head and neck, chest, abdomen, superficially the limbs, rudimentary neurological tests such as reflexes and sensation). The physical examination findings and relevant parameters are to be documented in the medical source documents. This examination will also include performance status and vital signs ( weight, height, heart rate and blood pressure, and body temperature). Any new conditions reported during the trial will be recorded on the AE forms. Only those findings that are in addition to the condition being treated will be recorded as AEs. Conditions that are considered by the investigator to be unequivocally disease -related will not be recorded as AEs. 5.4.6 Laboratory safety measurements Routine haematology, biochemistry and urine assessments will be performed at the l ocal laboratory at the trial centre within 7 days prior to the start of treatment. 5.5 Assessments during treatment phase Initial Treatment Period with GM -CSF /TG01 +/- chemotherapy Main group: Initial Treatment Period (up to week 11) +/ - chemotherapy for pati ents starting TG01 vaccination first (timings based on start of GM -CSF/TG01 treatment) – Table 1 : • GM-CSF/TG01 to start as soon as possible after the surgical resection. Day 1 will be the first day of GM -CSF/TG01 treatment with chemotherapy commencing a minimum on day 22 (3 weeks after the first TG01 treatment) but may also be started at day 36 or 50 (or later) of GM-CSF/TG01 treatment or may not be started at all . GM-CSF/TG01 treatment will be administered on days 1, 3, 5, 8, 15, and 22 and then 2- weekly until the end of chemotherapy treatment. Patients who do not start chemotherapy at all can move to a 4- weekly vaccination from vaccination week 10 to week 52. • If given, Gemcitabine will be administered on cycle day 1, 8 and 15 of a four week cycle for 6 cycles in total . 5-FU and Leucovorin will be administered on cycle day 1, 2, 15 and 16 of a four week cycle for 6 cycles • DTH application on days 1, 8 15, 22 36, 50 and 64. DTH is assessed 48 h ± 4 h after each injection • Haematology and blood chemistry at days 1, 8, 22, 36, 50 and 64 taken prior to injection of GM -CSF/TG01 and at days 1, 8 and 15 of each Gemcitabine cycle prior to injection of study treatments . Key laboratory values in accordance with the Prescribing Information for chemotherapy should be available prior to chemotherapy dosing. For patients who do not start chemotherapy at all, haematology and blood chemistry should be taken at days 1, 8, 22, 36, 50 and 64 and then every 12 weeks • Urinalysis as clinically indicated • Vital signs, concomitant medications and adverse events at each visit CT TG01 -01 Version v 10.0 27 June 2018 Confidential 62 / 87 • Physical exam and performance status before the start of each chemotherapy cycle. For patients who do not start chemotherapy at all, these assessments should be done every 12 weeks • Blood sampling for immunology – samples taken prior to GM -CSF/TG01 injection on day 1 and day 71 (or 78) • Blood sampling for CA19.9 will be taken prior GM -CSF/ TG01 injection on day 1 and prior chemotherapy day 1 of each cycle . For patients who do not start chemotherapy at all, these ass essments should be done on day 1 and prior every 4-weekly vaccination cycle • A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and stored for potential analysis of additional biomarkers on day 1 prior to GM -CSF/TG01 , prior chemotherapy 1st admi nistration and monthly thereafter until end of chemotherapy . For patients who do not start chemotherapy at all, these assessments should be done on day 1 and prior every 4-weekly vaccination cycle • CT scan every 6 months from start of vaccination and at any time point if indicated Phase II part – concomitant treatment group : Initial Treatment Period (up to week 13) +/- chemotherapy for patients starting TG01 vaccination and chemotherapy at the same time (Table 2) : • GM-CSF/TG01 will start within 9-12 weeks of the surgical resection. Day 1 will be the first day of GM -CSF/TG01 treatment . GM-CSF/TG01 treatment s will be administered on days 1, 3, 5, 8, 15 and then 2- weekly until the end of chemotherapy treatment . • Chemotherapy will start at the same time as GM -CSF/TG01 and no later than 12 weeks from surgery. Gemcitabine will be administered on cycle day 1, 8 and 15 of a four week cycle for 6 cycles in total. 5 -FU and Leucovorin will be administered on cycle day 1, 2, 15 and 16 of a four week cycle for 6 cycles • DTH application on days 1, 8 15, 29, 43, 57 and 71. DTH is assessed 48 h ± 4 h after each injection • Haematology and blood chemistry at days 1, 8 and 15 of each Gemcitabine cycle prior to injection of study treatments . Key laboratory values in accord ance w ith the Prescribing Information for chemotherapy should be available prior to chemotherapy dosing • Urinalysis as clinically indicated • Vital signs , concomitant medications and adverse events at each visit • Physical exam and performance status before the start of each chemotherapy cycle • Blood sampling for immunology – samples taken prior to GM -CSF/TG01 injection on day 1 and week 13 • Blood sampling for CA19.9 will be taken on day 1 of each chemotherapy cycle prior GM -CSF/TG01 administration • A further 10 ml sample (5 ml serum; 5 ml plasma) will be taken and stored for potential analysis of additional biomarkers on day 1 of each chemotherapy cycle prior GM -CSF/TG01 administration • CT scan every 6 months from start of vaccination and at any time point if indicated CT TG01 -01 Version v 10.0 27 June 2018 Confidential 63 / 87 Phase II – modified vaccination group : Initial Treatment Period (up to week 8) +/- chemotherapy for patients starting TG01 vaccination first (timings based on start of GM - CSF/TG01 treatment) - Table 3 . • GM-CSF/TG01 will start as soon as possible after surgical resection. Day 1 will be the first day of TG01 treatment. GM -CSF/TG01 will be administered on Days 1, 8, 15, 22 and 36 then if chemotherapy hasn’t started vaccination will be given 4-weekly until the start of chemotherapy at which point vaccination will be put on hold until the end of chemotherapy treatment. Patients who do not start chemotherapy at all will continue to receive 4 -weekly vaccinations from week 10 to week 52. • Chemotherapy will commence at least 3 weeks after start of GM -CSF/TG01. Patie nts can however start chemotherapy later or not start at all if more appropriate. For patients receiving chemotherapy, 6 cycles of chemotherapy will be given. Note that chemotherapy will not be delayed if it is considered important to start within 3 weeks of the start of vaccinations. • DTH skin test injections on days 36 and 50. DTH reaction is assessed 48 h ± 4 h after each injection • Haematology and blood chemistry at days 1, 8, 22, 36, 50, and 64 taken prior to injection of GM -CSF/TG01 and Days 1, 8 and 15 of each gemcitabine cycle. Key laboratory values in accordance with the Prescribing Information for chemotherapy should be available prior to chemotherapy dosing. For patients who do not start chemotherapy at all, haematology and blood chemistry should be taken at days 1, 8, 22, 36, 50 and 64 and then every 12 weeks • Urinalysis as clinically indicated • Vital signs, concomitant medications and adverse events at each visit. • Physical examination and Performance Status before the start of each gemcitabine cycle. For patients who do not start chemotherapy, these assessments should be done every 12 weeks. • Blood sampling for immunology – samples taken prior to GM -CSF/TG01 injection on day 1 and at week 8 • Blood sampling for CA19.9 on day 1 prior to GM -CSF/TG01, pri or chemotherapy 1st administration and monthly thereafter until end of chemotherapy. For patients who do not start chemotherapy, these assessments should be done on Day 1 and prior every 4- weekly vaccination cycle • A further 10 ml sample (5 ml serum; 5 ml p lasma) will be taken and stored for potential analysis of additional biomarkers on day 1 prior to GM -CSF/TG01, prior chemotherapy 1st administration and monthly thereafter until end of chemotherapy. For patients who do not start chemotherapy, these assessm ents should be done on Day 1 and prior every 4- weekly vaccination cycle • CT scan every 6 months from the start of vaccination and at any other time point if indicated After the end of chemotherapy or from week 10 for patients who do not get chemotherapy : Main group and concomitant group: • GM-CSF/TG01 every 4 weeks until 52 weeks and then every 12 weeks for up to 2 years . For all these subsequent GM -CSF /TG01 administrations the patients should be given prophylactic treatment (30 minutes before treatment) to prevent possible occurrence of allergic reactions. CT TG01 -01 Version v 10.0 27 June 2018 Confidential 64 / 87 • DTH skin test injections at the 2nd GM-CSF/TG01 injection after end of chemotherapy (8 weeks after last chemotherapy injection ) and at week 52. DTH reaction is to be assessed 48 h ± 4 h after TG01 injectio n. For patients who do not start chemotherapy at all, these assessments should be done at week 52 only • Immunology blood samples – samples taken at week 52 prior GM-CSF/TG01 injection • CA19.9 and additional biomarkers blood samples – samples taken at week 52 prior GM-CSF/TG01 injection. For patients not starting chemotherapy, samples should be taken prior every 4- weekly cycle and at week 52 • Physical examination and performance status at 52 weeks . For patients who do not start chemotherapy, these assessments s hould be done every 12 weeks and at week 52 • Vital signs, haematology and biochemistry at 12 weekly intervals • Concomitant medications and adverse events at each visit • CT scan every 6 months from start of vaccination and at any time point if indicated Modif ied vaccination group: • GM-CSF/TG01 will be given 4 weeks and 5 weeks after end of chemotherapy and then every 4 weeks from week 8 post -chemotherapy until week 52 and then every 12 weeks until week 104 (2 years). Patients who do not start chemotherapy at all will receive 4 -weekly vaccinations from week 10 to week 52 and then every 12 weeks until week 104 (2 years). • DTH skin test at 3rd vaccination post -chemotherapy (8 weeks post - chemotherapy). The DTH reaction is to be assessed 48 h ± 4 h after TG01 injectio n. For patients not starting chemotherapy at all, the DTH test and assessment are to be done at week 52 . • Blood sampling for immunology – sample to be collected 4 weeks after the last chemotherapy injection (1st vaccination injection) and at week 52 • Blood sampling for CA19.9 and additional biomarkers – samples to be taken prior to GM -CSF/TG01 injection at week 52. For patients not starting chemotherapy, samples should be taken prior every 4- weekly vaccination cycle and at week 52 • Physical examination and performance status to be taken at week 52. For patients who do not start chemotherapy, these assessments should be done every 12 weeks and at week 52 • Vital signs, haematology and biochemistry every 12 week s • Concomitant medications and adverse events at each visit • CT scan every 6 months from the start of vaccination and at any other time point if indicated End of Study Visit ( 104 weeks or 4 week s after last GM -CSF /TG01 injection if patient is to be discontinued) • Haematology and blood chemistry • Physical exam and performance status • Vital signs, c oncomitant medications and adverse events • Blood sampling for immunology, CA19.9 and additional biomarkers taken prior to GM -CSF/TG01 injection CT TG01 -01 Version v 10.0 27 June 2018 Confidential 65 / 87 • CT-scan For all patients where possible, a survival follow -up will con tinue to be performed every 6 months after the initial 2 years of study period and until the last remaining patient in the modified cohort reaches the 2 years study period or withdraws consent or experiences toxicity, whichever is the earliest . Thereafter, a survival follow -up will continue to be performed approximately every 12 months until end of life. 5.6 Immunological effect An immune responder is defined as having a positive DTH and/or a positive T -cell test from a blood sample at least once by the end of the initial treatment period ( week 11 in main group, week 13 in the concomitant group and week 8 in the modified vaccination group) (see below): T-cell Assay Patients will have a blood sample taken prior to GM -CSF/TG01 for further testing of immune response , at: - Day 1 - Week 11 (main group) or week 13 (concomitant group) or week 8 (modified vaccination group) - 4 weeks after end of chemotherapy - Week 52 - End of study All samples will be processed and stored under appropriate conditions until being analysed. Blood samples from each time point will be analysed for TG01 specific T -cell responses by proliferation assays. Specific T -cell responses will be considered positive if the stimulation index (SI) is ≥2. Delayed Type Hypersensitivity (DTH) It is performed in order to demonstrate whether an immune response has been elicited. Administration of TG01 only (without GM -CSF or proceeded by GM -CSF administration) must be injected intradermally in the lower area of the contralateral arm acting as a Del ayed Type Hypersensitivity (DTH) test. Phase I part and phase II part – main group : the DTH test is administered on days 1, 8, 15, 22, 36, 50, 64, at the 2nd GM-CSF/TG01 injection after the end of the chemotherapy (8 weeks after the last chemotherapy injection) and at week 52. For patients not receiving chemotherapy at all, the DTH test is administered on days 1, 8, 15, 22, 36, 50, 64 and at week 52. Phase II part – concomitant group : the DTH test is administered on days 1, 8, 15, 29, 43, 57, 71, at the 2 nd GM-CSF/TG01 injection after the end of the chemotherapy (8 weeks after the last chemotherapy injection) and at week 52. Phase II part – modified vaccination group : the DTH test is administered on days 36 and 50, at the 3rd GM-CSF/TG01 injection after the end of the chemotherapy (8 weeks after the last chemotherapy injection) and at week 52. For patients not starting chemotherapy at all, the DTH test and assessment are to be done on days 36 and 50 and at week 52 . CT TG01 -01 Version v 10.0 27 June 2018 Confidential 66 / 87 The DTH skin reaction assessment is to be performed 48 hours (+/ - 4 hours) after each administration. The DTH -test will be considered positive if the area of the skin reaction has an average diameter * of ≥ 5mm at the 48 hours (+/- 4 hours) assessment. Figure 6: DTH Skin Reaction Registration (induration and erythema ) * Average diameter: a mm + b mm 2 5.7 CT-scan An abdominal CT or MRI scan should be performed for full tumour assess ment at baseline, every 6 months from the start of vaccination and at the last or end of study visit . Additional CT-scans should also be done if indicated during the study period. 5.8 Efficacy measurements and endpoints 5.8.1 Immunology response Response by week 1 1 or 12 (main group) or by week 13 (concomitant group) or by week 8 (modified vaccination group) assessed by: • DTH responses • Proliferative T- cell responses Response at end of chemotherapy treatment assessed by: • DTH responses • Proliferative T -cell responses Response at week 52 assessed by: • DTH responses • Proliferative T -cell responses Response at end of study assessed by: • Proliferative T -cell responses 5.8.2 Disease -free survival • Time from randomisation to 1 st disease progression or death from any cause Note that although scanning at regular intervals during the study i s not mandated it is expected that a CT scan will be performed every 6 months from the start of vaccination and if there is clinical evidence of disease recurrence • Number of patients alive a nd disease free at 1 and 2 years 5.8.3 Overall survival • Time from randomisation to death due to any cause • Number of patients alive at 1 and 2 years DTH a bDTH a b CT TG01 -01 Version v 10.0 27 June 2018 Confidential 67 / 87 5.8.4 KRAS status expression Relationship between KRAS status and recurrence 5.8.5 CA19.9 levels Level of CA19- 9 during treatm ent period, at week 52 and at end of the study. 5.8.6 Other markers levels Level of other biomarkers during treatment period, at week 52 and at end of the study.