Consequently, no additional non- clinical studies investigating local effects are planned. 2.1.4 Clinical experience During the earlier phases of developm ent, a significant body of clinical data from over 230 cancer patients has been established and indicates that the RAS peptides comprising TG01 are safe, well tolerated and have the capacity to elicit immune responses in man. To date, 120 patients with pa ncreatic cancer have received treatment with TG01 in combination with GM -CSF (studies CTN RAS 98010 and EMR 62200- 001) and 55 patients with pancreatic cancer have received either several injections of RAS peptide- pulsed autologous PBMC (7 patients), or act ive immunization with 1 or 4 mutated RAS peptides combined with GM -CSF (48 patients; Studies CTN RAS 93001, CT TG01 -01 Version v10.0 27 June 2018 Confidential 28 / 87 CTN RAS 95002, CTN RAS 97004) . Sixty three patients with colorectal cancer have received treatment RAS peptide -pulsed autologous PBMC ( 8 patients), or active immunization with 1 or 5 mutated RAS peptides combined with GM -CSF ( 55 patients ; Studies CTN RAS 95003, CTN RAS 97005 and CTN RAS 98008). Immunization with a single RAS peptide pulsed PBMC in study CTN RAS 93001 resulted in specific T cell res ponses in only 2 out of 5 patients which led to the selection of active immunization as the optimal approach for induction of measurable immune responses. Using this approach, both DTH and proliferative responses could be demonstrated in approximately hal f of the pancreatic cancer patients who received active immunisation with either one or 4 RAS peptide ASCI (Studies CTN RAS 95002 and 97004). In the clinical study with the 7 RAS peptide ASCI (CTN RAS 98010), the results showed that all (100%) of the eval uable patients in the resected group and 14 (56%) in the non-resected group report ed a DTH immune response. From all the clinical studies so far in patients with resected and advanced pancreatic cancer it seems that the ability to induce an effective immu ne response may be reduced as the disease burden increases. It is therefore of outmost importance to start to vaccinate as soon as possible after diagnosis and to use an aggressive initial immunotherapy regimen in order to induce an immune response as quickly as possible. Long term follow up of resected pancreatic cancer patients immunised with a single peptide – specific RAS peptide vaccine ( Study CTN RAS 95002) and the 7 RAS peptide vaccine (Study CTN RAS 98010) suggest that the induction of a RAS -speci fic cellular response may confer a survival advantage since patients who develop a DTH response seem to live longer than those who do not. Five year survival rates were 3 out of 10 patients in Study CTN RAS 95002 and 2 out of 11 patients in Study CTN RAS 98010. Collectively these data suggest that vaccination with TG01 could induce potent anti -tumour activities capable of improving the patient’s survival and pivotal studies are being planned to test this hypothesis . Whilst the safety of co -administration of GM-CSF/TG01 with gemcitabine has not been established, their mode of action and toxicity profiles should not be additive and it is not expected that toxicity will be a factor in progressing to the formal Phase II/III study. The production of immune responses with this combination is also not known and it is considered prudent to explore this initially before embarking on the main P hase II/III study. 2.2 Trial objectives 2.2.1 Primary objective The primary objective of the study is defined as: • To assess the safet y of GM -CSF/TG01 vaccination and adjuvant chemotherapy • To assess the immune response to GM -CSF/TG01 and the effect of adjuvant chemotherapy in patients receiving GM -CSF/TG01 after primary resection of pancreatic adenocarcinoma. CT TG01 -01 Version v10.0 27 June 2018 Confidential 29 / 87 2.2.2 Secondary objective The secondary objective of the study is : • To assess at 2 years the clinical efficacy of GM -CSF/TG01 in patients with resected pancreatic cancer 2.2.3 Exploratory objectives The exploratory objectives are: • Assess the r elationship of KRAS status to recurrence • Monitor C A19-9 levels 3. INVESTIGATIONAL PLAN 3.1 Overall trial design and plan This is a Phase I /II trial of TG01 and gemcitabine as adjuvant therapy for treating patients with r esected adenocarcinoma of the p ancreas. Patients will be enrolled in 4-5 study centre (s) and the study duration will be approximately 5 years . The phase I part of the study ( Figure 1 ) will be initiated with 6-12 patients enrolled within 1 -8 weeks after surgery to receive GM-CSF given 10- 15 minutes before TG01 . Gemcitabine will be started at least 3 weeks after the initiation of immunotherapy but not later than 12 weeks after surgery . Note that , in some centres where transaminases are > 2.5 x ULN at the time of chemotherapy, 5 -FU/Leucovorin may be substit uted. However , the number of patients in the study refers to those receiving gemcitabine and therefore, for every patient who receives 5 -FU rather than gemcitabine, a further patient will be added. The patients ’ safety will be reviewed on an on-going basis and the immunological response will be monitored (DTH) and assessed by week 11 (DTH and T cell proliferation ). Initially, 6 patients will be treated with GM -CSF/TG01 within 1 -8 weeks after surgery and when these 6 patients have reached week 11: • If 0/6 patients have an immune response and/or there are > 3/6 patients with GM-CSF/TG01 related dose- limiting toxicities observed, the study will be terminated . • If 1-3/6 patients have an immune response and/ or if there are 3/6 patients with GM-CSF/TG01 related do se-limiting toxicities observed, 6 new patients will be enrolled and will be treated in the same way as the previous patients. • If ≥ 4/6 patients have an immune response and ≤ 2/6 patients have a GM - CSF/TG01 related dose -limiting toxicity, the phase II study will be initiated If the enrolment of the phase I part is expanded to 12 patients, then at week 11: CT TG01 -01 Version v10.0 27 June 2018 Confidential 30 / 87 • If < 4/12 patients have an immune response and/or there are > 4/12 patients with GM-CSF/TG01 related dose -limiting toxicities , the study will be terminated • If ≥ 4/12 patients have an immune response and ≤ 4/12 patients have a GM - CSF/TG01 related dose -limiting toxicity, the phase II study will be initiated The Phase II part of the study (an additional 18-24 patients - Figure 2 ) will be initiated if: • ≥ 4/6 patients have an immune response and ≤ 2/6 patients have a GM - CSF/TG01 related dose -limiting toxicity • ≥ 4/12 patients have an immune response and ≤ 4/12 patients have a GM- CSF/TG01 related dose -limiting toxicity The above Phase II part has established a vaccination protocol that provides a positive immune response. A new cohort with up to 13 patients is to be enrolled to test if a modified schedule of administration of GM-CSF/TG01 can induce and maintain the same immune response and reduce the severity of or avoid side effects related to allergic reactions (Table 3). These patients will constitute the modified vaccination group. The efficiency of this modified vaccination group will be assessed after 6 patients ha ve data for DTH assessments after 8 weeks. The cohort will continue if the tolerability is acceptable and there are at least 4/6 patients with a positive immune response by week 8. If <4/6 patients have an acceptable immune response, the next patients will revert to the previous induction schedule of 3 vaccinations in the first week. There will therefore be a total number of up to 32 patients for the whole study. In both parts of the study, patients who are withdrawing for reasons other than toxicity may be replaced if they received less than 4 weeks of vaccination and have not started gemcitabine treatment. Dose Limiting Toxicities will be defined as follows (based on CTCAE V 4): • Injection site reaction of grade 3 • ANC < 0.5 × 109/L associated with fever ( temperature > 38.5oC) • ANC < 0.5 × 109/L lasting ≥ 5 days without fever • Grade 4 thrombocytopenia for ≥ 5 days • Grade 3 or 4 renal or hepatic toxicity • Grade 3 or 4 diarrhoea despite aggressive anti -diarrhoeal therapy • Other non- haematological toxicity ≥ grade 3 (excluding treatable alopecia or t reatable nausea and vomiting) • > Grade 3 'allergic reaction/anaphylactic reaction ' in spite of prophylaxis with antihistamine and steroids • Treatment delay > 2 weeks prior to start of next cycle of treatment due to unresolved toxicity CT TG01 -01 Version v10.0 27 June 2018 Confidential 31 / 87 • In the case of grade 4 ANC or thrombocytopenia, haematology should be assessed daily until recovery to < grade 2 GM-CSF and TG01 The first day of GM-CSF/TG01 treatment will be considered Day 1 for the Visits. Phase I and phase II part - main group: the GM -CSF/TG01 will be given on days 1, 3, 5, 8, 15 and 22 and then every 2 weeks until the end of chemotherapy treatment . If patients do not start chemotherapy at all, they will receive GM -CSF/TG01 on days 1, 3, 5, 8, 15, 22, 36, 50, 64 and then every 4 weeks until week 52. In th e case of early termination of chemotherapy treatment (prior to completion of 6 cycles) GM -CSF/TG01 will be continued as per the treatment schedule. Phase II part - concomitant group : GM-CSF/TG01 will be given on days 1, 3, 5, 8, 15 and then every 2 weeks until the end of chemotherapy treatment. In the case of early termination of chemotherapy treatment (prior to completion of 6 cycles) GM -CSF/TG01 will be continued as per the treatment schedule. Phase II part – modified vaccination group : GM -CSF/TG01 will be given on days 1, 8, 15, 22 and 36 and then after the end of chemotherapy treatment. If patients start chemotherapy after week 10 or do no start chemotherapy at all, they will receive GM - CSF/TG01 every 4 weeks from week 10 until chemotherapy starts or until week 52. In the case of early termination of chemotherapy treatment (prior to completion of 6 cycles) GM-CSF and TG01 will be continued as per the treatment schedule. Main group and concomitant group: Patients who are recurrence -free (with or without a detected immune response), will continue to receive GM-CSF/TG01 treatment every 4 weeks until 52 weeks, then every 12 weeks until 2 years or until withdrawal of consent or toxicity whichever is the earliest. Patients who recur and have an immune respons e during the treatm ent period should continue every 4 weeks until 52 weeks, then every 12 weeks until 2 years or until withdrawal of consent or toxicity whichever is the earliest. The same applies to patients who do not start chemotherapy . Modified vaccina tion group: patients who are recurrence- free (with or without a detected immune response) will continue to receive 4 -weekly GM -CSF/TG01 (plus one vaccination at week 5 post -chemotherapy) until week 52 then every 12 weeks until 2 years or until withdrawal o f consent or toxicity whichever is the earliest. Patients who recur during the study and had a positive immune response during the study treatment period should continue to receive 4 -weekly GM -CSF/TG01 (plus one vaccination at week 5 post -chemotherapy) until week 52 then every 12 weeks until 2 years or until withdrawal of consent or toxicity whichever is the earliest. All groups : Patients who recur and do not have an immune response during the treatment period will be withdrawn . For all patients where po ssible , a survival follow -up will continue 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, w hichever is the earliest . Thereafter, a survival follow -up will continue to be performed approximately every 12 months until end of life. CT TG01 -01 Version v10.0 27 June 2018 Confidential 32 / 87 Chemotherapy Phase I and phase II part - main group : Patients will receive chemotherapy starting a minimum 3 weeks af ter the start of GM -CSF/TG01 treatment and not later than 12 weeks from surgery . Chemotherapy will start on a day when TG01 is administered ( GM- CSF/TG01 treatment Day 22, 36 or 50). For patients who do not receive chemotherapy, vaccinations will be continued according to the same schedule except that from week 10 the vaccinations will be 4 -weekly until week 52. Phase II part - concomitant group : Patients will receive GM -CSF/TG01 and chemotherapy starting between 9 and 12 weeks after the surgery and not later than 12 weeks from surgery. Phase II part – modified vaccination group : Chemotherapy will preferably commence at least 3 weeks after start of GM -CSF/TG01 on a day when GM -CSF and TG01 is administered ( TG01 treatment Day 22, 36 or 50). Patients can howe ver start chemotherapy later or not start at all if more appropriate. Chemotherapy should however not be delayed if it is considered important to start within 3 weeks of the start of vaccinations. For patients who do not receive chemotherapy, vaccinations will be 4 - weekly from week 10 until week 52. Gemcitabine will be given as 1000 mg/m 2 iv over 30 minutes on days 1, 8 and 15 of a four- week cycle for 6 cycles in total. However if at start of chemotherapy or prior to next gemcitabine administration , AST and ALT are >2.5 x UNL, patients may receive 5 -FU/Leucovorin instead of gemcitabine and continue vaccination with TG01 as per protocol. The use of 5- FU/leucovorin under these circumstances is not mandatory but depending on the usual practice at the study site When applicable, c hemotherapy is to be given on the same day and after TG01 injection. In this respect, in the main group and concomitant group, patients will receive GM - CSF/TG01 in combination with chemotherapy for 6 cycles of 4 weeks. CT TG01 -01 Version v10.0 27 June 2018 Confidential 33 / 87 Figure 1: Study Design – Immune response assessment Phase I Part (if DLT criteria satisfied) 6 Patients GM-CSF+TG01 DTH and or T cell response? ≥ 4/6 Proceed to Phase II part (if DLT criteria satisfied) Terminate Study + 6 Patients GM-CSF + TG01 1-3/6 DTH and or T cell response? ≥ 4/12 < 4/12 0/6 CT TG01 -01 Version v10.0 27 June 2018 Confidential 34 / 87 Figure 2: Study Design – Dose Limiting Toxicity Assessment 6 Patients GM-CSF+TG01 DLT Assessment < 2/6 Proceed to Phase II Part (if immune response criteria satisfied) Terminate Study + 6 Patients GM-CSF + TG01 3/6 DLT Assessment ≤ 4/12 > 4/12 > 3/6 Phase I Part (if immune response criteria satisfied) CT TG01 -01 Version v10.0 27 June 2018 Confidential 35 / 87 Figure 3: Treatment schedule for patients starting vaccination and receiving chemotherapy later – Main group TG01 + GM -CSF Start as soon as possible after surgery Start of Gemcitabine treatment or or Gemcitabine Cont. up to total 6 cycles d8 w2 d15 w3 w11 d71 w7 d43 w5 d29 d22 w4 d36 w6 w10 d64 w8 d50 w9 d57 Injections every 4 week s w52 Immune response analysis w104 (2 years) or 4 weeks after last treatment Survival FU Injections every 12 weeks Injections every 2 weeks during Gemcitabine cycles Gemcitabine d22 d36 d50 Initial treatment period Post - Gemcitabine w1 d1,3,5 End of study visit CT TG01 -01 Version v10.0 27 June 2018 Confidential 36 / 87 Figure 4: Treatment schedule for patients starting vaccination and chemotherapy at the same time – concomitant group End of study visit TG01 + GM -CSF Gemcitabine Cont. up to total 6 cycles d8 w2 d15 w3 w11 d71 w5 d29 d22 w4 d36 w6 w10 d64 w8 d50 w9 d57 Injections every 4 week s w52 Immune response analysis w104 (2 years) or 4 weeks after last treatment Injections every 12 weeks Injections every 2 weeks during Gemcitabine cycles Gemcitabine Initial treatment period Post - Gemcitabine d43 w7 w1 d1,3,5 Survival FU CT TG01 -01 Version v10.0 27 June 2018 Confidential 37 / 87 Figure 5: Treatment schedule for patients starting vaccination and receiving chemotherapy later – Modified vaccination group GM-CSF + TG01 Start as soon as possible after surgery Start of Gemcitabine treatment or or Gemcitabine Cont. up to total 6 cycles d8 w2 d15 w3 w11 d71 w7 d43 w5 d29 d22 w4 d36 w6 w10 d64 w8 d50 w9 d57 At w4 & w5 post-chemo & every 4 weeks from w8 post - chemo w52 w104 (2 years) or 4 weeks after last treatment End of study visit Injections every 12 weeks Gemcitabine d22 d36 d50 Initial treatment period Post -Gemcitabine w1 d1 * *: vaccination to be continued every 4 weeks until chemotherapy starts or until week 52 (if chemotherapy never starts) Immune response analysis Survival FU CT TG01 -01 Version v10.0 27 June 2018 Confidential 38 / 87 Table 1: Schedule of visits Page in protocol Screening Initial Treatment Period* Repeat Cycles with chemotherapy * After chemo to W 52 *** W52- 104 Patient end of Study visit ** Survival FU Study Week (W) 1 1 1 2 3 4 5 6 7 8 9 10 11 j 1 5 9 13 17 21 2 6 10 14 18 22 3 7 11 15 19 23 4 8 12 16 20 24 Every 4 weeks** Every 12 weeks ** W104 or 4 weeks after last TG01 / GM- CSFk Every 6 months and at study end** Thereafter ~every 12 month s Study Day -56 to -7 -7 1 3 5 8 15 22 29 36 43 50 57 64 71j Cycle D1 Cycle D8 Cycle D15 Cycle D22 TG01 / GM -CSFa 51 to 59 x x x x x x x x x x x xn xn DTH injectionb 51 to 59 x x x x x x x xi xe Gemcitabinec 51 to 59 x x x 5-FU and Leucovoring 51 to 59 x x Informed Consent 60 x Patient eligibility 60 x Demography/Medical history 60 x Resect pancreas 60 x Tumour sample 60 x ECG 61, 68 x <-------------------------------------------------------- --------- ------------ As clinically indicated ---------------------------- ------ ---------------------------------------------------  Physi cal Exam/ PS 61, 68 x x xm xe x Vital Signs 61 x x x x x x x x x x x x x x xf x x Haematology / Chemistryd 61, 68 x x x x x x x x x x xf x x Pregnancy test 61 x Concurrent illness 61 x DTH assessmentb 55, 66 x x x x x x x xi xe Immunology sampled 65, 66 x x xe x CA19.9 / other biomarkersd 67 x x xl xe x Urinalysis 61, 68 x <--------------------------------------- ---------------------------------------- As clinically indicated -----------------------------------------------------------------  CT/MRI / assess diseaseh 61, 66 x <-------------------------------------------------------------------------- ------------ ---------- Every 6 months --------------------------------------------------------  x Adverse events 67, 71 <---------------------------------------------------------------------------------------------- As clinically indicated -------------------------------------------------------------------- Concomitant medications 60, 61 x <----------------------------------------------------------------------------------------- As clinically indicated -------------------------------------------------------------------------- Survival follow -up X CT TG01 -01 Version v10.0 27 June 2018 Confidential 39 / 87 a: Start as soon as possible after surgery. GM- CSF given 10- 15 min before TG01 . During chemotherapy treatment: every 2 weeks After end of chemotherapy treatment may be given for up to 2 years or until withd rawal of consent, toxicity or the need for additional treatment for pancreatic cancer whichever is the earliest Patients should be observed for at least 30 minutes after all vaccinations b: DTH injection should be performed 30 minutes before the GM-CSF/T G01 injection . Assessment of DTH injection site to be done 48 hours (+/ - 4 hours) after each GM - CSF/TG01 injections. c: Start at Study Day 22, 36 or 50 (once patients are able to receive chemotherapy see repeated cycles) d: Blood samples to be taken pri or to all treatments. e: At 52 weeks f: Every 12 weeks g: Given on Day 1 and 2 every 2 weeks . 5-FU/Leucovorin should be used as an alternative if required due to raised ALT. h: CT -scan to be done at baseline ( if possible ), then every 6 months from the st art of vaccination (+/- 4 weeks’ time window) and at end of the study visit.