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 collec ted 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 . • Reas on 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 c ontinuing collect ion of long term follow up data. This will be discussed and agreed by the Sponsor and CI based on emerging data. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 39 of 72 EudraCT number : 2016 -002577 -35 Cancer Research UK 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continue to be followed up every three months by telephone until the end of the trial (unless the patient has died or withdrawn from the trial).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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 48 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 adver se 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 medica lly 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 CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 49 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK (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 relate d adverse event which meets the stopping rule criteria (as outlined in Section 3.3.3 ) are considered a trial specific medically important event s 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 legislat ion (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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 50 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 opinio n 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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 51 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK • 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 R eporting of SA Es 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 pr ovided. 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 Versio n 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 s afety 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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 52 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 not i fication 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 CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 53 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 ac t. 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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 54 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 55 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 the ir 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- measur able (<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 applicabl e overall response category must be recorded in the eCRF . CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 56 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 57 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 latt er). 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 patient s 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 interest s. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 58 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 patient s administered AST -VAC2 ha ve 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 t o 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 t reatment 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 vaccinat ion 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 CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 60 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 14 ADMINISTRATION This trial is conducted under a C linical Trial Authorisation (CTA) and approval from the MHRA , HRA and the relevant R EC 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 w ith 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 G ood Clinical Practice A serious breach is a breach which is lik ely 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 Completi on 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 e CRFs. 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 eCRF s. 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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 61 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 i nto 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 di rectly 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 list ings and a supplemental report based on the final data listings at the end of the trial. The CSR and supplemental report s 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 . CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 62 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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 eCRF s, 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 S ponsor, 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 applicab le) whenever new information (in nature or severity) becomes available that might affect the patient’s willingness to continue in the trial. The C I/PI must ensure this is documented in the patient’s medical notes and the patient is re- consented. The Spons or and C I/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 th e 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 i n 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 . CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 63 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK The contribution of the Sponsor should be recognised by at least one member of staff being included as an author on any publication. T he 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. CONFIDENTIAL CRUKD/17/003 Protocol Final 5.0 dated 08Jun2021 Page 64 of 72 EudraCT number: 2016 -002577 -35 Cancer Research UK 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.