6.3.2 Secondary e ndpoints 6.3.2.1 Disease- free survival Summary measures: Median time to progression or death. Proportion alive and disease- free at 1 and 2 years (Median and proportion calculated by Kaplan- Meier, ITT population). 6.3.2.2 Overall survival Summary measures: Median time to death. Proportion alive at 1 and 2 years . (Median and proportion calculated by Kaplan- Meier, ITT population). 6.3.2.3 CA19 -9 Evaluation Summary measures: Changes over time (trend and absolute changes); ITT population. 6.3.2.4 Other biomarkers Summary measures: Changes over time (trend and absolute changes); ITT population. 6.4 Sample size and power No formal sample size has been calculated. 6 -32 patients are deemed sufficient to assess the safety and immune response in this pilot study and given an early indication of efficacy in terms of DFS and OS based on historical controls. 7. DRUG SAFETY 7.1 Definitions of adverse events and serious adverse events It is important that all the staff involved in the trial is familiar with the content of this section of the protocol. 7.1.1 Adverse events An adverse event (AE) is the development of an undesirable medical condition or the deterioration of a pre -existing medical condition in a patient under clinical investigation who has been administered an investigational pharmaceutical product (in this case GM - CSF/TG01 or chemotherapy ( gemcitabine or 5-FU and Leucovorin)) but which does not necessarily have a causal relationship with this treatment. An undesirable medical condition can be symptoms (e .g., nausea, chest pain) signs (e .g., tachycardia, enlarged liver) or abnormal results of an investigation (e .g., laboratory findings, ECG). An AE can include any undesirable condition occurring at any time, even if no trial treatment has been administered or recently administered. A grading severity scale is provided for each AE term. The Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 includes five grades (1-5), with grade 5 being death. Any events that are unequivocally due to disease recurrence must not be reported as AEs. CT TG01 -01 Version v 10.0 27 June 2018 Confidential 71 / 87 7.1.2 Serious adverse events A serious AEs (SAE) is an event that is known with certainty, or suspected with good reason, to constitute a threat to life or to cause severe or permanent damage. A SAE can occur during any phase of the trial and at any dose of the investigational product . This is particularly true for an AE that: • results in death • is immediately life -threatening • requires patient hospitalisation or prolongation of existing hospitalisation • results in persistent or significant disability/incapacity or • is a congenital anomaly/birth defect • is an important medical event that may have jeopardised the patient or may have required medical intervention to prevent one of the outcomes listed above. Medi cal and scientific judgment is to be exercised in deciding on the seriousness of a case. Important medical events may not be immediately life -threatening or result in death or hospitalisation, but may jeopardise the patient or may require intervention to prevent one of the listed outcomes in the definitions above. In such situations, or in doubtful cases, the case should be considered as serious. Drug misuse and drug overdose and should be regarded as serious, even if they may not result in the above mentioned outcomes. Hospitalisation for administrative reason (for observation or social reasons) is allowed at the investigator’s discretion and will not qualify as serious unless there is an associated adverse event warranting hospitalisation (see APPENDIX II for additional safety information). The causality of AE/SAEs ( i.e., their relationship to trial treatment) will be assessed by the individual investigators at each trial centre who must while completing the CRF answer yes/ no to the question ‘do you consider that there is a reasonable possibility that the AE/SAE may have been caused by the investigational drug? (see APPENDIX II for guidelines on interpretation of causalit y). Any events that are unequivocally due to disease recurrence must not be reported as AEs. The specialist group handling the pharmacovigilance for the study is: ICON Clinical Research UK Ltd 2 Globeside Business Park Marlow Buckinghamshire United Kingdom, SL7 1HZ The ICON Pharmacovigilance group is specialised and has the appropriate expertise in handling and reporting SAEs. CT TG01 -01 Version v 10.0 27 June 2018 Confidential 72 / 87 7.2 Recording of adverse events For the purpose of this trial, any detrimental change in a patient’s condition, subsequent to their en tering the trial and during the 28- day follow -up period after the final treatment, should be considered an AE. The development of a new cancer should be regarded as an AE. New cancers are those that are not the primary reason for the administration of the trial treatment and have been identified after the patient’s inclusion in this clinical trial. Any events that are unequivocally due to disease recurrence must not be reported as AEs. If the same AE occurs at several investigation times in one patient, th en the AE in question must be documented and assessed anew each time. All AEs are to be recorded on the CRFs provided and Serious Adverse Events also on the Serious Adverse Event Form . A description of the event, including its severity, duration, any acti on taken (e.g. treatment and follow -up tests) and the outcome is to be provided, along with the investigator’s assessment of the relationship to the trial treatment. AEs and laboratory values will be graded according to the National Cancer Institute Common Toxicity Criteria (NCI -CTC) version 4.0 and recorded on the appropriate CRF page. Laboratory/vital signs abnormalities should not be reported as adverse events unless any criterion for an AE is fulfilled i.e. that it is clinically significant and because it is detrimental to the patient, the abnormality causes study drug dose adjustment, leads to patient’s discontinuation from the study, or the investigator insists the abnormality should be reported as an AE. Laboratory/vital signs abnormalities should not be reported as separate adverse events if they are part of an overall diagnosis All patients who have new or worsening NCI -CTC grade 3 or 4 laboratory values at the time of withdrawal must have further tests performed and the results recorded on the appropriate CRF, until the laboratory values have returned to NCI -CTC grade 1 or 2, unless these values are not likely to improve because of the underlying disease. In these cases, the investigators must record their opinions on the CRFs and in the patients’ medical records. For an AE to be a suspected drug- related event there should be at least a reasonable possibility of a causal relationship between the trial medicinal product and the AE (see APPENDIX II for guidelines on interpretation of causality). It is important to distinguish between serious and severe AEs. Severity is a measure of intensity whereas seriousness is defined by the criteria in Section 7.1.2. An AE of severe intensity need not necessarily be considered serious. For example, nausea that persists for several hours may be considered severe nausea, but is not an SAE. On the other hand, a stroke that results in only a limited degree of disability may be co nsidered a mild stroke, but would be an SAE. Lack of efficacy When there is deterioration in the condition for which the medicine is being used there may be uncertainty as to whether this is lack of efficacy or an AE. In such cases, unless Targovax or the reporting physician considers that the medicine contributed to the deterioration or local regulations state to the contrary, the deterioration should be considered to be a lack of efficacy and not an AE. CT TG01 -01 Version v 10.0 27 June 2018 Confidential 73 / 87 Handling unresolved SAEs/AEs at completion/withdraw al All trial treatment- related toxicities and SAEs must be followed until resolution unless, in the investigator’s opinion, the condition is unlikely to resolve because of the patient’s underlying disease. 7.2.1 Exposure to GM -CSF /TG01 or chemotherapy during pregnancy/lactation In principle, pregnancy and lactation are exclusion criteria and pregnancy itself is not regarded as an AE unless there is a suspicion that the investigational product under trial may have interfered with the effectiveness of a contracepti ve medication. In the event of a pregnancy occurring during the course of the trial, the patient must be withdrawn from trial medication immediately and the pregnancy notified to ICON PV and the sponsor without delay. The patient must be followed -up during the entire course of the pregnancy and lactation period. Perinatal and neonatal outcomes must be recorded even if com pletely normal and without AEs. All reports of congenital abnormalities/birth defects are SAEs. Spontaneous miscarriages should also be reported and handled as SAEs (See Section 8.3 below ). Elective abortions without complications should not be handled as AEs. All outcomes of pregnancy must be reported to ICON PV, on the ‘pregnancy outcomes report form’. 7.3 Procedure for reporting serious adverse events Investigators and other site personnel must inform the study monitor of any SAE that occurs in the course of the study as soon as possible but definitely within 24 hours of when he or she becomes aware of it. The following minimal information must be faxed immediately to +44 870 710 7157 • Patient identifier – patient number, investigator • Details of the event or outcome (see section 7.1.2) To discuss the medical aspects of the SAE investigators should call: Dr Robert Miller, or deputy, on +44 203 291 3032 This number should also be called to report a life- threatening or fatal adverse event within 2 hours of knowledge of the event if this occurs before recognised recurrence of disease. The dedicated email address for SAE information is: safety@aptivsolutions.com The SAE must be documented in the patient’s medical source documents and the outcome described. The monitor will work with the investigator to compile all the necessary information and ensure that the appropriate Drug Safety Department receives a report by day 1 for all fatal and life -threatening cases and by day 5 for all other SAEs. Follow- up information on SAEs must also be reported by the inves tigator within the same time frames. CT TG01 -01 Version v 10.0 27 June 2018 Confidential 74 / 87 If a non -serious AE becomes serious, this and other relevant follow -up information must also be provided to safety group within 24 hours as described above. All SAEs have to be reported, whether or not considered causal ly related to the investigational product. All SAEs will be recorded in the CRF. The investigator is responsible for informing the Ethics Committee and/or the Regulatory Authority of the SAE as per local requirements. Additional information will be requested, if necessary, by the Trial Physician within 5 days of the receipt of the SAE report. This is to ensure that the initial reporting of SAEs is made to the regulatory authorities within the required time -frame. All withdrawals from trial treatment must be notified to the trial physician. Withdrawals from treatment due to a new, previously unreported SAE must be notified to the Trial Physician, along with the SAE. Withdrawal from trial treatment for a previously reported SAE can be made within the 7 d ays after the decision has been made to withdraw the patient and for a non- serious AE within 21 days of the decision to withdraw. After withdrawal from treatment patients mus t be followed up for AEs for 28 days after the last dose of trial medication. All SAEs recorded during that period must be reported to the safety group, and followed up until resolved unless in the Investigator’s opinion the condition is unlikely to resolve due to the patient’s underlying progressive disease. 7.4 Death All deaths occurring within the trial period or within 28 days of the last dose of Study Drug (TG01 and GMCF or chemotherapy ( gemcitabine or 5-FU/Leucovorin) ) must be reported to the safety group, for the purpose of SAE reporting. However, deaths due unequivocally to diseas e recurrence/ progression are not SAEs. Any deaths occurring more than 28 days after the last dose of Study Drug (TG01 and GMCF or chemotherapy ) will not be reported to the regulatory authorities, for the purposes of safety reporting. 7.5 Procedures to be follo wed in the event of abnormal laboratory test values The severity grading used for laboratory measurements will be the NCI -CTC, version 4.0 grading for laboratory parameters. Laboratory parameters not rated by the NCI -CTC, version 4.0, scoring will not be graded. The AEs based on laboratory tests will be recorded and reported as described in Section 7.2. In the event of unexplained abnormal laboratory test values, the tests should be repeated immediately and followed up until the test values have returned to the normal or baseline range, and/or an adequate explanation of the abnormality is found. If a clear explanation is established it should be recorded in the patient’s medical source documents. 7.6 Overdosing with the trial medication An overdose is a deliberate or inadvertent administration of a treatment at a dose higher than specified in the protocol. For the purposes of this trial, any dose administered to a patient that exceeds the planned protocol dose should be reported as an overdose. It must be reported as an SAE irrespective of outcome and even if no toxic effects were observed. There is no clinically proven antidote available for TG01, GM -CSF or gemcitabine. CT TG01 -01 Version v 10.0 27 June 2018 Confidential 75 / 87 The expected manifestation s of overdose are likely to be: TG01 Significant toxicities have not been seen to date and the mode of action of TG01 makes it unlikely that an overdose will cause additional toxicity GM-CSF The dose of GM -CSF used is very low and overdose symptoms are likely to mimic the toxicities of do ses more commonly used to support neutropenia such as bone and musculoskeletal pain Gemcitabine: Myelosuppression, paraesthesia, and severe rash were the principal toxicities seen when a single dose as high as 5700 mg/m2 was administered by intravenous infusion over 30 minutes every 2 weeks to several patients in a Phase 1 study. In the event of suspected overdose, the patient should be monitored with appropriate blood counts and should receive supportive therapy, as necessary.