominal scan. 
Additionally, a second uterine USS will be undertaken prior to second evacuation to 
ensure the disease remains amenable to second evacuation (disease within the 
uterine cavity and not within 5mm of the serosal surface). The second scan will 
routinely be carried out as a transvaginal study. 
For the Pembrolizumab arm only, two optional MRI scans may be performed (funding 
permitted); the first of which would be given during the screening period and the 
second within two days before the second evacuation visit. The MRIs will be used for 
exploratory analysis separate from the main study. 
 
(ix) 
Assessment of adverse events 
Adverse events will be assessed as indicated in the schedule of assessments table, 
according to the data detailed in section 7.1. 
 
(x) 
Assessment of concomitant medications 
Concomitant medications will be assessed as indicated in schedule of assessments 
table, with the following data recorded for each medication: 
• Name  
• Start date / whether ongoing / end date  
• Indication 
• Dosage 
• Frequency 
• Route of administration 
If a COVID-19 vaccine is administered during treatment, this will be recorded as a 
concomitant medication, with each dose recorded separately 

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(xi) 
Research samples 
An archival tissue sample in the form of formalin fixed paraffin embedded (FFPE) 
tumour block will be collected from each patient, as well as blood (up to 20 ml) at 
baseline. Further blood for research and fresh tissue from second evacuation will be 
collected as indicated in schedule of assessments table. Tissues will be studied in an 
ongoing research project to better understand the mechanisms of immune evasion 
and sensitivity in GTN.   
Further details on sample processing, handling and shipment are provided in the 
Laboratory Manual. 
 
(xii) Sample storage and analysis 
Written informed consent which include the collection and use of specified biological 
samples and a full chain of custody will be maintained for all samples throughout the 
study. 
PIs are responsible for maintaining full traceability of biological samples collected 
from patients while these are in storage at their site, until shipment to Imperial College 
London ECMC Laboratory and from return to site and/or disposal.  Any person(s) 
responsible for temporarily holding samples, e.g. sub-contracted service provider 
must keep full traceability of samples from initial receipt of sample to onward 
shipment, return or disposal as appropriate.  
Samples shipped to the ECMC Laboratory will be stored and analysed according to 
this protocol, a separate study laboratory manual, and any additional documentation 
produced by CCTS as required. 
Imperial College London, CCTS has oversight of each sample’s lifecycle through 
internal procedures and monitoring of study sites.   
Archival tissue samples will be retained for further study and will be registered with 
the Imperial College Healthcare NHS Tissue Bank (ICHTB). Samples will be returned 
once the planned translational project is complete or earlier upon written request. 
 
5.9 
Incidental Findings 
Incidental findings are defined as observations of potential clinical significance 
unexpectedly discovered in research participants and unrelated to the purpose of the 
study. These may include for example abnormal or unexpected findings from 
laboratory samples or from radiology images. 
We would not expect many incidental findings to be identified during this study. 
However, any incidental findings that were discovered would be reported back by the 
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If an incidental finding is observed during the study, and it is considered a significant 
abnormality, then the study team should report these to the PI who should take action 
accordingly. It is the PI’s responsibility to ensure findings are communicated to the 
participant, GPs or other clinicians as appropriate. Incidental findings should be 
reported to the sponsor trials team. 

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6. TREATMENTS 
 
6.1 
Investigational Medicinal Product Details 
Pembrolizumab is an IMP for the purposes of this study. It is currently approved by 
NHS England for treatment of patients with GTN who have failed chemotherapy. 
 
The Summary of Product Characteristics (SmPC) will be used as reference safety 
information (RSI) for the study, as submitted for CTA and amended where required 
during the trial e.g., when submitting DSURs, substantial amendment to study etc. 
 
6.2 
Labelling and Packaging  
Packaging and labelling of pembrolizumab should be according to local practice. 
There are no trial-specific requirements. 
 
6.3 
Storage and Dispensing  
Storage of pembrolizumab must be in line with the current relevant SmPC. 
Once the pembrolizumab has been diluted for infusion, it should ideally be used 
immediately. If not used immediately it should be refrigerated at 2-8oC for a maximum 
of 96 hours (including up to 6 hours at ≤ 25oC) and not frozen. If refrigerated, the vials 
and/or IV bags must be allowed to come to room temperature prior to use.  
Dispensing will be according to local standard practice.  
 
6.4 
Dosage, Duration and Compliance 
 
A single 200 mg IV dose of pembrolizumab will be administered in the treatment arm. 
 
6.5 
Accountability 
The investigator and appropriately trained and delegated staff will document the 
receipt, dispensing, administration and destruction of pembrolizumab as per local 
policy.  
Please refer to the IMP Handling Manual for further details.  
 
6.6 
Drug interactions / Precautions / Contraindications 
Interactions 
No formal pharmacokinetic drug interaction studies have been conducted with 
pembrolizumab. Since pembrolizumab is cleared from the circulation through 
catabolism, no metabolic drug-drug interactions are expected. 

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Systemic corticosteroids or other immunosuppressants can be used after starting 
pembrolizumab to treat immune-related adverse reactions. 
Precautions 
None. Management of specific adverse events is detailed in section 6.9. 
Contraindications 
Hypersensitivity to the active substance or to any of the excipients: L-histidine, L-
histidine hydrochloride monohydrate, sucrose, polysorbate 80, water for injections. 
 
6.7 
Overdose of IMP 
There is no information on overdose with pembrolizumab. 
In case of overdose, patients must be closely monitored for signs or symptoms of 
adverse reactions, and appropriate symptomatic treatment instituted. 
 
6.8 
Dose Modifications for Toxicity  
The pembrolizumab dose given will be a single dose before second evacuation. Any 
toxicity resulting from the Pembrolizumab should be treated as per standard of care.  
 
6.9 
Study drug administration  
 
Drug administration is as per local standard procedures. 
 
6.10 Pre-medications / Non-IMP details 
There are no premedications. 
 
6.11 Withdrawal from Study  
 
Withdrawal from the study refers to discontinuation of study treatment and study 
procedures and can occur for the following reasons: 
 
• Participant decision 
• In the intervention arm, development of indications for urgent chemotherapy 
in the period between receiving pembrolizumab and awaiting second 
evacuation, discussed further below* 
 
*Patients who develop vaginal bleeding, rising hCG >100,000 IU/L or any other indication for 
urgent chemotherapy will be withdrawn from the study to commence chemotherapy as 
determined by the treating team.  

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(i) 
Procedures for Withdrawal from Study 
 
In the event of a patient withdrawing from the study, no further visits or follow up will 
be conducted. The primary reason must be recorded in the eCRF and the patient’s 
medical records. Any data and samples already collected will be retained and 
analysed. 
 
Where the patient has withdrawn due to an AE, the investigator should follow the 
procedures in section 7.0. 
 
 
6.12 Lost To Follow Up 
In the event that a patient has been lost to follow up, this should be recorded on the 
eCRF with their last known contact date and survival status at the time. Lost to follow 
up status and steps taken to try to contact patient should also be noted in the patient’s 
medical notes. 
 
6.13 Trial Closure 
End of trial is defined as collection of the last data point of the last patient, which is 1 
year after their second evacuation visit. Samples taken for ongoing research will be 
registered with the Imperial College Tissue Bank at this point to support ongoing 
work. In the event that the study is closed early or terminated, the sponsor will notify 
the participating site that all study related activities will need to stop. Patients are to 
continue being cared for as per Trusts standard procedures.  
 

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7. PHARMACOVIGILANCE 
7.1 
Definitions   
 
Adverse Event (AE): any untoward medical occurrence in a patient or clinical trial 
subject administered a medicinal product and which does not necessarily have a 
causal relationship with this treatment.  An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of an investigational medicinal product (IMP), 
whether or not considered related to the IMP. 
 
Adverse Reaction (AR): all untoward and unintended responses to an IMP related 
to any dose administered.  All AEs judged by either the reporting investigator or the 
sponsor as having reasonable causal relationship to a medicinal product qualify as 
adverse reactions.  The expression reasonable causal relationship means to convey 
in general that there is evidence or argument to suggest a causal relationship. 
 
Unexpected Adverse Reaction: an AR, the nature or severity of which is not listed 
in the reference safety information (RSI) e.g. list of expected medical events within 
investigator’s brochure for an unapproved investigational product or section 4.8 of 
the summary of product characteristics (SmPC) for an authorised product.  When the 
outcome occurs this adverse reaction should be considered as unexpected. Side 
effects documented in the SmPC which occur in a more severe form than anticipated 
are also considered to be unexpected. 
 
Serious Adverse Event (SAE) or Serious Adverse Reaction: any untoward 
medical occurrence or effect that at any dose: 
• 
Results in death. 
• 
Is life-threatening – refers to an event in which the subject was at risk 
of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe. 
• 
Requires hospitalisation, or prolongation of existing inpatients’ 
hospitalisation. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly or birth defect. 
 
Medical judgement should be exercised in deciding whether an AE/AR is serious in 
other situations.  Important AE/ARs that are not immediately life-threatening or do not 
result in death or hospitalisation but may jeopardise the subject or may require 
intervention to prevent one of the other outcomes listed in the definition above, should 
also be considered serious. 
 

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Suspected Unexpected Serious Adverse Reaction (SUSAR): any suspected 
adverse reaction related to an IMP that is both unexpected and serious 
 
 
 
 
7.2 
Causality  
Most adverse events and adverse drug reactions that occur in this study, whether 
they are serious or not, will be expected treatment-related toxicities due to the drugs 
used in this study.  The assignment of the causality should be made by the 
investigator responsible for the care of the participant using the definitions in the table 
below.  
If any doubt about the causality exists the local investigator should inform the study 
coordination centre who will notify the Chief Investigators.  The pharmaceutical 
companies and/or other clinicians may be asked to advise in some cases.  
In the case of discrepant views on causality between the investigator and others, all 
parties will discuss the case.  In the event that no agreement is made, the MHRA will 
be informed of both points of view.   
 
 
Relationship 
Description 
Unrelated 
There is no evidence of any causal relationship 
Unlikely 
There is little evidence to suggest there is a causal relationship (e.g. the 
event did not occur within a reasonable time after administration of the 
trial medication).  There is another reasonable explanation for the event 
(e.g. the participant’s clinical condition, other concomitant treatment). 
Possible 
There is some evidence to suggest a causal relationship (e.g. because 
the event occurs within a reasonable time after administration of the trial 
medication).  However, the influence of other factors may have 
contributed to the event (e.g. the participant’s clinical condition, other 
concomitant treatments). 
Probable 
There is evidence to suggest a causal relationship and the influence of 
other factors is unlikely. 
Definitely 
There is clear evidence to suggest a causal relationship and other 
possible contributing factors can be ruled out. 
Not 
assessable 
There is insufficient or incomplete evidence to make a clinical judgement 
of the causal relationship. 
 
 

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7.3 
 Severity of Adverse Events 
Severity of AEs will be assessed using the grading scales found in the National 
Cancer Institute CTCAE version 5.0 (27th November 2017), by attributing the most 
relevant CTCAE term. Where it is not possible to attribute a specific CTCAE term, a 
term may be attributed by the investigator and assessed according to the introduction 
under Grades in CTAE version 5.0 i.e., grade 1=mild; grade 2=moderate; grade 
3=severe; grade 4=life-threatening; grade 5= fatal.  
 
CTCAE version 5.0 is accessible online here: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/ctc.htm 
 
7.4 
 
Reporting Procedures 
All adverse events should be reported.  Depending on the nature of the event the 
reporting procedures below should be followed.  Any questions concerning adverse 
event reporting should be directed to the study coordination centre in the first 
instance.  A flowchart is given below to aid in the reporting procedures. 
 
(i) 
7.4.1 Non serious AR/AEs 
All such toxicities, whether expected or not, should be recorded in the toxicity section 
of the relevant case report form and sent to the study coordination centre within one 
month of the form being due.   
 
(ii) 
7.3.2 Serious AR/AEs 
Fatal or life threatening SAEs and SUSARs should be reported on the day that the 
local site is aware of the event.  The SAE form asks for nature of event, date of onset, 
severity, corrective therapies given, outcome and causality (i.e. unrelated, unlikely, 
possible, probably, definitely).  The responsible investigator should sign the causality 
of the event.  Additional information should be sent within 5 days if the reaction has 
not resolved at the time of reporting.  
  
SAEs 
An SAE form should be completed and emailed to the study coordination centre for 
all SAEs within 24 hours.  However, relapse and death due to disease under study 
and hospitalisations for elective treatment of a pre-existing condition do not need 
reporting as SAEs. 
 
SUSARs  
In the case of suspected unexpected serious adverse reactions, the staff at the site 
should:  
 

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Complete the SAE case report form & send it immediately (within 24 
hours,), signed and dated to the study coordination centre together with 
relevant treatment forms and anonymised copies of all relevant 
investigations. 
Or 
 
 
Contact the study coordination centre by phone and then send the 
completed SAE form to the study coordination centre within the 
following 24 hours as above. 
 
The study coordination centre will notify the MHRA, REC and the Sponsor of all 
SUSARs occurring during the study according to the following timelines; fatal and 
life-threatening within 7 days of notification and non-life threatening within 15 days.   
All investigators will be informed of all SUSARs occurring throughout the study. 
 
Local investigators should report any SUSARs and /or SAEs as required by their 
Local Research Ethics Committee and/or Research & Development Office 
 
 
Contact Details for Reporting SAEs and SUSARs: 
RESOLVE@imperial.ac.uk 
Tel: 02033117740 (Mon to Fri 09:00 – 17:00) 
RGIT.ctimp@imperial.ac.uk  

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7.5 
Developmental Safety Update Reports / Annual Safety Reports  
Developmental Safety Update Reports (DSUR) will be submitted to the Sponsor, the 
Ethics Committee and Regulatory Authority in accordance with local / national 
regulatory requirements. 
 
7.6 
Pregnancy 
Pembrolizumab is contraindicated in pregnancy. Pregnancy is not considered an 
SAE but where the patient gives their consent the pregnancy will be recorded and 
followed up in the eCRF. 
 
7.7 
Reporting urgent safety measures  
If any urgent safety measures are taken the CI/Sponsor shall immediately and in any 
event no later than 3 days from the date the measures are taken, give written notice 
to the MHRA and the relevant REC of the measures taken and the circumstances 
giving rise to those measures. 
 
8. STATISTICAL ANALYSES 
8.1 
Sample Size and power considerations 
8.1.1 Feasibility of the treatment strategy 
A primary goal of the study is to determine the proportion of patients in the treatment 
arm who complete the planned protocol of pembrolizumab followed by second 
evacuation. To justify a larger study of this intervention, we would expect 90% of 
patients to complete the protocol with a lower bound of 70% below which we would 
not consider the strategy to be practicable.  With 10 patients, assuming 90% 
complete protocol treatments, the 95% confidence interval is 71 – 100%. 
 
8.1.2 Feasibility of recruitment 
Estimated cure rate with second evacuation alone is approximately 25% in our 
cohort3. The cure rate with single agent chemotherapy is approximately 66%. 
Therefore under conservative assumptions, in order to demonstrate a clinically 
significant benefit of pembrolizumab prior to second evacuation of 66% cure vs. 
second evacuation alone (25% cure), 40 patients in total are required (80% power, 
significance level 0.05). To justify a larger study, this cohort would be recruited in no 
more than 3 years (14 patients/year). 
Based on current caseloads, we estimate approximately 50 patients per year in the 
UK are eligible for the study, of whom 30 are managed at CXH. With 30 eligible 
patients, assuming 66% (n=20) are recruited in 1 year, the 95% confidence interval 

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is 50 – 84%. This is consistent with the recruitment target of at least 15 patients per 
year at CXH (30 patients/year x 0.5 [lower bound of the 95% confidence interval for 
the recruitment rate]). Thus recruitment of 20 patients in 1 year would give us 
confidence that a definitive study would be feasible. 
 
8.1.3 Detection of a clinical meaningful result 
Given the challenges of carrying out definitive randomised controlled trials in the rare 
disease setting, data from small scale studies have been highly influential in driving 
treatment advances. The global adoption of pembrolizumab for GTN is a case in 
point. Our initial observation was exceptionally high pembrolizumab efficacy amongst 
a series of 4 patients. These data were sufficient to result in a change in NHS 
guidelines to support funding of this agent for patients with resistant disease. As we 
and the global community have accrued more data, use of pembrolizumab is now 
recommended in global GTN management guidelines. 
While, as per recommendations for feasibility studies, we did not conduct sample size 
calculations for the pembrolizumab vs control comparison, we note that even with 
such a small sample size we would have adequate power to detect a clinically 
significant difference between the arms. Second evacuation for disease recurrence 
has a complete response (CR) rate of ~25% based on a study done at our centre. 
Amongst the remainder who relapse, we estimate a 75% CR rate to pembrolizumab 
based on multicentre data on patients with drug resistant, metastatic disease. We 
thus estimate the CR rate of neoadjuvant pembrolizumab to be 81% (100*[0.25+(1-
0.25)*0.75]). For 80% power with α of 0.05, 9 patients per arm are required. This is 
consistent with 20 patients in total, randomised 1:1 to the control and neoadjuvant 
pembrolizumab arms. 
 
8.1.4 Translation aims 
A co-primary objective of the study is to obtain second evacuation tissue and blood 
for translational research. We have carried out sample size estimation to evaluate 
the number of patients required to identify immunotherapy triggered differences in 
the transcriptional profile of key tumour infiltrating T cell populations. Assuming 1000 
genes are tested with average read count of 50, to identify 50 genes which are 
differentially expressed with a fold change of 4 or more at a false discovery rate (FDR) 
of 0.05, requires 9 patients per group (determined using the RnaSeqSampleSize 
package; Zhao 2018). 
In summary, 10 patients per arm is justified to achieve the goals of this study. 
 
8.2 
 Planned recruitment rate 
Analysis of our current caseload reveals approximately 30 cases/year are eligible. 
We aim to enrol all patients within 12 months of opening and will determine 

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recruitment rates at a planned 6 month interim review. If recruitment targets are not 
met (<40% of patients recruited), we will open a second site at Weston Park Hospital 
(the only other centre for GTN management in England and Wales). 
 
8.3 
Statistical analysis 
8.3.1 Analysis populations 
In order to describe feasibility of the approach and collect tissue for translational 
activities, the primary analysis population will be Intention to Treat (ITT). To 
determine patient interest as a second measure of feasibility, we will additionally 
consider the population of patients assessed for eligibility 
 
8.3.2 Primary Endpoint Analysis 
We will carry out descriptive data analyses with respect to the feasibility of recruitment 
and completing protocoled treatments on the intervention arm. 
Firstly, participant flows will be evaluated using a CONSORT diagram adapted for 
feasibility studies38. We will record the numbers of patients: 
1. With low risk GTN following primary evacuation of CHM 
2. Consented 
3. Screened 
4. Eligible 
5. Randomised 
6. Who complete per protocol treatments 
The number of patients who drop-out at each stage will additionally be recorded.  
We will calculate the proportion of eligible patients who consent to participation as a 
measure of the potential to recruit to a larger study, along with the proportion of 
patients randomised to the intervention arm who complete per protocol treatments. 
In the intervention arm, the proportion of patients who are withdrawn from the study 
after pembrolizumab but before second evacuation and the reasons for this. The 95% 
confidence intervals will be calculated along with these proportions. 
 
8.3.3 Secondary Endpoint Analysis 
Recurrence free survival rate will be evaluated at the 1 year landmark post second 
evacuation. Safety data analysis will be conducted as below (8.3.4).  
 

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8.3.4 Safety Analysis  
Safety data analysis will be conducted on all subjects randomised within the trial. 
Data will be collected on the number of patients who are withdrawn from the study in 
order to commence chemotherapy due to tumour progression. The number and 
proportion of patients who experience complications arising from second evacuation 
will be reported. In the intervention arm, the number and percentage of subjects 
experiencing an AE and the number of events will be reported. Information regarding 
severity will be examined with a focus on Grade 3-5 events using the Common 
Terminology Criteria for Adverse Events (CTCAE v5.0). 
 
 

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9. REGULATORY, ETHICAL AND LEGAL ISSUES 
9.1 
Declaration of Helsinki 
The investigator will ensure that this study is conducted in full conformity with the 
1964 Declaration of Helsinki and all subsequent revisions. 
 
9.2 
Good Clinical Practice  
The study will be conducted in accordance with the guidelines laid down by the 
International Conference on Harmonisation for Good Clinical Practice (ICH GCP E6 
guidelines).  
 
9.3 
Research Ethics Committee (REC) Approval  
 
(i) 
Initial Approval 
Prior to the shipment of IMP and the enrolment of participants, the REC must provide 
written approval of the conduct of the study at named sites, the protocol and any 
amendments, the Participant Information Sheet and Consent Form, any other written 
information that will be provided to the participants, any advertisements that will be 
used and details of any participant compensation.  
 
(ii) 
Approval of Amendments 
Proposed amendments to the protocol and aforementioned documents must be 
submitted to the REC for approval. Amendments requiring REC approval may be 
implemented only after a copy of the REC’s approval letter has been obtained.  
 
Amendments that are intended to eliminate an apparent immediate hazard to 
participants may be implemented prior to receiving Sponsor or REC approval. 
However, in this case, approval must be obtained as soon as possible after 
implementation. 
 
The sponsor trials team will make amendments and make the decision to amend the 
protocol and decide whether changes are substantial or non-substantial, with support 
from the Protocol Development Group where applicable. Changes will be 
communicated to stakeholders, including participating sites, electronically and be 
version controlled according to tracked changes and in accordance with the relevant 
standard operating procedures. The amended protocol will be reviewed by all 
members of the Protocol Development Group prior to finalising. 
 
(iii) 
Annual Progress Reports 
Annual Progress Reports will be submitted to the Research Ethics Committee (REC) 
and the Sponsor in accordance with local / national requirements. The Annual 
Progress Report will also detail all SAEs recorded. 
 

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(iv) 
End of Trial Notification 
The REC will be informed about the end of the trial, within the required timelines.  
The end of trial notification will be submitted within 90 days of the end of trial definition 
being met. In the event of a premature halt of the trial, the timeframe is 15 days, and 
the reasons should be clearly explained in the notification. 
 
9.4 
Regulatory Authority Approval 
The study will be performed in compliance with UK regulatory requirements. Clinical 
Trial Authorisation from the appropriate Regulatory Authority must be obtained prior 
to the start of the study. In addition, the Regulatory Authority must approve 
amendments prior to their implementation (as instructed by the Sponsor), receive 
SUSAR reports and DSURs, and be notified of the end of the trial. 
This study has Clinical Trials Authorisation from the UK Competent Authority; MHRA. 
Reference: CTA 19174/0438/001-0001   
 
9.5 
HRA approval 
Health Research Authority (HRA) approval will be obtained prior to starting the study. 
Each participating site will confirm capacity and capability prior to commencing. 
The HRA and all participating sites also need to be notified of all protocol 
amendments to assess whether the amendment affects the institutional approval for 
each site.  
 
9.6 
Other Required Approvals 
The procedures are compliant with the Ionising Radiation (Medical Exposure) 
Regulations, and appropriate review by a Medical Physics Expert and Clinical 
Radiation Expert will be undertaken before the study commences. 
 
9.7 
Non-Compliance and Serious Breaches  
All protocol deviations and protocol violations will be reported via the eCRF and 
reviewed by the Chief Investigator and reported to the Research Governance and 
Integrity Team (RGIT) on a monthly basis.  
An assessment of whether the protocol deviation/violation constitutes a serious 
breach will be made.  
A serious breach is defined as: 
A breach of the conditions and principles of GCP in connection with a trial or the trial 
protocol, which is likely to affect to a significant degree:  
• The safety or physical or mental integrity of the UK trial participants; or 
• The overall scientific value of the trial 
 

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RGIT will be notified within 24 hours of identifying a likely Serious Breach. If a 
decision is made that the incident constitutes a Serious Breach, this will be reported 
to the MHRA and REC within 7 days of becoming aware of the serious breach. 
 
9.8 
Insurance and Indemnity and Sponsor 
Imperial College London holds negligent harm and non-negligent harm insurance 
policies which apply to this study. 
Imperial College London will act as the main Sponsor for this trial. Delegated 
responsibilities will be assigned to the NHS trusts taking part in the trial. 
 
9.9 
Funding 
Funding for this study has been provided by the Imperial Biomedical Research Centre 
and the Cancer Treatment and Research Trust Charity. Funding for the translational 
aspects of the study will be from Cancer Research UK. Funding allocated to the sites 
is detailed in the participant site agreement. Requests and queries regarding 
payment should be sent to resolve@imperial.ac.uk,  
  
 
9.10 Trial Registration 
The study will be registered on the following trial databases in accordance with 
requirements of the International Committee of Medical Journal Editors (ICMJE) 
regulations: 
• Clinicaltrials.gov 
• Cancer Research UK 
• EC Trial Finder 
 
9.11 Informed Consent 
Consent to enter the study must be sought from each participant only after a full 
explanation has been given, an information leaflet offered and time allowed for 
consideration. Signed participant consent should be obtained. The right of the 
participant to refuse to participate without giving reasons must be respected. After 
the participant has entered the trial, the clinician remains free to give alternative 
treatment to that specified in the protocol at any stage if he/she feels it is in the 
participant’s best interest, but the reasons for doing so should be recorded. In these 
cases, the participants remain within the study for the purposes of follow-up and data 
analysis. All participants are free to withdraw at any time from the protocol treatment 
without giving reasons and without prejudicing further treatment. 
 
 

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9.12 Contact with General Practitioner  
It is the investigator’s responsibility to inform the participant’s General Practitioner 
(where applicable) by letter that the participant is taking part in the study provided the 
participant agrees to this, and information to this effect is included in the Participant 
Information Sheet and Informed Consent. A copy of the letter should be filed in the 
Investigator Site File. 
 
9.13 Participant Confidentiality 
The investigator must ensure that the participant’s confidentiality is maintained. On 
the eCRF or other documents submitted to the Sponsors, participants will be 
identified by a participant ID number only. Documents that are not submitted to the 
Sponsor (e.g., signed informed consent form) should be kept in a strictly confidential 
file by the investigator. 
 
The investigator shall permit direct access to participants’ records and source 
documents for the purposes of monitoring, auditing, or inspection by the Sponsor, 
authorised representatives of the Sponsor, NHS, Regulatory Authorities and RECs. 
 
Data will be transferred to (insert third party name as appropriate or delete)  
 
 
9.14 Data Protection and Participant Confidentiality 
The investigators and study site staff will comply with the requirements of the Data 
Protection Act 2018 concerning the collection, storage, processing and disclosure of 
personal information and will uphold the Act’s core principles. 
 
9.15 End of Trial 
The end of the trial is defined as collection of the last data point for the last participant. 
Samples taken for translational research will be held under Imperial College Tissue 
Bank ethics for ongoing work. 
 
9.16 Study Documentation and Data Storage 
The investigator must retain essential documents until notified by the Sponsor, and 
for at least ten years after study completion. Participant files and other source data 
(including copies of protocols, CRFs, original reports of test results, IMP dispensing 
logs, correspondence, records of informed consent, and other documents pertaining 
to the conduct of the study) must be retained. Documents should be stored in such a 
way that they can be accessed/data retrieved at a later date. Consideration should 
be given to security and environmental risks. 
 

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No study document will be destroyed without prior written agreement between the 
Sponsor and the investigator. Should the investigator wish to assign the study 
records to another party or move them to another location, written agreement must 
be obtained from the Sponsor. 
 
 

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10. DATA MANAGEMENT 
10.1 Source Data 
All original records and certified copies of original records of clinical findings, 
observations, or other activities 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 medical records, clinical and office charts, 
laboratory notes, memoranda, patient 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, radiological imaging, patient 
files, and records kept at the pharmacy, laboratories and any medico-technical 
departments involved in the clinical trial.  
 
10.2 Language 
eCRFs will be in English. Generic names for concomitant medications should be 
recorded in the CRF wherever possible. All written material to be used by participants 
must use vocabulary that is clearly understood and be in the language appropriate 
for the study site. 
 
10.3 Database 
The electronic case report form (eCRF) is in OpenClinica. 
 
The method of entry and validation, procedure for raising queries, and other core 
data entry aspects will be detailed in a separate Data Management Plan held by 
CCTS and in eCRF Completion Guidelines circulated to participating sites. 
 
10.4 Data Collection 
In compliance with GCP, the medical records/notes should be clearly marked and 
allow 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 assessments and procedures, laboratory, safety and efficacy data 
in the eCRF. Details of procedures for eCRF completion will be provided in eCRF 
Completion Guidelines circulated to participating sites. 
Details of procedures for eCRF/CRF completion will be provided in a study manual. 
 
10.5 Archiving  
All trial documentation, including that held at participating sites and the trial 
coordinating centre, will be archived for a minimum of 10 years following the end of 
the study.  

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11. STUDY MANAGEMENT STRUCTURE  
11.1 Trial Steering Committee  
A Trial Steering Committee (TSC) will be convened as a joint Committee with the 
Independent Data Monitoring Committee (IDMC) 
 
11.2 Trial Management Group 
A Trial Management Group (TMG) will be convened including the Chief Investigator, 
co-investigators and key collaborators, trial statistician and trial co-ordinator. The 
TMG will be responsible for day-to-day conduct of the trial and operational issues. 
Details of membership, responsibilities and frequency of meetings will be defined in 
a separate Charter. 
 
11.3 Data Monitoring Committee 
An IDMC will be convened as a joint committee with the TSC to monitor data collected 
during the study and to make recommendations to the TMG on whether there are 
any ethical or safety reasons as to why the trial should not continue. It will consist of 
at least an independent Chair, an independent statistician, an independent clinician, 
the Chief Investigator and Trial Coordinator.  Details of membership, responsibilities 
and frequency of meetings will be defined in a separate Charter 
 
11.4 Early Discontinuation of the Study 
Any stopping criteria will be defined by the IDMC, including a required procedure for 
future visits / assessments if the study needs to be discontinued early. 
 
11.5 Risk Assessment 
A study-specific risk assessment will be performed prior to the start of the study to 
assign a risk category of ‘low’, ‘medium’ or ‘high’ to the trial. The risk assessment will 
be carried out by RGIT in collaboration with the Study co-ordinator and the result will 
be used to guide the monitoring plan. The risk assessment will consider all aspects 
of the study and will be updated as required during the course of the study. 
 
11.6 Monitoring  
The study will be monitored periodically by the trial co-ordinator to assess the 
progress of the study, verify adherence to the protocol, ICH GCP E6 guidelines and 
other national/international requirements and to review the completeness, accuracy 
and consistency of the data. 
 

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Monitoring will incorporate central, remote and on-site elements. 
 
Monitoring procedures and requirements will be documented in a Monitoring Plan, 
developed in accordance with the risk assessment. 
 
11.7 Quality Control and Quality Assurance 
Quality Control will be performed according to Sponsor internal procedures. The 
study may be audited by a Quality Assurance representative of the Sponsor. All 
necessary data and documents will be made available for inspection. 
 
The study may be participant to inspection and audit by regulatory bodies to ensure 
adherence to GCP and the NHS Research Governance Framework for Health and 
Social Care (2nd Edition).  
 
11.8 Peer review 
Internal review has been conducted by Imperial College London as follows: 
• Imperial College Trials Unit - Cancer Peer Review Committee 
 
The study has furthermore been presented and discussed at 2022 EOTTD and 
ISSTD international meetings. 
 
11.9 Public Involvement 
This study will use public involvement throughout the life cycle of the study. Public 
involvement will include: 
• Design of the research – review of protocol and all patient facing 
documentation; 
• Management and undertaking of the research – advising on recruitment 
strategies and contribution to TSC meetings; 
• Dissemination of results – production of a plain English summary and advising 
on avenues for dissemination. 
 
11.10 Publication and Dissemination policy 
Information concerning the study, patent applications, processes, scientific data or 
other pertinent information is confidential and remains the property of the Sponsor. 
The investigator may use this information for the purposes of the study only. 
 
It is understood by the investigator that the Sponsor will use information developed 
in this clinical study in connection with the development of the IMP/device and, 
therefore, may disclose it as required to other clinical investigators and to Regulatory 
Authorities. In order to allow the use of the information derived from this clinical study, 

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the investigator understands that he/she has an obligation to provide complete test 
results and all data developed during this study to the Sponsor. 
 
Verbal or written discussion of results prior to study completion and full reporting 
should only be undertaken with written consent from the Sponsor. 
 
Therefore all information obtained as a result of the study will be regarded as 
CONFIDENTIAL, at least until appropriate analysis and review by the investigator(s) 
are completed.  
 
Any request by site investigators or other collaborators to access the study dataset 
must be formally reviewed by the joint TSC / IDMC.    
 
A Clinical Study Report summarising the study results will be prepared and submitted 
to the REC within a year of the end of study. The results will also be submitted to the 
EudraCT results database in accordance with regulatory requirements. 
 
 

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2 
Seckl MJ, Sebire NJ, Fisher RA, Golfier F, Massuger L, Sessa C. Gestational 
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Savage P, Seckl MJ. The role of repeat uterine evacuation in trophoblast 
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Ghorani E, Kaur B, Fisher R, et al. Pembrolizumab is effective in drug resistant 
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Forde PM, Spicer J, Lu S, et al. Neoadjuvant Nivolumab plus Chemotherapy in 
Resectable Lung Cancer. N Engl J Med 2022; 386: 1973–85. 
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Blank CU, Rozeman EA, Fanchi LF, et al. Neoadjuvant versus adjuvant 
ipilimumab plus nivolumab in macroscopic stage III melanoma. Nat Med 2018; 
24: 1655–61. 
7 
Fisher RA, Maher GJ. Genetics of gestational trophoblastic disease. Best Pract 
Res Clin Obstet Gynaecol 2021; 74: 29–41. 
8 
FIGO staging for gestational trophoblastic neoplasia 2000. FIGO Oncology 
Committee. Int J Gynaecol Obstet 2002; 77: 285–7. 
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Osborne RJ, Filiaci VL, Schink JC, et al. Second Curettage for Low-Risk 
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Vandewal A, Delbecque K, Van Rompuy AS, et al. Curative effect of second 
curettage for treatment of gestational trophoblastic disease - Results of the 
Belgian registry for gestational trophoblastic disease. Eur J Obstet Gynecol 
Reprod Biol 2021; 257: 95–9. 
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Pezeshki M, Hancock BW, Silcocks P, et al. The role of repeat uterine 
evacuation in the management of persistent gestational trophoblastic disease. 
Gynecol Oncol 2004; 95: 423–9. 
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Ireson J, Jones G, Winter MC, Radley SC, Hancock BW, Tidy JA. Systematic 
review of health-related quality of life and patient-reported outcome measures 
in gestational trophoblastic disease: a parallel synthesis approach. Lancet 
Oncol. 2018; 19: e56–64. 
13 
McNeish IA, Strickland S, Holden L, et al. Low-risk persistent gestational 
trophoblastic disease: outcome after initial treatment with low-dose 
methotrexate and folinic acid from 1992 to 2000. J Clin Oncol 2002; 20: 1838–
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Alifrangis C, Agarwal R, Short D, et al. EMA/CO for high-risk gestational 
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cisplatin and genetic analysis. J Clin Oncol 2013; 31: 280–6. 
15 
Savage P, Cooke R, O’Nions J, et al. Effects of single-agent and combination 
chemotherapy for gestational trophoblastic tumors on risks of second 
malignancy and early menopause. J Clin Oncol 2015; 33: 472–8. 
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Tidy JA, Gillespie AM, Bright N, Radstone CR, Coleman RE, Hancock BW. 
Gestational trophoblastic disease: a study of mode of evacuation and 
subsequent need for treatment with chemotherapy. Gynecol Oncol 2000; 78: 
309–12. 
17 
Berkowitz RS, Desai U, Goldstein DP, Driscoll SG, Marean AR, Bernstein MR. 
Pretreatment curettage-A predictor of chemotherapy response in gestational 
trophoblastic neoplasia. Gynecol Oncol 1980; 10: 39–43. 
18 
van Trommel NE, Massuger LFAG, Verheijen RHM, Sweep FCGJ, Thomas 
CMG. The curative effect of a second curettage in persistent trophoblastic 
disease: a retrospective cohort survey. Gynecol Oncol 2005; 99: 6–13. 
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Ahmadzadeh A, Najafian M, Lalvand K. The Curative Effect of a Second 
Curettage in Low-Risk Gestational Trophoblastic Neoplasia. J Mol Biol Res 
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Yarandi F, Jafari F, Shojaei H, Izadi-Mood N. Clinical response to a second 
uterine curettage in patients with low-risk gestational trophoblastic disease: a 
pilot study. J Reprod Med 2014; 59: 566–70. 
21 
Osborne RJ, Filiaci VL, Schink JC, et al. Second Curettage for Low-Risk 
Nonmetastatic Gestational Trophoblastic Neoplasia. Obstet Gynecol 2016; 
128: 535–42. 
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Ayatollahi H, Yekta Z, Afsari E. A pilot randomized controlled clinical trial of 
second uterine curettage versus usual care to determine the effect of re-
curettage on patients’ need for chemotherapy among women with low risk, 
nonmetastatic gestational trophoblastic neoplasm in Urmia, Iran. Int J Womens 
Health 2017; 9: 665–71. 
23 
Brahmer J, Reckamp KL, Baas P, et al. Nivolumab versus Docetaxel in 
Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med 2015; 
373: 1–13. 
24 
Robert C, Long G V., Brady B, et al. Nivolumab in previously untreated 
melanoma without BRAF mutation. N Engl J Med 2015; 372: 320–30. 
25 
Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in 
Advanced Renal-Cell Carcinoma. N Engl J Med 2015; : 150925150201006. 
26 
Klein G, Sjogren HO, Klein E, Hellstrom KE. Demonstration of Resistance 
against Methylcholanthreneinduced Sarcomas in the Primary Autochthonous 
Host. Cancer Res 1960; 20: 1561–72. 
27 
Srivastava PK. Peptide-binding heat shock proteins in the endoplasmic 
reticulum: role in immune response to cancer and in antigen presentation. Adv 
Cancer Res 1993; 62: 153–77. 
28 
Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines 
sensitivity to PD-1 blockade in non-small cell lung cancer. Science (80- ) 2015; 

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348: 124–8. 
29 
Linnemann C, Buuren MM Van, Bies L, et al. High-throughput epitope discovery 
reveals frequent recognition of neo-antigens by CD4+ T cells in human 
melanoma. Nat Med 2014; 21: 81–5. 
30 
Tran E, Ahmadzadeh M, Lu YC, et al. Immunogenicity of somatic mutations in 
human gastrointestinal cancers. Science (80- ) 2015; 350: 1387–90. 
31 
Thommen DS, Schumacher TN. T Cell Dysfunction in Cancer. Cancer Cell 
2018; 33: 547–62. 
32 
Ghorani E, Rosenthal R, McGranahan N, et al. Differential binding affinity of 
mutated peptides for MHC class I is a predictor of survival in advanced lung 
cancer and melanoma. Ann Oncol 2018; 29: 271–9. 
33 
Larkin J, Chiarion-Sileni V, Gonzalez R, et al. Five-Year Survival with Combined 
Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med 2019; 381: 
1535–46. 
34 
Garon EB, Hellmann MD, Rizvi NA, et al. Five-Year Overall Survival for Patients 
With Advanced Non‒Small-Cell Lung Cancer Treated With Pembrolizumab: 
Results From the Phase I KEYNOTE-001 Study. J Clin Oncol 2019; 37: 2518–
27. 
35 
Rowe M, Eastlake L, Norris T, Farley T, Talbot T. A Multicentre Retrospective 
Analysis of Toxicity in 6-weekly Versus 3-weekly Pembrolizumab. J 
Immunother 2021; 44: 175–8. 
36 
Hemida R, Vos EL, El-Deek B, et al. Second Uterine Curettage and the Number 
of Chemotherapy Courses in Postmolar Gestational Trophoblastic Neoplasia: 
A Randomized Controlled Trial. Obstet Gynecol 2019; 133: 1024–31. 
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Khan F, Everard J, Ahmed S, Coleman RE, Aitken M, Hancock BW. Low-risk 
persistent 
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trophoblastic 
disease 
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2197–201. 
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extension to randomised pilot and feasibility trials. BMJ 2016; 355: i5239. 
 
 

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13. REVISION HISTORY  
 
Version 
Date 
Summary of changes 
1.0 
14/Feb/2023 
First version 
2.0 
10/Jul/2023 
Second 
version 
drafted 
post 
initial 
REC/MHRA review and addressed a number 
of changes required to conform with PIS as 
well as a number of wording and formatting 
changes.  
 
 
 

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SIGNATURE PAGE 1 (Chief Investigator) 
 
The signature below constitutes approval of this protocol by the signatory, on behalf 
of the Protocol Development Group, and provides the necessary assurances that this 
study will be conducted according to all stipulations of the protocol including all 
statements regarding confidentiality. 
 
 
Study Title: RESOLVE: A feasibility window study of pembrolizumab prior to 
second evacuation for post-molar gestational trophoblastic neoplasia. 
 
 
Protocol Number: C/43/2022 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Name of Chief Investigator 
 
 
 
Title 
 
 
 
 
 
Date:  
 
_____________________ 
  

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SIGNATURE PAGE 2 (SPONSOR) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: RESOLVE: A feasibility window study of pembrolizumab prior to 
second evacuation for post-molar gestational trophoblastic neoplasia. 
 
 
 
Protocol Number: C/43/2022 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Name of Sponsor’s Representative 
 
 
 
Title 
 
 
 
Sponsor name 
 
 
 
 
 
 
Date:  
 
_____________________ 

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SIGNATURE PAGE 3 (STATISTICIAN) 
 
The signatures below constitute approval of this protocol by the signatory.  
 
 
Study Title: RESOLVE: A feasibility window study of pembrolizumab prior to 
second evacuation for post-molar gestational trophoblastic neoplasia. 
 
 
 
Protocol Number: C/43/2022 
 
 
 
 
Signed: 
 
___________________________________________ 
 
 
 
 
Name of Statistician 
 
 
 
Title 
 
 
 
Organisation/Company 
 
 
Date:  
 
_____________________ 
 
 

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SIGNATURE PAGE 4 (PRINCIPAL INVESTIGATOR) 
 
The signature of the below constitutes agreement of this protocol by the signatory 
and provides the necessary assurance that this study will be conducted at his/her 
investigational site according to all stipulations of the protocol including all statements 
regarding confidentiality. 
 
 
Study Title: RESOLVE: A feasibility window study of pembrolizumab prior to 
second evacuation for post-molar gestational trophoblastic neoplasia. 
 
 
Protocol Number: C/43/2022 
 
 
Address of Institution:  
____________________________________________ 
 
 
 
 
 
 
 
 
 
 
____________________________________________ 
 
 
 
 
 
 
____________________________________________ 
 
 
 
Signed: 
 
 
____________________________________________ 
 
 
Print Name and Title: 
____________________________________________ 
 
 
Date:  
 
 
_____________________