A Cancer Research UK Phase I Trial of AST-VAC2 (Allogeneic Dendritic Cell Vaccine) Administered Weekly Via Intradermal Injection in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)
Phase: PHASE1
Conditions: Advanced Non-small Cell Lung Cancer
Sponsor: Cancer Research UK



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EudraCT number: 2016-002577-35 
 
Cancer Research UK  
 
 
 
 
CANCER RESEARCH UK  
Centre for Drug Development  
 
A Cancer Research UK Phase I trial of  
AST-VAC2 (allogeneic dendritic cell vaccine) 
administered weekly via intradermal injection in 
patients with advanced non-small cell lung cancer. 
 
             Sponsor protocol number: CRUKD/17/003 
                         EudraCT number: 2016-002577-35 
 
 
Chief Investigator: 
Professor Christian Ottensmeier 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: 
Cancer Research UK 
 
  
 
 
 
 
 
 
         
 
 

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PARTICIPATING INVESTIGATORS AND CENTRES: 
Details of Principal Investigators and Investigational Sites are recorded on the Participating 
Investigators and Centres list in the Sponsor’s Trial Master File. 
VERSION HISTORY: 
 
Version No. 
Date of issue 
Reason for update 
1.0 
03MAR2017 
Initial version for REC/HRA and MHRA submission.  
2.0 
15MAY2017 
Revised version post initial review by the MHRA and REC.  
3.0 
18JUL2017 
Revised version post 2nd review by the REC. 
4.0 
19NOV2018 
Protocol Amendment 01: Clarification that the requirement 
for dose delays excludes AEs of ISR, amendment to the 
exclusion criteria regarding the use of prohibited concomitant 
steroid medication, amendment to when the expansion 
cohort can open, requirement for related AEs meeting the 
stopping rule criteria to be reported as an SAE added, 
caveat around the use of systemic steroids to treat AEs 
added, change in container closure system used for the IMP, 
clarification on imaging requirements and objectives, 
 
 change to the 
lymphocyte count required for inclusion into the study. Other 
minor changes and clarifications.  
5.0 
08JUN2021 
Protocol Amendment 02: Removal of the control arm in the 
safety cohort and removal of the expansion cohort; change 
to end of trial definition; changes to reasons for withdrawal; 
other minor changes and clarifications. 

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TABLE OF CONTENTS 
 
 
 
TITLE PAGE 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
PROTOCOL SIGNATURES 
 
1 
PROTOCOL SYNOPSIS ..................................................................................................... 12 
1.1 
Full title: ................................................................................................................................ 12 
1.2 
Short title: ............................................................................................................................. 12 
1.3 
Clinical trial objectives and endpoints: ................................................................................. 12 
1.4 
Trial Design: ......................................................................................................................... 12 
1.5 
Trial treatment: ..................................................................................................................... 12 
1.6 
Patient Population: ............................................................................................................... 13 
2 
INTRODUCTION ................................................................................................................. 14 
2.1 
Background .......................................................................................................................... 14 
2.1.1 
Background on non-small cell lung cancer .......................................................................... 14 
2.2 
Investigational medicinal product ......................................................................................... 14 
2.2.1 
Structure of AST-VAC2 ....................................................................................................... 14 
2.2.2 
Mechanism of action of AST-VAC2 ..................................................................................... 15 
2.3 
Safety considerations for the trial ......................................................................................... 15 
2.3.1 
Non-clinical pharmacology .................................................................................................. 15 
2.3.2 
Pharmacokinetics ................................................................................................................ 16 
2.3.3 
Toxicology............................................................................................................................ 16 
2.4 
Clinical experience (other compounds in the same class) ................................................... 17 
2.5 
Rationale for the trial ............................................................................................................ 17 
2.5.1 
Justification for dose and schedule ..................................................................................... 17 
3 
TRIAL DESIGN ................................................................................................................... 19 
3.1 
Clinical trial objectives and endpoints .................................................................................. 19 
3.1.1 
Primary objectives and endpoints ....................................................................................... 19 
3.1.2 
Secondary objectives and endpoints ................................................................................... 19 
3.1.3 
Tertiary objectives and endpoints ........................................................................................ 20 
3.2 
Design of the clinical trial ..................................................................................................... 20 
3.3 
Safety Review ...................................................................................................................... 22 
3.3.1 
Safety considerations .......................................................................................................... 22 
3.3.2 
Safety Evaluation ................................................................................................................. 22 
3.3.2.1 
Data to be discussed at safety review meetings. ............................................................ 23 
3.3.3 
Stopping rule criteria. ........................................................................................................... 23 
3.4 
Patient evaluability ............................................................................................................... 24 
3.4.1 
Response............................................................................................................................. 24 
3.4.2 
Safety ................................................................................................................................... 24 
3.4.3 
Immunogenicity ................................................................................................................... 24 
4 
PATIENT SELECTION ........................................................................................................ 25 
4.1 
Eligibility criteria ................................................................................................................... 25 
4.1.1 
Inclusion criteria ................................................................................................................... 25 
4.1.2 
Exclusion criteria ................................................................................................................. 25 
4.2 
Patient enrolment ................................................................................................................. 27 
5 
TREATMENT ...................................................................................................................... 28 
5.1 
Selection of the Phase I clinical dose and schedule ............................................................ 28 
5.2 
Dosing schedule/treatment schedule ................................................................................... 28 
5.3 
Enrolment ............................................................................................................................. 28 

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5.3.1 
Dose reductions ................................................................................................................... 28 
5.3.2 
Dose delays & interruptions................................................................................................. 28 
5.4 
Duration of treatment ........................................................................................................... 29 
5.4.1 
Replacement of patients ...................................................................................................... 29 
5.5 
Concomitant medication and treatment ............................................................................... 29 
6 
PHARMACEUTICAL INFORMATION ................................................................................ 31 
6.1 
Supply of AST-VAC2 vaccine .............................................................................................. 31 
6.2 
Pharmaceutical data ............................................................................................................ 31 
6.2.1 
Formulation of AST-VAC2 ................................................................................................... 31 
6.2.2 
Storage conditions ............................................................................................................... 31 
6.2.3 
Method of dilution/reconstitution of AST-VAC2 ................................................................... 31 
6.2.4 
Stability and labelling of the AST-VAC2 .............................................................................. 31 
6.2.5 
AST-VAC2 administration .................................................................................................... 32 
6.2.6 
Vein extravasation/accidental spillages ............................................................................... 32 
6.3 
AST-VAC2 accountability ..................................................................................................... 32 
7 
INVESTIGATIONS SCHEDULE ......................................................................................... 34 
7.1 
Pre-treatment evaluations .................................................................................................... 34 
7.1.1 
Obtaining written informed consent ..................................................................................... 34 
7.1.1.1 
Pre-screening: HLA testing .............................................................................................. 34 
7.1.1.2 
Main trial consent and screening ..................................................................................... 34 
7.1.2 
Evaluations within 28 days prior to administration of AST-VAC2 (Baseline) ...................... 35 
7.1.3 
Evaluations within 7 days of study enrolment ..................................................................... 36 
7.2 
Evaluations during the trial ................................................................................................... 36 
7.3 
Evaluations after vaccination ............................................................................................... 37 
7.3.1 
Two weeks post vaccination visit ........................................................................................ 37 
7.3.2 
End of Vaccination visit ....................................................................................................... 37 
7.4 
Follow-up .............................................................................................................................. 38 
7.4.1 
3, 6, 9 and 12 months post first vaccination ........................................................................ 38 
7.4.2 
15, 18 and 21 month post first vaccination .......................................................................... 38 
7.4.3 
Two years post first vaccination visit (Ssurvival follow up data collection). ........................ 38 
7.4.4 
Extended follow up (>2 years to 5 years post first vaccination) .......................................... 39 
7.5 
Schedule of events  .............................................................................................................. 40 
8 
PHARMACODYNAMIC ASSESSMENTS .......................................................................... 42 
8.1 
Summary of Pharmacodynamic assessments ..................................................................... 42 
8.2 
Primary assessments ........................................................................................................... 45 
8.3 
Secondary assessments ...................................................................................................... 45 
8.3.1 
Pharmacodynamic blood biomarkers (secondary) .............................................................. 45 
8.3.1.1 
Identification of peptide specific T cells (Secondary assay 2a) ....................................... 45 
8.4 
Tertiary/research assessments ............................................................................................ 46 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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9 
ASSESSMENT OF SAFETY............................................................................................... 48 
9.1 
Investigator Responsibilities................................................................................................. 48 
9.1.1 
Medical Cover ...................................................................................................................... 48 
9.2 
Adverse event definitions ..................................................................................................... 48 
9.2.1 
Adverse event ...................................................................................................................... 48 
9.2.2 
Serious adverse events ....................................................................................................... 48 
9.2.3 
Suspected, unexpected, serious adverse reactions ............................................................ 49 
9.2.4 
Determining adverse event causality .................................................................................. 49 
9.2.5 
Expectedness ...................................................................................................................... 50 
9.3 
Collection of safety information ............................................................................................ 50 
9.3.1 
Screening failures ................................................................................................................ 50 
9.3.2 
Patients who consent to HLA screening .............................................................................. 50 
9.3.3 
Eligible patients ................................................................................................................... 50 
9.3.4 
Follow-up of AEs and SAEs ................................................................................................ 50 
9.3.5 
Other safety information of interest ..................................................................................... 50 
9.4 
Reporting of SAEs to the Sponsor Pharmacovigilance Department.................................... 51 
9.4.1 
Events exempt from being reported as SAEs to the Pharmacovigilance Department ........ 51 
9.5 
Recording of adverse events and serious adverse events in eCRFs .................................. 51 
9.6 
Urgent safety measures ....................................................................................................... 52 
9.7 
Pregnancy ............................................................................................................................ 52 
9.8 
Protocol specific grading: Injection Site Reactions .............................................................. 54 
10 
ASSESSMENT OF EFFICACY ........................................................................................... 55 
10.1 
Timing and type of tumour assessments ............................................................................. 55 
10.2 
Tumour response ................................................................................................................. 55 
10.2.1 
Recording of response in the eCRF ................................................................................ 55 
11 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT   SCHEDULE ..... 56 
12 
DEFINING THE END OF TRIAL ......................................................................................... 57 
13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS ............................................ 58 
13.1 
Interim analysis .................................................................................................................... 58 
13.2 
Final analysis ....................................................................................................................... 58 
13.3 
Presentation of data ............................................................................................................. 58 
13.4 
Safety ................................................................................................................................... 58 
13.5 
Pharmacodynamics .............................................................................................................. 59 
13.6 
Tumour response ................................................................................................................. 59 
14 
ADMINISTRATION ............................................................................................................. 60 
14.1 
Protocol deviations and amendments .................................................................................. 60 
14.2 
Serious breach of Good Clinical Practice ............................................................................ 60 
14.3 
Completion of the electronic case report form ..................................................................... 60 
14.4 
Trial performance, monitoring, auditing and inspection ....................................................... 61 
14.5 
Source document verification ............................................................................................... 61 
14.6 
Clinical study report .............................................................................................................. 61 
14.7 
Record retention ................................................................................................................... 62 
14.8 
Ethical considerations .......................................................................................................... 62 
14.9 
Indemnity .............................................................................................................................. 62 
14.10 
Publication policy and press releases .................................................................................. 62 
14.11 
Guidance for disruption to trial conduct ............................................................................... 63 
15 
REFERENCES .................................................................................................................... 64 
16 
APPENDICES ..................................................................................................................... 67 

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16.1 
APPENDIX 1: WHO PERFORMANCE STATUS SCALE .................................................... 67 
16.2 
APPENDIX 2: NEW YORK HEART ASSOCIATION (NYHA) SCALE ................................. 68 
16.3 
APPENDIX 3: MEASUREMENT OF DISEASE ................................................................... 69 
 
 
 

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PROTOCOL SIGNATURES 
Sponsor Signature: 
The Sponsor has read and agrees to the protocol, as detailed in this document.  I am aware of my 
responsibilities as the Sponsor under the UK Clinical Trials Regulations1, the guidelines of Good 
Clinical Practice (GCP)2, the Declaration of Helsinki3, the applicable regulations of UK law and the trial 
protocol.  The Sponsor agrees to conduct the trial according to these regulations and guidelines and to 
appropriately direct and assist Sponsor’s staff who will be involved in the trial, and ensure that all staff 
members are aware of their clinical trial responsibilities. 
 
Name: 
 
 
 
 
 
Title: 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6 (R1): Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, 
adopted by CPMP July 1996. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 

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PROTOCOL SIGNATURES  
Investigator Signature: 
I have read and agree to the protocol, as detailed in this document.  I am aware of my responsibilities 
as an Investigator under the UK Clinical Trials Regulations1, the guidelines of Good Clinical Practice 
(GCP)2, the Declaration of Helsinki3, the applicable regulations of the relevant NHS Trusts and the trial 
protocol.  I agree to conduct the trial according to these regulations and guidelines and to 
appropriately direct and assist the staff under my control, who will be involved in the trial, and ensure 
that all staff members are aware of their clinical trial responsibilities. 
 
Investigator's Name: 
 
 
 
 
 
Name of site: 
 
 
 
 
 
Signature: 
 
 
 
 
 
Date: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 The Medicines for Human Use (Clinical Trials) Regulations (S.I. 2004/1031) and any subsequent amendments to it. 
2 ICH Harmonised Tripartite Guideline E6 (R1): Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) Step 5, 
adopted by CPMP July 1996. 
3 WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects adopted by the 18th WMA 
General Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 

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1 
PROTOCOL SYNOPSIS 
1.1 
Full title:  
A Cancer Research UK Phase I trial of AST-VAC2 (allogeneic dendritic cell vaccine) administered 
weekly via intradermal injection in patients with advanced non-small cell lung cancer (NSCLC). 
1.2 
Short title:  
A Phase I trial of AST-VAC2 vaccine in patients with non-small cell lung cancer.   
1.3 
Clinical trial objectives and endpoints: 
Primary objective 
Endpoint 
To assess the safety and tolerability of the target 
dose of AST-VAC2 given as six intradermal (id) 
injections at Weeks 1, 2, 3, 4, 5 and 6 in patients 
with advanced NSCLC.  
Determining frequency and causality of each 
adverse event (AE) to AST-VAC2 and grading 
severity according to the National Cancer 
Institute (NCI) Common Terminology Criteria for 
Adverse Events (CTCAE) Version 4.02 or 
protocol specific grading system for injection site 
reactions (ISRs). 
The secondary and tertiary objectives and endpoints of the trial can be found in Section 3.1. 
1.4 
Trial Design:  
This is a first in man, open label, multi-centre Phase I trial to investigate the safety, immunogenicity 
and patient survival following administration of the dendritic cell (DC) vaccine AST-VAC2 in patients 
with advanced NSCLC (metastatic or locally advanced).  
All enrolled patients will receive AST-VAC2. 
Safety review and stopping rule criteria are detailed in Section 3.3. If stopping criteria are met as per 
protocol, this will trigger an independent review of the data.  Pharmacodynamic data will also be 
reviewed as available.  
All potential trial patients will be asked to consent to a pre-screening assessment of Human Leucocyte 
Antigen (HLA) typing. Once the HLA result is known, patients who are HLA A*02:01 positive will be 
asked to consent to participate in the main trial. Patients who are HLA A*02:01 negative will not be 
eligible for the trial.  
Patients receiving AST-VAC2 will be followed up for safety (primary endpoint), pharmacodynamic 
analyses in blood samples (secondary endpoint) 
 
.   
All patients will be followed up for up to two years post first vaccination for overall survival and for five 
years post first vaccination for safety.  
1.5 
Trial treatment:  
Patients will receive AST-VAC2 vaccinations, administered by id injection at six time points over a period 
of six weeks (Figure 1). An interval of 7 days (+/- 1 day) should occur between each of the vaccination 
days.  Two intradermal injections (totalling 1x107 cells of AST-VAC2) will be administered on each 
vaccination day.  The target administered dose of vaccine is 1x107 cells of AST-VAC2.   
 

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myelogenous leukaemia (see Section 2.4 and IB Section 5.1.2.1).  In this trial, a target dose of 1x107 
cells has been proposed based on the tolerability of this dose in the AST-VAC1 trial discussed in Section 
2.4 and IB Section 5.1.2.1. 
Each patient will receive a maximum of six vaccinations based on previous clinical experience with AST-
VAC1 in prostate cancer patients, where six vaccinations were found to induce the highest levels of anti-
hTERT immune responses.  Based on the vaccination regimens used for AST-VAC1, AST-VAC2 will 
be given at Weeks 1, 2, 3, 4, 5 and 6, 7 days apart (+/- 1 day).  

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All potential patients will be asked to consent to a pre-screening assessment of HLA typing. Only 
patients who are screened and found to be HLA A*02:01 positive will be asked to consent to the main 
trial and continue into screening to establish eligibility for trial treatment.   
It is expected that up to eight patients will be recruited, the final number depending on the emerging 
safety data, patient replacement and vaccine availability.   
Patients will receive six AST-VAC2 vaccinations (administered by two id injections for each vaccination), 
once a week (every 7 days +/- 1 day) for six weeks. Only one target dose of AST-VAC2 will be explored 
i.e. 1x107 cells.  A reduced dose of AST-VAC2 or a reduction in number of vaccinations administered, 
may be considered following observation of unacceptable toxicity at this dose level. Any modification to 
the vaccination dose/schedule will be determined and agreed by the Sponsor & Chief Investigator based 
on emerging data as the trial progresses. 
The ‘End of Trial’ will be declared once all patients have either withdrawn (see Section 11.0) from the 
trial or died, or the last patient has completed their final  safety follow-up visit (5 years post the first 
vaccination), whichever is the latter. 
3.3 
Safety Review 
3.3.1 
Safety considerations 
AST-VAC2 has never been investigated in the clinic so no clinical safety data are available. Based upon 
experience with other autologous and allogeneic DC vaccines, including AST-VAC1, the potential 
toxicities of AST-VAC2 are expected to be minimal. Severe AEs related to AST-VAC1 (related 
autologous DC cell therapy, Section 2.4 and IB section 5.1.2.1) have not been observed in Phase I and 
II clinical trials with the possible exception of an occurrence of thrombocytopenia in one patient with 
acute myeloid leukaemia (AML).  
The principal potential toxicity of AST-VAC2 is likely to be related to the allogeneic nature of the 
AST-VAC2 vaccine which could lead to injection site inflammation. However, it is noted that the mixed 
leucocyte reaction could elicit an adjuvant effect which may be beneficial in the context of this trial. 
Systemic inflammatory responses associated with cytokine release have not been demonstrated in 
dendritic cell vaccines to date and therefore are not considered to be a significant risk for AST-VAC2. 
Chronic toxicities, particularly related to unintended proliferation of AST-VAC2, are not anticipated. 
AST-VAC2 is derived from a hESC line.  The cells are terminally differentiated during manufacture to 
generate cells with a phenotype comparable to that of autologous dendritic cells, which are known to 
have a low proliferative potential and a short biological half-life.  Furthermore, these cells are irradiated 
post-cryopreservation to minimise the risk of any cells with proliferative potential remaining in the IMP.  
Finally, AST-VAC2 is only partially haplotyped to the recipient therefore the recipient may also induce a 
rejection reaction to the cells causing rapid elimination. Overall, the drug product is therefore expected 
to have no proliferative potential in vivo and the potential for tumourgenicity/ectopic growth is considered 
to be remote. 
All AEs observed during this trial will be assessed using NCI CTCAE Version 4.02, with the exception 
of Injection Site Reactions (ISR) which are defined using the protocol specific grading system detailed 
in Section 9.8.  
 
The risk of developing any of the AEs noted above and in Section 3.3.3 is low and largely theoretical 
however if any of the above is seen or suspected during the vaccination schedule or follow up period, 
investigators should investigate as per standard clinical practice and may include assessments as 
appropriate. If any of these AEs meet the stopping rule criteria as set out in Section 3.3.3, this will trigger 
an independent review as stated. 
3.3.2 
Safety Evaluation 
Only one target dose level is being explored in this trial.  

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Safety evaluations by the Sponsor and collaborating Investigators will be conducted after the first patient 
has received AST-VAC2 and then again after the second and third patients have been treated, Figure 
4. Once open recruitment has been initiated, safety review will be performed at regular intervals (as 
required).   
Figure 3. Safety Evaluation 
 
 
A safety review committee, consisting of all Investigators, representatives of the Sponsor and 
representatives of the drug company (observers only), will review emerging study data (to include all 
clinical data, safety data listings and applicable PD data) on an ongoing basis, with particular reference 
to ensuring that patients are able to complete the vaccination schedule without AST-VAC2 
toxicity-related delays.  Should the committee have significant concerns about toxicity seen during the 
trial they will have the authority to suspend or terminate the trial and/or make recommendations to the 
Sponsor to modify the vaccination administration.  
Pending discussions between the Sponsor and CI and based on vaccine availability, the following 
options may be considered during the trial: 
• 
Reduced dose and/or 
• 
Modified number of vaccinations, e.g. if plateaued immune responses are observed with fewer 
vaccinations in those patients already treated. 
3.3.2.1 
Data to be discussed at safety review meetings. 
Data which should be discussed at the safety review meeting will include:  
• 
Patients treated since the last safety review meeting including vaccine related adverse events 
noted and duration of treatment.  
• 
Assessment and agreement on any related adverse events that may have occurred and 
resulting actions.  
• 
Relevant PD data available since the last meeting. 
• 
Any additional relevant information relating to adverse events or patient safety which may 
have arisen following distribution of listings for the meeting and will therefore not be 
documented in the listings.  
• 
Any possible concern after the review of cumulative data e.g. toxicities. 
• 
Assessment and agreement on continuation of patient enrolment to the study.  
 
3.3.3 
Stopping rule criteria. 
On observation of any of the following related adverse events, the study data (defined above) will be 
reviewed by the independent Protocol Safety and Review Board (PSRB) for an opinion. 
 
• 
ISR Grade 3 or 4 (as per protocol specific grading system). 
• 
Clinically significant systemic allergic reaction (in the judgement of the investigator) 
• 
Evidence of clinically significant autoimmunity (in the judgement of the investigator) 
• 
Cytokine release syndrome Grade 3 or 4. 
• 
Evidence of tumorgenicity/ectopic growth (including teratoma formation). 
• 
Any other clinically significant toxicity (in the judgement of the investigator)  
 

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3.  
Systemic steroids or other drugs with a likely effect on immune competence are forbidden during 
the trial with the exception of replacement treatment. Inhaled and topical steroids are permitted. 
The predictable need of their use will preclude the patient from trial entry. 
4.  
Female patients who are able to become pregnant (or are already pregnant or lactating). 
However, those patients who have a negative serum or urine pregnancy test before enrolment 
and agree to use two forms of contraception (one effective form plus a barrier method) [oral, 
injected or implanted hormonal contraception and condom; intra-uterine device and condom; 
diaphragm with spermicidal gel and condom] or agree to sexual abstinence*, effective from the 
first administration of AST-VAC2 throughout the trial and for six months afterwards are 
considered eligible.  
5.  
Male patients with partners of child-bearing potential (unless they agree to take measures not to 
father children by using a barrier method of contraception [condom plus spermicide] or to sexual 
abstinence* effective from the first administration of AST-VAC2, throughout the trial and for six 
months afterwards. Men with partners of child-bearing potential must also be willing to ensure 
that their partner uses an effective method of contraception for the same duration for example, 
hormonal contraception, intrauterine device, diaphragm with spermicidal gel or sexual 
abstinence). Men with pregnant or lactating partners must be advised to use barrier method 
contraception (for example, condom plus spermicidal gel) to prevent exposure of the foetus or 
neonate. 
6.  
Major thoracic or abdominal surgery from which the patient has not yet recovered. 
7.  
At high medical risk because of non-malignant systemic disease including active uncontrolled 
infection. 
8.  
Known to be serologically positive for Hepatitis B, Hepatitis C or Human Immunodeficiency Virus 
(HIV). 
9.  
Evidence of any ongoing active autoimmune disease.  
10.  
Concurrent congestive heart failure, prior history of class III/ IV cardiac disease (New York Heart 
Association [NYHA]), prior history of cardiac ischaemia or prior history of cardiac arrhythmia.  
11.  
Is a participant or plans to participate in another interventional clinical trial, whilst taking part in 
this Phase I trial of AST-VAC2.  Participation in an observational trial or interventional clinical 
trial which does not involve administration of an IMP and which would not place an unacceptable 
burden on the patient in the opinion of the Investigator and Medical Advisor would be acceptable. 
  
12.  
Any vaccination given within four weeks before the first AST-VAC2 vaccination (except for 
COVID-19 vaccinations, which are permitted at the Investigator’s discretion).  
13.  
Any planned prophylactic vaccination from trial entry until completion of the AST-VAC2 
vaccinations (except for planned COVID-19 vaccinations, which are permitted at the 
Investigator’s discretion).  
14.  
Any condition which might interfere with the patient’s ability to generate an immune response.  
15.  
Any other condition which in the Investigator’s opinion would not make the patient a good 
candidate for the clinical trial. 
 
 
* Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and 
usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and 
withdrawal are not acceptable methods of contraception. 

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4.2 
Patient enrolment 
Before enrolling the patient in the trial, the Investigator or designated representative should determine 
the eligibility of the patient during the trial screening period.  Please ensure that the Sponsor is notified 
of any eligibility concerns at least four working days before treatment is planned. 
Eligible patients must be enrolled in the electronic data capture (EDC) system by site staff and then 
registered by the Sponsor before they start treatment with AST-VAC2.   
Eligible patients will be allocated a trial number by the EDC system during the enrolment process. The 
Sponsor will send confirmation of the patient registration and dose level, to the investigator following 
enrolment of the patient; trial treatment may only be administered after this confirmation has been 
received. 

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5 
TREATMENT 
5.1 
Selection of the Phase I clinical dose and schedule 
The therapeutic vaccine will be administered via two intradermal (id) injections at a target dose of 1x107 
cells on each vaccination day. The actual cell dose patients may receive will vary, up to a maximum of 
2 x107 viable cells, to achieve a target dose of 1 x 107 viable cells – Section 6.2.5 for further details on 
dose.  
The dose of AST-VAC2 has been selected based on previous clinical experience with autologous 
dendritic cells (DCs) 
 in which a dose of 1x107 cells 
was shown to induce anti-hTERT T cell responses in patients with either prostate cancer or AML.   
5.2 
Dosing schedule/treatment schedule 
Patients will receive six AST-VAC2 vaccinations, administered by id injection weekly over a period of 
six weeks. An interval of 7 days (+/-1 day) should occur between each of the vaccination days.   The 
target total administered dose of vaccine is 1x107 cells of AST-VAC2 which will be administered as two 
id injections for each vaccination. 
AST-VAC2 vaccine will be given by id injection in the deltoid muscle of the arm, the outer thigh surface, 
anterior abdominal wall or buttock. If an injection site reaction (ISR) has resolved after the first 
vaccination /previous vaccination days then for subsequent injections, injections can be administered at 
the same body site. If an ISR from a previous vaccination is still present (>Grade 1) then the injections 
should be administered into an alternative site. 
Only one dose of AST-VAC2 will be explored in this trial. A reduced dose/administration schedule may 
be considered as per Section 3.3 based on emerging safety data.  
5.3 
Enrolment  
Initially, one patient will be recruited and will receive their first four vaccinations before the second and 
third patients are recruited. It is acceptable for these next patients to receive treatment in parallel. The 
second and third patients must receive their first four vaccinations before recruitment is opened to the 
remaining patients. 
Safety evaluations by the Sponsor and collaborating Investigators (Section 3.3) will be conducted after 
the first patient has received AST-VAC2 and then again after the second and third patients have been 
treated. Once open recruitment has been initiated, safety review will be performed at regular intervals 
(as required).   
5.3.1 
Dose reductions 
Pending discussions between the Sponsor and Chief Investigator (CI) and based on vaccine availability, 
the following options may be considered during the trial: 
• 
Reduced dose and/or 
• 
Modified number of vaccinations, e.g. if plateaued immune responses are observed with fewer 
vaccinations in those patients already treated. 
5.3.2 
Dose delays & interruptions 
If at the time of the next scheduled vaccination day, one or more adverse events (AEs) (excluding ISRs) 
related to the AST-VAC2 vaccine (highly probably, probably or possibly related) are still present, have 
not resolved to Grade ≤1 and are considered by the Investigator to be clinically significant and a clear 
contraindication to vaccination, the next vaccination day should be delayed for up to two weeks until the 
AE(s) have recovered to this level. In case of uncertainty, individual cases should be discussed with the 
Sponsor. Patients who require a dose interruption of greater than two weeks will be reviewed on a case 
by case basis to determine whether the patient should be withdrawn from the trial. The Sponsor will 
confirm whether an extended interruption is acceptable or if the patient should be withdrawn from further 
trial treatment.  

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If the patient is administered a COVID-19 vaccination during the AST-VAC2 vaccination period, there 
should be a 48 hours interval between the two vaccinations and they should be administered to different 
sites. The AST-VAC2 vaccination should be delayed as needed to accommodate this interval. 
If the patient is withdrawn from further trial treatment, follow up information and post vaccination 
research blood
 sampling will still be applicable unless the patient withdraws consent from 
further follow up and participation in the trial or if the Sponsor advises that further sampling is not 
required. 
5.4 
Duration of treatment 
Treatment should continue so that the patient receives six vaccinations unless (a) the patient asks to 
be withdrawn, (b) there is evidence of disease progression (as per Immune-Related Response  
Criteria (irRC) given in Appendix 3), (c) the patient is experiencing unacceptable toxicity or (d) the 
investigator feels the patient should stop the vaccinations for any other reason.  Other reasons are listed 
in Section 11.0. 
An End of Vaccination visit will be carried out 30 days post the last vaccination day. This visit will 
document any emerging AEs since the last vaccination.  Adverse events present at this visit, attributed 
to AST-VAC2 (highly probably, probably or possibly related) will be followed up until resolution or 
stabilisation of these events (even if  the patient starts another anti-tumour treatment).  
If a patient terminates treatment prematurely, an End of Vaccination visit should be performed within 30 
days of the last vaccination day or when the decision is taken to withdraw the patient from further 
vaccinations or the trial. These patients should also be asked to continue attending hospital for the 3, 6 
and 12 month from first vaccination follow-up visits to provide blood samples for immune analysis 
(unless the patient withdraws consent from further follow up and participation in the trial or if the Sponsor 
advises that further sampling is not required). 
Patients will be asked to attend follow up as per Section 7.4 until the end of trial (EoT) is declared.  The 
‘End of Trial’ will be declared when all patients have either withdrawn (see Section 11.0) from the trial 
or died, or the last patient has completed their final follow-up visit (5 years post the first vaccination), 
whichever is the latter. 
 
5.4.1 
Replacement of patients 
Three administrations of AST-VAC1 (i.e. three complete doses) have previously been shown to 
demonstrate the first indications of an immune response therefore patients who receive fewer than three 
AST-VAC2 vaccinations (for reasons other than toxicity) will be replaced, pending vaccine availability. 
5.5 
Concomitant medication and treatment 
Concomitant medication may be given as medically indicated.  Details (including name, indication for 
use and start and stop dates) of the concomitant medication given must be recorded in the patient’s 
medical records and details entered into the eCRF.   
The patient must not receive other anti-cancer therapy or investigational drugs during the vaccination 
phase of the trial. Following the vaccination period, if other treatment is received during the follow up 
period, this should be documented accordingly however, follow up information (including AEs related to 
AST-VAC2) should still be collected as per protocol, Section 7.4.  
Use of immunosuppressive medication, including corticosteroids (other than replacement dosing for 
adrenal insufficiency/pituitary failure), is excluded in this protocol.  Inhaled and topical steroids are 
permitted. A short course of systemic steroids may be permitted for management of adverse events, 
however, this should be discussed and agreed in advance by the CDD Medical Advisor and/or the Chief 
Investigator.   
Patients may be administered a COVID-19 vaccine during the trial (including during screening), at the 
discretion of the Investigator. Where possible, the COVID-19 vaccination should be administered before 

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trial entry or after completion of the AST-VAC2 vaccination period. However, if the COVID-19 
vaccination is to be administered during the AST-VAC2 vaccination period, there should be an interval 
of 48 hours between administration of the two vaccines and they should be administered to different 
sites. Details of the COVID-19 vaccination should be recorded in the medical records and details entered 
in the eCRF.  
 

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The product is supplied in Crystal Zenith (CZ)  vials packed into a CZ box containing six individual 
doses and must not be removed from the primary packaging until time of administration. It must not be 
placed in any other container.   
Labelling requirements for the AST-VAC2 must include the following information: 
• 
Cancer Research UK,   
• 
AST-VAC2,  
• 
Batch XXX.XX.XX, 
• 
For Intra-Dermal admin,  
• 
Protocol No CRUKD/17/003,   
• 
0.6 mL at 2.0 x 107 cells/vial  
Expiry date will not be detailed on the vial but will be shown on the secondary packaging (CZ boxes). 
The actual cell dose patients may receive will vary, up to a maximum of 2 x107 viable cells, to achieve 
a target dose of 1 x 107 viable cells - please see Section 6.2.5.  
6.2.5 
AST-VAC2 administration 
Before administering the AST-VAC2 vaccine, the exact dosage must always be double-checked by a 
second suitably qualified person at site.  All checks and double-checks must be documented (signed 
and dated) and the documentation must be available for the CRA/CSM to verify. 
Each weekly AST-VAC2 vaccine dose will be administered as a split dose via two id injections at a 
target dose defined as 1 × 107 viable cells.  Each vial of AST-VAC2 will be filled at a concentration of 
2 x 107 viable cells per vial (pre-cryopreservation) and the release specification for the product strength 
has been set at >1 x 107 viable cells/vial post thawing (based on stability data).  The actual cell dose 
patients may receive will vary, up to a maximum of 2 x107 viable cells, to achieve a target dose of 1 x 
107 viable cells.  There is no dose escalation planned during CRUKD/17/003. 
Each vial of AST-VAC2 will contain 0.6 mL.  For each vaccination, vial contents should be drawn into 
one needle from the vial and delivered as two separate id injections.  Each injection will be a maximum 
of 0.3 mL each. The injections should be administered to the same body site approximately 1 cm apart.  
Patients should receive the id injections in either the deltoid muscle on the arm, the outer thigh surface, 
anterior abdominal wall or buttock. If an injection site reaction (ISR) has resolved after the first 
vaccination day/previous vaccination days then for subsequent injections, injections can be 
administered at the same body site. If an ISR from a previous vaccination is still present (>Grade 1) 
then the injection should be administered into an alternative site. The site of injection will be documented 
for each vaccination.  
If a patient is administered a COVID-19 vaccination during the AST-VAC2 vaccination period, there 
should be an interval of 48 hours between the administration of the vaccines and they should be 
administered to different sites. 
 
6.2.6 
Vein extravasation/accidental spillages  
As AST-VAC2 is administered intradermally, vein extravasation should not be a potential risk.  
Accidental spillages should be dealt with according to hospital policy.   
6.3 
AST-VAC2 accountability 
Accurate records of all AST-VAC2 shipments and vials dispensed must be maintained in the local 
pharmacy. Once the product is thawed the injection must be administered within two hours. If this cannot 
occur, the product cannot be re-frozen and must be disposed of as per hospital policy. This must be 
noted on the inventory for authorisation by CRA/ CSM.  This inventory record must be available for 
inspection at any time by CRAs or CSMs of the Sponsor.  AST-VAC2 supplies are to be used only in 
accordance with this protocol and under the supervision of the Investigator. 

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Unused product (thawed or frozen) should be returned to pharmacy for destruction. The Investigator 
undertakes not to destroy any unused or returned AST-VAC2 unless authorised to do so by the Sponsor.  
Any unused AST-VAC2 must be destroyed according to hospital procedures and properly accounted 
for using the IMP Destruction Form and also on the IMP Accountability Record.  During the course of 
the trial the CRA will check the numbers of vials of AST-VAC2 shipped to the centre, the number used 
and the number destroyed. The pharmacy will give an account of any discrepancy. 

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7.1.3 
Evaluations within 7 days of study enrolment 
The following must be performed within 7 days before study enrolment: 
• 
Female patients able to have children must have a negative result on a human chorionic 
gonadotropin (HCG) pregnancy test (serum or urine test is acceptable). 
• 
Complete physical examination;  
• 
Height, weight, WHO PS,  
• 
Vital signs (temperature, seated BP and pulse rate);  
• 
ECG;  
• 
Laboratory tests (blood/urine samples). Laboratory tests relating to specific eligibility 
criteria must be performed to confirm a patient’s eligibility prior to study enrolment: 
- 
Haematology – haemoglobin (Hb), white blood cells (WBC) with differential 
count (neutrophils, lymphocytes, platelets and eosinophils). 
- 
Biochemistry – sodium, potassium, adjusted calcium, phosphate, urea, 
creatinine, total protein, albumin, bilirubin, alkaline phosphatase (ALP) and 
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) and 
C-reactive protein (CRP). 
- 
CEA sample 
- 
Urinalysis – pH, glucose, protein and blood. 
- 
Baseline research bloods (Please see Section 8.0) 
Investigators must enrol the patient on the trial once confirmed as eligible (see Section 4.2) and prior to 
the patient’s first AST-VAC2 vaccination. 
7.2 
Evaluations during the trial 
Day of vaccination 
• 
Symptom-directed physical examination: if clinically indicated, a symptom-directed 
physical examination is to be performed on the day of each vaccination before      
AST-VAC2 administration. 
• 
WHO PS on the day of each vaccination. 
• 
Vital signs, temperature, seated BP, pulse rate: must be assessed within 15 mins before 
the vaccination and within 15 mins after the vaccination.  
• 
Adverse events and concomitant medications: At each visit, before each AST-VAC2 
vaccination, an assessment of any AE experienced since the previous visit must be 
made by the Investigator, Research Nurse or suitably qualified member of the 
Investigator’s team.  
The start and stop dates of the AE together with the relationship of the event to 
AST-VAC2 must be recorded in the medical records. 
All AEs must be graded according to NCI CTCAE Version 4.02 and protocol specific 
ISR grading system (See Section 9.0 for further details regarding AE reporting 
requirements and ISR grading system). 
Any concomitant treatment must be recorded in the medical records. (See Section 9.0 
for further details regarding AE reporting requirements.) 
• 
COVID-19 vaccines: If a patient is administered a COVID-19 vaccination during the 
AST-VAC2 vaccination period, there should be an interval of 48 hours between the 
administration of the vaccines and they should be administered to different sites. The 
COVID-19 vaccine should be documented in the eCRF as a concomitant medication 
and any AEs should be assessed for causality to AST-VAC2 and the COVID-19 
vaccination. 
• 
Laboratory tests: 
Haematology and biochemistry:  
 
Week 1 vaccination: laboratory tests must be repeated and reported prior to the first 
vaccination if the results used for enrolment purposes are >7 days prior to the day of 
vaccination.  

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• 
Female patients able to have children must have a human chorionic gonadotropin 
(HCG) pregnancy test (serum or urine test is acceptable). 
• 
Radiological assessment of disease: This must be repeated at the end of the 
vaccination schedule.  Tumour measurements must be documented according to 
Immune-Related Response Criteria (irRC). (Refer to Section 10.0). Thereafter, 
assessment of disease to be performed as per standard clinical practice.   
7.4 
Follow-up 
7.4.1 
3, 6, 9 and 12 months post first vaccination 
Patients should undergo the following assessments: 
• 
Research blood samples 3, 6 and 12 months (all +/-1 week) post the first vaccination.  
• 
At the above time points, an evaluation of any AST-VAC2 related AEs will also be 
performed. Assessments can be performed as clinically indicated.  
• 
A further AE evaluation should be performed at 9 months post the first vaccination also. 
This can be in the form of a phone call to the patient.  
• 
Any concomitant medications relevant to AST-VAC2-related AEs should be recorded. 
 
All new and ongoing AST-VAC2-related AEs should be followed up until resolution or stabilisation, even 
if the patient goes onto another anti-cancer treatment. SAEs considered related to AST-VAC2 are 
always reportable regardless of the time elapsed.  
 
7.4.2 
15, 18 and 21 month post first vaccination 
Evaluation of any new or ongoing AST-VAC2-related AEs should be performed at 15, 18 and 21 months 
(i.e. quarterly). This can be in the form of a phone call to the patient. Any concomitant medications 
related to these AEs should also be recorded. 
It is acceptable for there to be flexibility around when these quarterly visits take place but this should be 
checked with the Sponsor who will document the revised visit accordingly. 
 
7.4.3 
Two years post first vaccination visit (survival follow up data collection). 
All vaccinated patients should be followed up for OS, two years post the first vaccination. Evaluation of 
new or ongoing AST-VAC2-related AEs should be performed. Any concomitant medications relevant to 
these AEs should also be recorded. The AE information can be collected via a phone call to the patient. 
Survival information may be obtained from the patient’s medical records. 
 
For survival follow up, sites will be asked to provide the following information if known:  
• 
Date of death or date of last contact if alive.  
• 
Reason for death.  
• 
All post trial anti-cancer treatment for primary disease.  
• 
Date of radiological confirmed relapse(s), if post trial.  
• 
WHO PS at time of relapse.  
• 
Any other medically important information, in the opinion of the investigator.  
No further patient trial related visits or assessments are required to collect this survival data. Survival 
follow up information may cease to be collected based on emerging data showing limited immune 
response and therefore limited benefit of continuing collection of long term follow up data. This will be 
discussed and agreed by the Sponsor and CI based on emerging data. 

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7.4.4 
Extended follow up (>2 years to 5 years post first vaccination) 
After the 2-year survival follow up has been completed, any patients who are still alive will continue to 
be followed up every three months by telephone until the end of the trial (unless the patient has died or 
withdrawn from the trial). If the patient has died, the date of death and cause of death will be recorded. 
Evaluation of new or ongoing AST-VAC2-related AEs should be performed. Any concomitant 
medications relevant to these AEs should also be recorded. It is acceptable for there to be flexibility 
around when these quarterly calls take place but this should be checked with the Sponsor who will 
document the revised visit accordingly. 

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9 
ASSESSMENT OF SAFETY 
9.1 
Investigator Responsibilities 
The investigator is responsible for monitoring the safety of patients who have enrolled in the trial and for 
accurately documenting and reporting information as described in the following sections.   
9.1.1 
Medical Cover 
The chief/principal investigator (CI/PI) is also responsible for ensuring patients have access to 24 hour 
advice and/or care.  Patients will be provided with the necessary contact numbers for both normal 
working and out of hours care.  A copy of the protocol must be made available out of hours to ward staff 
and clinicians on call so that the appropriate advice may be given to the patient, the patient’s relative or 
other care giver (for example general practitioner (GP)).  The CI/PI must ensure that should the on call 
clinician or ward staff require more advice than is in this protocol, that they have access to the 
Investigator or delegated members of the investigator’s team who can answer any questions.   
9.2 
Adverse event definitions 
9.2.1 
Adverse event 
Adverse events for this trial will be graded according to NCI CTCAE version 4.02. In addition, Injection 
Site Reactions will be graded according to protocol specific grading system as per Section 9.8. 
An adverse event (AE) is any untoward, undesired or unplanned medical occurrence in a patient 
administered an IMP, a comparator product or an approved drug.   
An AE can be a sign, symptom, disease, and/or laboratory or physiological observation that may or may 
not be related to the IMP or comparator.   
An AE includes but is not limited to those in the following list.  
• 
A clinically significant worsening of a pre-existing condition.  This includes conditions that 
may resolve completely and then become abnormal again.  
• 
AEs occurring from an overdose of an IMP, whether accidental or intentional. 
• 
AEs occurring from lack of efficacy of an IMP, for example, if the Investigator suspects that a 
drug batch is not efficacious or if the Investigator suspects that the IMP has contributed to 
disease progression. 
9.2.2 
Serious adverse events 
A serious adverse event (SAE) is any AE, regardless of dose, causality or expectedness, that: 
• 
results in death; 
• 
is life-threatening*; 
• 
requires in-patient hospitalisation or prolongs existing in-patient hospitalisation (some 
hospitalisations are exempt from SAE reporting – e.g. hospital admissions planned prior to the 
patient entering the trial; overnight stays for planned procedures such a blood transfusions 
(Section 9.4.1); 
• 
results in persistent or significant incapacity or disability; 
• 
is a congenital anomaly or birth defect; 
• 
is any other medically important event** 
* A life-threatening event is defined as an event when the patient was at substantial risk of dying at the 
time of the adverse event, or use or continued use of the device or other medical product might have 
resulted in the death of the patient. 
** A medically important event is defined as any event that may jeopardise the patient or may require 
intervention to prevent one of the outcomes listed above. Examples include allergic bronchospasm (a 
serious problem with breathing) requiring treatment in an emergency room, serious blood dyscrasias 

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(blood disorders) or seizures/convulsions that do not result in hospitalization. The development of drug 
dependence or drug abuse would also be examples of important medical events. 
For fatal SAEs, wherever possible report the cause of death as an SAE with a fatal outcome rather than 
reporting death as the SAE term.  When available, the autopsy report will be provided to the Sponsor. 
If during the course of the trial, other medically important events are identified and there is a requirement 
to report specific events outside of the standard criteria, this will be communicated to sites and the 
protocol will be updated to reflect this. 
Other reportable events that must be treated as SAEs are listed below.   
• 
Any AST-VAC2 related adverse event which meets the stopping rule criteria (as outlined in 
Section 3.3.3) are considered a trial specific medically important events and therefore an SAE. 
• 
Pregnancy exposure to the IMP.  Any pregnancy occurring in a patient or a patient’s partner 
during treatment with an IMP or occurring within six months of the last IMP administration, 
must be reported to the Pharmacovigilance Department in the same timelines as an SAE.  
These should be reported even if the patient is withdrawn from the trial. 
• 
Overdose with or without an AE. 
• 
Inadvertent or accidental exposure to an IMP with or without an AE, including for example, 
spillage of the IMP that contaminates staff.   
• 
Any AE that could be related to the protocol procedures, and which could modify the conduct 
of the trial. 
9.2.3 
Suspected, unexpected, serious adverse reactions 
A SUSAR is a suspected, unexpected, serious adverse reaction.  All AEs and SAEs will be assessed 
by the Sponsor for seriousness, causality and expectedness.  The Pharmacovigilance Department will 
expedite all suspected unexpected serious adverse reactions (SUSARs) to the relevant Competent 
Authority/Authorities and the relevant Ethics Committee(s) within the timelines specified in legislation 
(SI 2004/1031 as amended).  
9.2.4 
Determining adverse event causality 
The relationship of an AE to the IMP is determined as follows. 
Highly probable 
• 
Starts within a time related to the IMP administration and 
• 
No obvious alternative medical explanation. 
Probable 
• 
Starts within a time related to the IMP administration and 
• 
Cannot be reasonably explained by known characteristics of the patient’s clinical 
state. 
Possible 
• 
Starts within a time related to the IMP administration and 
• 
A causal relationship between the IMP and the AE is at least a reasonable possibility. 
Unlikely 
• 
The time association or the patient’s clinical state is such that the trial drug is not 
likely to have had an association with the observed effect. 
Not related 
• 
The AE is definitely not associated with the IMP administered. 
Note: Drug-related refers to events assessed as possible, probable or highly probable. 

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The Investigator must endeavour to obtain sufficient information to determine the causality of the AE 
(i.e. IMP, other illness, progressive malignancy etc.) and must provide his/her opinion of the causal 
relationship between each AE and IMP.  This may require instituting supplementary investigations of 
significant AEs based on their clinical judgement of the likely causative factors and/or include seeking a 
further opinion from a specialist in the field of the AE. 
The following guidance should be taken in to account when assessing the causality of an AE: 
• 
Previous experience with the IMP and whether the AE is known to have occurred with the IMP. 
• 
Alternative explanations for the AE such as concomitant medications, concurrent illness, 
non-medicinal therapies, diagnostic tests, procedures or other confounding effects. 
• 
Timing of the events between administration of the IMP and the AE. 
• 
De-challenge, that is, if the IMP was discontinued or the dosage reduced, what happened to the 
adverse reaction? 
• 
Re-challenge, that is, what happened if the IMP was restarted after the AE had resolved? 
9.2.5 
Expectedness 
Assessment of expectedness for AST-VAC2 will be made by the Pharmacovigilance Department 
against Reference Safety Information in the current version of the IB, current at the time of the event.  
9.3 
Collection of safety information 
9.3.1 
Screening failures 
For patients who fail screening, SAEs must be reported to the Pharmacovigilance Department, CDD 
from the date of consent until the date the patient is confirmed as ineligible. 
9.3.2 
Patients who consent to HLA screening 
AEs and SAEs related to the HLA test procedure should be reported from the time of HLA test consent 
to the time of consent to the main trial. Thereafter, should the patient consent to the main trial, reporting 
requirements as per Section 9.3.4.  
9.3.3 
Eligible patients 
For eligible patients, SAE and AE collection and monitoring will commence at the time the patient gives 
their written consent to participate in the trial by signing the main trial consent form and will continue 
until 30 days after the last vaccination (administration of IMP). From this time point until the patient 
withdraws, dies or completes the trial, new or ongoing AST-VAC2-related AEs will be collected 
(regardless of whether the patient goes on to other anti-cancer therapies). 
Should an Investigator become aware of any AST-VAC2 -related SAEs after the patient has completed 
the protocol-mandated follow-up period (as specified above), these must also be reported to the 
Sponsor within the expedited timelines in Section 9.4. 
9.3.4 
Follow-up of AEs and SAEs 
Follow-up of AEs with a causality of possible, probable or highly probable will continue until the events 
resolve, stabilise or the patient starts another anti-cancer therapy.   
The Pharmacovigilance Department will make requests for further information on SAEs to the trial site 
at regular intervals.  Requested follow-up information should be reported to the Pharmacovigilance 
Department in a timely manner and as soon as possible after receipt of the follow-up request.  For fatal 
or life-threatening cases, follow-up information must be reported to the Pharmacovigilance Department 
as soon as possible. 
9.3.5 
Other safety information of interest 
We will also collect information on the following situations, whether they are associated with an AE or 
not: 
• 
Abuse or misuse. 

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• 
Occupational exposure (to a person other than the patient, for example spilling of IMP on hands 
of nurse or splashing in the eye). 
Any occurrences of these should be reported in the same manner as SAEs (Section 9.4). 
9.4 
Reporting of SAEs to the Sponsor Pharmacovigilance Department 
All SAEs, regardless of causality, must be reported to the Pharmacovigilance Department in an 
expedited manner. 
SAEs should be documented on an SAE report form, using the completion guidelines provided.  
The SAE report form should be e-mailed to Pharmacovigilance Department within 24 hours 
of site staff becoming aware of the SAE. 
 
Each episode of an SAE must be recorded on a separate SAE report form.  The NCI CTCAE 
Version 4.02 and protocol specific grading system for injection site reactions, must be used to grade the 
severity of each SAE, and the worst grade recorded.  If new or amended information on a previously 
reported SAE becomes available, the Investigator should report this to the Pharmacovigilance 
Department on a new SAE report form.  
If the SAE has not been reported within the specified timeframes, a reason for lateness must be added 
to the email when sending the SAE report form to the Pharmacovigilance Department. 
Should the Investigator become aware of any AST-VAC2-related SAEs after the patient has withdrawn 
from the trial, these must also be reported to the PV Department within the specified timelines specified 
above. 
9.4.1 
Events exempt from being reported as SAEs to the Pharmacovigilance Department 
Events specified in this section do not require reporting as SAEs in this trial, unless hospitalisation is 
prolonged for any reason and then an SAE form must be completed.  The events must still be recorded 
in the appropriate section of the eCRF. 
Elective admissions – Elective admissions to hospital for procedures which were planned prior to 
entering the trial are not SAEs.  Hospitalisation for administration of the IMP according to the trial 
protocol is also exempt from being reported as an SAE. 
 
Prolongation of hospitalisation - Prolongation of hospitalisation without an associated adverse 
event (for example, prolonged hospitalisation while appropriate social care is set up for elderly 
patients). 
Death due to disease progression- Cases of death due to disease progression do not require SAE 
reporting, unless considered related to the IMP.  
9.5 
Recording of adverse events and serious adverse events in eCRFs 
All AEs, including SAEs, must be recorded in the eCRF for eligible patients.  All concomitant 
medications, including herbal medications and supplements must be recorded.  Any therapy used to 
treat the event must be recorded.  The eCRF will be reconciled with the safety database during and at 
the end of the trial.  Therefore, the sites should ensure the data entered on the SAE report form and the 
data entered into the eCRF are consistent.  The Sponsor’s Medical Advisor and the Investigator(s) will 
regularly review the safety data from both the safety and the clinical database. 

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9.6 
Urgent safety measures 
The Sponsor or Investigator may take appropriate urgent safety measures (USMs) in order to protect 
the patient of a clinical trial against any immediate hazard to their health or safety.  This includes 
procedures taken to protect patients from pandemics or infections that pose serious risk to human 
health.  
USMs may be taken without prior authorisation from the competent authority. 
The Medicines and Healthcare products Regulations Agency (MHRA) and the Research Ethics 
Committee (REC) must be notified within three days of such measures being taken. 
Should the site initiate a USM, the Investigator must inform the Sponsor immediately either by: 
 
 
 
 
The notification must include:  
• 
the date of the USM;  
• 
who took the decision; and  
• 
why action was taken. 
The Sponsor will then notify the MHRA and the REC within three days of USM initiation.   
9.7 
Pregnancy 
Female patients who become pregnant during the trial treatment period must be withdrawn from trial 
treatment immediately. 
The Investigator must make every effort to try and ensure that a clinical trial patient or a partner of a 
clinical trial patient does not become pregnant during the trial or for six months afterwards.  This should 
be done as part of the consent process by explaining clearly to the patient the potential dangers of 
becoming pregnant and also providing each patient with information about appropriate medically 
approved contraception. Two forms of medically approved contraception should be used, such as:   
• 
oral contraceptives and condom; (oral, injected or implanted hormonal contraceptives should 
be used for four weeks before the patient joins the trial)  
• 
intra-uterine device (IUD) and condom; 
• 
diaphragms with spermicidal gel and condom. 
Contraception should be effective before the patient is enrolled on the trial, throughout the trial and for 
six months after completing the trial. 
Alternatively the patient may agree to sexual abstinence, effective from the first administration of IMP, 
throughout the trial and for six months afterwards. Abstinence is only considered to be an acceptable 
method of contraception when this is in line with the preferred and usual lifestyle of the subject. Periodic 
abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
It should be explained to the patient that if his partner is pregnant or breast-feeding when he is enrolled 
on the trial, the patient should use barrier method contraception (condom plus spermicidal gel) to prevent 
the unborn baby or the baby being exposed to AST-VAC2. 
However, if a patient or a partner of a patient does become pregnant, the reporting procedures below 
must be followed. 
Any pregnancy occurring in a patient or a patient’s partner during treatment with an IMP or occurring 
within six months of last IMP administration must be reported to the Pharmacovigilance Department 
within 24 hours of the site staff becoming aware of it using a Pregnancy Report Form (provided in the 
ITF). It is the Investigator’s responsibility to obtain consent for follow-up from the patient or patient’s 

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partner.  In addition, the Investigator must be made aware of the need to obtain contact details for the 
patient’s partner’s GP. The Pharmacovigilance Department will follow-up all pregnancies for the 
pregnancy outcome via the Investigator, using a Pregnancy Report Form.  
The Investigator should document within the patient notes, that the patient confirms consent for the 
Sponsor to collect pregnancy follow-up information. In the case that the partner of a patient becomes 
pregnant, a consent form should be provided to the patient’s partner in order to obtain consent for 
collecting privacy data, in accordance with the data protection act. 
The Investigator must ensure that all patients are aware at the start of a clinical trial of the importance 
of reporting all pregnancies (in themselves and their partners) that occur whilst being treated with the 
IMP and occurring up to six months after the last IMP administration.  The Investigator should offer 
counselling to the patient and/or the partner, and discuss the risks of continuing with the pregnancy and 
the possible effects on the foetus.  Monitoring of the patient should continue until the conclusion of the 
pregnancy, if the patient or patient’s partner has consented to this. Monitoring of the baby should 
continue until 12 months after birth, if the patient or patient’s partner has consented to this.  
 
 

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9.8 
Protocol specific grading: Injection Site Reactions 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
 
Tenderness with or 
without: 
Itching  
Erythema 
Swelling  
Ulceration (fluid vesicle 
or ulcer <10mm) 
 
 
 
Minimal effect on 
activities of daily 
living. 
 
Pain with or without: 
Erythema  
Swelling  
Phlebitis 
Lipodystrophy 
Oedema  
Ulceration (blood 
vesicle or ulcer ≥10mm) 
 
 
Restricts activities of 
daily living. 
 
Severe tissue damage; 
operative intervention 
indicated  
 
 
 
 
 
 
 
Prevents or severely 
limits activities of daily 
living. 
 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
 
 
 
 
 
 
 

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10 
ASSESSMENT OF EFFICACY 
Response will be assessed to measure any potential responses to trial treatment. 
Disease 
will 
be 
measured 
according 
to 
the 
modified 
Immune-Related 
Response  
Criteria (irRC) given in Appendix 3. 
10.1 Timing and type of tumour assessments 
All patients will have been evaluated by radiological (CT, MRI) disease assessment as part of their 
routine care and prior to trial entry. A pre-treatment, baseline assessment must be performed within 28 
days of the planned first vaccination. This can be an assessment performed specifically for the trial or 
may be an assessment which was performed as per clinical practice which complies with the 28 day 
timeframe for baseline assessments.  
All patients that receive at least one AST-VAC2 vaccination will be further evaluated following their last 
vaccination by the imaging modality performed at baseline.  
Index and non-index lesion(s) should be selected from the pre-treatment scan. Index lesions are 
measurable (≥5x5 mm) and non-index lesions are non-measurable (<5x5 mm). 
At baseline, the sum of products of the two largest perpendicular diameters (SPD) of all index lesion(s) 
is calculated. At the post-treatment tumour assessment, the SPD of the index lesion(s) and of any new 
measurable lesions (≥5x5 mm) are added together to provide the total tumour burden.  
All tumour measurements must be clearly documented on the pre and post treatment scan reports. 
Copies of the scans (including those taken pre-trial) must be available for external independent review 
if requested by the Sponsor. 
10.2 Tumour response 
All patients who meet the eligibility criteria, receive at least one AST-VAC2 vaccination, have a baseline 
assessment and at least one repeat assessment of measurable disease will be evaluable for response.  
Response assessment will be performed in accordance with irRC by defining the change in total tumour 
burden relative to baseline measurements (Appendix 3).  Response categories as per Appendix 3.  Should 
rapid tumour progression occur before the completion of the scheduled six AST-VAC2 vaccinations the 
patient will be classified as having early progression (EP). 
Expert reviewers appointed by the Sponsor may undertake an independent review of the Investigator’s 
assessed objective responses immune response complete response (irCR) and immune response 
partial response (irPR). Any independent reviewer’s assessment will also be documented in the final 
Clinical Study Report (CSR) along with the original assessment made by the Investigator. The eCRF 
will reflect the Investigator’s opinion. 
10.2.1 Recording of response in the eCRF 
All pre and post treatment tumour measurements and an applicable overall response category must be 
recorded in the eCRF. 

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11 
PATIENT WITHDRAWAL BEFORE COMPLETION OF TREATMENT   
SCHEDULE 
AST-VAC2 has been classified as an ATIMP therefore extended follow up (up to five years post first 
vaccination) is applicable for all patients who receive the IMP.  
The Investigator must make every reasonable effort to keep each patient on trial for the whole duration 
of the trial in order to collect long term safety and pharmacodynamic data. However, if the Investigator 
removes a patient from the trial (prior to completion of the vaccinations) or if the patient declines further 
participation, final assessments (as per the ‘End of Vaccination’ visit), should be performed ideally 
before any subsequent therapeutic intervention.  All the results of the evaluations and observations, 
together with a description of the reasons for withdrawal from the trial, must be recorded in the patient’s 
medical records and in the eCRF. 
A patient may stop vaccination due to AEs but would not be withdrawn from the trial and would continue 
for follow-up of safety, survival and tertiary endpoints unless they withdraw. 
The following are justifiable reasons for the Investigator to withdraw a patient from the trial. 
• 
Withdrawal of consent. 
• 
Serious deviation from the trial protocol (including persistent patient attendance failure and 
persistent non-compliance). 
• 
Sponsor’s decision to terminate the trial. 
• 
Withdrawal by the Investigator for clinical reasons not related to AST-VAC2. 
• 
Loss to follow up. 

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12 
DEFINING THE END OF TRIAL  
The ‘End of Trial’ is defined as the date when all patients have either withdrawn (see Section 11.0) from 
the trial or died, or the last patient has completed their final follow-up visit (whichever is the latter). The 
final follow-up visit is scheduled to take place five years after the patient’s first vaccination. 
It is the responsibility of the Sponsor to inform the MHRA and the REC within 90 days of the End of the 
Trial that the trial has closed. 
In cases of early termination of the trial (for example, due to toxicity) or a temporary halt by the Sponsor, 
the Sponsor will notify the MHRA and the REC within 15 days of the decision and a detailed, written 
explanation for the termination/halt will be given. 
Recruitment will cease when: 
• 
The drug is considered too toxic to continue treatment before the required number of patients 
have been recruited.   
• 
The stated number of treated patients to be recruited has been reached. 
• 
The stated objectives of the trial have been achieved. 
Regardless of the reason for termination, all data available for patients at the time of discontinuation of 
follow-up must be recorded in the eCRF.  All reasons for discontinuation of treatment must be 
documented.   
In terminating the trial, Sponsor and the Investigators must ensure that adequate consideration is given 
to the protection of the patient’s interests. 
 

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13 
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS 
Further development of the AST-VAC2 program will consider the following factors: 
• 
Demonstration that vaccination administration is feasible with an acceptable safety profile, 
• 
Demonstration of durable immune response as per the trial secondary endpoint, 
• 
Demonstration of an increase in OS. 
13.1 Interim analysis 
An interim analysis will be conducted once all patients administered AST-VAC2 have withdrawn, died 
or completed their two-year follow-up visit for survival. 
Once this condition is met, a data cut-off will be established. All patient visits occurring on or before this 
date will be analysed and summarised in the clinical study report including safety data to date and 
assessment of overall survival at two years.  
Any data collected after this date will be summarised in a supplemental report produced for the final 
analysis to satisfy the safety reporting requirements for AST-VAC2 as an ATIMP.  
13.2 Final analysis 
The final analysis will be conducted after one of the following conditions is met: 
• 
The trial is terminated early e.g. due to toxicity 
• 
The End of Trial as defined in Section 12.0 has been reached.    
Once one of the conditions is met, a data cut-off date will be established. All patient visits occurring on 
or before this date will be analysed and summarised in a supplemental report. 
13.3 Presentation of data 
Data will be presented in a descriptive fashion.  Variables will be analysed to determine whether the 
criteria for the trial conduct are met.  This will include a description of patients who did not meet all the 
eligibility criteria, an assessment of protocol deviations, IMP accountability and other data that impact 
on the general conduct of the trial. 
Baseline characteristics will be summarised for all enrolled patients.  Patients who died or withdrew 
before treatment started or did not complete the required safety observations will be described and 
evaluated separately. 
Treatment administration will be described for all cycles.  Vaccine administration, modifications or delays 
and the duration of treatment will be described. 
13.4 Safety 
Safety data will be collected from the date of written consent until patients have completed their required 
follow up period.  Safety variables will be summarised by descriptive statistics.  Laboratory variables will 
be described using the NCI CTCAE Version 4.02 and the protocol specific grading system for ISRs.  
Adverse events will be reported as tables of frequency of AEs by body system and by worse severity 
grade observed.  Tables should indicate related and unrelated events.   
Deaths reported within 30 days of the last vaccination and SAEs will be described separately.  
A safety review committee, consisting of all investigators and representatives of the Sponsor, will review 
emerging safety data on an ongoing basis, with particular reference to ensuring that patients are able 
complete the vaccination schedule without AST-VAC2 toxicity-related delays. Should the committee 

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14 
ADMINISTRATION 
This trial is conducted under a Clinical Trial Authorisation (CTA) and approval from the MHRA, HRA and 
the relevant REC will be obtained before the start of this trial.  This trial is sponsored and monitored by 
the Cancer Research UK, CDD.  Applicable regulatory requirements are described in this section. 
14.1 Protocol deviations and amendments 
The protocol should be adhered to throughout the conduct of the trial, if a situation arises where the 
conduct of the trial may not be in line with the protocol, then the site should contact the Sponsor to 
discuss this. 
Amendments to the protocol may only be made with the approval of the Sponsor.  A protocol amendment 
may be subject to review by the assigned REC, HRA and the MHRA.  Written documentation of the 
REC, HRA (and if appropriate the MHRA) ‘favourable opinion’ (i.e. approval) must be received before 
the amendment can be implemented and incorporated into the protocol if necessary. 
14.2 Serious breach of Good Clinical Practice 
A serious breach is a breach which is likely to effect to a significant degree: the safety or physical or 
mental integrity of the subjects of the trial, or the scientific value of the trial. 
In order that the Sponsor can fulfil their obligations in terms of reporting serious breaches of GCP to the 
MHRA within seven calendar days of identification, site staff must inform the Sponsor of any unplanned 
deviations to the trial protocol (or GCP principles) as soon as possible after the deviation occurs to allow 
prompt evaluation by the Sponsor. 
14.3 Completion of the electronic case report form 
Electronic CRFs approved by the Sponsor will be used to collect the data. The Investigator is responsible 
for ensuring the accuracy, completeness, clarity and timeliness of the data reported in the eCRFs. 
Only the Investigator and those personnel who have signed the Delegation Log provided by the Sponsor 
and have been authorised by the Investigator should enter or change data in the eCRFs.  Authorised 
users will be included on a user list in order to be provided access to the eCRF.  All protocol required 
investigations must be reported in the eCRF.  The Investigators must retain all original reports, traces 
and images from these investigations for future reference.   
Amendments to eCRF data will be made directly to the system and the system audit trail will retain 
details of the original value(s), who made the change, a date and time, and a reason for the change. 
Once an eCRF form has been entered by the site personnel, the data are cleaned using manual and 
automated checks. Queries will be issued electronically to the site. Authorised personnel must answer 
the queries by making relevant amendments to data or providing a response. Answered queries will be 
closed or reissued as appropriate. 
Once the patient has completed or withdrawn from the trial and the eCRF has been fully completed, the 
Investigator must provide an electronic signature to authorise the complete subject casebook.  At the 
end of the trial all eCRFs are retained and archived by the Sponsor and a portable document format 
(PDF) copy provided to the Investigator who is responsible for archiving at site. 
The collection and processing of personal data from the patients enrolled in this clinical trial will be 
limited to those data that are necessary to investigate the efficacy, safety, quality and usefulness of the 
trial drug used in this trial.  The data must be collected and processed with adequate precautions to 
ensure patient confidentiality and compliance with applicable data privacy protection according to the 
applicable regulations.  The data collected will comply with Directive 95/46/EC of the European 
Parliament and of the Council of 24 October 1995 on the protection of individuals with regard to the 
processing of personal data. 

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14.4 Trial performance, monitoring, auditing and inspection 
Before the trial can be initiated, the prerequisites for conducting the trial must be clarified and the 
organisational preparations made with the trial centre.  The Sponsor must be informed immediately of 
any change in the personnel involved in the conduct of the trial. 
During the trial the Sponsor’s CRA will be responsible for monitoring data quality in accordance with the 
Sponsor’s SOPs.  A strategic monitoring approach, including targeted source data verification (SDV), 
will be implemented where appropriate. 
Before the trial start, the Investigator will be advised of the anticipated frequency of the monitoring visits.  
The Investigator will receive reasonable notification before each monitoring visit. 
It is the responsibility of the CRA to: 
• 
review trial records and compare them with source documents; 
• 
check pharmacodynamic samples and storage; 
• 
discuss the conduct of the trial and the emerging problems with the Investigator; 
• 
check that the drug storage, dispensing and retrieval are reliable and appropriate; and 
• 
verify that the available facilities remain acceptable. 
At the end of the trial all unused AST-VAC2 supplied must be destroyed at site (only once authorised to 
do so by the CRA or CSM) or if authorised by the Sponsor returned to the supplier.  
It is the responsibility of the Sponsor to notify the MHRA and REC of the EoT.  (See definition in Section 
12.0). 
During the course of the trial, the QA Department of the Sponsor, or external auditors contracted by the 
Sponsor, may conduct an on-site audit visit (ICH Topic E6 (R1) Guideline for Good Clinical Practice 
Sections 1.6). 
Principal Investigators conducting this trial will accept the potential for inspection by the MHRA. 
14.5 Source document verification 
Unless agreed in writing, all data collected in the eCRF must be verifiable by the source data.  Therefore 
it is the Investigator’s responsibility to ensure that both he/she and his/her trial team records all relevant 
data in the medical records.  The Investigator must allow the CRA direct access to relevant source 
documentation for verification of data entered into the eCRF, taking into account data protection 
regulations.  Entries in the eCRF will be compared with patients’ medical records and the verification 
will be recorded in the eCRF.   
Some source data may exist only electronically and be entered, or loaded directly into the eCRF.   
The patients’ medical records, and other relevant data, may also be reviewed by appropriate qualified 
personnel independent from the Sponsor appointed to audit the trial, National Health Service (NHS) 
Trust staff and by regulatory authorities.  Details will remain confidential and patients’ names will not be 
recorded outside the hospital. 
14.6 Clinical study report 
At appropriate intervals, interim data listings will be prepared to give the Investigator the opportunity to 
review the data and check the completeness of information collected.  All clinical data available will be 
presented at the interim analysis and at the end of the trial on final data listings.  The Sponsor will 
prepare a CSR based on the interim final data listings and a supplemental report based on the final data 
listings at the end of the trial.  The CSR and supplemental reports will be submitted to the Investigator(s) 
for review and confirmation that it accurately represents the data collected during the course of the trial.  
Summary results of the interim and final analysis of the trial will be provided by the Sponsor to the MHRA 
and to the REC. 

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14.7 Record retention 
During the clinical trial and after trial closure the Investigator must maintain adequate and accurate 
records to enable both the conduct of a clinical trial and the quality of the data produced to be evaluated 
and verified.  These essential documents (as detailed in Chapter V of Volume 10 (Clinical Trials) of The 
Rules Governing Medicinal Products in the European Union based upon Section 8 of the ICH GCP 
Guidelines), including source documents such as scans, trial related documents and copies of the 
eCRFs, associated audit trail and SAE report forms, shall show whether the Investigator has complied 
with the principles and guidelines of GCP. 
All essential documents required to be held by the Investigator must be stored in such a way that 
ensures that they are readily available, upon request, to the Regulatory Agency or Sponsor, for the 
minimum period required by national legislation or for longer if needed by the Sponsor.  Records must 
not be destroyed without prior written approval from the Sponsor. 
The medical files of trial subjects shall be retained in accordance with national legislation and in 
accordance with the maximum period of time permitted by the hospital, institution or private practice. 
14.8 Ethical considerations 
Before starting the trial, the protocol and patient ICDs must go through the Sponsor’s external review 
process, and be approved by the Protocol and Safety Review Board (PSRB) and receive the favourable 
opinion of the assigned REC. 
It is the CI/PI’s responsibility to update patients (or their authorised representatives, if applicable) 
whenever new information (in nature or severity) becomes available that might affect the patient’s 
willingness to continue in the trial.  The CI/PI must ensure this is documented in the patient’s medical 
notes and the patient is re-consented. 
The Sponsor and CI/PI must ensure that the trial is carried out in accordance with the GCP principles 
and requirements of the UK Clinical Trials regulations (SI 2004/1031 and SI 2006/1928 as amended), 
the ICH GCP guidelines and the World Medical Association (WMA) Declaration of Helsinki - Ethical 
Principles for Medical Research Involving Human Subjects adopted by the 18th WMA General 
Assembly, Helsinki, Finland, June 1964 and all subsequent amendments including Oct 2013. 
14.9 Indemnity 
This trial is sponsored by Cancer Research UK and therefore injury to a patient caused by the 
compounds under trial will not carry with it the right to seek compensation from the pharmaceutical 
industry.  Cancer Research UK will provide patients with compensation for adverse side effects, in 
accordance with the principles set out in the Association of the British Pharmaceutical Industry (ABPI) 
guidelines on compensation for medicine-induced injury. 
14.10 Publication policy and press releases 
Results of this trial must be submitted for publication.  The Sponsor must be involved in reviewing all 
drafts of the manuscripts, abstracts, press releases, presentations and any other publications.  
Manuscripts must be submitted to the Sponsor at least 45 days in advance of being submitted for 
publication to allow time for the Sponsor to schedule a review and resolve any outstanding issues.  
Abstracts, press releases and presentations must be submitted to the Sponsor at least 14 days in 
advance of being released.   
The CI should be the principal author and any Investigator recruiting ≥10% of patients should be listed 
as an author in order of numbers of patients recruited. 
Authors must acknowledge that the trial was sponsored by and performed with the support of the 
Sponsor. 

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The contribution of the Sponsor should be recognised by at least one member of staff being included 
as an author on any publication.  The BDU have manufactured AST-VAC2 and so at least one member 
of the BDU staff should also be included as an author. 
14.11 Guidance for disruption to trial conduct 
In the event of disruption to trial activities, as demonstrated during the COVID-19 pandemic, the Sponsor 
‘Trial Disruption’ policy should be reviewed to flag trial activities which the study team should consider 
for adaptation during the event. A risk-based approach will be applied to each trial to inform trial conduct 
throughout the period in order to protect the health and well- being of existing and future trial participants 
and ensure compliance with current regulatory guidance.   
 

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15 
REFERENCES 
Note for Guidance on Good Clinical Practice.  ICH Topic E6.  CSMP/ICH/135/95.  EMEA, May 1996, 
updated September 1997 with post Step 4 errata included  
Directive 2001/20/EC of the European Parliament and the Council of 4 April 2001 on the 
approximation of the laws, regulations and administrative provisions of the Member States relating to 
the implementation of good clinical practice in the conduct of clinical trials on medicinal products for 
human use. Official Journal of the European Communities L121/34-44 
Detailed guidance for the request for authorisation of a clinical trial on a medicinal product for human 
use to the competent authorities, notification of substantial amendments and declaration of the end of 
the trial. October 2005.  ENTR/F2/BL D (2003) CT 1 (Revision 2) 
Detailed guidance on the application format and documentation to be submitted in an application for 
an Ethics Committee opinion on the clinical trial on medicinal products for human use. February 2006. 
ENTR/CT 2 (Revision 1) 
Detailed guidance on the collection, verification and presentation of adverse reaction reports arising 
from clinical trials on medicinal products for human use. April 2006.  ENTR/CT 3 (Revision 2) 
The Medicines for Human Use (Clinical Trials) Regulations 2004 (Statutory Instrument 1031) 
Commission Directive 2005/28/EC of 8 April 2005 laying down principles and detailed guidelines for 
good clinical practice as regards investigational medicinal products for human use, as well as the 
requirements for authorisation of the manufacturing or importation of such products.  Official Journal of 
the European Union L 91/13 
The Medicines for Human use (Clinical Trials) Amendment Regulations 2006 (Statutory Instrument 
2006/1928). 
1. 
Reck, M., et al., Metastatic non-small cell lung cancer (NSCLC):   ESMO Clinical Practice 
Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 2014. Supplement 
3.iii27-iii39 
2. 
Cancer Research UK http://www.cancerresearchuk.org/health-professional/cancer-
statistics/statistics-by-cancer-type/lung-cancer/incidence#heading-Zero, Accessed February 
2017. 
3. 
Vansteenkiste, J., et al., Early and locally advanced non-small cell lung cancr (NSCLC): 
ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2013. Supplement 
6.vi89-vi98 
4. 
Gonzalez-Galarza, F.F., et al., Allele frequency net: a database and online repository for 
immune gene frequencies in worldwide populations. Nucleic Acids Res, 2011. 39(Database 
issue): p. D913-9. 
5. 
Danovitch, G.M., Handbook of kidney transplantation. 5th ed2010, Philadelphia: Lippincott 
Williams & Wilkins. xvi, 471 p., 8 p. of plates. 
6. 
Wu, T.C., et al., Engineering an intracellular pathway for major histocompatibility complex 
class II presentation of antigens. Proc Natl Acad Sci U S A, 1995. 92(25): p. 11671-5. 
7. 
Nair, S.K., et al., Induction of primary carcinoembryonic antigen (CEA)-specific cytotoxic T 
lymphocytes in vitro using human dendritic cells transfected with RNA. Nat Biotechnol, 1998. 
16(4): p. 364-9. 
8. 
Lin, K.Y., et al., Treatment of established tumors with a novel vaccine that enhances major 
histocompatibility class II presentation of tumor antigen. Cancer Res, 1996. 56(1): p. 21-6. 

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9. 
Eskelinen, E.L., Roles of LAMP-1 and LAMP-2 in lysosome biogenesis and autophagy. Mol 
Aspects Med, 2006. 27(5-6): p. 495-502. 
10. 
Morse, M.A., et al., Migration of human dendritic cells after injection in patients with metastatic 
malignancies. Cancer Res, 1999. 59(1): p. 56-8. 
11. 
Ruedl, C., et al., Anatomical origin of dendritic cells determines their life span in peripheral 
lymph nodes. J Immunol, 2000. 165(9): p. 4910-6. 
12. 
 
Anguille, S., et al., Clinical use of dendritic cells for cancer therapy. Lancet Oncol, 
2014. 15(7): p. e257-e267. 
13. 
Brunsvig, P.F., et al., Telomerase peptide vaccination: a phase I/II study in patients with non-
small cell lung cancer. Cancer Immunol Immunother, 2006. 55(12): p. 1553-64. 
14. 
Brunsvig, P.F., et al., Telomerase peptide vaccination in NSCLC: a phase II trial in stage III 
patients vaccinated after chemoradiotherapy and an 8-year update on a phase I/II trial. Clin 
Cancer Res, 2011. 17(21): p. 6847-57. 
15. 
Chu, C.S., et al., Phase I/II randomized trial of dendritic cell vaccination with or without 
cyclophosphamide for consolidation therapy of advanced ovarian cancer in first or second 
remission. Cancer Immunol Immunother, 2012. 61(5): p. 629-41. 
16. 
Khoury J, et al., Prolonged administration of the telomerase vaccine GRNVAC1 Is well 
tolerated and appears to be associated with favorable outcomes in high-risk acute myeloid 
leukemia (AML). 2010. 
17. 
Su, Z., et al., Telomerase mRNA-transfected dendritic cells stimulate antigen-specific CD8+ 
and CD4+ T cell responses in patients with metastatic prostate cancer. J Immunol, 2005. 
174(6): p. 3798-807. 
18. 
Ellebaek, E., et al., Metastatic melanoma patients treated with dendritic cell vaccination, 
Interleukin-2 and metronomic cyclophosphamide: results from a phase II trial. Cancer 
Immunol Immunother, 2012. 61(10): p. 1791-804. 
19. 
Rapoport, A.P., et al., Combination immunotherapy using adoptive T-cell transfer and tumor 
antigen vaccination on the basis of hTERT and survivin after ASCT for myeloma. Blood, 2011. 
117(3): p. 788-97. 
20. 
Hunger, R.E., et al., Vaccination of patients with cutaneous melanoma with telomerase-
specific peptides. Cancer Immunol Immunother, 2011. 60(11): p. 1553-64. 
21. 
Haining, W.N., et al., CpG oligodeoxynucleotides alter lymphocyte and dendritic cell trafficking 
in humans. Clin Cancer Res, 2008. 14(17): p. 5626-34. 
22. 
Puri, N. and J. Girard, Novel therapeutics targeting telomerase and teolmeres. J Cancer Sci 
Ther, 2013. 5(10): p. 3. 
23. 
Ouellette, M.M., W.E. Wright, and J.W. Shay, Targeting telomerase-expressing cancer cells. J 
Cell Mol Med, 2011. 15(7): p. 1433-42. 
24. 
Draube, A., et al., Dendritic cell based tumor vaccination in prostate and renal cell cancer: a 
systematic review and meta-analysis. PLoS One, 2011. 6(4): p. e18801. 
25. 
Murthy, V., et al., Clinical considerations in developing dendritic cell vaccine based 
immunotherapy protocols in cancer. Curr Mol Med, 2009. 9(6): p. 725-31. 

CONFIDENTIAL 
CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 
            Page 66 of 72 
EudraCT number: 2016-002577-35 
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26. 
Reck, M., et al., Ipilimumab in combination with paclitaxel and carboplatin as first-line therapy 
in extensive-disease-small-cell lung cancer: results from a randomized, double-blind, 
multicenter phase 2 trial. Ann Oncol, 2013. 24(1): p. 75-83. 
27. 
Lynch, T.J., et al., Ipilimumab in combination with paclitaxel and carboplatin as first-line 
treatment in stage IIIB/IV non-small-cell lung cancer: results from a randomized, double-blind, 
multicenter phase II study. J Clin Oncol, 2012. 30(17): p. 2046-54. 
28. 
Quoix, E., et al., Therapeutic vaccination with TG4010 and first-line chemotherapy in 
advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol, 2011. 12(12): 
p. 1125-33. 
29. 
Chen, Z., et al., Non-small-cell lung cancers: a heterogeneous set of diseases. Nat Rev 
Cancer, 2014. 14(8): p. 535-46. 
30. 
Quoix E, Lena H, Losonczy G, Forget F, Chouaid C, Papai Z, Gervais R, Ottensmeier C, 
Szczesna A, Kazarnowicz A, Beck JT, Westeel V, Felip E, Debieuvre D, Madroszyk A, Adam 
J, Lacoste G, Tavernaro A, Bastien B, Halluard C, Palanché T, Limacher JM.  TG4010 
immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): 
results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 
trial. Lancet Oncol. 2016 Feb;17(2):212-23. doi: 10.1016/S1470-2045(15)00483-0. Epub 2015 
Dec 23. 
31. 
Li, H., Katik, I., Liu, JP., Uses of telomerase peptides in anti-tumour immune therapy.  
Methods Mo Biol.  2007;405:61-86 
 
 

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16.2  
APPENDIX 2: NEW YORK HEART ASSOCIATION (NYHA) SCALE 
 
Class I – 
Patients with cardiac disease but without resulting limitation of physical activity; 
ordinary physical activity does not cause undue dyspnoea (or fatigue, palpitation 
or anginal pain). 
Class II – 
Patients with cardiac disease resulting in slight limitation of physical activity; they 
are comfortable at rest; ordinary physical activity results in dyspnoea (or fatigue, 
palpitation or anginal pain). 
Class III – 
Patients with cardiac disease resulting in marked limitations of physical activity; 
they are comfortable at rest; less than ordinary physical activity causes 
dyspnoea (or fatigue, palpitation or anginal pain). 
Class IV – 
Patients with cardiac disease resulting in inability to carry out physical activity 
without discomfort; symptoms of dyspnoea (or of angina) may be present even 
at rest; if any physical activity is undertaken, discomfort is increased. 
 

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16.3 APPENDIX 3: MEASUREMENT OF DISEASE 
Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumours: Immune-Related 
Response Criteria (irRC) 
Wolchok J. et al. Guidelines for the Evaluation of Immune Therapy Activity in Solid Tumours: Immune-
Related Response Criteria. Clin Cancer Res 2009;15(23):7412–20. 
Introduction 
Investigators have relied on Response Evaluation Criteria in Solid Tumours (RECIST) or modified WHO 
criteria to evaluate anti-tumour responses to chemotherapeutic agents. However, the responses that 
are seen with immunotherapeutic agents may extend beyond those of cytotoxic agents and could 
include responses after disease progression that are not captured by Response Evaluation Criteria in 
Solid Tumours or WHO criteria. The current report presents novel criteria, designated immune-related 
response criteria (irRC), which can better capture the response patterns observed with some 
immunotherapeutic agents.  
 
Novel to the irRC is the measurement of overall tumour burden as a metric of disease progression, 
compared to the limitation to baseline lesion measurements taken with WHO and RECIST. According to 
irRC, new lesions do not constitute disease progression if net tumour burden (including new lesions) is 
stable or decreases. The irRC also permit disease progression prior to response and introduce the 
concept of confirmation of progression at a subsequent time point after first detection. This accounts for 
the period required for activated T-cells to infiltrate the tumour, which may cause initial tumour volume 
increase but can subsequently translate into tumour shrinkage. The irRC also classify durable stable 
disease as clinical activity. 
 
Immune-related response criteria 
To systematically characterize additional patterns of response in patients with advanced cancer treated 
by immunotherapy, underlying WHO criteria were evolved into immune-related response criteria. The 
definitions of the irRC and guidelines on how they can be used in clinical practice are detailed below.  
 
Antitumour response based on total measurable tumour burden 
For the irRC, only index and measurable new lesions are taken into account (in contrast to conventional 
WHO criteria, which do not require the measurement of new lesions, nor do they include new lesion 
measurements in the characterization of evolving tumour burden). At the baseline tumour assessment, 
the sum of the products of the two largest perpendicular diameters (SPD) of all index lesions (five lesions 
per organ, up to 10 visceral lesions and five cutaneous index lesions) is calculated. At each subsequent 
tumour assessment, the SPD of the index lesions and of new, measurable lesions (≥5 × 5 mm; up to 5 
new lesions per organ: 5 new cutaneous lesions and 10 visceral lesions) are added together to provide 
the total tumour burden: 
 
Tumour Burden + SPDindex lesions + SPDnew, measurable lesions 
 
A comparison of the use of SPD in WHO criteria versus the use of tumour burden in irRC is presented 
in Table 1.  
 
 

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Table 1. Comparison between WHO criteria and the irRC 
 
WHO 
irRC 
New, measurable 
lesions (i.e., ≥5 × 5 
mm) 
Always represent PD 
Incorporated into tumour burden 
New, non-
measurable lesions 
(i.e., <5 × 5 mm) 
Always represent PD 
Do not define progression (but preclude 
irCR) 
Non-index lesions 
Changes contribute to defining BOR of 
CR, PR, SD, and PD 
Contribute to defining irCR (complete 
disappearance required) 
CR 
Disappearance of all lesions in two 
consecutive observations not less than 4 
wk apart 
Disappearance of all lesions in two 
consecutive observations not less than 
4 wk apart 
PR 
≥50% decrease in SPD of all index 
lesions compared with baseline in two 
observations at least 4 wk apart, in 
absence of new lesions or unequivocal 
progression of non-index lesions 
≥50% decrease in tumour burden 
compared with baseline in two 
observations at least 4 wk apart 
SD 
50% decrease in SPD compared with 
baseline cannot be established nor 25% 
increase compared with nadir, in 
absence of new lesions or unequivocal 
progression of non-index lesions 
50% decrease in tumour burden 
compared with baseline cannot be 
established nor 25% increase 
compared with nadir 
PD 
At least 25% increase in SPD compared 
with nadir and/or unequivocal 
progression of non-index lesions and/or 
appearance of new lesions (at any single 
time point) 
At least 25% increase in tumour burden 
compared with nadir (at any single time 
point) in two consecutive observations 
at least 4 wk apart 
 
Time-point response assessment using irRC 
Percentage changes in tumour burden per assessment time point describe the size and growth kinetics 
of both conventional and new, measurable lesions as they appear. At each tumour assessment, the 
response in index and new, measurable lesions is defined based on the change in tumour burden (after 
ruling out irPD). Decreases in tumour burden must be assessed relative to baseline measurements (i.e., 
the SPD of all index lesions at screening). The irRC were derived from WHO criteria and, therefore, the 
thresholds of response remain the same (Table 2).However, the irRC response categories have been 
modified from those of WHO criteria as detailed in Tables 1 and 2. 
 
 

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Table 2.  Derivation of irRC overall responses 
 
Measurable Response 
Non-Measurable Response 
Overall Response 
using irRC 
Index and new 
measurable lesions 
(total measurable 
tumour burden)* 
Non-index lesions 
New, non –
measurable lesions 
100% decrease 
Absent 
Absent 
irCR† 
100% decrease 
Stable 
Any 
irPR† 
100% decrease 
Unequivocal 
progression 
Any 
irPR† 
≥50%decrease 
Absent/Stable 
Any 
irPR† 
≥50%decrease 
Unequivocal 
progression 
Any 
irPR† 
<50 decrease to < 25% 
increase 
Absent/Stable 
Any 
irSD 
<50 decrease to < 25% 
increase 
Unequivocal 
progression 
Any 
irSD 
≥25 increase  
Any 
Any 
irPD† 
 
Index and non-index lesions are selected at baseline. Index lesions are measurable (≥5 x 5mm) and 
non-index lesions are non-measurable (<5 x 5mm, ascites, bone lesions, pleural/pericardial effusion 
etc.). *Changes are assessed relative to baseline and include measurable lesions only (> 5 x 5 mm) 
† Assuming response and progression are confirmed by a second, consecutive assessment at least 4 
weeks apart.  
 
Overall response using irRC 
 
The overall response according to the irRC is derived from time-point response assessments (based on 
tumour burden) as follows: 
 
irCR, complete disappearance of all lesions (whether measurable or not, and no new lesions) 
confirmation by a repeat, consecutive assessment no less than 4 wk from the date first documented 
 
irPR, decrease in tumour burden ≥50% relative to baseline confirmed by a consecutive assessment at 
least 4 wk after first documentation 
 
irSD, not meeting criteria for irCR or irPR, in absence of irPD 
 
irPD, increase in tumour burden ≥25% relative to nadir (minimum recorded tumour burden) confirmation 
by a repeat, consecutive assessment no less than 4 wk from the date first documented 
 
Patients were considered to have irPR or irSD even if new lesions were present, as long as they met 
the respective thresholds of response as described above. Furthermore, patients were not considered 
to have irPD if new lesions were present and the tumour burden of all lesions did not increase by ≥25%. 
In contrast to irCR, irPR, and irPD, a response of irSD does not require confirmation. It is important to 
note that irCR, irPR, and irSD include all patients with CR, PR, or SD by WHO criteria as well as those 
patients that shift to these irRC categories from WHO PD. Patients with irSD, particularly those with 
slow-declining tumour burden ≥25% from baseline at the last tumour assessment, are considered 
clinically meaningful because they show an objectively measurable reduction in tumour burden without 
reaching the 50% threshold that defines irPR (it represented an objectively measured reduction not 

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commonly observed in the natural history of advanced melanoma patients).  
 
If a patient is classified as having irPD at a post-baseline tumour assessment, then confirmation of irPD 
by a second scan in the absence of rapid clinical deterioration is required. The definition of confirmation 
of progression represents an increase in tumour burden ≥25% compared with the nadir at two 
consecutive time points at least 4 wk apart. It is recommended that this be done at the discretion of the 
investigator because follow-up with observation alone may not be appropriate for patients with a rapid 
decline in performance status. Confirmation of irPD allows for the capture of all observed responses 
using the irRC (Table 2), as most of these late-responding patients have a trend toward response within 
4 wk after initial irPD. Whereas WHO criteria consider any new measurable lesion to indicate PD, 
determination of immune-related best overall response (irBOR) is based on changes in total tumour 
burden from the baseline (nadir, for irPD) tumour assessment, regardless of any initial increase in 
baseline lesions or the appearance of new lesions.