Conditions: Esophageal Cancer
Keywords: Oesophageal Cancer Oesophageal adenocarcinoma Oesophageal squamous cell carcinoma Immunotherapy Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) Programmed cell death protein 1 (PD-1) Programmed death ligand 1 (PD-L1)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 73
Healthy volunteers: no

Brief summary:
This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (MEDI4736) in combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC) and with neoadjuvant chemo(radio)therapy before surgery in operable OC. The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts. The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B, C, C-FLOT, D/D2).

Detailed description:
This is an open-label, Phase 1/2 study to evaluate the safety of immunotherapy in combination with chemo (radio) therapy with the following cohorts:

* Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal cancer (OC).
* Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in operable OC.
* Cohort C-FLOT: Neoadjuvant 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy before surgery in operable OC.
* Cohort D/D2: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before surgery in operable OC.

The immunotherapy will be given for a 4-week period before starting the standard chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts for all cohorts except Cohort D.

The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B including the higher dose tremelimumab cohort from Cohort A2, C, C-FLOT, and D/D2).

Phase 1 will evaluate the safety of durvalumab alone (Cohort A1) administered before chemotherapy (oxaliplatin + capecitabine) in subjects with metastatic or locally advanced OC. After completion of Cohort A1, Phase 2 in Cohorts C, C-FLOT, and D/D2 will begin, and a safety review will determine whether to explore the tremelimumab + durvalumab combination (Cohort A2).

Phase 2 includes the expansion into Cohorts B, C, C-FLOT, and D/D2. Once Cohort A1 is cleared, there will be concurrent enrollment into Phase 2 expansion for Cohorts C, C-FLOT and D/D2 (subjects with operable OC with neoadjuvant chemotherapy or chemoradiotherapy before surgery) and the tremelimumab dose-escalation phase for Cohort A2 (37.5 mg and 75 mg). Once Cohort A2 is completed, another safety review will determine the dose of tremelimumab to be included in the recommended combination dose (RCD) to start enrollment into the Cohort B (subjects with metastatic/locally advanced OC) expansion phase. Subjects treated at the RCD in Cohort A2 (tremelimumab 75 mg) will be included in Cohort B.

Subjects in Cohorts C, C-FLOT and D/D2 will undergo surgery after completing treatment, and they will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this is within 3 months of surgery. Subjects in Cohort C-FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at the discretion of the investigator.

Arms:
arm 1: Durvalumab (750 mg IV every two weeks \[Q2W\]) was to be given for up to 11 doses. Oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses. arm 2: Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (37.5 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses. arm 3: Durvalumab (750 mg IV Q2W) was to be given for up to 11 doses. One dose of tremelimumab (75 mg IV) was given on the same day as the first dose of durvalumab. Oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy was started on the day of the third dose of durvalumab and continued for 6 doses. arm 4: Durvalumab (750 mg IV Q2W) was to be given for up to 5 doses. Two cycles of neoadjuvant oxaliplatin (130 mg/m\^2 IV)/capecitabine (1250 mg/m\^2/day given orally) chemotherapy were to be administered before surgery. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery. arm 5: Durvalumab (750 mg IV Q2W) was to be given for up to 6 doses. Two cycles of neoadjuvant 5-fluorouracil (5-FU) (2600 mg/m\^2 24-hr IV), leucovorin (200 mg/m\^2 IV), oxaliplatin (85 mg/m\^2 IV), and docetaxel (50 mg/m\^2 IV) chemotherapy (FLOT) were to be administered before surgery starting on the day of the third dose of durvalumab. Subjects were to undergo surgery 6 to 8 weeks after completing chemotherapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions), FLOT or durvalumab plus FLOT at the discretion of the Investigator once recovered from surgery, provided that this was within 3 months of surgery. arm 6: Durvalumab (750 mg IV Q2W) was to be given for 2 doses. This was followed by five weekly doses of neoadjuvant paclitaxel (50 mg/m\^2 IV) / carboplatin (AUC 2) IV chemotherapy + radiotherapy (41.4 Gy radiotherapy given over 23 fractions) before surgery. Subjects could receive an additional dose of durvalumab after completion of chemoradiation.

In Cohort D2, subjects continued durvalumab for 3 additional doses while receiving chemoradiation. Subjects were to undergo surgery 6 to 8 weeks after completing chemo(radio)therapy or according to institutional policies for surgery; and would be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided that this was within 3 months of surgery.

Interventions: intervention 1: Durvalumab intervention 2: Tremelimumab intervention 3: Oxaliplatin intervention 4: Capecitabine intervention 5: Radiotherapy intervention 6: Paclitaxel intervention 7: Carboplatin intervention 8: 5-fluorouracil (5-FU) intervention 9: Leucovorin intervention 10: Docetaxel
Intervention descriptions: intervention 1: Anti PD-L1 antibody intervention 2: Anti CTLA-4 antibody intervention 3: IV administered chemotherapy intervention 4: orally-administered chemotherapy intervention 5: None intervention 6: IV administered chemotherapy intervention 7: IV administered Chemotherapy intervention 8: IV administered chemotherapy intervention 9: chemo-protective agent intervention 10: IV administered chemotherapy

Protocol document:
Prot_SAP_000.pdf: 
 
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Study Protocol 
LUD2015-005 
US-IND #: Not applicable 
EudraCT #: 2015-005298-19 
AstraZeneca Ref #: ESR 15-10891 
Amendment 8 
Final 
11-JAN-2022 
 
Protocol Title 
Phase 1/2 Study of anti-PD-L1 in Combination with Chemo(radio)therapy for Oesophageal 
Cancer 
 
Objectives and Synopsis 
This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (MEDI4736) (and 
tremelimumab for certain cohorts as described in Section 3.1.7) in combination with chemo 
(radio) therapy according to the following cohorts:  
• 
Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally 
advanced oesophageal cancer (OC). 
• 
Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in 
operable OC.  
• 
Cohort C-FLOT: Neoadjuvant 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and 
docetaxel (FLOT) chemotherapy before surgery in operable OC. (Added per 
Amendment 6, See Section 2.2 for details): 
• 
Cohort D: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before 
surgery in operable OC. 
The immunotherapy will be given for a 4-week period before starting the standard 
chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts for all 
cohorts except Cohort D. (Note: For a subset of Cohort D subjects (Cohort D2), durvalumab 
doses will continue during chemoradiotherapy, after the initial 4-week immunotherapy 
period. Upon approval of Amendment 7, enrollment will proceed to Cohort D2, unless there is 
a medical reason to enroll a specific subject to Cohort D.) 
The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion 
Phase 2 (Cohorts B, C/C-FLOT, and D/D2).  
Phase 1 will evaluate the safety of durvalumab alone (Cohort A1) administered before 
chemotherapy (oxaliplatin + capecitabine) in subjects with metastatic or locally advanced OC.  
After completion of Cohort A1, Phase 2 in Cohorts C/C-FLOT, and D/D2 will begin, and a safety 
review will determine whether to explore the tremelimumab + durvalumab combination and 
dose-escalation for tremelimumab (Cohort A2). 
Phase 2 includes the expansion into Cohorts B, C/C-FLOT, and D/D2. Once Cohort A1 is 
cleared, there will be concurrent enrollment into Phase 2 expansion for Cohorts C/C-FLOT and 
D/D2 (subjects with operable OC with neoadjuvant chemotherapy or chemoradiotherapy 
before surgery) and the dose-escalation phase for Cohort A2, if the safety review determines 
that Cohort A2 will be opened.  Once Cohort A2 is completed, another safety review will 
determine whether to use the recommended combination dose (RCD) from Cohort A1 or A2 
to start enrollment into the Cohort B (subjects with metastatic/locally advanced OC) 
expansion phase. 
Subjects in Cohorts C/C-FLOT and D/D2 will undergo surgery after completing treatment, and 
they will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once 


 
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recovered from surgery, provided that this is within 3 months of surgery. Subjects in Cohort 
C-FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at the discretion of the 
investigator. 
Primary objectives:  
• 
Assess the Safety/Tolerability of durvalumab alone and tremelimumab + durvalumab in 
combination with oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced 
OC (Endpoint: CTCAE version 4.03). 
• 
Assess the Safety/Tolerability of durvalumab in combination with neoadjuvant 
chemo(radio)therapy (oxaliplatin/capecitabine, FLOT, and 
paclitaxel/carboplatin/radiotherapy) in operable OC. (Endpoint: CTCAE version 4.03). 
Secondary objectives:  
• Assess the Clinical Efficacy of durvalumab alone and tremelimumab + durvalumab in 
combination with oxaliplatin/capecitabine chemotherapy in metastatic or locally advanced 
OC.  (Endpoints: Tumor Response by irRECIST, progression-free survival (PFS) and overall 
survival (OS)) 
• Assess the Clinical Efficacy of durvalumab in combination with neoadjuvant 
chemo(radio)therapy (oxaliplatin/capecitabine, FLOT, and 
paclitaxel/carboplatin/radiotherapy) in operable OC.  (Endpoints: PFS after surgery, 1-year 
survival rate, OS, pathological and metabolic response rate) 
Exploratory objectives: 
• Evaluate the immunological effects of durvalumab and tremelimumab + durvalumab in 
tumor and peripheral blood samples.  
• Relate the effects of immune modulation to allele variance, gene expression and host-
pathogen relationships in the upper gastrointestinal tracts of OC subjects. 
• Evaluate genomic differences between subjects who exhibit differential immune and 
therapeutic responses to durvalumab and tremelimumab + durvalumab therapy. 
Per Amendment 8: 
All subjects have completed treatment and On Study Follow-up. This amendment provides 
that the Post Study Follow-up for the collection of survival data will be discontinued as of 
30 June 2022, and the study will be completed. As of 30 June 2022, all but up to 8 subjects 
will have completed the 3-year Post Study Follow-up, which would have occurred by 
December 2022 for the remaining subjects. 
 
 
 


 
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Sponsor: Ludwig Institute for Cancer Research Ltd., 
New York, NY 
 
Local Sponsor: Ludwig Institute for Cancer Research 
Ltd., Oxford, UK 
 
 
 
 
 
 
 
 
 
Sponsor Representative Signature and Date 
Study Chair/Chief Investigator: Professor Mark 
Middleton, Department of Oncology, University of 
Oxford, UK 
 
 
 
 
 
 
 
 
 
 
 
Study Chair/Chief Investigator Signature and Date 
 
Confidentiality Statement 
The confidential and proprietary information in this document is owned by the Ludwig Institute for Cancer Research and 
provided to you as an Investigator, potential Investigator, or consultant, for review by you, your staff, and applicable institutional 
review board(s)/ethics committees.  The information cannot be used, or divulged to any third party or published without the 
written consent of the Ludwig Institute for Cancer Research, except to the extent necessary to obtain informed consent from 
those persons to whom study medication may be administered.  Any misappropriation of this information is prohibited by law. 
 
 
 


 
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Table of Contents 
1 
Background ............................................................................................................................. 8 
1.1 
Oesophageal Cancer ....................................................................................................... 8 
1.2 
Oesophageal Cancer and Immunotherapy ..................................................................... 8 
1.3 
CTLA-4 ............................................................................................................................. 8 
1.4 
PD-1 and PD-L1................................................................................................................ 9 
1.5 
Combination Therapy ...................................................................................................... 9 
1.6 
Study Drugs ................................................................................................................... 10 
1.6.1 
Capecitabine .......................................................................................................... 10 
1.6.2 
Oxaliplatin .............................................................................................................. 10 
1.6.3 
Paclitaxel ................................................................................................................ 10 
1.6.4 
Carboplatin ............................................................................................................ 11 
1.6.5 
Durvalumab (MEDI4736) ....................................................................................... 11 
1.6.6 
Tremelimumab ...................................................................................................... 12 
2 
Study Rationale ..................................................................................................................... 14 
2.1 
Rationale for Amendment 2 .......................................................................................... 14 
2.1.1 
Change from Oxaliplatin-Capecitabine CRT to Paclitaxel-Carboplatin .................. 14 
2.1.2 
Elimination of the induction chemotherapy prior to neoadjuvant CRT ................ 15 
2.1.3 
Reduction of the radiotherapy dose ..................................................................... 15 
2.2 
Rationale for Amendment 6 .......................................................................................... 15 
2.3 
Rationale for Amendment 7 .......................................................................................... 17 
3 
Experimental Plan ................................................................................................................. 19 
3.1 
Study Design .................................................................................................................. 19 
3.1.1 
Study Phase ........................................................................................................... 19 
3.1.2 
Enrollment/Randomization ................................................................................... 19 
3.1.3 
Blinding/Unblinding ............................................................................................... 20 
3.1.4 
Subject Population................................................................................................. 20 
3.1.5 
No. of Sites/Subjects.............................................................................................. 20 
3.1.6 
Sample Size and Statistical Considerations ........................................................... 20 
3.1.7 
Treatment Arms and Treatment Schema .............................................................. 21 
3.1.7.1 
Phase 1 – Safety Run-in ................................................................................. 25 
3.1.7.2 
Phase 2 – Expansion Phase ............................................................................ 26 
3.1.8 
Dosing Adjustments, Delays and Discontinuations ............................................... 27 
3.1.9 
DLT ......................................................................................................................... 27 
3.1.10 
Subject Withdrawal ............................................................................................... 29 
3.1.10.1 Treatment Beyond Progression ..................................................................... 30 
3.1.11 
Subject Replacements ........................................................................................... 30 
3.1.12 
Optional Study Treatment Extension .................................................................... 30 
3.1.13 
Interim Analysis ..................................................................................................... 30 
3.1.14 
Safety Monitoring and Study Stopping Rules ........................................................ 30 
3.1.15 
Duration of Study .................................................................................................. 31 


 
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3.1.16 
On Study and Post Study Follow-up ...................................................................... 31 
3.1.16.1 End of Study Visit ........................................................................................... 32 
3.2 
Study Flowcharts ........................................................................................................... 33 
3.2.1 
Study Flowchart for All Cohorts Except Cohort C-FLOT and Cohort D2 ................ 34 
3.2.2 
Study Flowchart for Cohort C-FLOT ....................................................................... 37 
3.2.3 
Study Flowchart for Cohort D2 .............................................................................. 40 
4 
Study Objectives & Endpoints .............................................................................................. 43 
4.1 
Safety and Tolerability .................................................................................................. 43 
4.1.1 
Endpoints & Assessment Methods ........................................................................ 43 
4.1.2 
Subject Evaluation & Statistics .............................................................................. 44 
4.2 
Clinical Efficacy .............................................................................................................. 45 
4.2.1 
Endpoints & Assessment Methods ........................................................................ 45 
4.2.1.1 
Tumor Response Assessment by irRECIST ..................................................... 45 
4.2.1.2 
Progression-free Survival Rate ...................................................................... 45 
4.2.1.3 
Objective Response Rate ............................................................................... 45 
4.2.1.4 
Overall Survival .............................................................................................. 46 
4.2.2 
Subject Evaluation & Statistics .............................................................................. 46 
4.3 
Immune Monitoring ...................................................................................................... 46 
4.3.1 
Endpoints & Assessment Methods ........................................................................ 46 
4.3.2 
Subject Evaluation & Statistics .............................................................................. 47 
4.4 
Genomic Investigation .................................................................................................. 47 
5 
Subject Eligibility ................................................................................................................... 48 
5.1 
Inclusion Criteria ........................................................................................................... 48 
5.2 
Exclusion Criteria ........................................................................................................... 49 
5.3 
Restrictions on Concomitant Therapies ........................................................................ 53 
5.3.1 
Non-Permitted Concomitant Therapies ................................................................ 53 
5.3.2 
Permitted Concomitant Therapies ........................................................................ 55 
6 
Study Drug Preparation and Administration and Radiotherapy Delivery ............................ 56 
6.1 
Oxaliplatin ..................................................................................................................... 56 
6.2 
Capecitabine .................................................................................................................. 56 
6.3 
Paclitaxel ....................................................................................................................... 56 
6.4 
Carboplatin .................................................................................................................... 56 
6.5 
5-Fluorouracil ................................................................................................................ 56 
6.6 
Leucovorin ..................................................................................................................... 56 
6.7 
Docetaxel....................................................................................................................... 56 
6.8 
Tremelimumab .............................................................................................................. 57 
6.8.1 
Tremelimumab Study Drug Information ............................................................... 57 
6.8.2 
Tremelimumab Investigational Product Inspection .............................................. 57 
6.8.3 
Tremelimumab Preparation .................................................................................. 57 
6.8.4 
Tremelimumab Administration ............................................................................. 58 
6.9 
Durvalumab (MEDI4736) ............................................................................................... 59 
6.9.1 
Durvalumab (MEDI4736) Study Drug Information ................................................ 59 
6.9.2 
Durvalumab Investigational Product Inspection ................................................... 59 


 
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6.9.3 
Durvalumab Preparation ....................................................................................... 59 
6.9.4 
Durvalumab Administration .................................................................................. 60 
6.10 
Estimated Study Drug Requirements ............................................................................ 61 
6.11 
Monitoring of Tremelimumab and Durvalumab Administration .................................. 61 
6.12 
Drug Overdose Management ........................................................................................ 62 
6.12.1 
Capecitabine, Oxaliplatin, Paclitaxel, Carboplatin, and FLOT (5-fluorouracil (5-FU), 
leucovorin, oxaliplatin, and docetaxel) ................................................................................. 62 
6.12.2 
Durvalumab and Tremelimumab........................................................................... 62 
6.13 
Radiotherapy Delivery ................................................................................................... 62 
7 
Administrative, Legal & Ethical Requirements ..................................................................... 63 
7.1 
Documentation and Reporting of Adverse Events ........................................................ 63 
7.1.1 
General AE/SAE Definitions per ICH Guidelines .................................................... 63 
7.1.2 
Additional Expedited Reporting Requirements for this Study .............................. 64 
7.1.2.1 
Pregnancy ...................................................................................................... 64 
7.1.2.2 
Overdose ....................................................................................................... 65 
7.1.2.3 
Hepatic Function Abnormality ....................................................................... 65 
7.1.3 
Severity of an Adverse Event ................................................................................. 65 
7.1.4 
Relationship of Adverse Events to Study Drug ...................................................... 65 
7.1.5 
General Reporting Requirements .......................................................................... 66 
7.1.6 
Expedited Serious Adverse Event (SAE) Reporting Requirements ........................ 67 
7.1.7 
Serious Adverse Event (SAE) Follow-up Requirements ......................................... 68 
7.1.8 
Adverse Events of Special Interest (AESIs) ............................................................ 68 
7.2 
Administrative Sponsor Requirements ......................................................................... 71 
7.2.1 
Pre-Study Requirements........................................................................................ 71 
7.2.2 
Study Master Files ................................................................................................. 71 
7.2.3 
Case Report Form Data Collection ........................................................................ 71 
7.2.4 
Language ................................................................................................................ 72 
7.2.5 
Monitoring ............................................................................................................. 72 
7.2.6 
Protocol Amendments ........................................................................................... 72 
7.2.7 
Premature Subject Withdrawal ............................................................................. 72 
7.2.8 
Early Trial Termination .......................................................................................... 73 
7.2.9 
Study Drug Shipments & Accountability ............................................................... 73 
7.3 
Regulatory, Legal & Ethical Requirements .................................................................... 73 
7.3.1 
Good Clinical Practice (GCP), Laws and Regulations ............................................. 73 
7.3.2 
Informed Consent .................................................................................................. 74 
7.3.3 
Research Ethics Committee ................................................................................... 74 
7.3.4 
Subject Confidentiality .......................................................................................... 74 
8 
Appendices ........................................................................................................................... 75 
8.1 
Protocol Version History ............................................................................................... 75 
8.2 
Participating Study Sites, Investigators and Staff ......................................................... 96 
8.3 
Participating Laboratories ............................................................................................. 96 
8.4 
Sponsor Information ..................................................................................................... 96 
8.5 
Dose Adjustments and Delays for Durvalumab ............................................................ 97 
8.5.1 
Durvalumab Dose Modification Due to Toxicity ................................................... 97 


 
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8.5.2 
Durvalumab Dose Modification Not Due to Toxicities ........................................ 100 
8.6 
Dose Modification and Management Guidelines for Oxaliplatin/Capecitabine, FLOT, 
and Surgery ............................................................................................................................. 101 
8.6.1 
Non Haematological Toxicity ............................................................................... 101 
8.6.1.1 
Rash 101 
8.6.1.2 
Diarrhoea ..................................................................................................... 101 
8.6.1.3 
Mucositis/Stomatitis.................................................................................... 102 
8.6.1.4 
Neuropathy .................................................................................................. 102 
8.6.1.5 
Hand/Foot Syndrome .................................................................................. 102 
8.6.1.6 
Allergic Reactions to Oxaliplatin .................................................................. 102 
8.6.1.7 
Dose Modification for Other Non-haematological Toxicity ........................ 103 
8.6.2 
Haematological Toxicity ...................................................................................... 104 
8.6.3 
Surgery ................................................................................................................. 104 
8.7 
Dose Modification and Management Guidelines for Paclitaxel/Carboplatin, 
Radiotherapy, and Surgery ..................................................................................................... 105 
8.7.1 
Haematologic Related Toxicity ............................................................................ 105 
8.7.2 
Non-Haematologic Toxicity ................................................................................. 106 
8.7.3 
Radiotherapy Toxicity .......................................................................................... 108 
8.7.4 
Surgery ................................................................................................................. 109 
8.8 
RECIST 1.1 and irRECIST Guidelines ............................................................................ 110 
8.9 
Laboratory Procedures ................................................................................................ 118 
8.9.1 
Additional Translational and Exploratory Studies ............................................... 118 
8.10 
List of Abbreviations.................................................................................................... 119 
9 
References .......................................................................................................................... 121 
 
 
Table of Figures 
Figure 1: Treatment Schema ......................................................................................................... 25 
Figure 2: Dose Escalation Schema ................................................................................................. 26 
 
 


 
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1 Background 
1.1 
Oesophageal Cancer 
Oesophageal adenocarcinoma (OAC) and oesophageal squamous cell carcinoma (OSCC) are the 
main types of oesophageal cancer (OC) and have an overall 5-year survival of less than 15%.1  
Oesophageal cancer is the sixth leading cause of cancer death world-wide.  In western countries, 
its incidence has risen six fold in less than 40 years.2  Despite large scale prospective studies of 
varying therapeutic regimes, mortality has remained closely related with OC incidence, 
indicating a failure to improve overall survival outcomes.3  Treatment is broadly separated into 
endoscopic, for in-situ disease, surgical with neoadjuvant chemo(radio)therapy, and palliative 
approaches.  Oesophageal cancer is often diagnosed late; hence only 23% of cases are suitable 
for curative surgery, complicated by a poor quality of life postoperatively and a 2-year 
recurrence rate of almost 50%.4  Recent studies investigating novel chemotherapeutic regimes 
and targeted molecular inhibitors have been disappointing, conferring no overall survival 
advantages; therefore, new treatment strategies are urgently needed. 
1.2 
Oesophageal Cancer and Immunotherapy 
Both OAC and OSCC have been characterized as promoting a strong immune response, in 
addition to their well-established inflammatory aetiologies.5  Oesophageal adenocarcinoma 
occurs as a stepwise progression via Barrett’s metaplasia in the distal oesophagus.  The immune 
response to oesophageal inflammation is a key process driving the aberrant differentiation 
steps, which result in Barrett’s metaplasia and subsequent adenocarcinogenesis.  Specific 
cytokines related to Th2 response, and a range of gene mutations, are shown to drive columnar 
differentiation, predict subsequent carcinogenesis, and associate with prognosis.6,7  Tumors, in 
general, have developed immune silencing abilities that can turn off the innate and effector 
elements of the immune system.  Thus, subversion of key immune checkpoints has emerged as 
an exciting cancer therapeutic strategy directed at augmenting host-immune response to the 
tumor microenvironment.  Oesophageal cancer is spontaneously targeted by the immune 
system and increased anti-tumor immune response has been associated with improved 
outcomes.  This would suggest that emerging immunotherapy-based treatments could provide a 
desperately needed strategy for successful OC treatment.  
Identifying specific tumor rejection antigens in OC has not yielded success, limiting efficacious 
molecular vaccine design.  Current treatment relies on chemotherapy and targeted 
radiotherapy, relying on a direct tumoricidal effect rather than immune-mediated cell killing.  
Existing OC neoadjuvant strategies include chemotherapy alone with platinum and 
fluoropyrimidine agents, or chemoradiotherapeutic approaches also based on platinum agents.  
Radiotherapy can augment immune activation in the tumor microenvironment, via increased 
tumor production of IFN-β, which leads to T-cell priming and T-cell dependent tumor 
regression.8  
1.3 
CTLA-4 
Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) is a member of the immunoglobulin family and 
locates on the T-cell surface following activation.  Activation of CTLA-4 has been established as 
having a direct effect on T-cell attenuation and an inhibitor of this action formed the first FDA 
approved immune checkpoint blockade therapy.9  Inhibition of CTLA-4 demonstrates frequent 
tumor rejection in immunocompetent mouse models of cancer; however, human trials in 


 
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melanoma have been less successful with anti-CTLA-4 monotherapy, as efficacy is largely 
dependent on tumor immunogenicity.10  Activity in OC has to date been limited, with only 1 of 
18 subjects treated with tremelimumab responding. More recent anti-CTLA-4 studies have 
involved combination therapeutic approaches with success in murine and melanoma models.11  
1.4 
PD-1 and PD-L1 
The programmed cell death-1 (PD-1) pathway is expressed by activated T-cells, but not resting T-
cells, and is regarded as a broadly negative T-cell regulator.  Programmed cell death-1 is 
demonstrated to mostly restrain the immune response in chronic inflammation, infection, and 
cancer.  Two ligands, PD-L1 and PD-L2, bind PD-1.  PD-L1 is upregulated in many inflammatory 
cancers, and OCs, suggesting that PD-1 PD-L1/2 interaction is a key checkpoint employed by 
tumors to evade host-immune response.  Expression of PD-L1, which is associated with 
increased chance of response to PD-1 and PD-L1 targeted agents in multiple tumor types, is 
evident in half of OCs.12  Ligand expression is associated with a poorer prognosis after 
oesophageal resection.  
The safety, tolerability, pharmacokinetics, and anti-tumor activity of MEDI4736 (durvalumab) is 
being evaluated in an ongoing multicenter, open-label, Phase 1/2 study in advanced solid 
tumors including gastroesophageal cancer (Study CD-ON-MEDI4736-1108). As of 21 August 
2014, preliminary data were available for 41 gastroesophageal subjects treated with MEDI4736 
10 mg/kg Q2W in the expansion phase of Study CD-ON-MEDI4736-1108.13 In this population, 
MEDI4736 demonstrated an acceptable safety profile, which appeared to be consistent with the 
overall study population treated with MEDI4736 10 mg/kg Q2W. Among 41 gastroesophageal 
subjects, 35 (85%) experienced an adverse event (AE) of any grade, regardless of causality, while 
22 (54%) experienced a treatment-related AE. Treatment-related Grade ≥ 3 AEs were reported 
in 7 (17%) of patients. No treatment-related AEs led to permanent discontinuation or death. As 
of this data cutoff, 28 subjects were evaluable for response with the potential for ≥ 12 weeks of 
follow up (including subjects with ≥1 follow up disease assessment or death or discontinuation 
to due disease progression prior to first assessment). Among the 28 evaluable subjects, 2 (7%) 
achieved an objective response and 5 (18%) maintained stable disease for ≥ 12 weeks. PD-L1 
expression data were not available for subgroup analyses of response. 
1.5 
Combination Therapy 
Targeting PD-1 and PD-L1 has yielded exciting and durable anti-tumor activity in some advanced 
solid organ cancers14 and enabled fast tracking of durvalumab (MEDI4736), amongst other 
agents, directly to Phase 3 trials.  Specific to OC, PD-1/PD-L1 immune targeted approaches 
demonstrate efficacy in immunocompetent mouse models of cancer and objective responses 
have been observed in the Phase 1 study of durvalumab.  These clinical and preclinical findings 
indicate that PD-1/PD-L1 is an attractive therapeutic target in oesophageal cancer.13  
Accumulating evidence suggests that immune priming of the tumor microenvironment is 
specifically beneficial in immune therapy approaches.  Chemotherapy mediated immune 
priming, either in combination or in sequence with anti-PD-L1, offers an exciting novel 
therapeutic strategy in operable OC.  
Characterization of anti-CTLA-4/anti-PD-L1 effects in human studies has been mainly clinically 
based.  The impact of anti-CTLA4 or anti-PD-L1 immune modulation on gene expression in OC 
has not been explored.  A multidisciplinary clinical and scientific investigative team, 


 
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encompassing genomics, molecular biology, immunology, and oncology, provides a novel 
opportunity to holistically characterize anti PD-L1 and CTLA-4 therapeutic consequence in OC.  
The track record of this collaboration is validated with several high impact co-authored 
publications.15,16 
Existing protocols for immune monitoring and clinical response provide important quantitative 
details of individual immune response, but cannot inform individual subject response to 
immune priming at a protein level, or whether a differential OC response is anticipated. 
Furthermore, relevant cytokine responses are linked to specific gastrointestinal microbiomic 
features that associate with oesophageal metaplasia,17 a key target in cancer prevention 
strategies.  Additionally, comparison between stratified response groups has not been reported 
at a genomic resolution to explore the determination and organisation of effective immune 
responses to cancer, in the context of new immunotherapeutic combinations.  Combining 
immune monitoring and genomic data obtained before and during the proposed OC therapy 
regimen will provide greater understanding of the mechanistic effects of immunotherapy, and 
whether immune checkpoint blockade response in humans can be determined in a personalised 
fashion. 
1.6 
Study Drugs 
The drugs used in this study are Investigational Medicinal Products (IMPs). 
1.6.1 Capecitabine 
Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, which functions as an orally 
administered precursor of the cytotoxic moiety 5-fluorouracil (5-FU).  Capecitabine is activated 
via several enzymatic steps.  The enzyme involved in the final conversion to 5-FU, thymidine 
phosphorylase (ThyPase), is found in tumor tissues, but also in normal tissues, albeit usually at 
lower levels.  Fluorouracil is further metabolized to 2 active metabolites, 5-fluoro-2-
deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP), within normal 
and tumor cells.  FdUMP inhibits DNA synthesis by reducing normal thymidine production, while 
FUTP inhibits RNA and protein synthesis by competing with uridine triphosphate. 
1.6.2 Oxaliplatin 
Oxaliplatin is an antineoplastic active substance belonging to a class of platinum-based 
compounds in which the platinum atom is complexed with 1,2-diaminocyclohexane (DACH) and 
with an oxalate ligand as a leaving group.  After displacement of the labile oxalate ligand leaving 
group, active oxaliplatin derivatives, such as monoaquo and diaquo DACH platinum, alkylate 
macromolecules, forming both inter- and intra-strand platinum-DNA crosslinks, which result in 
inhibition of DNA replication and transcription and cell-cycle nonspecific cytotoxicity.  
Oxaliplatin exhibits a wide spectrum of both in vitro cytotoxicity and in vivo anti-tumor activity 
in a variety of tumor model systems including various cisplatin resistant models.  A synergistic 
cytotoxic action has been observed in combination with 5-fluorouracil both in vitro and in vivo.  
1.6.3 Paclitaxel 
Paclitaxel belongs to a class of chemotherapy drugs called plant alkaloids. The vinca alkaloids are 
made from the periwinkle plant, while taxanes are made from the bark of the Pacific Yew tree 
(taxus). The vinca alkaloids and taxanes are also known as antimicrotubule agents. Paclitaxel’s 


 
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mechanism of action involves interference with the normal breakdown of microtubules during 
cell division.  See Section 2.1 for additional information. 
1.6.4 Carboplatin 
Carboplatin is a platinum coordination complex and alkylating agent which is used as a 
chemotherapeutic agent for the treatment of various cancers.  It is an alkylating agent and 
causes cross linking in DNA strands, which leads to inhibition of DNA and RNA and triggers cell 
death in rapidly dividing cells.  See Section 2.1 for additional information. 
1.6.5 Durvalumab (MEDI4736) 
Durvalumab is briefly described in this section below.  Refer to the current Investigator Brochure 
(IB) for complete and current information. 
Durvalumab is a human immunoglobulin G1 kappa monoclonal antibody (mAb) directed against 
human PD-L1.  Durvalumab is selective for recombinant PD-L1 and blocks the binding of 
recombinant PD-L1 to the PD-1 and cluster of differentiation (CD) 80 receptors.  
As of the data cutoff dates in the IB (15Apr2015 to 12Jul2015), a total of 1,883 subjects have 
been enrolled and treated in 30 ongoing durvalumab clinical studies, including 20 sponsored (6 
monotherapy and 14 combination therapy) and 10 collaborative studies. Of the 1,883 subjects, 
1,279 received durvalumab monotherapy, 440 received durvalumab in combination with 
tremelimumab or other anticancer agents, 14 received other agents (1 gefitinib, 13 MEDI6383), 
and 150 have been treated with blinded investigational product. No studies have been 
completed or terminated prematurely due to toxicity. 
The safety profile of durvalumab as monotherapy and combined with other anticancer agents 
was consistent with the pharmacology of the target and other agents in the immune checkpoint 
inhibitor class. No tumor types appeared to be associated with unique AEs, with the exception 
of patients with squamous cell carcinoma of the head and neck (SCCHN) where a higher 
incidence of bleeding has been reported. Immune-related AEs (irAEs), which are important risks 
of immune checkpoint inhibitors, have been observed with durvalumab and include colitis, 
pneumonitis, hepatitis/hepatotoxicity, neuropathy / neuromuscular toxicity, endocrinopathies 
such as hypo- and hyper-thyroidism, hypophysitis, adrenal insufficiency and type I diabetes 
mellitus, dermatitis, and nephritis. In addition, pancreatitis is an important potential risk 
particularly with durvalumab and tremelimumab combination therapy. These events are 
manageable by available/established treatment guidelines as described in the study protocols.  
Partial efficacy data are available for 2 monotherapy studies (CD-ON-MEDI4736-1108 and 
D4190C00007) and 2 combination therapy studies (CD-ON-MEDI4736-1161 and D4190C00006). 
Clinical activity has been observed across the 4 studies. 
According to MedImmune, the recommended dosing schedule for durvalumab is 20 mg/kg Q4W 
or 10mg/kg Q2W. The fixed dosing for durvalumab was selected based on pharmacokinetic (PK) 
models.   
Using population PK models, simulations indicated that both body weight-based and fixed 
dosing regimens of durvalumab yield similar median steady state PK concentrations with slightly 
less between-subject variability with fixed dosing regimens.  A fixed dosing approach is 
preferred by the prescribing community due to ease of use and reduced dosing errors. Given 


 
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expectation of similar PK exposure and variability, MedImmune considers it feasible to switch to 
fixed dosing regimens. Based on an average body weight of 75 kg, a fixed dose of 750 mg Q2W 
durvalumab is equivalent to 10 mg/kg Q2W, and 1500 mg Q4W durvalumab is equivalent to 20 
mg/kg Q4W.  This study will use a fixed dose of 750 mg Q2W for durvalumab. 
1.6.6 Tremelimumab 
Tremelimumab is briefly described in this section below.  Refer to the current IB for complete 
and current information. 
Tremelimumab (formerly CP-675,206) is a human immunoglobulin G2 (IgG2) mAb being 
investigated as a cancer immunotherapeutic agent.  Tremelimumab is specific for human CTLA-
4, with no cross-reactivity to related human proteins. 
As of the data cutoff date of 12Nov2014 (for all studies except D4190C00006 that has a cutoff 
date of 04Dec2014), 22 sponsored clinical studies have been conducted as part of the 
tremelimumab clinical development program. Of these studies, 13 have been completed and 9 
are ongoing. Tremelimumab has been administered as monotherapy to 973 subjects 
participating in 10 of the 22 clinical studies, 2 of which are ongoing. An additional 497 subjects 
have received tremelimumab or placebo in the ongoing double-blinded, Phase 2b mesothelioma 
study, D4880C00003(DETERMINE). Tremelimumab in combination with other anticancer agents 
has been administered to 208 subjects with a variety of tumor types in 12 of the 22 clinical 
studies, 7 of which are ongoing. 
In clinical subjects, tremelimumab exhibits linear (dose-proportional) PK following intravenous 
(IV) infusion. 
Across the clinical development program for tremelimumab, a pattern of efficacy has emerged, 
also observed for the related anti-CTLA-4 antibody, ipilimumab, which appears to be consistent 
across tumor types for this mechanism of action. Response rates to anti-CTLA-4 antibodies are 
generally low, approximately 10%. However, in subjects who respond, the responses are 
generally durable, lasting several months even in subjects with aggressive tumors such as 
refractory metastatic melanoma. Some subjects may have what is perceived to be progression 
of their disease in advance of developing disease stabilization or a tumor response. Overall, the 
impact on conventionally-defined progression-free survival (PFS) can be small; however, the 
durable response or stable disease seen in a proportion of subjects can lead to significant 
prolongation of overall survival (OS).  
The profile of adverse events (AEs) and the spectrum of event severity have remained stable 
across the tremelimumab clinical program and are consistent with the pharmacology of the 
target. To date, no tumor type or stage appears to be associated with unique AEs (except for 
vitiligo that appears to be confined to subjects with melanoma).  As of the data cutoff date of 
12Nov2014 (for all studies except D4190C00006 that has a cutoff date of 04Dec2014), AEs (all 
grades, regardless of causality) reported in > 10% of subjects in the completed and rollover 
tremelimumab monotherapy studies (N = 973, integrated data) were diarrhea (45.3%), fatigue 
(37.5%), nausea (32.5%), rash (28.8%), pruritus (27.3%), decreased appetite (22.8%), vomiting 
(22.5%), pyrexia (15.3%), cough (15.0%), constipation (14.4%), abdominal pain (13.9%), 
headache (13.8%), dyspnea (12.4%), and decreased weight (10.2%). Based on integrated data 
from completed studies of tremelimumab in combination with other agents (N = 116), AEs (all 
grades, regardless of causality) reported in > 15% of subjects were diarrhea (54.3%); nausea 


 
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(40.5%); fatigue (38.8%); rash (35.3%); pruritus, decreased appetite (30.2% each); vomiting 
(27.6%); pyrexia (26.7%); influenza like illness (20.7%); arthralgia (19.8%); constipation (19.0%); 
thrombocytopenia, injection site reaction (18.1% each); and increased aspartate 
aminotransferase (15.5%). Most of these events occurred at a higher rate with tremelimumab 
plus sunitinib than with other combinations. The events of diarrhea, rash, and pruritus are 
considered identified risks of tremelimumab. Acute renal failure was reported in subjects who 
received the combination of tremelimumab and sunitinib; however, acute renal failure has not 
been an expected AE for single-agent tremelimumab. The incidence and/or severity of many of 
the AEs observed following administration of tremelimumab can be reduced by following 
current guidelines for the management of immune-related toxicities. 
According to MedImmune, the dose selection of 1 mg/kg Q4W for tremelimumab when 
combined with 20 mg/kg Q4W for durvalumab was based on the identification of an optimal 
dose of durvalumab that would “yield sustained target suppression, optimize synergy of the 
combination, while maintaining the balance of safety in combination with tremelimumab.” This 
is consistent with the dosing regimen to be evaluated in the MedImmune program going 
forward. 
The fixed dosing for tremelimumab is based on information from MedImmune, which indicates 
that the dose and schedule of 75 mg tremelimumab Q4W when combined with durvalumab was 
selected based on PK models as described below.   
Using population PK models, simulations indicated that both body weight-based and fixed 
dosing regimens tremelimumab yield similar median steady state PK concentrations with slightly 
less between-subject variability with fixed dosing regimens.  A fixed dosing approach is 
preferred by the prescribing community due to ease of use and reduced dosing errors. Given 
expectation of similar PK exposure and variability, MedImmune considers it feasible to switch to 
fixed dosing regimens. Based on an average body weight of 75 kg, a fixed dose of 75 mg Q4W 
tremelimumab is equivalent to 1 mg/kg Q4W. 
 
 


 
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2 Study Rationale 
While combination anti-CTLA-4/anti-PD-L1 therapy for OC is potentially interesting, its toxicity 
makes building this into existing treatment regimens difficult.  In particular, the overlapping 
toxicity profiles of fluoropyrimidines and CTLA-4 antibodies present a challenge.  The evidence is 
not yet sufficiently developed to justify anti-CTLA-4/anti-PD-L1 therapy use in place of 
chemo(radio)therapy.  There is, however, preclinical work that supports the combination of 
anti-PD-L1 with radiotherapy 18 and oxaliplatin 19. 
This study will focus on subjects with operable tumors so the tumor, microenvironment, and 
surrounding organ can be studied in detail.  This also serves as a point of distinction from 
existing work in OC with durvalumab.  As these subjects can potentially be cured, safety 
considerations, specifically ensuring that oesophagectomy is not compromised, are paramount.  
In the United Kingdom (UK), the standard of care for operable OC is platinum and 
fluoropyrimidine chemotherapy for two 3-week cycles, followed by surgery, 6 to 8 weeks later.  
Pre-operative chemoradiation with the same drugs is the standard approach for middle and 
higher OCs, including squamous cell histologies.  
In this study, the documented tolerability of existing durvalumab regimens will be combined 
with neoadjuvant chemotherapy, or it will be given prior to chemoradiotherapy (CRT) in subjects 
with operable OC. 
2.1 
Rationale for Amendment 2 
For Amendment 2, the following key changes were implemented for Cohort D: 
1. The oxaliplatin-capecitabine backbone of the CRT regimen was replaced with a 
paclitaxel/carboplatin regimen. 
2. The Induction chemotherapy component of the neoadjuvant CRT regimen was 
eliminated 
3. The radiotherapy (RT) dose was changed to 41.4 Gy in 23 fractions compared to the 
previous 45 Gy in 25 fractions).  
2.1.1 
Change from Oxaliplatin-Capecitabine CRT to Paclitaxel-Carboplatin 
The fluoropyrimidine–platinum (traditionally 5Fu-cisplatin) based CRT regimen has long been a 
standard of care in the pre-operative management of oesophageal cancer. The use of this 
combination has been largely historic, with only one small positive phase trial, and several meta-
analyses supporting its use over surgery alone.20,21 
The oxaliplatin-capecitabine based CRT regimen was selected over the cisplatin-fluoropyrimidine 
regime prior to Amendment 2 based on several factors including: (1) maintaining the same 
chemotherapy backbone as proposed in the neoadjuvant chemotherapy arm of the trial; (2) a 
randomized Phase 2 study in definitive chemoradiation showing comparable efficacy and less 
toxicity of oxaliplatin-5FU combination in comparison to cisplatin-5FU combination22; (3) 
Emerging Phase 1b/2 data suggesting feasibility and activity of oxaliplatin-fluoropyrimidine 
based CRT regimens in the pre-operative setting23-25; and (4) use of this regimen in the 
NEOSCOPE trial, a randomized Phase 2 trial that was ongoing in the UK at the time when this 
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However, over the last 2-3 years, there has been an increasing shift in international practice in 
favor of a neoadjuvant CRT regimen consisting of weekly paclitaxel and carboplatin as the 
chemotherapy backbone. This shift is based on the CROSS trial,27 which is the largest trial to 
date in neoadjuvant CRT. For this trial, 368 subjects were randomized between surgery alone or 
pre-op CRT and showed a near doubling of median survival, with low level of Grade 3/4 
hematological (7%) and non-hematological (13%) toxicity. The NEOSCOPE trial, a Phase 2 trial, 
randomized 85 subjects to oxaliplatin based CRT vs weekly paclitaxel/carboplatin based CRT.28 
The study demonstrated inferior outcome with the oxaliplatin/capecitabine arm (pathological 
complete response rate 14%) compared to paclitaxel/ carboplatin based CRT (pathological 
complete response rate 29%). Based on the low response rates in the oxaliplatin arm, it is 
unlikely to be pursued as the chemotherapy backbone in future CRT trials. Additionally, a 
retrospective study (n=165) comparing cisplatin-5FU based pre-operative CRT to 
paclitaxel/carboplatin based regimen has also suggested lower toxicity with the 
paclitaxel/carboplatin regimen with non-significant differences in response rates and long term 
survival.29  
2.1.2 Elimination of the induction chemotherapy prior to neoadjuvant CRT 
The CRT arm of the pre Amendment 2 protocol was adapted from the NEOSCOPE study and 
therefore included induction chemotherapy. In the past few years, there have been emerging 
data questioning the role of induction chemotherapy (ICT) prior to neoadjuvant CRT. Two 
randomized Phase 2 studies have failed to show benefit for ICT, and one of the studies has 
shown an increase risk of thrombocytopenia and reduction in dose intensity in the ICT arm.30,31 
In the NEOSCOPE trial there was an increase in Grade 3/4 hematological toxicity compared to 
CROSS; all 3 treatment-related deaths occurred during ICT and no deaths were seen during CRT. 
Thus, based on likely benefits and harm, ICT is no longer viewed as advisable in the neoadjuvant 
setting. 
2.1.3 Reduction of the radiotherapy dose 
Per Amendment 2, the RT dose will be reduced from 45 Gy/25 fractions (NEOSCOPE regimen) to 
41.4 Gy/23 fractions (CROSS regimen).  This decision was based on retrospective data suggesting 
that higher dose of RT may increase post-operative respiratory complications32 and the positive 
outcome of the CROSS trial. 
2.2 
Rationale for Amendment 6 
FLOT is a regimen combining 5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel. 
Based on emerging data, a proposal was made to add Cohort C-FLOT to the study, in addition to 
Cohort C. The proposal for Cohort C-FLOT includes the following: 
1. Replace Oxaliplatin and capecitabine as neo-adjuvant chemotherapy with the FLOT 
regimen to run concurrently with durvalumab treatment. 
2. Introduce post-operative chemotherapy, also with FLOT. This will run concurrently with 
durvalumab immunotherapy. 
3. Subjects allocated to oxaliplatin and capecitabine in Cohort C before the introduction of 
Cohort C-FLOT will not be replaced and will be included in the total 20 Subjects for 
Cohort C + Cohort C-FLOT.  
 


 
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Pre-operative fluoropyrimidine–platinum chemotherapy has long been a standard of care in the 
pre-operative management of oesophageal cancer. Opinions have differed as to the relative 
merits of continuing treatment post-operatively and of adding in an anthracycline (usually 
epirubicin). In metastatic disease taxane chemotherapy has established a role, either as a single 
agent or in combination with platinum and fluoropyrimidine therapy. However, the perceived 
potential for toxicity has limited taxane use in this often frail group of patients.   
More recently the AIO, a German collaborative group, has advocated the use of FLOT (5-FU 2600 
mg/m2 (24-hr IV), leucovorin 200 mg/m2 IV, oxaliplatin 85 mg/m2 IV, and docetaxel 50 mg/m2 IV, 
every two weeks, all on Day 1). The regimen has proved fairly well-tolerated in patients with 
metastatic disease, although the addition of the taxane did increase the rate of higher grade 
adverse events. In older patients, in the FLOT65+ trial, this increase was driven by higher rates of 
Grade 3 or 4 neutropaenia, leucopaenia and nausea. However, the rates of complicated 
neutropenia and of serious adverse events were not increased. As expected, alopecia was also 
significantly more common with the use of a taxane. Diarrhoea was also more common. 
The results of the neo-adjuvant use of FLOT were presented at the ESMO 2017 Congress.33 The 
data demonstrate increased progression-free and overall survival compared with 
fluoropyrimidine–platinum chemotherapy (in this case ECX or ECF). Median PFS improved to 30 
months with FLOT (HR 0.75 vs ECX/ECF; 95% CI 0.62-0.91; p=0.004) and overall survival to 50 
months (HR 0.77; 95% CI 0.63 - 0.94; p=0.012). 
To date, detailed toxicity data have not been presented, but 97% of subjects proceeded to 
surgery (compared with 91% for neo-adjuvant CF in OE05, and 94% for ECF/ECX in FLOT4). SAE, 
post-operative complications and post-operative death rates were the same in both arms of the 
FLOT4 study, but more subjects started post-operative chemotherapy in the taxane arm (60% vs 
52%). 
Following these results, the FLOT regimen is being introduced in the UK and Europe as a 
standard of care for operable oesophageal cancer. As the goal of the LUD2015-005 study is to 
evaluate the addition of durvalumab and/or tremelimumab to standard treatments for this 
cancer, the use of this regimen for Cohort C-FLOT is proposed. The higher rates of neutropaenia 
and nausea are readily manageable and distinct from the side effect profile of checkpoint 
inhibitors. The increase in diarrhea incidence might pose questions of IMP attribution, but we 
are considering the use of FLOT only with durvalumab, as tremelimumab use is confined to the 
metastatic setting. 
Regarding the need for prior evaluation of durvalumab combined with FLOT before use in the 
adjuvant setting, the safety of oxaliplatin, capecitabine and durvalumab has been established 
and there will be information from several subjects in the adjuvant setting before implementing 
the proposed change. Meanwhile, the safety of using anti-PD-1/PD-L1 agents with 
chemotherapies, including taxanes, has been established in multiple trials in neo-adjuvant and 
metastatic settings (e.g., Keynote-059 and -522). For these reasons it is proposed to implement 
FLOT in Cohort C-FLOT, without prior evaluation in subjects with more advanced disease, and to 
monitor safety closely. 
Post-operative chemotherapy will become necessary in Cohort C-FLOT. This will not affect the 
plans for post-operative durvalumab, nor the duration of immunotherapy after surgery. The 


 
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decision as to the implementation of FLOT and durvalumab post-operatively will be delegated to 
the investigator, with the option of using one or other modality as well as the combination. 
Enrollment to Cohort C and Cohort C-FLOT will be managed to ensure that each treatment will 
have at least 8 evaluable subjects. 
2.3 
Rationale for Amendment 7 
Cohort D2: 
For Cohort D of the study, subjects with operable OC receive 2 doses of durvalumab during a 4-
week immunotherapy period, followed by neoadjuvant chemoradiotherapy (5 weekly doses of 
paclitaxel + carboplatin + radiotherapy) without concurrent durvalumab. Per Amendment 7, 
Cohort D2 is added. Cohort D2 is a subset of Cohort D subjects for whom durvalumab doses will 
continue during chemoradiotherapy, after the initial 4-week immunotherapy period. Upon 
approval of Amendment 7, enrollment will proceed to Cohort D2, unless there is a medical 
reason to enroll a specific subject to Cohort D. The rationale for the addition of Cohort D2 is as 
follows. 
There is considerable interest in the potential for radiotherapy to augment the response to 
checkpoint blockade, with pre-clinical and mechanistic evidence for synergy. Until recently 
clinical data have been lacking, with the potential for overlapping toxicities of enteritis or 
pneumonitis a concern according to the site irradiated. 
Trial reports now indicate that PD-1 inhibitors may be safely combined with thoracic irradiation 
at standard doses for the immunotherapies and radiation doses of up to 50 Gy. Maity et al. 
identified no Grade 3 or 4 toxicities in 24 subjects treated with pembrolizumab and radiotherapy 
up to 24Gy, and only 1 Grade 2 episode was reported.34 Luke and colleagues in Chicago found up 
to 50 Gy irradiation well-tolerated with pembrolizumab in 62 subjects.35 Six subjects 
experienced a Grade 3 treatment-related toxicity, but those in which radiotherapy was 
implicated were confined to the field treated. In a retrospective analysis, French oncologists 
found toxicity with nivolumab to be unaffected by the timing of treatment with respect to 
irradiation, including co-administration.36  
The study at Perelman observed an expansion in PD-1+CTLA-4+CD8 cells after irradiation, a 
population associated with anti-tumour efficacy and exhaustion.34 In the PACIFIC trial, where 
durvalumab administration after chemoradiotherapy for NSCLC improved survival over placebo, 
the effect was greatest in the sub-group treated soonest (<14 days) after chemoradiotherapy.37 
These data provide impetus to explore extending durvalumab treatment to overlap with 
chemoradiotherapy and confidence that any additional toxicities will be manageable. We plan 
further mitigation by allowing overlapping treatment only where the study team (e.g., 
Investigator, Chief Investigator, and Sponsor Medical Monitor) have agreed that it is 
appropriate based on a review of the size of the radiation field as well as any potential 
impact on organ function. 
Additional blood testing in long-term survivors: 
Although deep and durable responses to immunotherapy have been observed in many tumour 
types, considerable uncertainty remains regarding their basis. Specifically, there is yet little 


 
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information on the specificity of the T cell populations thought to drive these responses. T cell 
clonal expansion is seen in subjects responding to date, and it is possible to track these over 
time and to look for common specificities in responding subjects. Data from TCR seq allow us to 
identify V beta and alpha chains, but there is considerable value in acquiring samples to purify 
and grow rare tumour-specific T cells from long term responders to better characterize their 
specificities. 
Thus, per Amendment 7, the Investigator(s) will have the option to approach subjects with long-
term survival (PFS > 1 year, still in remission) from the metastatic cohorts (A and B) of the trial to 
request blood (up to 300 mL) for additional testing. 


 
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3 Experimental Plan 
3.1 
Study Design 
This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (and tremelimumab 
for certain cohorts as described in Section 3.1.7) in combination with chemo (radio) therapy 
according to the following cohorts:  
• 
Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally 
advanced oesophageal cancer (OC). 
• 
Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in 
operable OC.  
• 
Cohort C-FLOT: Neoadjuvant FLOT chemotherapy before surgery in operable OC 
(adjuvant FLOT may also be used as described in Sections 3.1.7 and 3.1.12). 
• 
Cohort D/D2: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before 
surgery in operable OC. 
For Cohorts A1, A2, B and C, and C-FLOT, the immunotherapy will be given for a 4-week period 
before starting the chemotherapy, continuing durvalumab treatment once the chemotherapy 
starts.  For Cohort D, the immunotherapy will be given for a 4-week period before starting 
chemoradiotherapy, but the durvalumab dosing will not continue during the 
chemoradiotherapy. A dose of durvalumab will be given following chemoradiotherapy on Day 64 
(±3 days).  If the subject has not completely recovered (per Investigator assessment) by Day 64 
(±3 days), the durvalumab dose may be delayed until Day 71 (±3 days). For a subset of Cohort D 
subjects (Cohort D2), durvalumab doses will continue during chemoradiotherapy, after the 
initial 4-week immunotherapy period. For the chemoradiotherapy period of Cohort D2, 
durvalumab will be given on Cycle 1/Day 1, Cycle 1/Day 15, and Cycle 2/Day 8; durvalumab will 
not be given on Day 64 or 71. Note: Upon approval of Amendment 7, enrollment will proceed to 
Cohort D2, unless there is a medical reason to enroll a specific subject to Cohort D. 
The study will include 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion 
Phase 2 (Cohorts, B, C, C-FLOT, and D/D2).  
3.1.1 Study Phase 
Phase 1/2 
3.1.2 Enrollment/Randomization 
Subjects will be enrolled in a non-randomized manner.  Subject enrollment and the safety of the 
combination regimen will be reviewed on an ongoing basis by an internal data safety monitoring 
panel (see Section 3.1.14). 
Phase 1 will be a safety run-in for Cohort A1 and possibly Cohort A2, as described below.  For 
Cohorts A1 and A2, the start of the study drug administration for the first and second subject 
will be separated by at least 24 hours.  The safety data for subjects in Cohorts A1 and A2 will be 
reviewed for dose-limiting toxicities (DLTs); see Sections 3.1.7.1 and 3.1.9.   
Enrollment will start in Cohort A1. Once this cohort is cleared, enrollment will begin in the Phase 
2 expansion for Cohorts C, C-FLOT, and D/D2.  A safety review will determine whether to open 
the dose-escalation phase for Cohort A2, which will explore the tremelimumab + durvalumab 


 
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combination with a dose-escalation for tremelimumab. Once Cohort A2 is completed, another 
safety review will determine whether to use the recommended combination dose (RCD) from 
Cohort A1 or A2 to start enrollment into the Cohort B expansion phase (see Section 3.1.7). 
Note: Enrollment to Cohort C and Cohort C-FLOT will be managed to ensure that each treatment 
will have at least 8 evaluable subjects. 
See note in Section 3.1 regarding enrollment to Cohort D2. 
See notes in Section 3.1.7 (Cohort D), for information regarding safety assessment of subjects in 
Cohort D and prior to enrollment into Cohort D2. 
3.1.3 Blinding/Unblinding 
This is an open label study. 
3.1.4 Subject Population 
Subjects must have a histological diagnosis of oesophageal or gastrooesophageal cancer.  See 
Section 5 for complete eligibility criteria. 
Cohorts A (A1 and A2) and B will include subjects with metastatic/locally advanced OC, and 
Cohorts C, C-FLOT and D/D2 will include subjects with operable OC.   
Subjects with operable disease will be allocated to Cohort C, C-FLOT or D/D2 based on the decision 
taken by the multidisciplinary team (MDT) on the standard treatment approach for any individual 
patient. The MDT will determine (1) operability and (2) whether neoadjuvant chemotherapy or 
chemoradiotherapy should be offered. These decisions will guide eligibility for enrollment to 
Cohorts C, C-FLOT, and D/D2.  The radiotherapy offered in Cohort D/D2 will be provided per 
Section 6.13 for these subjects, as already determined by MDT. 
3.1.5 No. of Sites/Subjects 
Up to 4 sites; and 75 evaluable subjects are estimated for this study: 
• 
Phase 1: 6-9 subjects for Cohort A1 and 6-12 subjects for Cohort A2. 
• 
Phase 2: 54 subjects for Cohorts B (n = 14), C/C-FLOT (n = 20) and D/D2 (n = 20). 
Note: Enrollment to Cohort C and Cohort C-FLOT will be managed to ensure that each treatment 
will have at least 8 evaluable subjects. 
3.1.6 Sample Size and Statistical Considerations 
Preceding standard chemo(radio)therapy with immunotherapy is not anticipated to yield 
significant additional toxicities; however, this needs to be verified.  If dose limiting toxicities 
attributable to the addition of immunotherapy are found in only 0 or 1 of 6 evaluable subjects 
with metastatic disease, this would provide the necessary reassurance to proceed to treatment 
of potentially curable subjects.  Allowing for replacement of inevaluable subjects (see Section 
3.1.11) accounts for the projected sample size of Cohort A1 (n = 6-9 subjects) and Cohort A2 
(n=6-12 subjects). 
The sample sizes of Cohorts B (n = 14), C/C-FLOT (n = 20) and D/D2 (n = 20) are driven by the 
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of efficacy. The study is not designed to provide definitive information, but to deliver the basis 
for design of future trials and to allow interpretation of exploratory translational endpoints.  
For example, in Cohort C/C-FLOT the study will allow us to estimate 6-month progression-free 
survival (PFS) and the R0 resection rate associated with combination therapy.  The 6-month PFS 
rate taken from the time of surgery and R0 resection rate are surrogate markers for longer term 
clinical outcomes.  If we observe a 6-month PFS of at least 78% in 20 subjects, we can be 95% 
confident that the true PFS at 6 months is at least 54.4% (lower 1-side 95% confidence 
limit=54.4%).  Assuming an observed R0 resection rate of 80%, to reach alpha = 0.1 (1-side), if 20 
subjects are recruited, we can be 80% confident that the true R0 rate is at least 64.0% (lower 1-
side 80% confidence limit=64.0%).  Achievement of these figures would suggest a regimen 
worthy of further study. 
3.1.7 Treatment Arms and Treatment Schema 
The study consists of 2 phases, a safety run-in Phase 1 (Cohorts A1 and A2) and an expansion 
Phase 2 (Cohorts, B, C/C-FLOT, and D/D2).   
Subjects in all cohorts will have a 4-week period of immunotherapy at the start of the study: 
• 
Cohorts A1, C/C-FLOT, and D/D2 will receive durvalumab alone, 750 mg Q2W  
• 
Cohort A2 will receive tremelimumab (37.5 mg or 75 mg) on Day 1 (see dose escalation, 
Section 3.1.7.1) + durvalumab (750 mg Q2W) combination.  
• 
Cohort B will receive immunotherapy at RCD from Cohort A1 or A2. 
Chemo(radio)therapy will follow the 4-week immunotherapy. For all cohorts except Cohort D, 
the 4-week immunotherapy period will be followed by a specific number of cycles for 
chemotherapy and durvalumab Q2W, depending on the cohort. 
For Cohorts A1, A2, B and C, chemotherapy will start on the same day of the third durvalumab 
infusion (chemotherapy Cycle 1, Day 1; Study Day 29) and continue for up to six 3-week 
chemotherapy cycles (Cohorts A1, A2, and B) or two 3-week chemotherapy cycles (Cohort C), 
with durvalumab 750 mg administered Q2W.  For these cohorts, chemotherapy will consist of 
oxaliplatin given at 130 mg/m2 IV on Day 1 of each 3-week cycle and capecitabine 
1250 mg/m2/day, given orally in 2 divided doses continuously from Days 1 to 21 of each 3-week 
cycle. 
For Cohort C-FLOT, chemotherapy will start after the 4-week durvalumab immunotherapy 
period, i.e., on Cycle 1, Day 1 (Study Week 5, Study Day 29). Durvalumab (750 mg Q2W) and 
chemotherapy will continue for two 4-week cycles. Chemotherapy will consist of FLOT (5-FU 
2600 mg/m2 (24-hr IV), leucovorin 200 mg/m2 IV, oxaliplatin 85 mg/m2 IV, and docetaxel 50 
mg/m2 IV) given on Days 1 and 15 of each of the two 4-week cycles. 
See Section 2.2, regarding the rationale for not including a Phase 1 evaluation of durvalumab 
combined with FLOT. 
For Cohort D, chemoradiotherapy will start after the 4-week durvalumab immunotherapy 
period, i.e., on Cycle 1, Day 1 (Study Week 5, Study Day 29).  Subjects will receive 5 weekly doses 
of paclitaxel (50 mg/m2) and carboplatin (AUC 2) concurrent with radiotherapy (41.4 Gy in 23 
fractions), but without durvalumab.  Radiotherapy will be given over 23 fractions over a period 
of 5 weeks.  A dose of durvalumab will be given following chemoradiotherapy on Day 64 (±3 


 
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days).  If the subject has not completely recovered (per Investigator assessment) by Day 64 (±3 
days), the durvalumab dose may be delayed until Day 71 (±3 days).  For a subset of Cohort D 
subjects (Cohort D2), durvalumab doses will continue during chemoradiotherapy, after the 
initial 4-week immunotherapy period. For the chemoradiotherapy period of Cohort D2, 
durvalumab will be given on Cycle 1/Day 1, Cycle 1/Day 15, and Cycle 2/Day 8; durvalumab will 
not be given on Day 64 or 71. Upon approval of Amendment 7, enrollment will proceed to 
Cohort D2, unless there is a medical reason to enroll a specific subject to Cohort D. 
Note: For Cohort D, the durvalumab immunotherapy is not concurrent with chemoradiotherapy; 
therefore, a formal Phase 1 component is not proposed; however, safety for the first 6 subjects 
will be closely monitored. 
Note: The Cohort D subset, Cohort D2, will start enrollment after several Cohort D 
subjects have been treated with the non-concurrent immunotherapy/ 
chemoradiotherapy schedules; ongoing safety review of those Cohort D subjects will 
inform enrollment into Cohort D2. 
Subjects in Cohorts C/C-FLOT and D/D2 will undergo surgery 6 to 8 weeks after completing 
chemo(radio)therapy or according to institutional policies for surgery; they will be eligible to 
resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, 
provided that this is within 3 months of surgery. Subjects in Cohort C-FLOT may receive 
durvalumab, FLOT or durvalumab plus FLOT at the discretion of the Investigator. 
Phase 1 
Cohort A 1: The safety of durvalumab administered 4 weeks before and during chemotherapy 
(oxaliplatin + capecitabine) will be evaluated in subjects with metastatic or locally advanced OC.   
Treatment Schedule for Cohort A1 (subjects with metastatic/locally advanced OC) 
Period 
Durvalumab 
750 mg (IV) 
Oxaliplatin  
130 mg/m2 (IV) 
Capecitabine  
1250 mg/m2/day 
(oral) 
Radiation 
Week 1-4 
Days 1 and 15 of study  
No 
No 
No  
*Cycle 1-6 
First day of Cycle 1 (Day 
29), then every 2 weeks 
Day 1 of each cycle 
Days 1 to 21 of 
each cycle 
No 
*3-week cycle 
After completion of Cohort A1, Phase 2 expansion into Cohorts C/C-FLOT and D/D2 will begin, 
and a safety review will determine whether to explore the tremelimumab + durvalumab 
combination with a dose-escalation for tremelimumab (Cohort A2).  See Figure 1 and Section 
3.1.7.1.  
Once Cohort A1 is cleared, there will be concurrent enrollment into Phase 2 expansion for 
Cohorts C/C-FLOT and D/D2 (subjects with operable OC) and the dose-escalation phase for 
Cohort A2.  
Cohort A2: If a decision is made to open Cohort A2, tremelimumab will be given once only on 
Day 1 of the study.  These subjects will receive infusions of tremelimumab (dose escalation will 


 
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be determined according to Section 3.1.7.1 ) and durvalumab 750 mg on Day 1 of the study, 
with durvalumab repeated every 2 weeks (Q2W). 
Treatment Schedule for Cohorts A2 (subjects with metastatic/locally advanced OC) 
Period 
Tremelimumab** 
37.5 or 75 mg 
(IV)  
Durvalumab 
750 mg (IV) 
Oxaliplatin  
130 mg/m2 (IV) 
Capecitabine  
1250 mg/m2/day 
(oral) 
Radiation 
Week 1-4 
Day 1 of study 
Days 1 and 15 of 
study  
No 
No 
No  
*Cycle 1-6 
No 
First day of Cycle 1 
(Day 29), then 
every 2 weeks 
Day 1of each 
cycle 
Days 1 to 21 of 
each cycle 
No 
*3-week cycle 
**Cohort A2 with a dose-escalation for tremelimumab will only be opened if a decision is made to explore the 
tremelimumab + durvalumab combination (see Section 3.1.7.1).   
Phase 2 includes the expansion into Cohorts B, C, C-FLOT, and D/D2. 
Cohort B: Once Cohort A2 is completed, another safety review will determine whether to use 
the RCD from Cohort A1 or A2 to start enrollment into the Cohort B (subjects with 
metastatic/locally advanced OC) expansion phase. 
Cohort C:  Following the 4-week immunotherapy, subjects will be treated with neoadjuvant 
chemotherapy (oxaliplatin + capecitabine) with ongoing durvalumab before surgery. Subjects 
will undergo surgery 6 to 8 weeks after completing treatment or according to institutional 
policies for surgery; they will be eligible to resume durvalumab dosing (to a maximum of 12 
infusions) once recovered from surgery, provided that this is within 3 months of surgery. 
Treatment Schedule for Cohort C (subjects with operable OC) 
Period 
Durvalumab 
750 mg (IV) 
Oxaliplatin  
130 mg/m2 (IV) 
Capecitabine 
1250 mg/m2/day 
(oral) 
Radiation 
Week 1-4 
Days 1 and 15 of study 
No 
No 
No  
*Cycle 1-2 
First day of Cycle 1 (Day 
29), then every 2 weeks 
Day 1 of each cycle 
Days 1 to 21 of 
each cycle 
No 
*3-week cycle 
 
Cohort C-FLOT: Following the 4-week immunotherapy, subjects will be treated with neoadjuvant 
FLOT chemotherapy with ongoing durvalumab for 2 cycles before surgery. Subjects will undergo 
surgery 6 to 8 weeks after completing treatment or according to institutional policies for 
surgery; they will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once 
recovered from surgery, provided that this is within 3 months of surgery. Subjects in Cohort C-
FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at the discretion of the 
Investigator. 


 
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Treatment Schedule for Cohort C-FLOT (subjects with operable OC) 
Period 
Durvalumab 
750 mg  
(IV) 
5-Fluorouracil  
2600 mg/m2 
(24-hr IV) 
Leucovorin  
200 mg/m2 
(IV) 
Oxaliplatin  
85 mg/m2 
(IV) 
Docetaxel  
50 mg/m2 
(IV) 
Radiation 
Week 1-4 
Days 1 and 15 
of study 
No 
No 
No 
No 
No 
*Cycle 1-2 
Days 1 and 15 
of each cycle 
Days 1 and 15 
of each cycle 
Days 1 and 15 
of each cycle 
Days 1 and 15 
of each cycle 
Days 1 and 15 
of each cycle 
No 
*4-week cycles 
Cohort D:  Following the 4-week immunotherapy, subjects will be treated with neoadjuvant 
chemoradiotherapy (5 weekly doses of paclitaxel + carboplatin + radiotherapy) without 
concurrent durvalumab. A dose of durvalumab will be given following chemoradiotherapy on 
Day 64 (±3 days).  If the subject has not completely recovered (per Investigator assessment) by 
Day 64 (±3 days), the durvalumab dose may be delayed until Day 71 (±3 days). Subjects in 
Cohort D will undergo surgery 6 to 8 weeks after completing treatment or according to 
institutional policies for surgery; they will be eligible to resume durvalumab dosing (to a 
maximum of 12 infusions) once recovered from surgery, provided that this is within 3 months of 
surgery. 
Treatment Schedule for Cohort D (subjects with operable OC) 
Period 
Durvalumab  
750 mg (IV) 
Paclitaxel 
50 mg/m2  (IV) 
Carboplatin  
AUC 2 (IV) 
Radiation* 
Weeks 1-4 
Days 1 and 15 of study 
No 
No 
No  
Weeks 5-9 
No 
Day 1 of  
Study Weeks 5-9  
Day 1 of  
Study Weeks 5-9 
23 fractions over 
Study Weeks 5-9 
*The 41.4 Gy radiotherapy is given over 23 fractions, Weeks 5-9.   
Cohort D2: For a subset of Cohort D subjects, durvalumab doses will continue during 
chemoradiotherapy, after the initial 4-week immunotherapy period. Upon approval of 
Amendment 7, enrollment will proceed to Cohort D2, unless there is a medical reason to enroll a 
specific subject to Cohort D. 
Treatment Schedule for Cohort D2 (subjects with operable OC) 
Period 
Durvalumab  
750 mg (IV) 
Paclitaxel 
50 mg/m2  (IV) 
Carboplatin  
AUC 2 (IV) 
Radiation* 
Weeks 1-4 
Days 1 and 15 of study 
No 
No 
No  
Weeks 5-9 
Cycle 1/Day 1, Cycle 
1/Day 15, and Cycle 
2/Day 8 
Day 1 of  
Study Weeks 5-9  
Day 1 of  
Study Weeks 5-9 
23 fractions over 
Study Weeks 5-9 
*The 41.4 Gy radiotherapy is given over 23 fractions, Weeks 5-9.   
 
 


 
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Cohort A1 (n=6-9)
 Durvalumab  750 mg +
Chemotherapy
Cohort C/C-FLOT  
(n=20)
Durvalumab 750 mg + 
Chemotherapy
Cohort D/D2*  (n=20)
Durvalumab 750 mg 
(pre CRT) + 
Chemotherapy
Radiotherapy
≤ 1 DLT
≥ 2  DLTs
Alternative 
Treatment Plan
Surgery
 Cohort A2 (n=6-12) 
Tremelimumab 37.5/75 mg 
Dose-escalation +
Durvalumab 750 mg + 
Chemotherapy
Cohort B (n=14)
RCD A1 or A2 +
 Chemotherapy
Safety Review 
Determines if Cohort 
A2 will open
Safety Review 
Determines if Cohort B 
uses RCD
 from A1 or A2
 
 
 
Figure 1: Treatment Schema 
 
3.1.7.1 
Phase 1 – Safety Run-in 
For Cohorts A1 and A2, the start of the study drug administration for the first and second 
subject will be separated by at least 24 hours. See Section 3.1.9 for DLT evaluation for Cohorts 
A1 and A2. 
If the decision is made to proceed with Cohort A2, a dose-escalation will be performed to 
determine the RCD for tremelimumab + durvalumab administered before chemotherapy 
• Tremelimumab = Day 1 
• Durvalumab = Q2W 
• Chemo(radio)therapy (CRT): 
o 
Cohorts A1, A2, B and C =  
oxaliplatin + capecitabine 
o 
Cohort C-FLOT = 5-FU + leucovorin + 
oxaliplatin + docetaxel 
o 
Cohort D = paclitaxel + carboplatin +RT 
o 
*Cohort D2= paclitaxel + carboplatin +RT 
(a subset of Cohort D subjects for which 
durvalumab doses will continue during CRT, 
after the initial 4-week immunotherapy 
period.) 


 
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followed by durvalumab alone. The assessment for Cohort A2 will follow a standard 3 +3 dose-
escalation for tremelimumab.  Dose escalations for the determination of RCD will be performed 
based on the dose levels in the table below and the respective rules for a standard 3 + 3 dose 
escalation study design (see Figure 2). 
Dose Level Table for Cohort A2 Escalations 
Dose level 
Durvalumab 
Tremelimumab 
 
 
 
Starting 
750 mg Q2W 
37.5 mg (Day 1) 
+1 
750 mg Q2W 
75mg (Day 1) 
 
Dose Escalation and De-Escalation Schema (3 + 3 Design)
1
0
 ≤1   
>1
 >1 
Treat 3 
Subjects 
@ DL and 
assess 
DLTs
Expand 
to 6 
Subjects 
@ DL and 
assess 
DLTs
DL is not 
tolerated
DL is 
tolerated
Is DL + 1 available
and not
previously declared not 
tolerated?
Escalation
DL = DL + 1
Yes
No
DL = Starting 
Dose Level
Is DL + 1 available
and not
previously declared not 
tolerated?
Yes
DL is RCD
No
Is DL - 1 
available?
No
RCD cannot be 
determined
Was DL - 1 
previously declared 
tolerated?
No
3 subjects already 
treated @ DL?
Yes
Yes
No
Yes
De-Escalation
DL = DL - 1
DL - 1 is RCD
DL = Dose Level (per DL Table)         DLT = (Subjects with) Dose Limiting Toxicities         RCD = Recommended Combination Dose (per DL Table)
 
Figure 2: Dose Escalation Schema 
Per Figure 2, the RCD for Cohort A2 is defined as the highest dose level at which no more than 1 
of 6 subjects (i.e., < 33%) experience DLTs.  The RCD cannot be determined if none of the 
predefined dose level cohorts fulfill that criterion.   
3.1.7.2 
Phase 2 – Expansion Phase 
Once Cohort A1 is cleared, there will be concurrent enrollment into Phase 2 expansion for 
Cohorts C, C-FLOT, and D/D2 (operable OC with neoadjuvant chemotherapy or 
chemoradiotherapy before surgery) and the dose-escalation phase for Cohort A2 (see Section 
3.1.7.1) if the safety review determines that Cohort A2 will be opened.  Once Cohort A2 is 
completed, another safety review will determine whether to use the RCD from Cohort A1 or A2 
to start enrollment into the Cohort B (subjects with metastatic/locally advanced OC) expansion 
phase. 


 
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3.1.8 Dosing Adjustments, Delays and Discontinuations 
Dose adjustment and management guidelines for toxicity related to durvalumab and 
tremelimumab are outlined in Section 8.5; guidelines for oxaliplatin, capecitabine, and FLOT are 
provided in Section 8.6; guidelines for paclitaxel and carboplatin are provided in Section 8.7. 
If a toxicity occurs that requires toxicity management and the toxicity causing drug can be 
clearly identified, then the respective guideline should be followed. If the toxicity causing drug 
cannot be identified, then the more conservative guideline should be followed. 
3.1.9 DLT 
The aim of Phase 1 of the study (Cohorts A1 and A2) is to evaluate the feasibility/safety of 
administering durvalumab or tremelimumab + durvalumab pre-operatively to OC subjects.  If 
the starting regimen in Cohort A1 is deemed unsuitable for pre-operative use, a switch to only 
consecutive treatment may be considered.  If the decision is made to open Cohort A2 and the 
dose-escalation for tremelimumab is deemed unsuitable, tremelimumab will be omitted.  
For Cohort A1, the safety of durvalumab alone administered before and with chemotherapy 
(oxaliplatin + capecitabine) in subjects with metastatic or locally advanced OC will be 
determined. The DLT evaluation period for the study will encompass the 4 weeks of 
immunotherapy (durvalumab alone) plus the subsequent first 6 weeks of chemotherapy, for a 
total of 10 weeks.  If more than 1 of 6 subjects experience toxicity in the first 6 weeks of 
chemotherapy treatment that would in theory preclude oesophagectomy; then this dosing 
regimen will be deemed unsuitable for pre-operative administration in potentially curable 
subjects.  This definition will extend beyond the usual concept of DLT and will be based on the 
evaluation of the internal data safety monitoring panel.  If none of the 6 subjects in Cohort A1 
experience such toxicity, Cohorts C/C-FLOT and D will be opened to enrollment as outlined in 
Section 3.1.7.  If 1 subject in Cohort A1 experiences toxicity likely to interfere with surgery, the 
cohort will be expanded to 9 subjects, and the dosing regimen deemed tolerable only if none of 
the 3 additional subjects is similarly affected. 
If the decision is made to open Cohort A2, DLTs will be observed over a period of 10 weeks, 
defined as the DLT Evaluation Period. The decisions for dose-escalation and RCD, as described in 
Section 3.1.7.1, will primarily be based on the number of subjects with DLTs occurring during the 
DLT Evaluation Period.  DLTs occurring outside the DLT Evaluation Period will also be evaluated 
and may impact such decisions. 
DLTs are defined as any adverse events that are possibly, probably, or definitely related to the 
administration of durvalumab or tremelimumab and durvalumab, in addition to chemotherapy, 
and fulfill any of the following criteria: 
1. Any Grade ≥ 3 colitis, pneumonitis, neurological event, or uveitis 
2. Any Grade 2 pneumonitis, neurological event, or uveitis with the exception of those 
that downgrade to Grade ≤ 1 within 3 days after onset, whereby maximal 
supportive care, including systemic corticosteroids, is permitted. 
3. Any other Grade ≥ 3 toxicity, with the following exceptions: 
• 
Grade ≥ 3 chemotherapy-related toxicities, manageable according to the dose 
modification instructions in the product information and Sections 8.6 and 8.7. 


 
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• 
Grade 3 irAEs that downgrade to Grade ≤ 2 within 3 days, or to Grade ≤ 1 or 
baseline within 14 days after onset, whereby maximal supportive care, including 
systemic corticosteroids, is permitted. 
• 
Grade 3 endocrinopathy that becomes asymptomatic when managed with or 
without systemic corticosteroid therapy and/or hormone replacement therapy. 
• 
Grade 3 inflammatory reaction attributed to a local anti-tumor response (e.g., 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.). 
• 
Grade 3 fatigue for ≤ 7days. 
• 
Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management. 
• 
Liver transaminase elevation ≤ 8 times upper limit of normal (ULN) that 
downgrades to Grade ≤ 2 (≤ 5 times ULN) within 7 days after onset, whereby 
maximal supportive care, including systemic corticosteroids, is permitted.  
• 
Total bilirubin ≤ 5 times ULN that downgrades to Grade ≤ 2 (≤ 3 times ULN) 
within 7 days after onset, whereby maximal supportive care, including systemic 
corticosteroids, is permitted. 
• 
Grade ≥ 3 neutropenia that (1) is not associated with fever or systemic infection, 
(2) does not require medical intervention, and (3) improves to Grade 2 within 7 
days.  
• 
Grade 3 or Grade 4 lymphopenia. 
• 
Grade 3 thrombocytopenia that (1) is not associated with clinically significant 
bleeding, (2) does not require medical intervention, and (3) improves to Grade 2 
within 7 days. 
• 
Isolated Grade 3 electrolyte abnormalities that are not associated with clinical 
signs or symptoms and are reversed with appropriate maximal medical 
intervention within 3 days. 
• 
Any pre-existing laboratory abnormality that deteriorates to Grade 3/4, but 
where the increment of deterioration is considered not clinically significant by 
both Investigator and Sponsor. 
• 
Grade 3 or 4 asymptomatic increases in amylase or lipase levels for which 
appropriate evaluation shows no clinical evidence of pancreatitis. 
Immune-related adverse events (irAEs) are defined as AEs of immune nature (i.e., inflammatory) 
in the absence of a clear alternative etiology.  In the absence of clinical abnormality, repeat 
laboratory testing will be conducted to confirm significant laboratory findings prior to 
designation as a DLT. 
While rules for adjudicating DLTs are specified above, an AE that is Grade < 3 or listed as exempt 
above may also be defined as DLT after consultation with the Sponsor and Investigators, based 
on the emerging safety profiles of durvalumab and tremelimumab in combination with 
chemoradiotherapy.  Likewise, subjects who become not evaluable for DLT, because they 
discontinued or interrupted treatment due to toxicities other than DLTs, may be counted as DLT 


 
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subjects, if the toxicities cannot be managed in accordance with the dosing modifications 
described in Section 3.1.8. 
Subjects who experience a DLT will be allowed to continue on study at a lower dose level only 
after discussion with the Chief Investigator and Sponsor. Otherwise subjects will be discontinued 
from study therapy and will enter the On Study Follow-up phase of the study (see Study 
Flowchart, Section 3.2).   
The MTD will not be determined in this study. 
3.1.10 Subject Withdrawal 
A subject experiencing any of the following will be withdrawn from the relevant study 
treatment: 
1. Withdrawal of consent for further treatment. 
2. Pregnancy or intent to become pregnant. 
3. Dose-limiting toxicity that precludes re-treatment at a lower dose (see Section 3.1.9 for 
definition of DLT and permitted continuation). 
4. Grade ≥ 3 infusion reaction to durvalumab or durvalumab + tremelimumab 
5. Confirmation of progressive disease requiring alternative treatment. 
6. Significant protocol violation or noncompliance that, in the opinion of the Investigator 
or Sponsor, warrants withdrawal. 
7. Development of intercurrent, non-cancer related illnesses or complications that prevent 
either continuation of therapy or regular follow up. 
8. Best medical interest of the subject (at the discretion of the Investigator) 
Discontinuation from receiving study treatment does not mean that the subject is withdrawn 
from the study. Subjects who are withdrawn from the study treatment should enter the On 
Study Follow-up (see Section 3.1.16), if feasible.  Subjects who begin other anti-cancer therapy 
should immediately be considered off-study and proceed to the Post Study Follow-up (Section 
3.1.16). 
 
A subject will be withdrawn from the study for the following reasons: 
1. Best medical interest of the subject at the discretion of the Investigator 
2. Initiation of alternative anticancer therapy (marketed or investigational) 
3. Withdrawal of consent for all follow-up. 
4. Lost to follow-up. 
5. Death. 
General subject withdrawal criteria are outlined in the Administrative, Legal and Ethical 
Requirements section of the Protocol (see Section 7).  See also Sections 8.5 and 8.6 and 8.7 for 
treatment withdrawal due to necessary dosing interruptions or discontinuations. 
If consent is withdrawn, the subject will not receive any further investigational product or 
further study observation. 


 
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3.1.10.1 
Treatment Beyond Progression 
Subjects in Cohorts A and B meeting criteria for progression (Section 8.8) will be allowed to 
continue on therapy until confirmation of progression as long as the following criteria are met at 
the discretion of the Investigator: 
a. Absence of symptoms and signs (including worsening of laboratory values) indicating 
disease progression; 
b. No significant decline in ECOG performance status; 
c. Absence of rapid progression of disease or of progressive tumor at critical anatomical 
sites (e.g., cord compression) requiring urgent alternative medical intervention. 
See Section 8.8 for additional information regarding RECIST 1.1 and irRECIST. 
3.1.11 Subject Replacements 
In the dose escalation phase, subjects are fully evaluable for DLT if they fulfill the criteria for the 
Per-Protocol Population for DLT Assessment (as defined in Section 4.1.2). 
In Cohorts A1 and A2, subjects who are not evaluable for DLT will be replaced. 
Subjects who are not considered fully evaluable for the primary objective of overall safety and 
tolerability per Section 4.1.2 may be replaced.  
3.1.12 Optional Study Treatment Extension 
For Cohorts C/C-FLOT and D/D2, subjects will be eligible to resume durvalumab dosing (to a 
maximum of 12 infusions) once recovered from surgery, provided that this is within 3 months of 
surgery. Subjects in Cohort C-FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at 
the discretion of the Investigator. 
3.1.13 Interim Analysis 
No formal interim analyses will be performed, except for the cohort safety assessments for DLTs 
in Cohorts A1, and A2 (see Section 3.1.9).  
3.1.14 Safety Monitoring and Study Stopping Rules 
In accordance with the Administrative, Legal and Ethical Requirements section of the protocol 
(see Section 7), Safety Monitoring will be performed by an internal data safety monitoring panel, 
consisting of the Principal Investigators (and Co-investigators as needed), the sponsor Medical 
Monitor, and drug safety personnel from Medimmune, provider of the study drugs.  Additional 
investigators and staff, or additional sponsor personnel and consultants, shall participate in 
reviews as indicated.  An Independent Data Monitoring Board (IDMB) will not be utilized for this 
open label study. 
For Cohorts C/C-FLOT and D/D2, subjects undergoing surgery will also be closely monitored for 
post-operative complications (compared with outcomes in the Oxford Oesophago-Gastric 
Surgical Database). 
The study will be suspended or possibly stopped prematurely for any of the following reasons: 


 
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1. A death that is unexpected and at least probably related to durvalumab, tremelimumab, 
or to the combination of durvalumab or durvalumab and tremelimumab with 
chemo(radio)therapy. 
2. Severe anaphylactic reaction (i.e., with respiratory and cardiovascular failure) to 
durvalumab or durvalumab and tremelimumab in any subject. 
3. Any events that, in the judgment of the Medical Monitor, are deemed serious enough to 
warrant immediate review by the internal data safety monitoring panel.  This may 
include any symptomatic and/or irreversible treatment-related Grade 4 pneumonitis, 
colitis, dermatitis, or hepatitis or any symptomatic treatment-related Grade ≥3 
neurological toxicity or uveitis. 
4. Any other safety finding assessed as related to durvalumab, durvalumab and 
tremelimumab, or chemo(radio)therapy that, in the opinion of the internal data safety 
monitoring panel, contraindicates further dosing of study subjects. 
5. Any interim findings that, in the opinion of the Investigators and the sponsor, suggest 
that the study treatment has no clinical benefit for the subjects. 
If the study is suspended, dosing may not resume before obtaining approval of a substantial 
amendment from the Competent Regulatory Authority. 
General criteria for premature trial termination are outlined in the Administrative, Legal and 
Ethical Requirements section of the protocol. 
3.1.15 Duration of Study 
Recruitment will take 6 months for Cohort A1, 6 months for Cohort A2, increasing by a further 6 
months if alternative doses need to be explored, and 1 year for Cohorts B and C/C-FLOT.  Cohort 
D/D2 will require 15 months to recruit.  Treatment duration will be approximately 6 months (not 
accounting for maintenance durvalumab given post-operatively) and follow-up is likely to 
require a further 1 to 2 years depending upon efficacy.  Total study duration (to LPLV) is 
therefore predicted to be 4 to 5 years, although useful data will emerge within 12-15 months. 
Duration of Treatment: 
Up to 6 months for individual subjects (plus a further 6 months if 
on maintenance durvalumab) 
Enrollment Period: 
30 months 
Length of Study: 
5 years 
NOTE: Per Amendment 8, all post study follow-up for the collection 
of survival data will be discontinued as of 30 June 2022 (see 
rationale in Section 8.1, Amendment 8 on Page 96). 
3.1.16 On Study and Post Study Follow-up 
All subjects, whether they complete the study as planned, discontinue treatment, or 
prematurely withdraw from the study per Sections 3.1.10 and 7.2.7, will be followed per 
institutional guidelines in accordance with the usual standard of care principles.   
For all subjects who complete study treatment or who discontinue treatment prematurely 
according to Section 3.1.10, there will be an On Study Follow-up period for 110 days after the 
last study drug treatment, which will include collection of AE data.   
NOTE:  For each of the cohorts, additional details regarding the On Study Follow-up period are 
provided in Section 7.1.5.  


 
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See Section 7.1.5 for information on recording AEs during the On Study Follow-up.   
If the determination is made to remove a subject from treatment at a visit that coincides with 
the first On Study Follow-up visit (which is 14 days after the last dose of study treatment), any 
assessments required in the first On Study Follow-up visit that are not covered as part of the last 
on-treatment visit (usually correlative labs) should be done as soon as possible.  If these 
assessments cannot be done on the same day, the subject should be brought back in at the 
earliest opportunity.  Any assessments or correlative samples required by both the last on-
treatment visit and the first On Study Follow-up visit should not be repeated. 
Refer to Flowchart in Section 3.2 for post treatment biopsies.  If the subject discontinues from 
treatment early, the biopsy specimen should be collected at the last study visit or the first On 
Study Follow-up visit. 
Following the On Study Follow-up, there will be a Post Study Follow-up, where, clinical 
outcomes data (dates of progression/relapse and survival) will be collected at least every 6 
months for up to 3 years from the initiation of the treatment.   
The Post Study Follow-up will include a query to determine if there were any immune-related 
adverse events (irAEs) during the 110 days since the last administration of study drug. 
For subjects who do not continue Post Study Follow-up at one of the study sites after the end of 
study, the Principal Investigators or the clinical team, under the supervision of the Principal 
Investigator, will obtain this data through review of outside records or communication with the 
subject or his/her physician. 
NOTE: Per Amendment 8, all post study follow-up for the collection of survival data will be 
discontinued as of 30 June 2022 (see rationale in Section 8.1, Amendment 8 on Page 96). 
3.1.16.1 
End of Study Visit 
If a subject is withdrawn from study according to the criteria defined in Section 3.1.10, an End 
of Study visit must be conducted at the time of withdrawal. For subjects not yet in On Study 
Follow-up, this End of Study visit will be the first planned visit of the On Study Follow-up. For 
subjects already in On Study Follow-up, this End of Study visit will be the next planned visit of 
the On Study Follow-up. However, any procedures/assessments that were done within 7 days of 
the End of Study visit need not be repeated. All subjects of childbearing potential who withdraw 
from study must have a serum pregnancy test done at the End of Study visit, unless it was done 
within 7 days prior to the End of Study Visit. 
After the End of Study Visit, the subject will proceed into Post Study Follow-up as described 
above, unless otherwise unable to do so (e.g., subject withdraws consent for all follow-up). 
 


 
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3.2 
Study Flowcharts 
 
 


 
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3.2.1 Study Flowchart for All Cohorts Except Cohort C-FLOT and Cohort D2 
 
Cycle week
1
2
3
4
1
2
3
1
2
3
1
2
3
Visit Day per Cycle
1
8(±3)
15(±3) 22(±3)
1(±3)
8(±3)
15(±3)
1(±3)
8(±3)
15(±3)
1(±3)
8(±3)
15(±3)
Cumulative Study Week 
1
2
3
4
5
6
7
8
9
10
11
12
13
Cumulative Study Day
-28 to -1
1
8
15
22
29
36
43
50
57
64
71
78
85
Treatment for Cohort A1/Cohort BJ
Durvalumab
X
X
X
X
X
X
X
Oxaliplatin
X
X
X
Capecitabine
Treatment for Cohort  A2/Cohort BJ
Durvalumab
X
X
X
X
X
X
X
Tremelimumab
X
Oxaliplatin
X
X
X
Capecitabine
Durvalumab
X
X
X
X
X
Oxaliplatin
X
X
Capecitabine
Surgery - 6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryp
Durvalumab for Cohort DL
X
X
XL
Paclitaxel
X
X
X
X
X
Carboplatin
X
X
X
X
X
Radiotherapy (41.4 Gy over 23 fractions)
Surgery - 6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryp
Tumour & Disease Assessments
CT for Cohorts A1, A2, and Bo
X
X
X
PET/CT for Cohorts C and Dn,o
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)K
X
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
X
Medical history
X
Physical Exam (incl weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
XL
X
X
ECG (and as clinically indicated after Day 1)m
X
X
Vital Signs (T, HR, BP, RR)e 
X
X
X
X
X
X
X
X
XL
X
X
Concomitant Medication /Procedureg, p
X
X
X
X
X
X
X
X
X
X
XL
X
X
X
Adverse Events (starting or worsening after IC)d,g,p
X
X
X
X
X
X
X
X
X
X
XL
X
X
X
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
XL
X
X
Chemistry (gluc., BUN, creat., Na, K, Cl, CO2, Ca, PO4, 
Mg, prot., alb., TBili., AST, ALT,  ALP, GGT, LDH, Free  
T3, Free T4, TSH)a
X
X
X
X
Coh D 
only
X
Coh D 
only
X
XL
X
X
Chemistry cont. (amylase and lipase)a
X
X
X
X
X
X
XL
X
X
Urinalysisa
X
X
X
X
X
X
XL
X
X
Coagulation parametersf
X
Serum pregnancy test a
-7 to -1 days
Urine pregnancy testa
X
X
X
XL
X
Blood for Correlative Immune Monitoring
Total Lymph, CD4/5/8 T-cell counts; Phenotyping of 
T-cell/B-cell/NK cell subsets, flow cytometry; 
Activated T-cell expression markers, % Tregs, Treg 
to effector cell ratio; Myeloid derived suppressor 
cells; serum cytokine profilingr
X
Xa
Xa
Tumour Biopsy Sample Collections
Tumour infiltrating lymphocytes; PD-1 expressing 
lymphocytes; measurement of tumour/stromal cell 
PD-L1 expression
X
X
Genomic investigations
X
X
Saliva samples and photographsq
X
X
Treatment for Cohort C - see separate flowchart for Cohort C-FLOT
Treatment for Cohort D - see separate flowchart for Cohort D2
Routine Lab Specimens
X
Daily
Daily
Daily
LUD2015-005 
Study Flowchart for all 
Cohorts except C-FLOT and D2
Part 1
Treatment
Cycle 2
(3 weeks)
Cycle 3
(3 weeks)
Daily
Screening / 
Baseline
Daily
Daily
Daily
Immunotherapy Only  Period
(4 weeks)
Cycle 1
(3 weeks)
Daily


 
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Cycle week
1
2
3
1
2
3
1
2
3
4
1
3
Visit Day per Cycle
1(±3)
8(±3)
15(±3)
1(±3)
8(±3)
15(±3)
1(±3)
8(±3)
15(±3)
22(±3)
1(±3)
15(±3)
Cumulative Study Week 
14
15
16
17
18
19
20
21
22
23
Cumulative Study Day
92
99
106
113
120
127
134
141
148
155
Treatment for Cohort A1/Cohort BJ
Durvalumab
X
X
X
X
Oxaliplatin
X
X
X
Capecitabine
Treatment for Cohort  A2/Cohort BJ
Durvalumab
X
X
X
X
Tremelimumab
Oxaliplatin
X
X
X
Capecitabine
Durvalumab
Xc
Xc
Oxaliplatin
Capecitabine
Surgery - 6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryp
Durvalumab for Cohort DL
Xc
Xc
Paclitaxel
Carboplatin
Radiotherapy (41.4 Gy over 23 fractions)
Surgery - 6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryp
Tumour & Disease Assessments
CT for Cohorts A1, A2, and Bo
X
Xh
PET/CT for Cohorts C and Dn,o
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)K
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
Medical history
Physical Exam (incl weight and ECOG Perf Status)b
X
X
X
X
X
X
Xc
Xc
X
X
X
X
ECG (and as clinically indicated after Day 1)m
X
Vital Signs (T, HR, BP, RR)e 
X
X
X
X
X
X
Xc
Xc
X
X
X
X
Concomitant Medication /Procedureg, p
X
X
X
X
X
X
X
X
X
X
Xc
Xc
X
X
X
X
Adverse Events (starting or worsening after IC)d,g,p
X
X
X
X
X
X
X
X
X
X
Xc
Xc
X
X
X
X
Routine Lab Specimens
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
Xa,c
Xa,c
X
X
X
X
Chemistry (gluc., BUN, creat., Na, K, Cl, CO2, Ca, PO4, 
Mg, prot., alb., TBili., AST, ALT,  ALP, GGT, LDH, Free  
T3, Free T4, TSH)a
X
X
X
X
Xa,c
Xa,c
X
X
X
X
Chemistry cont. (amylase and lipase)a
X
X
X
X
Xa,c
Xa,c
X
X
X
X
Urinalysisa
X
X
X
X
Xa,c
Xa,c
X
X
X
X
Coagulation parametersf
Serum pregnancy test a
Urine pregnancy testa
X
X
Xa,c
X
X
X
X
Blood for Correlative Immune Monitoring
Total Lymph, CD4/5/8 T-cell counts; Phenotyping of 
T-cell/B-cell/NK cell subsets, flow cytometry; 
Activated T-cell expression markers, % Tregs, Treg 
to effector cell ratio; Myeloid derived suppressor 
cells; serum cytokine profilingr
Xi
Xh
xr
Tumour Biopsy Sample Collections
Tumour infiltrating lymphocytes; PD-1 expressing 
lymphocytes; measurement of tumour/stromal cell 
PD-L1 expression
Xi
Xh
Genomic investigations
Xi
Xh
Saliva samples and photographsq
Xi
Xh
LUD2015-005 
Study Flowchart for all 
Cohorts except C-FLOT and D2
Part 2
Post Study 
Follow-ups
Cycle 4
(3 weeks)
Post Surgery 
Durvalumabc
(4 week cycle)
On Study Follow-upd, p
 Last Study 
Drug Dose 
+ 91( ±7) 
days  
Last Study 
Drug Dose 
+42 (±7) 
days
Cycle 5
(3 weeks)
Last Study 
Drug Dose 
+14( ±4) 
days
Cycle 6
(4weeks)
 Last Study 
Drug Dose 
+ 110( ±7) 
days  
Treatment
Daily
Daily
Every 6 months for up to 3 years post initiation of treatment(see footnote "s").
Telephone contact or medical record review to include clinical outcomes data (dates of progression/relapse and survival).
Daily
Daily
X
X
Daily
Daily
Treatment for Cohort C - see separate flowchart for Cohort C-FLOT
Treatment for Cohort D - see separate flowchart for Cohort D2


 
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Flowchart Footnotes for all Cohorts except C-FLOT and D2:
a- Pre-dose; record times as well as dates. If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1.
     Day 1 lab assessments may be performed within 3 days prior to Day 1.  Results for safety blood tests (chem,  hematology, and pregnancy [when applicable]) must be 
     available and reviewed before commencing an infusion. GGT tested at Screening, Day 1 and as clinically indicated. For each on-treatment cohort, hematology, chem,  
     urine & pregnancy safety assessments should coincide with drug administration study visits. With the exception of On Study Follow-up, Lab assessments are not  
     applicable if there is no drug administration visit for a particular cohort. End of study pregnancy test for women of child-bearing potential must be done on serum.
b- Full physical examination (including neurological exam) at baseline; targeted physical examination (including neurological exam) at other time points
     For each on-treatment cohort, physical exams should coincide with drug administration study visits. With the exception of On Study Follow-up, physical exams are  
     not applicable if there is no drug administration visit for a particular cohort.
c- Cohorts C and D will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided this is within 3 months of surgery. 
d- See Section 7.1.5  for details on collection of  AEs during On Study Follow-up
e- For each on-treatment cohort, vital signs assessments should coincide with drug administration study visits. With the exception of On Study Follow-up, vital sign 
    assessments are not applicable if there is no drug administration visit for a particular cohort. For durva and treme, vital signs are measured before, during 
    and after infusions according to Section 6.11.
f - Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated; record times as well as dates.
g - Concomitant med and AE information may be collected by telephone if there is no study drug administration/lab test/scan/procedure visit scheduled.
h - Post treatment for Coh A and B (a window of -7 to +14 days is allowed).  If subject discontinues from treatment early, include at last study visit or first On Study follow-up
i - On day of surgery for Cohorts C and D (blood draw must be pre-surgery and may be up 3 days before). If subject discontinues from treatment early, 
     include at last study visit or first On Study follow-up.
J- Once Cohort A1 is cleared, a safety review / decision will be made whether to start Cohort A2; A safety review will also determine whether the RCD of Cohort A1 or A2 
    will be used for Cohort B.
K- A screening log must be kept of all subjects considered for the study including any that are subsequently excluded; reason for exclusion must be recorded on this form. 
    A copy of the screening log should be sent to the trial office on request, but without subject identifiers. The original must be retained on site,
   Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
L- Cohort D: Subjects will discontinue durvalumab after Week 3; a dose of durvalumab will be given following chemoradiotherapy on Day 64 (±3 days). 
    If the subject has not completely recovered (per Investigator assessment) by Day 64 (±3 days), the durvalumab dose may be delayed until Day 71 (±3 days). 
    Lab assessments, pregnancy test and safety assessments should be done on the day (64 or 71) the durvalumab dose is given.
m - 12 Lead ECG - baseline and abnormal ECG at any time will be done in triplicate (2-5 minutes apart); others may be single measurements.
n - PET/CT scan  for Cohorts C and D:
     Scan scheduled after completion of therapy/before surgery may  be combined as part of the surgery workup or per local institutional standards.
     Post surgery scan may be done at first post surgery treatment visit.
     PET scan at the post-surgery and On-Study Follow-Up timepoints may be replaced with a CT scan.
o -Scans should be done per local institutional standards and reported per irRECIST/RECIST 1.1 guidance. See Sections 4.2.1 and 8.8 and eCRF.
     Scanning protocols and modalities should remain consistent throughout the study.
p -For subjects in Cohorts C and D: 
    1. All  AEs will be collected for 110 days after the last dose of pre-surgery durva, with the exception of those AEs that are related to the protocol-defined surgical 
    procedure(s). If the decision is made that a subject will not receive continued durva, the subject must start On Study Follow-up and have at least one On Study Follow-up
    visit at 110 days (+30 days) after last dose of durva or at the point of the decision (+30 days), whichever is later.
   2. If any subjects in Cohorts C and D continue durva treatment after the planned surgical procedure, they will follow the On Study Follow-up period according to the 
   Flowchart, and all AEs will be collected for 110 days after the last dose of durva.
   See Section 7.1.5 for details on Cohorts A and B
q - Saliva samples may be collected at each biopsy collection time point; photographs at endoscopy may be taken.
r - The Investigator(s) have the option to approach subjects with long-term survival (PFS > 1 year, still in remission) from the metastatic cohorts (A and B) to request  
     blood (up to 300 mL) for additional testing as described in Section 2.3.
s - Per Amendment 8, all post study follow-up for the collection of survival data will be discontinued as of 30Jun2022 (see Section 8.1, Amendment 8).


 
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3.2.2 Study Flowchart for Cohort C-FLOT 
 
Cycle week
1
2
3
4
1
3
1
3
Visit Day per Cycle
1
8(±3)
15(±3) 22(±3)
1(±3)
15(±3)
1(±3)
15(±3)
Cumulative Study Week 
1
2
3
4
5
7
9
11
Cumulative Study Day
-28 to -1
1
8
15
22
29
43
57
71
Treatment for Cohort C-FLOT
Durvalumab
X
X
X
X
X
X
5-Fluorouracil
X
X
X
X
Leucovorin
X
X
X
X
Oxaliplatin
X
X
X
X
Docetaxel
X
X
X
X
Surgery - 6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryK
Tumour & Disease Assessments
PET/CT scanL
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)J
X
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
X
Medical history
X
Physical Exam (incl weight and ECOG Perf Status)b
X
X
X
X
X
X
X
ECG (and as clinically indicated after Day 1)h
X
X
Vital Signs (T, HR, BP, RR)e 
X
X
X
X
X
X
X
Concomitant Medication /Procedureg, K
X
X
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)d,g,K
X
X
X
X
X
X
X
X
X
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
Chemistry (gluc., BUN, creat., Na, K, Cl, CO2, Ca, PO4, 
Mg, prot., alb., TBili., AST, ALT,  ALP, GGT, LDH, Free  
T3, Free T4, TSH)a
X
X
X
X
X
X
X
Chemistry cont. (amylase and lipase)a
X
X
X
X
X
X
X
Urinalysisa
X
X
X
X
X
X
X
Coagulation parametersf
X
Serum pregnancy test a
-7 to -1 days
Urine pregnancy testa
X
X
X
Blood for Correlative Immune Monitoring
Total Lymph, CD4/5/8 T-cell counts; Phenotyping of 
T-cell/B-cell/NK cell subsets, flow cytometry; 
Activated T-cell expression markers, % Tregs, Treg 
to effector cell ratio; Myeloid derived suppressor 
cells; serum cytokine profiling
X
Xa
Xa
Tumour Biopsy Sample Collections
Tumour infiltrating lymphocytes; PD-1 expressing 
lymphocytes; measurement of tumour/stromal cell 
PD-L1 expression
X
X
Genomic investigations
X
X
Saliva samples and photographsm
X
X
Routine Lab Specimens
LUD2015-005 
Study Flowchart for Cohort C-FLOT
Part 1
Screening / 
Baseline
Treatment
Immunotherapy Only  Period
(4 weeks)
Cycle 1
(4 weeks)
Cycle 2
(4 weeks)


 
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Cycle week
1
3
Visit Day per Cycle
1(±3)
15(±3)
Cumulative Study Week 
Cumulative Study Day
Treatment for Cohort C-FLOT
Durvalumab
Xc
Xc
5-Fluorouracil
Xc
Xc
Leucovorin
Xc
Xc
Oxaliplatin
Xc
Xc
Docetaxel
Xc
Xc
Surgery - 6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryK
Tumour & Disease Assessments
PET/CT scanL
X
X
Study Procedures and Examinations
Eligibility Assessment and Informed Consent (IC)J
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
Medical history
Physical Exam (incl weight and ECOG Perf Status)b
Xc
Xc
X
X
X
X
ECG (and as clinically indicated after Day 1)h
X
Vital Signs (T, HR, BP, RR)e 
Xc
Xc
X
X
X
X
Concomitant Medication /Procedureg, K
Xc
Xc
X
X
X
X
Adverse Events (starting or worsening after IC)d,g,K
Xc
Xc
X
X
X
X
Routine Lab Specimens
Blood Hematology (complete blood count, 
differential, platelets)a
Xa,c
Xa,c
X
X
X
X
Chemistry (gluc., BUN, creat., Na, K, Cl, CO2, Ca, PO4, 
Mg, prot., alb., TBili., AST, ALT,  ALP, GGT, LDH, Free  
T3, Free T4, TSH)a
Xa,c
Xa,c
X
X
X
X
Chemistry cont. (amylase and lipase)a
Xa,c
Xa,c
X
X
X
X
Urinalysisa
Xa,c
Xa,c
X
X
X
X
Coagulation parametersf
Serum pregnancy test a
Urine pregnancy testa
Xa,c
X
X
X
X
Blood for Correlative Immune Monitoring
Total Lymph, CD4/5/8 T-cell counts; Phenotyping of 
T-cell/B-cell/NK cell subsets, flow cytometry; 
Activated T-cell expression markers, % Tregs, Treg 
to effector cell ratio; Myeloid derived suppressor 
cells; serum cytokine profiling
Tumour Biopsy Sample Collections
Tumour infiltrating lymphocytes; PD-1 expressing 
lymphocytes; measurement of tumour/stromal cell 
PD-L1 expression
Genomic investigations
Saliva samples and photographsm
Last Study 
Drug Dose 
+14( ±4) 
days K-3
Post Study 
Follow-upn
 Last Study 
Drug Dose 
+ 91( ±7) 
days 
 Last Study 
Drug Dose 
+ 110( ±7) 
days  
Every 6 months for up to 3 years post initiation of treatment. (See footnote "n") 
Telephone contact or medical record review to include clinical outcomes data (dates of progression/relapse and survival).
Last Study 
Drug Dose 
+42 (±7) 
days
X
X
LUD2015-005 
Study Flowchart for Cohort C-FLOT
Part 2
Treatment
On Study Follow-upd,K
Surgery
Post Surgery 
treatmentc
(4 week cycle)
X
X
Xi
Xi
Xi
Xi


 
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Flowchart Footnotes for Cohort C-FLOT:
a- Pre-dose; record times as well as dates. If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at  
     Day 1. Results for safety blood tests (chem,  hematology, and pregnancy [when applicable]) must be available and reviewed before commencing an infusion.
     GGT tested at Screening, Day 1 and as clinically indicated. For each on-treatment cohort, hematology, chem, urine & pregnancy safety assessments should coincide with 
     drug administration study visits. With the exception of On Study Follow-up, Lab assessments are not  applicable if there is no drug administration visit for a particular
     cohort. End of study pregnancy test for women of child-bearing potential must be done on serum.
b- Full physical examination (including neurological exam) at baseline; targeted physical examination (including neurological exam) at other time points
     For each on-treatment cohort, physical exams should coincide with drug administration study visits. With the exception of On Study Follow-up, physical exams are  
     not applicable if there is no drug administration visit for a particular cohort.
c- Cohort C-FLOT will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided this is within 3 months of surgery.     
   Subjects in Cohort C-FLOT may receive durvalumab, FLOT, or durvalumab plus FLOT at the discretion of the investigator.
d- See Section 7.1.5  for details on collection of  AEs during On Study Follow-up
e- Vital signs assessments should coincide with drug administration study visits. With the exception of On Study Follow-up, vital sign 
    assessments are not applicable if there is no drug administration visit. For durvalumab, vital signs are measured before, during 
    and after infusions according to Section 6.11.
f - Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated; record times as well as dates.
g - Concomitant med and AE information may be collected by telephone if there is no study drug administration/lab test/scan/procedure visit scheduled.
h - 12 Lead ECG - baseline and abnormal ECG at any time will be done in triplicate (2-5 minutes apart); others may be single measurements.
i - On day of surgery (blood draw must be pre-surgery and may be up to 3 days before). If subject discontinues from treatment early, 
     include at last study visit or first On Study follow-up.
J- A screening log must be kept of all subjects considered for the study including any that are subsequently excluded; reason for exclusion must be recorded on this form. 
    A copy of the screening log should be sent to the trial office on request, but without subject identifiers. The original must be retained on site,
   Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
K -For subjects in Cohort C-FLOT: 
    1. All  AEs will be collected for 110 days after the last dose of pre-surgery durvalumab, with the exception of those AEs that are related to the protocol-defined surgical 
    procedure(s). If the decision is made that a subject will not receive continued durvalumab, the subject must start On Study Follow-up and have at least one On Study 
    Follow-up visit at 110 days (+30 days) after last dose of durvalumab or at the point of the decision (+30 days), whichever is later.
   2. If any subjects in Cohort C-FLOT continue durvalumab treatment after the planned surgical procedure, they will follow the On Study Follow-up period according to the 
   Flowchart, and all AEs will be collected for 110 days after the last dose of durvalumab. 
   3. If any subjects continue FLOT treatment alone (no durva) after the planned surgical procedure, they will complete the first On Study Follow-up at Day 28 (+14 days) post last 
     dose of FLOT. All AEs will be collected for at least 28 (+14) days after the last dose of FLOT; however, point #1 must still be followed for a visit post last dose of durvalumab. 
L - PET/CT scan  for Cohort C-FLOT:
     Scan scheduled after completion of therapy/before surgery may  be combined as part of the surgery workup or per local institutional standards.
     Post surgery scan may be done at first post surgery treatment visit.
     PET scan at the post-surgery and On-Study Follow-Up timepoints may be replaced with a CT scan.
     Scans should be done per local institutional standards and reported per irRECIST/RECIST 1.1 guidance. See Sections 4.2.1 and 8.8 and eCRF.
     Scanning protocols and modalities should remain consistent throughout the study.
m - Saliva samples may be collected at each biopsy collection time point; photographs at endoscopy may be taken.
n - Per Amendment 8, all post study follow-up for the collection of survival data will be discontinued as of 30Jun2022 (see Section 8.1, Amendment 8).


 
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3.2.3 Study Flowchart for Cohort D2 
 
Cycle week
1
2
3
4
1
2
3
1
2
Visit Day per Cycle
1
8(±3)
15(±3) 22(±3)
1(±3)
8(±3)
15(±3)
1(±3)
8(±3)
Cumulative Study Week 
1
2
3
4
5
6
7
8
9
Cumulative Study Day
-28 to -1
1
8
15
22
29
36
43
50
57
Durvalumab  for Cohort D2
X
X
X
X
X
Paclitaxel
X
X
X
X
X
Carboplatin
X
X
X
X
X
Radiotherapy (41.4 Gy over 23 fractions)
Surgery:  6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryk
PET/CT for Cohort D2L
X
Eligibility Assessment and Informed Consent (IC)J
X
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
X
Medical history
X
Physical Exam (incl weight and ECOG Perf Status)b
X
X
X
X
X
X
X
X
ECG (and as clinically indicated after Day 1)h
X
X
Vital Signs (T, HR, BP, RR)e 
X
X
X
X
X
X
X
X
Concomitant Medication /Procedureg, k
X
X
Xg
X
X
X
X
X
X
X
Adverse Events (starting or worsening after IC)d,g,k
X
X
Xg
X
X
X
X
X
X
X
Blood Hematology (complete blood count, 
differential, platelets)a
X
X
X
X
X
X
X
X
Chemistry (gluc., BUN, creat., Na, K, Cl, CO2, Ca, PO4, 
Mg, prot., alb., TBili., AST, ALT,  ALP, GGT, LDH, Free  
T3, Free T4, TSH)a
X
X
X
X
X
X
X
X
Chemistry cont. (amylase and lipase)a
X
X
X
X
X
X
Urinalysisa
X
X
X
X
X
X
Coagulation parametersf
X
Serum pregnancy test a
-7 to -1 days
Urine pregnancy testa
X
X
X
Total Lymph, CD4/5/8 T-cell counts; Phenotyping of 
T-cell/B-cell/NK cell subsets, flow cytometry; 
Activated T-cell expression markers, % Tregs, Treg 
to effector cell ratio; Myeloid derived suppressor 
cells; serum cytokine profiling
X
Xa
Xa
Tumour infiltrating lymphocytes; PD-1 expressing 
lymphocytes; measurement of tumour/stromal cell 
PD-L1 expression
X
X
Genomic investigations
X
X
Saliva samples and photographsm
X
X
Treatment for Cohort D2
Tumour & Disease Assessments
Study Procedures and Examinations
Routine Lab Specimens
Tumour Biopsy Sample Collections
Blood for Correlative Immune Monitoring
Treatment
Immunotherapy Only  Period 
(4 weeks)
Cycle 1
(3 weeks)
Cycle 2
(2 weeks)
X
LUD2015-005 
Study Flowchart for Cohort D2
Part 1
Screening / 
Baseline


 
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Cycle week
1
3
Visit Day per Cycle
1(±3)
15(±3)
Cumulative Study Week 
Cumulative Study Day
Durvalumab  for Cohort D2
Xc
Xc
Paclitaxel
Carboplatin
Radiotherapy (41.4 Gy over 23 fractions)
Surgery:  6 to 8 weeks after completion of therapy 
or according to institutional policies for surgeryk
PET/CT for Cohort D2L
X
X
Eligibility Assessment and Informed Consent (IC)J
Demographics (incl. DoB; sex; height; race; 
ethnicity) 
Medical history
Physical Exam (incl weight and ECOG Perf Status)b
Xc
Xc
X
X
X
X
ECG (and as clinically indicated after Day 1)h
X
Vital Signs (T, HR, BP, RR)e 
Xc
Xc
X
X
X
X
Concomitant Medication /Procedureg, k
Xc
Xc
X
X
X
X
Adverse Events (starting or worsening after IC)d,g,k
Xc
Xc
X
X
X
X
Blood Hematology (complete blood count, 
differential, platelets)a
Xa,c
Xa,c
X
X
X
X
Chemistry (gluc., BUN, creat., Na, K, Cl, CO2, Ca, PO4, 
Mg, prot., alb., TBili., AST, ALT,  ALP, GGT, LDH, Free  
T3, Free T4, TSH)a
Xa,c
Xa,c
X
X
X
X
Chemistry cont. (amylase and lipase)a
Xa,c
Xa,c
X
X
X
X
Urinalysisa
Xa,c
Xa,c
X
X
X
X
Coagulation parametersf
Serum pregnancy test a
Urine pregnancy testa
Xa,c
X
X
X
X
Total Lymph, CD4/5/8 T-cell counts; Phenotyping of 
T-cell/B-cell/NK cell subsets, flow cytometry; 
Activated T-cell expression markers, % Tregs, Treg 
to effector cell ratio; Myeloid derived suppressor 
cells; serum cytokine profiling
Tumour infiltrating lymphocytes; PD-1 expressing 
lymphocytes; measurement of tumour/stromal cell 
PD-L1 expression
Genomic investigations
Saliva samples and photographsm
Xi
Treatment for Cohort D2
Tumour & Disease Assessments
Study Procedures and Examinations
Routine Lab Specimens
Tumour Biopsy Sample Collections
Blood for Correlative Immune Monitoring
Treatment
Xi
Xi
Xi
X
X
On Study Follow-upd, k
Post Study 
Follow-upo
 Last Study 
Drug Dose 
+ 91( ±7) 
days  
 Last Study 
Drug Dose 
+ 110( ±7) 
days  
Every 6 months for up to 3 years post initiation of treatment. (see footnote "o")
Telephone contact or medical record review to include clinical outcomes data (dates of progression/relapse and survival).
Post Surgery 
Durvalumabc
(4 week cycle)
Last Study 
Drug Dose 
+14( ±4) 
days
Last Study 
Drug Dose 
+42 (±7) 
days
X
Post Treatment 
Safety  Assessmentsn
X
Surgery
LUD2015-005 
Study Flowchart for Cohort D2
Part 2
4 (±1) 
weeks 
post last 
dose 
up to 2 
weeks pre 
surgery
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


 
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Page 42 of 123 
 
 
Flowchart Footnotes for Cohort D2:
a- Pre-dose; record times as well as dates. If screening laboratory assessments are performed within 3 days prior to Day 1 they do not need to be repeated at Day 1.
     Day 1 lab assessments may be performed within 3 days prior to Day 1.  Results for safety blood tests (chem,  hematology, and pregnancy [when applicable]) must be 
     available and reviewed before commencing an infusion. GGT tested at Screening, Day 1 and as clinically indicated. 
     End of study pregnancy test for women of child-bearing potential must be done on serum.
b- Full physical examination (including neurological exam) at baseline; targeted physical examination (including neurological exam) at other time points
c- Cohort D2 subjects will be eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from surgery, provided this is within 3 months of surgery. 
d- See Section 7.1.5  for details on collection of  AEs during On Study Follow-up
e- For durvalumab, vital signs are measured before, during  and after infusions according to Section 6.11. 
f - Coagulation tests: prothrombin time, APTT and INR – only performed at Screening and as clinically indicated; record times as well as dates.
g - Concomitant med and AE information may be collected by telephone if there is no study drug administration/lab test/scan/procedure visit scheduled.
h - 12 Lead ECG - baseline and abnormal ECG at any time will be done in triplicate (2-5 minutes apart); others may be single measurements.
i - Collected on day of surgery for Cohort D2 (blood draw must be pre-surgery and may be up 3 days before). If subject discontinues from treatment early, 
     include at last study visit or first On Study follow-up.
J- A screening log must be kept of all subjects considered for the study including any that are subsequently excluded; reason for exclusion must be recorded on this form. 
    A copy of the screening log should be sent to the trial office on request, but without subject identifiers. The original must be retained on site,
   Standard of Care procedures may be used for eligibility assessments provided they meet the criteria specified in either the inclusion criteria or flowchart
K -For subjects in Cohort D2: 
    1. All  AEs will be collected for 110 days after the last dose of pre-surgery durvalumab, with the exception of those AEs that are related to the protocol-defined surgical 
    procedure(s). If the decision is made that a subject will not receive continued durva, the subject must start On Study Follow-up and have at least one On Study Follow-up
    visit at 110 days (+30 days) after last dose of durvalumab or at the point of the decision (+30 days), whichever is later.
   2. If any subjects in Cohort D2 continue durvalumab treatment after the planned surgical procedure, they will follow the On Study Follow-up period according to the 
   Flowchart, and all AEs will be collected for 110 days after the last dose of durvalumab (durva).
L - PET/CT scan  for Cohort D2:
     Scan scheduled after completion of therapy/before surgery may  be combined as part of the surgery workup or per local institutional standards.
     Post surgery scan may be done at first post surgery treatment visit.
     PET scan at the post-surgery and On-Study Follow-Up timepoints may be replaced with a CT scan.
     Scans should be done per local institutional standards and reported per irRECIST/RECIST 1.1 guidance. See Sections 4.2.1 and 8.8 and eCRF.
     Scanning protocols and modalities should remain consistent throughout the study.
m - Saliva samples may be collected at each biopsy collection time point; photographs at endoscopy may be taken.
n - For Cohort D2, the following additional visits are required during which all safety assessments are done and a safety review is conducted:
      1. A visit that occurs 4 weeks (± 1 week) after the completion of chemoradiotherapy + durvalumab
      2. A pre-surgery visit, up to 2 weeks before surgery 
      Note: During post surgery, there is regular contact between the PI and the surgical staff to assess status and whether post surgery durvalumab will be initiated.
o - Per Amendment 8, all post study follow-up for the collection of survival data will be discontinued as of 30Jun2022 (see Section 8.1, Amendment 8).


 
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4 Study Objectives & Endpoints 
Primary Objectives 
• Assess the Safety/Tolerability of durvalumab alone and 
tremelimumab + durvalumab in combination with oxaliplatin / 
capecitabine chemotherapy in metastatic/locally advanced OC. 
• Assess the Safety/Tolerability of durvalumab in combination with 
neoadjuvant chemo(radio)therapy (oxaliplatin/capecitabine, 
FLOT, and paclitaxel/carboplatin/radiotherapy) before surgery in 
operable OC. 
(Endpoint: CTCAE version 4.03) 
Secondary Objectives  • Assess the Clinical Efficacy of durvalumab alone and 
tremelimumab + durvalumab in combination with 
oxaliplatin/capecitabine chemotherapy in metastatic or locally 
advanced OC.  (Endpoints: Tumor Response by irRECIST, 
progression-free survival (PFS) and overall survival (OS)) 
• Assess the Clinical Efficacy of durvalumab in combination with 
neoadjuvant chemo(radio)therapy (oxaliplatin/capecitabine, 
FLOT, and paclitaxel/carboplatin/radiotherapy) in operable OC.  
(Endpoints: PFS after surgery, 1-year survival rate, OS, 
pathological and metabolic response rate) 
Exploratory objective • Evaluate the immunological effects of durvalumab and 
tremelimumab + durvalumab in tumor and peripheral blood 
samples.  
• Relate the effects of immune modulation to allele variance, gene 
expression and host-pathogen relationships in the upper 
gastrointestinal tracts of OC subjects. 
• Evaluate genomic differences between subjects who exhibit 
differential immune and therapeutic responses to durvalumab 
and tremelimumab + durvalumab therapy. 
In order to be fully evaluable (per protocol) for the primary endpoint, major protocol violations 
that interfere with the assessment of the primary endpoint must be absent. 
4.1 
Safety and Tolerability 
The assessment of safety and tolerability will be performed by the internal data safety 
monitoring panel on an ongoing basis, based on data review and regular conference calls with 
the investigators.   
4.1.1 Endpoints & Assessment Methods 
Standard safety evaluation and reporting for early phase trials will be used for Cohorts B, C/C-
FLOT, and D/D2. In addition, for Cohorts C/C-FLOT and D/D2, subjects undergoing surgery will be 
closely monitored for post-operative complications (compared with outcomes in the Oxford 
Oesophago-Gastric Surgical Database) to evaluate the possibility of an impact. 


 
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Laboratory tests, vital sign measurements, physical exams (including neurological exams) and 
subject interviews will be performed to detect new abnormalities and deteriorations of any pre-
existing conditions.  The investigator will evaluate any laboratory abnormalities for clinical 
significance, and clinically significant abnormalities will be recorded as adverse events.  All 
clinically significant abnormalities and deteriorations from time of signing of informed consent to 
the end of study visit should be recorded in the Case Report Forms as adverse events and graded 
according to the National Cancer Institute Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.03. 
4.1.2 Subject Evaluation & Statistics 
The Per-Protocol (PP) Population for DLT Assessment is defined as: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) and 
• 
All subjects with no DLT who received at least 75% of the scheduled doses of durvalumab 
and chemotherapy or tremelimumab, durvalumab and chemotherapy as well as, 
respective safety assessments without major protocol violations over the entire DLT 
Evaluation Period (as defined in Section 3.1.9).   
Refer to Section 3.1.11 for subject replacement. 
The Safety Population is defined as all subjects who receive at least one dose of durvalumab or 
tremelimumab. 
In Phase 1, for the primary endpoint of determining DLTs and the RCD, the analysis of safety and 
tolerability will be based on the PP Population for DLT Assessment. 
In both phases, the overall analysis of safety and tolerability will be based on the Safety 
Population. 
Appropriate summaries of AEs, laboratory data and vital sign data will be presented.  Adverse 
events will be coded using the MedDRA dictionary.  Incidences of treatment-emergent adverse 
events (TEAE, those events that started after dosing or worsened in severity after dosing) will be 
presented overall and by maximum severity (according to CTCAE version 4.03) and relationship to 
study medication. 
For each continuous laboratory parameter, results will be categorized as low, normal, or high 
based on the laboratory normal ranges.  Frequencies and percentages will be presented by 
treatment arm for the shifts in these categories (i.e., low to normal, low to high, high to low, etc.) 
from baseline to each post-treatment assessment time point.  Additionally, for each continuous 
hematology and chemistry parameter, descriptive statistics will be presented by treatment arm 
for the changes from baseline to each post-treatment assessment time point.  Descriptive 
statistics will be presented by cohort for the changes in vital signs from baseline to each post-
treatment assessment time point. 


 
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4.2 
Clinical Efficacy 
Clinical efficacy evaluation will include tumor response assessed by irRECIST, Progression-free 
Survival (PFS), Overall Survival (OS), and Objective Response Rate (ORR). In addition, metabolic 
response on PET scanning and histological response in resection specimens will be assessed in 
Cohorts C/C-FLOT and D/D2. 
4.2.1 Endpoints & Assessment Methods 
Clinical Efficacy is determined by measuring the PFS, response (objective, metabolic and 
histologic), and OS.  Every attempt should be made to use whichever imaging technique(s) and 
test(s) are used initially for repeat evaluations throughout the study, whereby the last tumor 
assessment will be at least 4 weeks from the prior assessment. 
The study will provide a preliminary assessment of the efficacy of durvalumab alone or 
tremelimumab+ durvalumab therapy with chemotherapy in metastatic or locally advanced OC. 
Endpoints will include tumor response rate according to irRECIST, PFS, and OS.  In addition, there 
will be a preliminary assessment of the efficacy of durvalumab therapy and neoadjuvant 
chemo(radio)therapy in operable OC. Progression-free survival after surgery, 1-year survival rate, 
and OS will be evaluated, along with metabolic response on PET scanning and histological 
response in resection specimens. Histologic response will record resection status (R0, R1, R2), 
Mandard grade and complete pathological response (present/absent).  
Evaluation according to irRECIST using CT scanning will be performed every 6 weeks for Cohorts A 
and B.  Subjects in Cohorts C/C-FLOT and D/D2, will undergo PET/CT scanning before and after 
treatment per the Study Flowchart in Section 3.2. The scans should be carried out according to 
local institutional standards and reported according to irRECIST and RECIST1.1 (see the guidelines 
in Section 8.8). The information to be captured at each scan is outlined in the eCRF. Scanning 
protocols and modalities should remain consistent throughout the study. Metabolic response will 
be assessed according to PERCIST.38  
4.2.1.1 
Tumor Response Assessment by irRECIST 
Tumor Response will be assessed by irRECIST (see Section 8.8).   
4.2.1.2 
Progression-free Survival Rate 
Progression-free Survival will be determined for each subject with time origin at the start of the 
treatment (Day 1) until the first occurrence of confirmed progression by irRECIST or date of death 
if the subject dies from any causes before progression.  For subjects in Cohorts C/C-FLOT and 
D/D2 undergoing successful surgery, post-operative PFS will also be monitored with time origin 
at the day of surgery until the first occurrence of confirmed progression by irRECIST or date of 
death if the subject dies from any causes before progression.  The 6-month PFS rate taken from 
the time of surgery and R0 resection rate are surrogate markers for longer term clinical 
outcomes.  Every effort will be made to follow subjects for progression after they discontinue the 
study. 
4.2.1.3 
Objective Response Rate 
Objective Response Rate is defined as the percentage of subjects meeting criteria of irCR or irPR 
over a period of at least 4 weeks. 


 
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4.2.1.4 
Overall Survival  
Overall survival (OS) will be measured for each subject with time origin at the start of the 
treatment (Day 1) until recorded date of death.  Every effort will be made to follow subjects for 
overall survival after they discontinue the study. 
NOTE: Per Amendment 8, all post study follow-up for the collection of survival data will be 
discontinued as of 30 June 2022 (see rationale in Section 8.1, Amendment 8 on Page 96). 
4.2.2 Subject Evaluation & Statistics 
All subjects who received at least one dose of durvalumab and/or tremelimumab, as well as 
baseline and at least one post-baseline disease assessments, will be evaluated for clinical 
efficacy.  Tumor Responses by irRECIST, PFS, and OS will be summarized and analyzed 
descriptively. 
4.3 
Immune Monitoring  
Samples for exploratory assessment of correlative immune monitoring will be collected according 
to the Study Flowchart in Section 3.2. 
Note: Per Amendment 7, the Investigator(s) will have the option to approach subjects with long-
term survival (PFS > 1 year, still in remission) from the metastatic cohorts (A and B) of the trial to 
request blood (up to 300 mL) for additional testing as described in Section 2.3. 
All subjects will be assessed for immunological biomarkers in peripheral blood collected prior to 
their first durvalumab or tremelimumab + durvalumab infusion and in the 3rd week of 
immunotherapy as well as on Cycle 1, Day 15.  Samples will also be collected on the day of 
surgery (blood may be collected up to 3 days before surgery) for Cohorts C/C-FLOT and D/D2 and 
post completion of treatment for Cohorts A and B.  
Pre-treatment biopsies, on treatment biopsies and post-operative resectional tissue (or post 
completion of treatment for Cohorts A and B) will be collected.  On treatment research biopsies 
will be taken during the 4th week of immunotherapy, i.e. prior to the start of chemotherapy.  
Longitudinal comparison of pre and post immunotherapy effects can thus be evaluated in OC 
tissue and provide critical measures of treatment impact on immune checkpoint inhibition. 
4.3.1 Endpoints & Assessment Methods 
Subjects who received at least one dose of tremelimumab or durvalumab, and provide baseline 
and at least one post-treatment sample, will be evaluated.  Peripheral blood samples will be 
assessed for: 
1. Total lymphocyte count and CD4/5/8 T-cell counts 
2. Phenotyping of T-cell/B-cell/NK cell subsets via antibody labelling and flow cytometry or 
mass cytometry.  This will include assessment of activated T-cell expression markers, 
percentage of regulatory T-cells (Tregs) and Treg to effector cell ratio, determination of 
activation of immune cells based on inducible costimulatory expression and 
quantification of myeloid derived suppressor cells. 
3. Serum cytokine profiling using ELISAs. 


 
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Pre-treatment biopsies, on treatment biopsies and post-operative resectional tissue will be 
evaluated retrospectively for the following: 
1. Tumor infiltrating lymphocytes, as above, by flow and/or mass cytometry, including 
assessment of PD-1 expressing lymphocytes  
2. Measurement of tumor/stromal cell PD-L1 expression by immunohistochemistry.  
Please refer to the Laboratory Manual for this study for additional information on lab specimen 
handling and logistics. 
4.3.2 Subject Evaluation & Statistics 
Results from the correlative studies will be summarized descriptively and evaluated in relation to 
outcome.   
4.4 
Genomic Investigation 
The study will determine genomic profiles that predict durvalumab and tremelimumab + 
durvalumab treatment response in OC subjects.  It will evaluate the effects of durvalumab and 
tremelimumab + durvalumab on allele variance, gene expression and pathogenicity in the upper 
gastrointestinal tract, and how this relates to subject outcomes, immune monitoring and disease 
characteristics.   
Pre-treatment biopsies and post-operative resectional tissue or post treatment biopsies will be 
RNA and DNA sequenced under existing ethical agreement and collection protocols.  Allele 
variants and gene expression profiles will be examined from OC tissue and multiple control sites 
in the upper gastrointestinal tract before and during immune modulation.  Relationships 
between high-throughput sequencing data, subject outcome measures, immune monitoring 
results and disease characteristics will be examined enabling novel study of the effects of 
immune modulation on the transcriptome in subjects with OC.  Application of these findings with 
an established pipeline for identification of non-human DNA in oesophageal disease also enables 
thorough interrogation of the host-pathogen relationship in oesophageal cancer, and how this is 
influenced by anti CTLA-4/PD-L1 immune therapy.   
 


 
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5 Subject Eligibility 
5.1 
Inclusion Criteria 
Note: Standard of Care procedures may be used for eligibility assessments provided they meet 
the criteria specified in either the inclusion criteria or flowchart. 
A screening log must be kept of all subjects considered for the study including any that are 
subsequently excluded; the reason for exclusion must be recorded on this form. A copy of the 
screening log should be sent to the trial office on request, but without subject identifiers. The 
original must be retained on site. 
Eligible subjects must fulfill all of the following criteria: 
1. 
Histological diagnosis of oesophageal or gastrooesophageal cancer. 
Have not received full dose systemic chemotherapy. 
• 
Cohorts A and B - metastatic/locally advanced cancer 
• 
Cohorts C, C-FLOT and D/D2 -  deemed suitable for surgery with curative intent 
Subjects with operable disease will be allocated to Cohort C/C-FLOT or D/D2 based on 
the decision taken by the multidisciplinary team (MDT) on the standard treatment 
approach for any individual patient. The MDT will determine (1) operability and (2) 
whether neoadjuvant chemotherapy or chemoradiotherapy should be offered. These 
decisions will guide eligibility for enrollment to Cohorts C/C-FLOT and D/D2.  The 
radiotherapy offered in Cohort D/D2 will be standard of care for these subjects, as 
already determined by MDT. 
2. 
Recovered from prior therapy (Grade 1 persistent AEs acceptable) 
3. 
Anticipated lifespan greater than 4 months 
4. 
ECOG performance status of 0 or 1. 
5. 
At the time of day 1 of the study, subjects with brain metastases must be 
asymptomatic for at least 4 weeks and: 
• 
at least 8 weeks without tumor progression after any whole brain radiotherapy 
• 
at least 4 weeks since craniotomy and resection or stereotactic radiosurgery 
• 
at least 3 weeks without new brain metastases as evidenced by MRI/CT 


 
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6. 
Adequate normal organ and marrow function as defined below.  
Laboratory parameters for vital functions should be in the normal range.  Laboratory 
abnormalities that are not clinically significant are generally permitted, except for the 
following laboratory parameters, which must be within the ranges specified, regardless 
of clinical significance: 
Hemoglobin 
≥ 9 g/dL 
Neutrophil count 
≥ 1.5 x 109/L 
Platelet count 
≥ 100,000/mm3 
Serum creatinine, or 
Creatinine Clearance 
≤ 1.5x Institutional Upper Limit of Normal 
(ULN), or ≥ 40 mL/min (by Cockcroft-Gault 
formula) 
AST/ALT 
AST (SGOT)/ALT (SGPT) ≤ 2.5 x institutional 
upper limit of normal  
Alkaline phosphatase 
≤ 2.5 x ULN 
Serum bilirubin 
≤ 1.5 x institutional upper limit of normal 
(ULN).  This will not apply to subjects with 
confirmed Gilbert’s syndrome (persistent or 
recurrent hyperbilirubinemia that is 
predominantly unconjugated in the absence of 
hemolysis or hepatic pathology), who will be 
allowed only in consultation with their 
physician. 
7. 
Written informed consent obtained from the subject prior to performing any protocol-
related procedures, including screening evaluations. 
8. 
Age ≥18 years. 
9. 
Have been informed of other treatment options 
10. 
Willing and able to comply with the protocol for the duration of the study including 
undergoing treatment, scheduled visits, examinations, biopsies and follow up  
5.2 
Exclusion Criteria 
Subjects may not enter the study if they fulfill any of the following criteria: 
1. 
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca 
staff and/or staff at the study site). Previous enrollment in the present study. 
2. 
Prior treatment in another clinical study with an investigational product within 4 weeks 
prior to Day 1 of the study; resolution of respective adverse event to Grade 1 or lower 
should have occurred. 
Note: all prior AEs, regardless of subject’s inclusion in a clinical trial, must have 
resolved to Grade 1 or lower. 
3. 
Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3 
electrocardiograms (ECGs) using Fredericia’s Correction 
4. 
Active or prior documented autoimmune disease within the past 2 years 
NOTE: Subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
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5. 
Active or prior documented inflammatory bowel disease (e.g., Crohn’s disease, 
ulcerative colitis) 
6. 
History of allogeneic organ transplant 
7. 
Uncontrolled intercurrent illness including, but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable 
angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active 
bleeding diatheses including any subject known to have evidence of acute or chronic 
hepatitis B, hepatitis C, known immunodeficiency or human immunodeficiency virus 
(HIV), or psychiatric illness/social situations that would limit compliance with study 
requirements or compromise the ability of the subject to give written informed 
consent 
8. 
Known history of previous clinical diagnosis of tuberculosis 
9. 
Prior exposure to tremelimumab / durvalumab or checkpoint inhibitors, such as anti-
CTLA4 and anti-PD1/anti-PD-L1 antibodies. 
10. 
History of severe allergic reactions to any unknown allergens or any components of the 
study drugs. 
11. 
Known dihydropyrimidine dehydrogenase (DPD) deficiency 
12. 
Treatment with sorivudine or its chemically related analogues, such as brivudine 
13. 
Peripheral sensitive neuropathy with functional impairment. 
14. 
History of sarcoidosis syndrome. 
15. 
Metastatic disease to the central nervous system for which other therapeutic options, 
including radiotherapy, may be available. 
16. 
History of pneumonitis or interstitial lung disease. 
17. 
Major surgical procedure (as defined by the Investigator) within 30 days prior to Day 1 
or still recovering from prior surgery. 
18. 
Women who are breast feeding or pregnant as evidenced by positive serum pregnancy 
test (minimum sensitivity 25 IU/L or equivalent units of HCG). 
Female subjects of childbearing potential who are sexually active with a nonsterilized 
male partner must use at least one highly effective method of contraception (see table 
below) from the time of screening, and must agree to continue using such precautions 
for 90 days after the last dose of durvalumab or for 6 months after the last dose of 
durvalumab + tremelimumab (whichever is longer). Nonsterilized male partners of a 
female subject must use male condom plus spermicide throughout this period. 
Cessation of birth control after this point should be discussed with a responsible 
physician. Not engaging in sexual activity for the total duration of the trial and the drug 
washout period is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of contraception. 
Female subjects should refrain from breastfeeding throughout the period described 
above. 
Females of childbearing potential are defined as those who are not surgically sterile 
(i.e., bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or 
post-menopausal. 
Females will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause.  The following age-specific requirements 
apply:  


 
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• 
Females <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
• 
Females ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous hormonal 
treatments, had radiation-induced menopause with last menses >1 year ago, had 
chemotherapy-induced menopause with last menses >1 year ago, or underwent 
surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or 
hysterectomy. 
Nonsterilized male subjects who are sexually active with a female partner of 
childbearing potential must use male condoms plus spermicide from screening through 
90 days after last dose of durvalumab or through 6 months after the last dose of 
durvalumab + tremelimumab (whichever is longer). Female partners (of childbearing 
potential) of a male subject must use a highly effective method of contraception (see 
table below) throughout this period. Cessation of birth control after this point should 
be discussed with a responsible physician. Not engaging in sexual activity for the total 
duration of the trial and the drug washout period is an acceptable practice; however, 
periodic abstinence, the rhythm method, and the withdrawal method are not 
acceptable methods of contraception.  
Male subjects should refrain from sperm donation throughout the period described 
above. 
Highly effective methods of contraception are described in the table below. A highly 
effective method of contraception is defined as one that results in a low failure rate 
(i.e. less than 1% per year) when used consistently and correctly. Note that some 
contraception methods are not considered highly effective (e.g. male or female 
condom with or without spermicide; female cap, diaphragm, or sponge with or 
without spermicide; non-copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills where inhibition of ovulation is not the primary mode of 
action [excluding Cerazette/desogestrel which is considered highly effective]; and 
triphasic combined oral contraceptive pills). 
Acceptable highly effective methods of contraception are described in the following 
table: 


 
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Highly Effectivea Methods of Contraception 
Barrier/Intrauterine Methods 
Hormonal Methods 
• 
Copper T intrauterine device 
• 
Levonorgesterel-releasing 
intrauterine system (eg, 
Mirena®)b 
• 
 
• 
“Implants”: Etonogestrel-releasing implants: e.g., 
Implanon® or Norplan®  
• 
“Intravaginal Devices”: 
Ethinylestradiol/etonogestrel-releasing intravaginal 
devices: e.g., NuvaRing®   
• 
“Injection”: Medroxyprogesterone injection: e.g., 
Depo-Provera®   
• 
“Combined Pill”: Normal and low dose combined 
oral contraceptive pill 
• 
“Patch”: Norelgestromin / ethinylestradiol-
releasing transdermal system: e.g., Ortho Evra®    
• 
“Minipillc”: Progesterone based oral contraceptive 
pill using desogestrel: e.g., Cerazette® 
a - Highly effective (i.e. failure rate of <1% per year)  
b - This is also considered a hormonal method 
c - Cerazette® is currently the only highly effective progesterone based pill 
 
NOTE: additional requirements for carboplatin, paclitaxel, or FLOT treatment. 
Women of childbearing potential should avoid becoming pregnant while taking 
carboplatin, paclitaxel, or FLOT; they should notify the treating physician immediately 
if pregnancy occurs. Female and male subjects of fertile age and/or their partners 
should use effective contraceptives during and for at least 6 months after treatment 
with these drugs. Male subjects should also avoid sperm donation during and for at 
least 6 months after treatment with these drugs. 
Breastfeeding should be discontinued for the duration of treatment with these drugs. 
Male subjects should be advised regarding cryoconservation of sperm prior to 
treatment because of the possibility of irreversible infertility due to the treatment. 
 
19. 
Any condition that, in the clinical judgment of the treating physician, is likely to 
interfere with evaluation of study treatment, interpretation of subject safety or study 
results, prevent the subject from complying with any aspect of the protocol or that 
may put the subject at unacceptable risk. 
20. 
Subjects should not donate blood while participating in this study or for at least 90 
days following the last infusion of durvalumab, 6 months following the last infusion of 
tremelimumab, or until the time specified in the prescribing information of oxaliplatin, 
capecitabine, paclitaxel, carboplatin, or FLOT (5-fluorouracil (5-FU), leucovorin, 
oxaliplatin, and docetaxel), whichever is longest 
21. 
For oxaliplatin, capecitabine, paclitaxel, carboplatin, and FLOT (5-fluorouracil (5-FU), 
leucovorin, oxaliplatin, and docetaxel): refer to prescribing information for additional 
information 
 


 
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5.3 
Restrictions on Concomitant Therapies 
5.3.1 Non-Permitted Concomitant Therapies 
Subject may not receive the following concomitant therapies during the study: 
1. 
Systemic treatment with high dose corticosteroids (greater than Prednisone 10 mg 
daily or equivalent) or other immunosuppressive treatments (e.g. methotrexate, 
chloroquine, azathioprine).  See Section 5.3.2 for exceptions. 
Wash-out period: 2 weeks prior to Day 1 
2. 
Other cancer therapy (e.g., drug, radiation (see Section 5.3.2) or immunotherapy). 
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1; 6 weeks 
for nitrosoureas). 
3. 
Live/attenuated vaccines 1 month prior to Day 1 and for at least 6 months after the 
last dose of treatment. 
4. 
Sunitinib within 3 months after the last dose of tremelimumab. 
5. 
Immunosuppressive doses of steroids or other immunosuppressive medication 
through 90 days post last dose of tremelimumab. Note however, that inhaled and 
topical steroids when medically indicated as treatment for an acute illness or as 
pretreatment before CT scans (for contrast allergies) are allowed. The investigator is 
permitted to use corticosteroids as treatment for infusion reactions.  
6. 
Drugs with laxative properties and herbal or natural remedies for constipation should 
be avoided through 90 days post last dose of tremelimumab because of the potential 
for exacerbation of diarrhea.  
The wash-out period prior to Day 1 of the study for all non-permitted drugs should be at least 
1 week, unless stated otherwise above. 
 
For oxaliplatin, capecitabine, paclitaxel, carboplatin, and FLOT (5-fluorouracil (5-FU), 
leucovorin, oxaliplatin, and docetaxel) refer to the prescribing information and the additional 
information below: 
Warfarin:  INR (International normalised ratio) control may be affected by capecitabine. If a 
subject requiring coumarin-derived anticoagulants such as warfarin is taking capecitabine, more 
frequent INR monitoring is required.  The use of low molecular weight heparin instead of 
warfarin is at the discretion of the Investigator. 
Phenytoin:  Blood phenytoin levels may increase with capecitabine or 5-fluorouracil.  If a subject 
is taking phenytoin concomitantly with these drugs, they should be monitored regularly for 
increased phenytoin plasma concentrations and associated clinical symptoms.  
Other anti-epileptic substances: Leucovorin may diminish the effect of anti-epileptic substances: 
phenobarbital, primidone, phenytoin and succinimides, and may increase the frequency of 
seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs may be 
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Allopurinol: Interactions with allopurinol have been observed for 5-fluorouracil; with possible 
decreased efficacy of 5-fluorouracil. Concomitant use of allopurinol with capecitabine or 5-
fluorouracil should be avoided.  
Antivirals:  Brivudine and sorivudine must not be prescribed with capecitabine as they may 
produce a life-threatening interaction. 
Brivudin, sorivudin and analogues: 5-fluorouracil must not be given in combination with 
brivudin, sorivudin and analogues. Brivudin, sorivudin and analogues are potent inhibitors of the 
5-fluorouracil metabolising enzyme dihydropyrimidine dehydrogenase (DPD). 
5-Fluorouracil must not be given to subjects known to be homozygotic for dihydropyrimidine 
dehydrogenase (DPD). 
Vaccination with a live vaccine should be avoided in subjects receiving 5-fluorouracil due to the 
potential for serious or fatal infections. Contact should be avoided with people who have recently 
been treated with polio virus vaccine. 
Photosensitivity: It is not advisable to have prolonged exposure to sunlight because of the risk of 
photosensitivity with 5-fluorouracil. 
Nephrotoxic/ototoxic drugs: Auditory defects have been reported during carboplatin therapy. 
Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as aminoglycosides, 
vancomycin, capreomycin and diuretics is not recommended as they may increase or exacerbate 
toxicity, particularly in renal failure patients, due to carboplatin induced changes in renal 
clearance. 
CYP2C8 or CYP3A4 inhibitors/inducers: Caution should be exercised when administering 
paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g., 
ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, 
cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be 
increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with 
medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, 
phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised 
because of lower paclitaxel exposures. 
The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, 
clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin and 
voriconazole) should be avoided.   
Cytochrome P450-3A: The metabolism of docetaxel may be modified by the concomitant 
administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit 
the enzyme competitively) cytochrome P450-3A such as ciclosporine, ketoconazole and 
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5.3.2 Permitted Concomitant Therapies 
Subject may receive the following concomitant therapies during the study: 
1. 
Prophylactic anti-emetic treatment, consisting of a 5-HT3 antagonist, steroids and 
other anti-emetics are to be administered in conjunction with chemotherapy as per 
local practice guidelines. For example: 
• 
Dexamethasone 4 mg b.d. x 1 day 
• 
Granisetron or ondansetron for 1-2 days od 
• 
Domperidone or metoclopramide prn 
Note: For subjects at high risk of steroid side effects (e.g. diabetics) or for those who 
develop toxicity attributable to steroids (e.g. dyspepsia, dysphoria), the oral steroid 
should be carefully monitored or omitted. 
2. 
Intranasal or inhaled steroids for treating mild to moderate asthma or allergies, 
physiological steroid replacement, intra-articular steroids, or topical steroids for 
localized dermatitis (<5% of body surface area). 
3. 
NSAIDs, acetylsalicylic acid and specific COX-2 inhibitors. 
4. 
Antihistamines and other non-steroidal anti-allergy medication. 
5. 
Hormone replacement therapy. 
6. 
At the discretion of the investigator, any drug or non-drug therapy necessary to treat 
any condition arising during the study, including high dose corticosteroids or anti-TNF 
agents (e.g. infliximab) to treat immune-mediated adverse reactions.  Subjects should 
receive full supportive care, including transfusions of blood and blood products, and 
treatment with antibiotics, anti-emetics, anti-diarrheal, and analgesics, and other care 
as deemed appropriate, and in accordance with their institutional guidelines.  
7. 
Subjects may receive localized palliative radiotherapy on study if clinically indicated 
after discussion with the LICR medical monitor. 
All prescription and nonprescription drugs must be recorded in the concomitant medications 
section of the case report form, listing generic (preferably) or brand name, indication, dose, 
route and dates of administration.  All non-drug therapies must be recorded in the respective 
sections of the case report form. 
For oxaliplatin, capecitabine, paclitaxel, carboplatin, and FLOT (5-fluorouracil (5-FU), 
leucovorin, oxaliplatin, and docetaxel), refer to prescribing information for additional 
information. 


 
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6 Study Drug Preparation and Administration and Radiotherapy 
Delivery 
On days with concurrent tremelimumab and durvalumab dosing, durvalumab administration will 
start at least 60 minutes after the end of the tremelimumab infusion.   
On days with concurrent durvalumab and oxaliplatin dosing, oxaliplatin administration will start 
at least 60 minutes after the end of the durvalumab infusion.  The morning dose of capecitabine 
is taken after the oxaliplatin infusion. 
On days with concurrent paclitaxel and carboplatin dosing, paclitaxel will be infused over 1 hour 
followed by carboplatin infusion over 1 hour according to local standards.   
On days with concurrent durvalumab and FLOT dosing, the cytotoxic chemotherapy drugs should 
be administered at least 60 minutes after the end of the durvalumab infusion. Local standard 
procedures for the administration of 5-fluorouracil, leucovorin, oxaliplatin and docetaxel will 
apply. Note that leucovorin should not be mixed in the same infusion as 5-fluorouracil because a 
precipitate may form.  
For chemotherapy, banded doses may be used according to institutional guidelines. 
6.1 
Oxaliplatin 
Refer to the prescribing information for oxaliplatin.   
Oxaliplatin should always be administered before fluoropyrimidines. 
6.2 
Capecitabine 
Refer to the prescribing information for capecitabine. 
6.3 
Paclitaxel 
Refer to the prescribing information for paclitaxel. 
6.4 
Carboplatin 
Refer to the prescribing information for carboplatin. 
6.5 
5-Fluorouracil 
Refer to the prescribing information for 5-fluorouracil. 
6.6 
Leucovorin 
Refer to the prescribing information for leucovorin.  
6.7 
Docetaxel 
Refer to the prescribing information for docetaxel. 


 
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6.8 
Tremelimumab 
6.8.1 
Tremelimumab Study Drug Information  
Manufacturer 
MedImmune 
Expiration/Retest Date 
Expiration/retest dates are documented in the QA Disposition of 
IMP Report. 
Container Description 
Type: 
Single use vial  
Material: 
clear glass 
Size: 
20 mL 
Formulation 
Liquid solution containing 400 mg tremelimumab per vial.  The 
solution contains 20 mg/mL tremelimumab, 20 mM 
histidine/histidine hydrochloride, 222 mM trehalose dihydrate, 
0.27 mM disodium edetate dihydrate, and 0.02% weight/volume 
(w/v) polysorbate 80; it has a pH of 5.5 
Active Ingredient Content 
Mass/Weight: 
400 mg/vial 
Volume: 
20 mL 
Concentration: 
20 mg/mL 
Storage Conditions 
2°C to 8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, route of administration, and storage 
conditions 
6.8.2 
Tremelimumab Investigational Product Inspection 
Each vial of tremelimumab selected for dose preparation should be inspected. If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.8.3 
Tremelimumab Preparation 
The dose of tremelimumab for administration must be prepared by the IP manager or designated 
personnel using aseptic technique. No incompatibilities between tremelimumab and 
polyvinylchloride or polyolefin have been observed. However, administration sets containing 
cellulose-based filters should not be used with tremelimumab. 
Dose Calculation: 
Subjects will receive a fixed dose of tremelimumab. The starting dose is 37.5 mg with dose 
escalation to 75 mg (see Section 3.1.7.1). Tremelimumab is given only on Day 1 for certain 
cohorts (See Section 3.1.7). 
The volume of tremelimumab required for 75 mg is 3.75 mL; the volume for 37.5 mg is 1.875 mL 
(see calculation below). 
Tremelimumab 
Dose (mL) 
= 
dose level (mg) 
 
÷ 
Tremelimumab 
concentration (20 mg/mL) 
 
The corresponding volume of investigational product should be rounded according to 
institutional practice. 


 
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Dose Preparation: 
Tremelimumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, and delivered through an IV administration set with a 0.2- or 0.22-μm in-line 
filter.  The calculated volume of tremelimumab is added to the IV bag, and the bag is mixed by 
gentle inversion to ensure homogeneity of the dose in the bag. 
Example: The volume of tremelimumab required for 75 mg dose is 3.75 mL. The corresponding 
volume of investigational product should be rounded according to institutional practice. For 
example, (for a 75 mg dose of tremelimumab), if the institutional practice is to round the volume 
to the nearest tenth mL, 3.75 mL would be rounded to 3.8 mL, which would be the volume of 
tremelimumab added to the bag; the bag is then mixed by gentle inversion. 
Tremelimumab does not contain preservatives and any unused portion must be discarded. 
6.8.4 
Tremelimumab Administration 
Following preparation of the dose, tremelimumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational product.  Fully functional 
resuscitation facilities should be available. 
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low temperatures. 
• 
Tremelimumab must not be administered via IV push or bolus but as an IV infusion. 
• 
Tremelimumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line.   
• 
Tremelimumab solution should not be infused with other solutions or medications. 
• 
The entire contents of the IV bag should be administered by IV infusion over 
approximately 60 (±5) minutes, using a 0.2, or 0.22-μm in-line filter. An infusion of less 
than 55 minutes is considered a deviation. 
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time from needle puncture of the tremelimumab vial to the start of 
administration should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C 
(36°F to 46°F). Standard infusion time is 60 ± 5 minutes. However, if there are 
interruptions during infusion, the total allowed infusion time should not exceed 8 
hours.  In the event that either preparation time or infusion time exceeds the time limits, 
a new dose must be prepared from new vials. 
• 
The date, start time, interruption, and completion time of tremelimumab administration 
must be recorded in the source documents.  
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.11 
• 
See Section 8.5.1 for guidelines for infusion-related reactions. 


 
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6.9 
Durvalumab (MEDI4736) 
6.9.1 Durvalumab (MEDI4736) Study Drug Information 
Manufacturer 
MedImmune 
Expiration/Retest 
Date 
Expiration/retest dates are documented in the QA Disposition of 
Investigational Medicinal Product (IMP) Report. 
Container 
Description 
Type: 
Single use vial  
Material: 
glass 
Size: 
10 mL 
Formulation 
Liquid solution containing 500 mg durvalumab per vial.  
The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-HCl, 275 mM trehalose dihydrate, 0.02% 
(weight/volume [w/v]) polysorbate 80, at pH 6.0. 
Active Ingredient 
Content 
Mass/Weight: 
500 mg 
Volume: 
10mL 
Concentration: 
50 mg/mL 
Storage Conditions 
2°C–8°C (36°F to 46°F) Do not freeze 
Labeling 
Product name, lot number, route of administration, and storage 
conditions 
6.9.2 Durvalumab Investigational Product Inspection 
Each vial of durvalumab selected for dose preparation should be inspected.  If there are any 
defects noted with the investigational product (IP), the Investigator and Sponsor should be 
notified immediately. 
6.9.3 Durvalumab Preparation 
Preparation of durvalumab and preparation of the intravenous (IV) bag are to be performed by 
the IP Manager or designated personnel using aseptic technique.  No incompatibilities between 
durvalumab and polyvinylchloride or polyolefin copolymers have been observed. 
Dose Calculation: 
Subjects will receive a fixed dose of durvalumab: 750 mg Q2W.   
The volume of durvalumab (in mL) to add to the IV bag is calculated as follows: 
Volume of 
Durvalumab 
(mL) 
= 
Dose level (mg) 
÷ 
Durvalumab 
Concentration 
(nominal 50 mg/mL) 
 
Dose Preparation: 
Durvalumab will be administered using a 250 mL IV bag containing 0.9% (w/v) saline or 5% (w/v) 
dextrose and delivered through an IV administration set with a 0.2 or 0.22 µm in-line filter.  A 
volume of diluent equal to the calculated volume of durvalumab to be added to the IV bag must 
be removed from the bag prior to addition of durvalumab.  The calculated volume of durvalumab 
is then added to the IV bag, and the bag is mixed by gentle inversion to ensure homogeneity of 
the dose in the bag. 


 
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Example: For a 750 mg dose, 15 mL of durvalumab is to be diluted in a 250 mL IV bag. First, 15.0 
mL of diluent is removed from the IV bag, and then 15.0 mL of durvalumab is added to the bag. 
The bag is mixed by gentle inversion to ensure homogeneity of the dose in the bag. 
Durvalumab does not contain preservatives, and any unused portion must be discarded. 
6.9.4 Durvalumab Administration 
Following preparation of the dose, durvalumab will be administered according to the following 
guidelines: 
• 
A physician must be present at the site or immediately available to respond to 
emergencies during all administrations of investigational products.  Fully functional 
resuscitation facilities should be available.  
• 
Prior to the start of the infusion, the IV bag contents must be at room temperature to 
avoid an infusion reaction due to the administration of the solution at low temperatures 
• 
Durvalumab must not be administered via IV push or bolus but as an IV infusion. 
• 
Durvalumab solution should not be infused with other solutions or medications. 
• 
Durvalumab must be administered at room temperature by controlled infusion into a 
peripheral vein or central line. 
• 
The entire contents of the IV bag should be administered as an IV infusion over 
approximately 60 (± 5) minutes, using a 0.2- or 0.22-μm in-line filter.  An infusion of less 
than 55 minutes is considered a deviation.   
• 
After the contents of the IV bag are fully administered, the IV line will be flushed with a 
volume of IV diluent equal to the priming volume of the infusion set used.  Alternatively, 
the infusion will be completed according to institutional policy to ensure the full dose is 
administered; documentation is required if the line was not flushed. 
• 
The total time between needle puncture of the durvalumab vial to start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2°C to 8°C (36°F to 46°F).  
Standard infusion time is 60 ± 5 minutes.  However, if there are interruptions during 
infusion, the total allowed infusion time should not exceed 8 hours. In the event that 
either preparation time or infusion time exceeds the time limits, a new dose must be 
prepared from new vials.   
• 
The date, start time, interruption, and completion time of durvalumab administration 
must be recorded in the source documents.   
• 
Subjects will be monitored before, during and after infusion with assessment of vital 
signs according to Section 6.11.  
• 
See Section 8.5.1 for guidelines for infusion-related reactions. 


 
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6.10 Estimated Study Drug Requirements  
Drug 
Required Quantity 
Oxaliplatin 
Sourced locally by sites 
Capecitabine 
Sourced locally by sites 
Paclitaxel 
Sourced locally by sites 
Carboplatin 
Sourced locally by sites 
5-fluorouracil (5-FU) 
Sourced locally by sites 
leucovorin 
Sourced locally by sites 
docetaxel 
Sourced locally by sites 
Tremelimumab 
35 x 400 mg vials 
Durvalumab 
2400 x 500 mg vials 
6.11 Monitoring of Tremelimumab and Durvalumab Administration 
Subjects will be monitored before, during and after infusion of tremelimumab and durvalumab 
with assessment of vital signs according to the table below: 
Vital Signs Assessment on Study Drug Administration Days 
Drug 
Pre 
Dose 
During  
Infusion 
End of Infusion 
(± 5 minutes) 
30 (± 5) Minutes 
Post Infusion  
60 (± 5) Minutes 
Post Infusion  
Tremelimumab 
X 
every 
30 (± 5) minutes 
X 
 
 
Durvalumab  
X 
every 
15 (± 5) minutes 
X 
X 
X 
Note: When durvalumab and tremelimumab are to be administered on the same day, 
durvalumab infusion will start at least 60 minutes after the end of tremelimumab infusion even 
though vital signs assessment is not required during the entire 60-minute period post 
tremelimumab. 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions for that subject can be monitored according to the table below.  
A longer duration of observation after the end of infusion can be used if the Investigator deems it 
clinically necessary. 
Vital Signs Assessment on Study Drug Administration Days (after first 4 doses) 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes 
Post Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
 


 
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6.12 Drug Overdose Management 
6.12.1 Capecitabine, Oxaliplatin, Paclitaxel, Carboplatin, and FLOT (5-fluorouracil (5-
FU), leucovorin, oxaliplatin, and docetaxel)  
Any overdose with these drugs should be managed according to the respective prescribing 
information. 
6.12.2 Durvalumab and Tremelimumab 
Any overdoses with tremelimumab and durvalumab should be managed symptomatically.  There 
are no known antidotes available for these drugs.  An overdose is defined as a subject receiving 
any dose in excess of that specified in this protocol by > 10%.  All such overdoses must be 
reported, with or without associated AEs/SAEs, according to Section 7.1.2.2. 
6.13 Radiotherapy Delivery 
Radiotherapy will be delivered per current best practice. Investigators are advised to refer to 
separate Radiotherapy and Planning document for guidance. 


 
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7 Administrative, Legal & Ethical Requirements 
7.1 
Documentation and Reporting of Adverse Events 
7.1.1 General AE/SAE Definitions per ICH Guidelines 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and that does not necessarily have a causal 
relationship with the treatment.  An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. 
N.B.: The definition above, provided for in the GCP-ICH Guideline E6, is being extended for the 
purpose of LICR studies to include any events, intercurrent diseases and accidents observed while 
the subject is on study, i.e., during the actual treatment period, as well as during drug-free, pre- 
and post-treatment periods, under placebo or in a reference group receiving drug or non-drug 
therapy or no treatment. 
A Serious Adverse Event (SAE) is any untoward medical occurrence that: 
1. 
Results in death, 
2. 
Is life-threateningA, 
3. 
Requires inpatient hospitalization or prolongation of existing hospitalization, 
4. 
Results in persistent or significant disability or incapacity, 
5. 
Is a congenital anomaly / birth defect or 
6. 
Is another medically important conditionB. 
A 
The term “life-threatening” in the definition of “serious” refers to an event in which the 
subject is at risk of death at the time of the event; it does not refer to an event, which 
hypothetically might have caused death if it were more severe. 
B 
Medically important conditions that may not result in death, be immediately life-
threatening or require hospitalization may be considered as SAE when, based upon appropriate 
medical judgment, they may jeopardize the subject or may require intervention to prevent one of 
the outcomes listed in the definition above.  Examples of such events are intensive treatment in 
an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; or development of drug dependency or drug abuse. 
N.B.: The term “severe” is often used to describe the intensity (severity) of an event (such as: 
mild, moderate, or severe, e.g., pain).  The event itself may be of relatively minor medical 
significance (such as severe headache).  This is not the same as “serious”, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to 
subject’s life or vital functions.  Seriousness (not severity) serves as a guide for defining 
regulatory reporting obligations. 
NOTE: If a subject is hospitalized for a planned standard of care procedure that is not related to 
an AE, the hospitalization does not require an SAE report.  However, if there is an additional AE or 


 
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complication during the hospitalization, or if the hospitalization is prolonged, the SAE procedures 
described in Section 7.1 must be followed. 
7.1.2 Additional Expedited Reporting Requirements for this Study 
For the purpose of this study, the following events must be reported by phone or email to the 
Sponsor within 24 hours of knowledge of the event (See Section 7.1.6 for Sponsor contact 
information) and may result in submission of an SAE based on certain criteria outlined below: 
1. Pregnancy 
2. Overdose (as defined in Section 6.12) 
3. Hepatic function abnormality (as defined in Section 7.1.8). 
7.1.2.1 
Pregnancy 
7.1.2.1.1 Maternal exposure 
Female subjects should avoid becoming pregnant and breastfeeding during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab 
(whichever is longer). 
If a subject becomes pregnant during the course of the study, the study drugs should be 
discontinued immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the drug under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled as 
SAEs (see Section 7.1.6).  Elective abortions without complications should not be handled as AEs.  
The outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic 
pregnancy, normal birth, or congenital abnormality) should be followed up and documented 
even if the subject was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
should inform the Sponsor (see Section 7.1.6 for Sponsor contact information) within 1 day, i.e., 
immediately, but no later than 24 hours of when he or she becomes aware of it.   
The Sponsor will work with the Investigator to ensure that all relevant information is provided 
within 1 to 5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available.   
7.1.2.1.2 Paternal exposure  
Male subjects should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab or for 6 months after the last dose of tremelimumab 
(whichever is longer).   
Pregnancy of the subject’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 90 days after the last dose 
should, if possible, be followed up and documented.   


 
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Where a report of pregnancy is received, prior to obtaining information about the pregnancy, the 
Investigator must obtain the consent of the subject’s partner.  Therefore, the local study team 
should adopt the generic ICF template in line with local procedures and submit it to the relevant 
Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.   
7.1.2.2 
Overdose 
Any overdose (as defined in Section 6.12) of a study subject with durvalumab + tremelimumab, 
with or without associated AEs/SAEs, is required to be reported within 24 hours of knowledge of 
the event to the Sponsor (see Section 7.1.6 for Sponsor contact information). If the overdose 
results in an AE, the AE must also be recorded as an AE according to Section 7.1.5. Overdose does 
not automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be recorded and reported as an 
SAE according to Section 7.1.6. There is currently no specific treatment in the event of an 
overdose of durvalumab or tremelimumab. The investigator will use clinical judgment to treat 
any overdose. See Section 6.12 for additional details. 
7.1.2.3 
Hepatic Function Abnormality 
Hepatic function abnormality (as defined in Section 7.1.8) in a study subject, with or without 
associated clinical manifestations, is required to be reported as “hepatic function abnormal” 
within 24 hours of knowledge of the event to the Sponsor, unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to 
investigational product has been confirmed (see Section 7.1.6 for Sponsor contact information). 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to investigational product, the decision to continue dosing of the study subject 
will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the Investigator and 
evaluated by the Sponsor and AstraZeneca/MedImmune. 
7.1.3 Severity of an Adverse Event 
The severity of all serious and non-serious adverse events should be assessed according to the 
National Cancer Institute CTCAE Scale (Version 4.03). 
7.1.4 Relationship of Adverse Events to Study Drug 
The relationship of all serious and non-serious adverse events to the investigational agent(s) will 
be determined by the Investigator on the basis of their clinical judgment, using one of the 
following terms (in accordance with NCI Guideline “Expedited Adverse Event Reporting 
Requirements for NCI Investigational Agents”, NCI Cancer Therapy Evaluation Program, January 
2001): 
Definitely related (The AE is clearly related to the investigational agent) 
Probably related (The AE is likely related to the investigational agent) 


 
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Possibly related (The AE may be related to the investigational agent) 
Unlikely related (The AE is doubtfully related to the investigational agent) 
Unrelated (The AE is clearly not related to the investigational agent) 
N.B.: When making the assessment on causality, it should be taken into consideration that 
immune-therapeutic agents have the potential to cause very late and/or permanent effects on 
the immune system, i.e., a causal relationship could exist despite a lack of apparent temporal 
relationship.  Information provided in the IB and/or in Section 1 of this protocol may support 
these evaluations. 
7.1.5 General Reporting Requirements 
All serious and non-serious adverse events must be documented in the source records and on the 
respective section of the CRF, regardless of the assumption of a causal relationship.  The 
documentation includes: dates of onset and resolution, severity, seriousness, study drug 
intervention, treatment and outcome, as well as, the causal relationship between the event and 
the study drug in accordance with Section 7.1.4  This documentation is required for all AEs that 
occur: 
a. from the date of signing the informed consent, and 
b. until the off-study date or 110 days after the last administration of study drug, whichever 
is longer, or until a new treatment is initiated (see Section 3.1.10 for subjects who begin 
other anti-cancer treatment). 
 
Immune Related Adverse Events (irAEs) will be collected from the time of informed consent 
through 110 days after the last dose of the last study treatment (regardless of initiation of 
another therapy). 
NOTE:  For subjects in Cohorts A and B: 
1. If durvalumab is discontinued early, subjects will follow the On Study Follow-up period 
according to the Flowchart in Section 3.2, and all AEs will be collected for 110 days after 
the last dose of durvalumab.   
2. If any subjects continue chemotherapy treatment alone (no durvalumab), they will 
complete the first On Study Follow-up at Day 28 (+14 days) post last dose of 
chemotherapy. All AEs will be collected for at least 28 (+14) days after the last dose of 
chemotherapy; however, per point #1, subjects must still be followed for On Study 
Follow-up post last dose of durvalumab for 110 days. 
NOTE:  For subjects in Cohorts C/C-FLOT and D/D2, the On Study Follow-up period is defined as 
follows: 
1. All AEs will be collected for 110 days after the last dose of pre-surgery durvalumab, with 
the exception of those AEs that are related to the protocol-defined surgical procedure(s). 
If the decision is made that a subject will not receive continued durvalumab, the subject 
must start On Study Follow-up and have at least one On Study Follow-up visit at 110 days 
(+30 days) after last dose of durvalumab or at the point of the decision (+30 days), 
whichever is later. See Flowchart in Section 3.2 for details. 


 
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2. If any subjects in Cohorts C/C-FLOT and D/D2 continue durvalumab treatment after the 
planned surgical procedure, they will follow the On Study Follow-up period according to 
the Flowchart in Section 3.2, and all AEs will be collected for 110 days after the last dose 
of durvalumab.  
3. If any subjects in Cohort C-FLOT continue FLOT treatment alone (no durvalumab) after 
the planned surgical procedure, they will complete the first On Study Follow-up at Day 28 
(+14 days) post last dose of FLOT. All AEs will be collected for at least 28 (+14) days after 
the last dose of FLOT; however, point #1 must still be followed for an On Study Follow-up 
visit post last dose of durvalumab. 
See Section 8.7.3 for Reference Safety Information (RSI) on radiotherapy; see Sections 8.6.3 and 
8.7.4 for RSI on surgery.  
7.1.6 Expedited Serious Adverse Event (SAE) Reporting Requirements 
In addition to the General Reporting Requirements specified in Section 7.1.5, all events 
meeting the criteria for an SAE as per Section 7.1.1, irrespective of suspected causation, must 
be reported by the Investigator to the Sponsor’s Drug Safety Contact (primarily) or, 
alternatively, to the Primary Sponsor Contact, within 24 hours of becoming aware of the event. 
This should be done using the “Initial Serious Adverse Event Report Form,” provided by the 
Sponsor, or, if Medidata RAVE data capture is utilized, using the respective Adverse Event and 
Safety Case Summary eCRFs.  This includes any deaths that occur after the off-study date, but 
within 30 days of last study drug administration.  Note: If an SAE cannot be reported through 
the “Initial Serious Adverse Event Report Form” or through Medidata RAVE within 24 hours of 
becoming aware of the event, the Sponsor’s Drug Safety Contact (primarily) or, alternatively, 
the Primary Sponsor Contact, must be contacted by phone or email within 24 hours of 
becoming aware of the event. In this case, the phone or email notification can then be followed 
up by an “Initial Serious Adverse Event Report Form” or through Medidata RAVE within one 
working day of the event. 
The expedited reports should be directed by fax or e-mail to the Drug Safety Contact (primarily) 
or, alternatively, the Primary Sponsor Contact.  Studies utilizing the Medidata “Safety Gateway”, 
built into the eCRF, and respective SAE reporting procedures, do not require reporting by fax or 
email.  Questions related to “Safety Gateway” procedures should be directed to the Drug Safety 
Contact or Primary Sponsor Contact (see table below). 
In urgent cases, pre-notification via phone or informal e-mail should be considered. 
Drug Safety Contact: 
Gary O’Donnell, MS 
Senior Manager, Drug Safety 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
600 3rd Ave 32nd Floor 
New York, New York 10016 
Tel: 
+1 212 450 1551 
Fax: 
+1 212 450 1535 
godonnell@lcr.org 
Primary Sponsor Contact: 
Mary Macri. 
Senior Director, Clinical Project Management 
Clinical Trials Management 
Ludwig Institute for Cancer Research 
600 3rd Ave 32nd Floor 
New York, New York 10016 
Tel: 
212-450-1546 
Fax: 
212-450-1535 
mmacri@lcr.org  


 
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Serious adverse events must also be reported by the Principal Investigator to the respective the 
appropriate Research Ethics Committee or Institutional Research Governance Committee in 
accordance with local rules and guidelines after being assigned a serious adverse event tracking 
number by the Sponsor.  Research Ethics Committee/Institutional Research Governance 
Committee may have specific rules on which Adverse Events need to be reported expeditiously, 
as well as, the time frames for such reporting. 
SAE Reports will be evaluated by the Sponsor’s Medical Monitor.  Regulatory authorities and 
other investigators, as well as institutional and corporate partners, will be informed by the 
Sponsor as required by ICH guidelines, laws and regulations in the countries where the 
investigational agent is being administered.  In particular, SAEs that are unexpected and for 
which a causal relationship with the study drug(s) cannot be ruled out, will be reported by the 
Sponsor within 15 calendar days; if they are life-threatening or fatal, they will be reported within 
7 Calendar days. 
Serious adverse event reporting to AstraZeneca/Medimmune is described in a separate 
agreement. 
7.1.7 Serious Adverse Event (SAE) Follow-up Requirements 
Subjects experiencing SAEs should be followed closely until the condition resolves or stabilizes, 
and every effort should be made to clarify the underlying cause.  Follow-up information related 
to SAEs must be submitted to the Sponsor as soon as relevant data are available, using the “SAE 
Follow-up Report form”, provided by the Sponsor or, if Medidata RAVE data capture is utilized, 
using the respective Adverse Event and Safety Case Summary eCRFs. 
7.1.8 Adverse Events of Special Interest (AESIs) 
An adverse event of special interest (AESI) is one of scientific and medical interest specific to 
understanding of the investigational products and may require close monitoring and rapid 
communication by the Investigator to the Sponsor. An AESI may be serious or non-serious. The 
rapid recording of all AEs, including AESIs, allows ongoing surveillance of these events in order to 
characterize and understand them in association with the use of the investigational products. 
AESIs for durvalumab and tremelimumab include but are not limited to events with a potential 
inflammatory or immune-mediated mechanism and which may require more frequent 
monitoring and/or interventions such as steroids, immunosuppressants and/or hormone 
replacement therapy. These AESIs are being closely monitored in clinical studies with durvalumab 
monotherapy and combination therapy. An immune-related adverse event (irAE) is defined as an 
adverse event that is associated with drug exposure and is consistent with an immune-mediated 
mechanism of action and where there is no clear alternate aetiology. Serologic, immunologic, 
and histologic (biopsy) data, as appropriate, should be used to support an irAE diagnosis. 
Appropriate efforts should be made to rule out neoplastic, infectious, metabolic, toxin, or other 
etiologic causes of the irAE.  
If the Investigator has any questions in regards to an AE being an irAE, the Investigator should 
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If an AESI also meets SAE criteria, the event will be reported as an SAE per Section 7.1.6. 
AESIs observed with durvalumab and tremelimumab and those considered AESIs for the 
purpose of this study are listed below.  Further information on these AESIs (e.g. presenting 
symptoms) can be found in the current versions of the durvalumab and tremelimumab 
Investigator Brochures. Guidelines for the management of subjects experiencing these toxicities 
can be found in Section 8.5 and in the following Medimmune guideline: “Medimmune’s Dosing 
Modification and Toxicity Management Guidelines for Immune- mediated, Infusion Related, 
and Non Immune-mediated Reactions (MEDI4736 (durvalumab) Monotherapy or Combination 
therapy with Tremelimumab or Tremelimumab monotherapy).” 
• 
Diarrhea/Colitis and intestinal perforation 
Diarrhea and colitis are the most commonly observed treatment-emergent AEs following 
dosing with study medications.  In rare cases, colon perforation may occur that requires 
surgery (colectomy) or can lead to a fatal outcome, if not properly managed. 
• 
Pneumonitis/Interstitial lung disease (ILD) 
Adverse events of pneumonitis have been observed with anti-PD-1, and anti-PD-L1 
antibodies.39,40  Initial work-up should include high-resolution CT scan, ruling out infection, 
and pulse oximetry.  Typically, pulmonary consultation is required. 
• 
Hepatic Function Abnormality (Hepatitis/transaminase increases) 
Increased transaminases have been reported during treatment with anti-PD-L1/anti-PD-1 
antibodies.39 Inflammatory hepatitis has been reported in 3% to 9% of subjects treated 
with anti-CTLA-4 monoclonal antibodies (e.g., ipilimumab).  The clinical manifestations of 
ipilimumab-treated subjects included general weakness, fatigue, nausea and/or mild fever 
and increased liver function tests such as AST, ALT, alkaline phosphatase, and/or total 
bilirubin. Hepatic function abnormality is defined as any increase in ALT or AST to greater 
than 3 × ULN and concurrent increase in total bilirubin to be greater than 2 × ULN.  
Concurrent findings are those that derive from a single blood draw or from separate blood 
draws taken within 8 days of each other.  Follow-up investigations and inquiries will be 
initiated promptly by the investigational site to determine whether the findings are 
reproducible and/or whether there is objective evidence that clearly supports causation by 
a concurrent or pre-existing disease (e.g., cholelithiasis and bile duct obstruction with 
distended gallbladder) or an agent other than the investigational product. Cases where a 
subject shows an AST or ALT ≥ 3 x ULN or total bilirubin ≥ 2 x ULN may need to be reported 
as SAEs. These cases should be reported as SAEs if, after evaluation they meet the criteria 
for a Hy’s Law case or if any of the individual liver test parameters fulfill any of the SAE 
criteria. 
• 
Neurotoxicity (Neuropathy/Neuromuscular toxicity) 
Immune-mediated nervous system events include encephalitis, peripheral motor and 
sensory neuropathies, Guillain-Barré, and myasthenia gravis. 
• 
Endocrine Disorders 
Immune-mediated endocrinopathies include hypo- and hyper-thyroidism, adrenal 
insufficiency, hypophysitis/hypopituitarism, and Type 1 diabetes mellitus. 
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should obtain an endocrinology consult and institute appropriate management which may 
include the administration of insulin.  
• 
Dermatitis/Rash 
Prompt treatment with steroids (topical or systemic based on severity) is important as per 
current established toxicity management guidelines. 
• 
Nephritis and increases in serum creatinine 
A consult with a Nephrologist should be done as well as monitoring for signs and symptoms 
that may be related to changes in renal function (e.g., routine urinalysis, elevated serum 
BUN and creatinine, decreased creatinine clearance, electrolyte imbalance, decrease in 
urine output, proteinuria, etc.). Subjects should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, infections, etc.). Steroids should be 
considered in the absence of clear alternative etiology even for low grade events (Grade 2), 
in order to prevent potential progression to higher grade event. 
• 
Pancreatic Disorders 
Immune-mediated pancreatitis includes autoimmune pancreatitis (or labs suggestive of 
pancreatitis - increased serum lipase, increased serum amylase). 
• 
Myocarditis 
Myocarditis, a rare but severe immune-mediated adverse event, presents with 
signs/symptoms such as decreased ejection fraction, arrhythmias, in particular occurrences 
of atrioventricular block. For subjects with suspected myocarditis, investigators should 
obtain a cardiology consult and institute full diagnostic work-up (that includes exclusion of 
other alternate causes such as infection). 
• 
Myositis / Polymyositis 
Myositis or polymyositis should be suspected in subjects who present with proximal muscle 
weakness and the evaluation should include an examination of the skin, muscle enzyme 
measurement, antibody testing, any systemic disease manifestations and exclusion of 
other diseases including drug-induced myopathy. Cases of myositis have been reported 
with myocarditis in which immune infiltration has been described in skeletal and cardiac 
muscle (see IB). 
• 
Other inflammatory responses that are rare / less frequent with a potential immune-
mediated aetiology include, but are not limited to, pericarditis, sarcoidosis, uveitis, and 
other events involving the eye, skin, hematological and rheumatological events. 
• 
Hypersensitivity and Infusion Reactions 
Hypersensitivity reactions as well as infusion-related reactions have been reported with 
anti-PD-L1 and anti-PD-1 therapy.39  As with the administration of any foreign protein 
and/or other biologic agents, reactions following the infusion of monoclonal antibodies 
(MAbs) can be caused by various mechanisms, including acute anaphylactic (IgE-mediated) 
and anaphylactoid reactions against the MAb, and serum sickness.  Acute allergic reactions 
may occur, may be severe, and may result in death.  Acute allergic reactions may include 
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hypotonia, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
 
7.2 
Administrative Sponsor Requirements 
7.2.1 
Pre-Study Requirements 
The following are required before study drug can be shipped to the study site: 
• 
Satisfactory Site Validation (conducted by Sponsor or a suitable delegate) 
• 
Signed Statement of Investigator 
• 
Regulatory Approval  
• 
Research Ethics Committee approval of Protocol and Informed Consent Form 
• 
NHS R and D Approval for the study site 
• 
Executed Clinical Trial Agreement (if applicable) 
7.2.2 Study Master Files 
The Investigator must retain a Sponsor-specified comprehensive and centralized filing system 
(Study Master File) of all trial-related documentation that is suitable for inspection by the 
Sponsor and regulatory authorities.  Upon completion of the trial, the Investigator is required to 
submit a summary report to the Sponsor. 
The Investigator must arrange for the retention of the Study Master File for a period of time 
determined by the Sponsor.  No part of the Study Master File shall be destroyed or relocated 
without prior written agreement between the Sponsor and the Investigator. 
A screening log must be kept of all subjects considered for the study including any that are 
subsequently excluded; the reason for exclusion must be recorded on this form. A copy of the 
screening log should be sent to the trial office on request, but without subject identifiers. The 
original must be retained on site. 
7.2.3 Case Report Form Data Collection 
Electronic Case Report Forms (eCRF) will be completed in accordance with respective guidance 
and after training provided by the Sponsor.  The use of eCRFs encompasses electronic data entry, 
query management and sign-off.  Systems used for electronic data capture will be compliant with 
FDA regulations 21 CFR Part 11 and within the constraints of the applicable local regulatory 
agency guidelines (whichever provides the greatest protection to the integrity of the data). 
All subjects who sign an informed consent form, regardless of study procedures performed, will 
be assigned a screening number and have their data entered into the eCRF. 
The Investigators electronic signature indicates a thorough inspection of the data in the CRF and 
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7.2.4 Language 
The protocol is written in English.  All correspondence between the study site and the Sponsor 
should be maintained in English.  Case Report Forms must be completed in English.  All written 
material to be used by subjects and para-clinical staff must use vocabulary that is clearly 
understood, and be in the language appropriate for the trial site. 
7.2.5 Monitoring 
The Sponsor will oversee the conduct of the study and perform clinical monitoring visits for site 
validation, site initiation, routine monitoring and site close-out.  Clinical Monitors and/or other 
sponsor staff will meet with the investigator staff and require direct access to source 
data/documents.  Such access may also be required for Research Ethics Committee review, 
regulatory inspection and sponsor audits.  Direct access is defined as permission to examine, 
analyze, verify, and reproduce any records and reports that are important to the evaluation of 
the study.  All reasonable precautions within the constraints of the applicable regulatory 
requirement(s) to maintain the confidentiality of subjects’ identities and sponsor’s proprietary 
information will be exercised. 
It is the Clinical Monitor’s responsibility to inspect the case report forms at regular intervals 
throughout the trial to verify adherence to the protocol, the completeness, accuracy and 
consistency of the data, and adherence to Good Clinical Practice guidelines.  The Clinical Monitor 
should have access to subject charts, laboratory reports and other subject records needed to 
verify the entries on the case report forms (“source data verification”). 
7.2.6 Protocol Amendments 
Protocol amendments may be implemented only after approval by the Investigator, Sponsor, 
Research Ethics Committee and, if required, the regulatory authorities.  Amendments that are 
intended to eliminate an apparent immediate hazard to subjects may be implemented prior to 
such approvals.  However, in this case, approval must be obtained as soon as possible after 
implementation. Implementation of administrative amendments (or non-substantial 
amendments in the UK) that do not affect the safety of the subjects do usually not require prior 
Research Ethics Committee approval, just notification. 
When immediate deviation from the protocol is required to eliminate an immediate hazard(s) to 
subjects, the Investigator will contact the Sponsor if circumstances permit, to discuss the planned 
course of action.  Any departures from the protocol must be fully documented in the source 
documentation. 
7.2.7 Premature Subject Withdrawal 
A subject may withdraw from treatment or from the study at any time for any reason without 
prejudice to his/her future medical care by the physician or at the study site.  Likewise, the 
Investigator and/or Sponsor have the right to withdraw subjects from treatment or from the 
study.  Specific subject withdrawal reasons are listed in Section 3.1.10.  Should a subject (or a 
subject’s legally authorized representative) decide to withdraw, all efforts will be made to 
complete the required study procedures and report the treatment observations as thoroughly as 
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A complete final evaluation should be made at the time of the subject’s withdrawal, the 
appropriate form in the Case Report Form should be completed with an explanation of why the 
subject is withdrawing, and an attempt should be made to perform a follow-up evaluation. 
7.2.8 Early Trial Termination 
“End of study” is defined as the last visit of the last subject.  Sponsor and Investigator have the 
right to terminate the study early.  Specific study stopping rules are listed in Section 3.1.14.  In 
such case, one party must notify the other in advance in writing about the intent of and the 
reasons for the termination.  The investigator must also notify the appropriate Research Ethics 
Committee or Institutional Research Governance Committee in accordance with local rules and 
guidelines. 
7.2.9 Study Drug Shipments & Accountability 
Study drug shipments will be addressed to the Principal Investigator’s authorized designee, 
preferably the site’s pharmacy.  The recipient will verify the amount and condition of the drug 
and will return a signed Acknowledgment of Receipt to the shipper. 
A drug dispensing log (inventory) will be kept by the study site, containing at least the following: 
• 
the subject’s identification (subject number and code) 
• 
date and quantity of drug dispensed 
• 
date and quantity of drug returned to the investigator/pharmacy (if applicable) 
• 
date and quantity of accidental loss of drug (if any)  
These inventories must be made available for inspection by the Clinical Monitor.  The Investigator 
is responsible for the accounting of all used and unused trial supplies.  At the end of the study, 
the Clinical Monitor will also collect the original study drug dispensing records. 
At the end of the study or as directed by the Sponsor, all used and unused supplies, including 
partially used or empty containers, will be disposed of or transferred as instructed by the 
Sponsor, and in accordance with local written procedures, if applicable.  Any disposal or transfer 
of investigational agent shall be noted on the investigational drug disposition log and signed-off 
by a second person.  At the end of the study, the Clinical Monitor will collect the original drug 
disposition logs. 
7.3 
Regulatory, Legal & Ethical Requirements 
7.3.1 Good Clinical Practice (GCP), Laws and Regulations 
The investigator must ensure that he/she and all authorized personnel for the study are familiar 
with the principles of Good Clinical Practice (GCP) and that the study is conducted in full 
conformity with the current revision of the Declaration of Helsinki, ICH Guidelines and applicable 
local laws and regulations, with the understanding that local laws and regulations take 
precedence over respective sections in the Declaration of Helsinki and/or the ICH Guidelines. 


 
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7.3.2 Informed Consent 
The investigator must obtain witnessed (if applicable) written informed consent from the subject 
or the subject’s legally authorized representative after adequate explanation of the aims, 
methods, anticipated benefits, and potential hazards of the study and before any study-specific 
procedures are performed.  The subject should be given a copy of the informed consent 
documentation.  The original signed and dated informed consent form must be retained in the 
study records at the study site, and is subject to inspection by representatives of the Sponsor, or 
representatives from regulatory agencies. 
7.3.3 Research Ethics Committee 
The investigator must obtain written approval from the appropriate Research Ethics Committee 
for the protocol and informed consent, and all amendments thereof, prior to recruitment of 
subjects and prior to shipment of investigational agents. 
The investigator must report Serious Adverse Events (SAEs) to the appropriate Research Ethics 
Committee or Institutional Research Governance Committee in accordance with local rules and 
guidelines (see also Section 7.1). 
The investigator must assure that continuing review (at least once per year) of the study is 
performed by the Research Ethics Committee throughout the duration of the study, by providing 
annual and other reports required.   
All correspondence with, and reports to, the Research Ethics Committee or Institutional Research 
Governance Committee must be maintained in the study files at the study site and copies must 
be sent to the Sponsor. 
7.3.4 Subject Confidentiality 
The investigator must ensure that the subject’s privacy is maintained.  A subject should only be 
identified by their initials, date of birth and subject number on the case report forms or other 
documents submitted to the Sponsor.  Documents that are not submitted to the Sponsor (e.g., 
signed informed consent form) should be kept in a strictly confidential section of the study file by 
the Investigator. 
The investigator shall permit the Sponsor and authorized representatives of regulatory agencies 
to review the portion of the subject’s medical record that is directly related to the study.  As part 
of the informed consent process, the subject must have given written consent that his/her 
records will be reviewed in this manner. 
 


 
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8 Appendices 
8.1 
Protocol Version History 
Original Issue 
Issue date: 11-NOV-2015 
Summary of Changes: n/a 
 
Amendment 001 
Issue date: 25-FEB-2016 
Summary of Changes:  
 
• 
Sections 3.1.4 and 5.1:  Added the following clarification: “Subjects with operable disease 
will be allocated to Cohort C or D based on the decision taken by the multidisciplinary team 
(MDT) on the standard treatment approach for any individual patient. The MDT will 
determine (1) operability and (2) whether neoadjuvant chemotherapy or 
chemoradiotherapy should be offered. These decisions will guide eligibility for enrollment to 
Cohorts C and D.  The radiotherapy offered in Cohort D will be standard of care for these 
subjects, as already determined by MDT.” 
• 
Section 3.1.14:  The following clarification was added: “If the study is suspended, dosing may 
not resume before obtaining approval of a substantial amendment from the Competent 
Regulatory Authority.”   
• 
Sections 3.1.16 and 7.1.5: On Study Follow-up was changed from 90 to 110 days; an 
additional follow-up visit at 110 days was added to the flowchart (Section 3.2). 
• 
Section 3.2 (Study flowchart): 
o Amylase and lipase assessments were added 
o Footnote b:  neurological examination was added to physical examination.   
• 
Section 4.1.1: clarification was added to indicate that physical exam includes neurological 
exam. 
• 
Section 5.3.1: the following points were added to Non-permitted Concomitant Therapies: 
o “Immunosuppressive doses of steroids or other immunosuppressive medication through 
90 days post last dose of tremelimumab. Note however, that inhaled and topical steroids 
when medically indicated as treatment for an acute illness or as pretreatment before CT 
scans (for contrast allergies) are allowed. The investigator is permitted to use 
corticosteroids as treatment for infusion reactions.” 
o “Drugs with laxative properties and herbal or natural remedies for constipation should be 
avoided through 90 days post last dose of tremelimumab because of the potential for 
exacerbation of diarrhea.” 
• 
Administrative changes:  
o EudraCT # and AstraZeneca Ref # were added to the header of the Title Page. 
o Section 8.10: MDT (multidisciplinary team) was added to abbreviations list. 
 


 
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Amendment 1.1 (Administrative Change) 
Issue date: 06-MAY-2016 
Summary of Changes: 
 
• 
Section 3.2, Flowchart: For Cohorts A1 and A2, oxaliplatin administration was deleted from 
Cycle 5/Day 15 and Cycle 6/Day 8; oxaliplatin administration was added to Cycle 6/Day1.  
 
Amendment 2  
Issue date: 23-JAN -2017 
Summary of Changes: 
• 
Synopsis: Chemoradiotherapy for Cohort D was changed as described in Section 2.1. Changes 
related to Cohort D were added as follows: 
o Paragraph 1 (changes in bold): This is an open-label, Phase 1/2 study to evaluate the 
safety of durvalumab (MEDI4736) (and tremelimumab for certain cohorts as described 
in Section 3.1.7) in combination with chemo (radio) therapy according to the following 
cohorts:  
 
Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally 
advanced oesophageal cancer (OC). 
 
Cohort C: Neoadjuvant oxaliplatin/capecitabine chemotherapy before surgery in 
operable OC.  
 
Cohort D: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before 
surgery in operable OC. 
oxaliplatin/capecitabine chemotherapy in metastatic/locally advanced oesophageal 
cancer (OC) and with neoadjuvant chemo(radio)therapy before surgery in operable OC 
The immunotherapy will be given for a 4-week period before starting the standard 
chemo(radio)therapy, continuing durvalumab treatment once the chemotherapy starts 
for all cohorts except Cohort D. The study will include 2 phases, a safety run-in Phase 1 
(Cohorts A1 and A2) and an expansion Phase 2 (Cohorts B, C, and D). 
o Primary and Secondary Objectives (changes in bold)  
Primary objective #2:  Assess the Safety/Tolerability of durvalumab in combination with 
neoadjuvant chemo(radio)therapy (oxaliplatin/capecitabine and 
paclitaxel/carboplatin/radiotherapy) in operable OC. (Endpoint: CTCAE version 4.03). 
Secondary objective #2:  Assess the Clinical Efficacy of durvalumab in combination with 
neoadjuvant chemo(radio)therapy (oxaliplatin/capecitabine and 
paclitaxel/carboplatin/radiotherapy) in operable OC.  (Endpoints: PFS after surgery, 1-
year survival rate, OS, pathological and metabolic response rate) 
• 
Sections 1.6.3 and 1.6.4 (Paclitaxel and Carboplatin) were added. 
• 
Section 1.6.5 (durvalumab): the following changes were made for paragraph 4 (changes in 
bold): “The safety profile of durvalumab as monotherapy and combined with other 
anticancer agents was consistent with the pharmacology of the target and other agents in the 
immune checkpoint inhibitor class. No tumor types appeared to be associated with unique 
AEs, with the exception of patients with squamous cell carcinaoma of the head and neck 
(SCCHN) where a higher incidence of bleeding has been reported. Immune-related AEs 
(irAEs), which are important risks of immune checkpoint inhibitors, have been observed with 
durvalumab and include colitis, pneumonitis, hepatitis/hepatotoxicity, neuropathy / 
neuromuscular toxicity, endocrinopathy endocrinopathies such as hypo- and hyper-


 
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thyroidism, hypophysitis, adrenal insufficiency and type I diabetes mellitus, dermatitis, and 
nephritis.” 
• 
Section 1.6.5 (Durvalumab): Paragraph 7 was changed FROM: “The fixed dosing for 
durvalumab is based on information from MedImmune, which indicates that the dose and 
schedule of 1500 mg durvalumab Q4W was selected based on PK models as described 
below.” TO: “The fixed dosing for durvalumab was selected based on pharmacokinetic (PK) 
models.” 
• 
Section 1.6.5 (Durvalumab): The following sentence was added after the last paragraph: “This 
study will use a fixed dose of 750 mg Q2W for durvalumab.” 
• 
Section 1.6.6 (Tremelimumab): For Paragraph 3, the phrase “data remain blinded” was 
removed from the DETERMINE study, as this is no longer applicable. 
• 
Section 2.1 (Rationale for Amendment 2) was added, and the key changes to Cohort D were 
described. 
• 
Section 3.1 (Study Design) Changes in bold: 
This is an open-label, Phase 1/2 study to evaluate the safety of durvalumab (and 
tremelimumab for certain cohorts as described in Section 3.1.7) in combination with chemo 
(radio) therapy according to the following cohorts:  
• 
Cohorts A1, A2, and B: Oxaliplatin/capecitabine chemotherapy in metastatic/locally 
advanced oesophageal cancer (OC). 
• 
Cohort C: and with nNeoadjuvant oxaliplatin/capecitabine chemotherapy before surgery 
in operable OC.  
• 
Cohort D: Neoadjuvant paclitaxel/carboplatin chemotherapy + radiotherapy before 
surgery in operable OC. 
For Cohorts A1, A2, B and C, the immunotherapy will be given for a 4-week period before 
starting the standard chemo(radio)therapy, continuing durvalumab treatment once the 
chemotherapy starts.  For Cohort D, the immunotherapy will be given for a 4-week period 
before starting chemoradiotherapy, but the durvalumab dosing will not continue during 
the chemoradiotherapy. A dose of durvalumab will be given following radiotherapy on Day 
64. 
• 
Section 3.1.6 (Sample Size): a reference to Section 3.1.11 was added for clarification of 
evaluable subjects. 
• 
Section 3.1.7 Treatment Arms and Treatment Schema).  This section was re-written and/or 
re-organized to reflect the changes to Cohort D. Figure 1 was also updated. 
• 
Section 3.1.8 (Dosing Adjustments, Delays and Discontinuations):  The following was added to 
the end of the paragraph: “ ….guidelines for paclitaxel and carboplatin are provided in Section 
8.7.  If a toxicity occurs that requires toxicity management and the toxicity causing drug can 


 
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be clearly identified, then the respective guideline should be followed. If the toxicity causing 
drug cannot be identified, then the more conservative guideline should be followed.” 
• 
Section 3.1.10 (Subject Withdrawal): Withdrawal from treatment criterion #7 (initiation of 
alternative anticancer therapy) was moved to withdrawal from study and re written as 
“Initiation of alternative anticancer therapy (marketed or investigational).” 
• 
Section 3.1.10.1 (Treatment beyond Progression) was added. 
• 
Section 3.1.11 (Subject Replacement) was updated according to current language (changes in 
bold): 
In the dose escalation phase, subjects are fully evaluable for DLT if they fulfill the criteria for 
the Per-Protocol Population for DLT Assessment (as defined in Section 4.1.2). 
• 
They experience a DLT at any time during the DLT Evaluation Period (as defined in 
Section 3.1.9), or 
In the absence of a DLT,they fulfill the criteria for the Per-Protocol Population (as 
defined in Section 4.1.2. 
In Cohorts A1 and A2, subjects who are not evaluable for DLT will be replaced. 
Subjects who are not considered fully evaluableper protocol for the primary objective of 
overall safety and tolerability per Section 4.1.2 may be replaced. 
In Cohorts A1 and A2, subjects who are not evaluable for DLT will be replaced 
• 
Section 3.1.13 (Interim Analysis) changes in bold:  No formal interim analyses will be 
performed, except for the cohort safety assessments for DLTs in Cohorts A1, and A2 (see 
Section 3.1.9). 
• 
Section 3.1.16 (On Study and Post Study Follow-up) changes in bold: “If the determination is 
made to remove a subject from treatment at a visit that coincides with the first visit of the 
On Study Follow-up visitPeriod (which is 14 days after the last dose of study treatment), any 
assessments required in the 14 day post-last treatment first On Study Follow-up visit that 
are not covered as part of the last on-treatment visit (usually correlative labs) should be done 
as soon as possible.  If these assessments cannot be done on the same day, the subject 
should be brought back in at the earliest opportunity.  Any assessments or correlative 
samples required by both the protocol last on-treatment visit and the first On Study Follow-
up 4 day post-last treatment visit should not be repeated. 
Following the On Study Follow-up, there will be a Post Study Follow-up, where, clinical 
outcomes data (dates of progression/relapse and survival) will be collected at least every 6 
months for up to 3 years from the initiation of the treatment.   
The Post Study Follow-up will include a query to determine if there were any immune-
related adverse events (irAEs) during the 110 days since the last administration of study 
drug. 
• 
Section 3.1.16.1 (End of Study Visit) was added 
• 
Section 3.2, Flowchart: 
o Cumulative Study Week Line was added 
o ± 3 was deleted from Day 1 
o ECOG Perf Status was added to Physical Exam, with same frequency as Physical Exam 
o Cohort D was updated to reflect changes in chemoradiotherapy regimen: 
 
Durvalumab dosing during Chemoradiotherapy (Weeks 5 to 9) was deleted; one dose 
of durvalumab was added to Day 64.  
 
Oxaliplatin and capecitabine doses over 4 cycles were deleted and replaced with 
paclitaxel and carboplatin doses once weekly, Weeks 5 to 8. 


 
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 
Footnote g regarding reduced dose of oxaliplatin was deleted 
 
Surgery was changed from Week 23 to Weeks 16 to 18.  This change was due to the 
change in timing of CRT for Cohort D 
 
Radiotherapy for Cohort D was changed FROM 45 Gy over 25 fractions (Weeks 11 to 
15) TO 41.4 Gy over 23 fractions; dosing was changed to a merged field over weeks 5 
to 9  
 
PET/CT was moved from Week 17 to Week 11 since this is the post CRT visit after the 
change for Cohort D.  This is also the post treatment visit for Cohort C, thus the 
PET/CT scan remains at this time point for Cohort C. 
o Cohorts C and D post surgery durvalumab visits:  
 
PET/CT scan was added to the first visit of the post-surgery durvalumab therapy 
(footnote c-1 was added to explain).  
 
Urine pregnancy was changed from Q2W to Q4W. 
o ECG was added to First On Study Follow-up visit. 
o Vital sign assessments were added to Days 36, 50, 64, 92, 127. 
o Notations were added to blood collections that pertain to Cohorts A1, A2, and B only; 
Footnote g was re-written as Cohorts A1, A2, and B only 
o Footnote h for correlative and biopsy testing was re-written as “Post treatment for 
Cohorts A and B (a window of -7 to +14 days is allowed).  If subject discontinues from 
treatment early, include at last study visit” 
o Footnote for correlative and biopsy testing for Cohorts C and D was changed to Footnote 
“i” and re-written as “On day of surgery for Cohorts C and D (blood draw must be pre-
surgery). If subject discontinues from treatment early, include at last study visit.” 
o Post Study Follow-up description was changed FROM “3 years post initiation of 
treatment:  every 6 months. Telephone contact or medical record review:  Vital status, 
tumor status; directed AE assessment for new onset or worsening of pre-existing 
autoimmune disease.” TO: “Every 6 months for up to 3 years post initiation of treatment. 
Telephone contact or medical record review to include clinical outcomes data (dates of 
progression/relapse and survival).”  This was updated for agreement with language in 
Section 3.1.16 and per current protocol language. 
• 
Section 4.0 (Study Objectives and Endpoints) 
o Primary Objective #2 was re-written as (changes in bold): “Assess the Safety/Tolerability 
of durvalumab in combination with neoadjuvant chemo(radio)therapy 
(oxaliplatin/capecitabine and paclitaxel/carboplatin/radiotherapy) before surgery in 
operable OC.” 
o Secondary Objective #2 was re-written as follows (changes in bold): “Assess the Clinical 
Efficacy of durvalumab in combination with neoadjuvant chemo(radio)therapy 
(oxaliplatin/capecitabine and paclitaxel/carboplatin/radiotherapy) in operable OC.  
(Endpoints: PFS after surgery, 1-year survival rate, OS, pathological and metabolic 
response rate).” 
• 
Section 4.1.2 (Subject Evaluation and Statistics) was changed FROM: “The Per-Protocol (PP) 
Population for safety and tolerability is defined as all subjects who received at least 75% of 
the scheduled doses of durvalumab or tremelimumab and durvalumab over the first 3 
months of the study, as well as, respective safety assessments without major protocol 
violations over the entire DLT Evaluation Period (as defined in Section 3.1.9).  The Intent-To-
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one dose of durvalumab or tremelimumab. In Phase 1, for the primary endpoint of 
determining DLTs and the RCD, the analysis of safety and tolerability will be based on the PP 
Population. In both phases, the overall analysis of safety and tolerability will be based on the 
ITT Population.”  
TO: “The Per-Protocol (PP) Population for DLT Assessment is defined as: 
• 
All subjects who experience a DLT at any time during the DLT Evaluation Period (as 
defined in Section 3.1.9) and 
• 
All subjects with no DLT who received at least 75% of the scheduled doses of durvalumab 
and chemotherapy or tremelimumab, durvalumab and chemotherapy as well as, 
respective safety assessments without major protocol violations over the entire DLT 
Evaluation Period (as defined in Section 3.1.9).   
Refer to Section 3.1.11 for subject replacement. The Safety Population is defined as all 
subjects who receive at least one dose of durvalumab or tremelimumab. In Phase 1, for the 
primary endpoint of determining DLTs and the RCD, the analysis of safety and tolerability will 
be based on the PP Population for DLT Assessment. In both phases, the overall analysis of 
safety and tolerability will be based on the Safety Population. 
• 
Section 5.1 (Inclusion Criteria):  
o the following standard protocol language statement was added “Note: Standard of Care 
procedures may be used for eligibility assessments provided they meet the criteria 
specified in either the inclusion criteria or flowchart.” 
• 
Section 5.2 (Exclusion Criteria): 
o Criterion #2 was changed FROM: “Participation in another clinical study with an 
investigational product during the last 6 weeks.”  TO: “Prior treatment in another clinical 
study with an investigational product within 4 weeks prior to Day 1 of the study; 
resolution of respective adverse event to Grade 1 or lower should have occurred.”  
Rationale for the change is to provide clarification using updated standard language.  The 
following note was also added: “Note: all prior AEs, regardless of subject’s inclusion in a 
clinical trial, must have resolved to Grade 1 or lower.” 
o Prior Criterion # 3 (“Prior or concurrent systemic anti-cancer therapy (chemotherapy, 
immunotherapy, endocrine therapy, targeted therapy, biologic therapy, tumor 
embolization, monoclonal antibodies, other investigational agent”) was deleted because 
a modified version of this statement is in Section 5.3.1 (Non-Permitted Concomitant 
Therapies) Criterion #2. 
o Prior Criterion #5 (“Current or prior use of immunosuppressive medication within 28 days 
before the first dose of study drugs, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiological doses, which are not to 
exceed 10 mg/day of prednisone, or an equivalent corticosteroid”) was deleted because 
a modified version of this statement is in Section 5.3.1 (Non-Permitted Concomitant 
Therapies) Criterion #1. 
o Prior Criterion #11 (“Receipt of live attenuated vaccination within 30 days prior to study 
entry or within 30 days of receiving durvalumab”) was deleted because a modified 
version of this statement is in Section 5.3.1 (Non-Permitted Concomitant Therapies) 
Criterion #3. 
o Contraception language was updated according to current recommendations from 
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o Prior Criterion # 23 was updated (changes in bold): “Subjects should not donate blood 
while participating in this study or for at least 90 days following the last infusion of 
durvalumab, 6 months following the last infusion of tremelimumab, or until the time 
specified in the prescribing information of oxaliplatin, capecitabine, paclitaxel, or 
carboplatin, whichever is longest.” 
o Prior Criterion #24 was updated (changes in bold): “For oxaliplatin, capecitabine, 
paclitaxel, and carboplatin: refer to prescribing information for additional information.” 
• 
Section 5.3.1 (Non-permitted Concomitant Therapies):  
o Criterion #2 was changed FROM: “Any investigational anticancer therapy other than the 
protocol specified therapies (wash-out period: 4 weeks prior to Day 1; 6 weeks for 
nitrosoureas).”  TO: “Other cancer therapy (e.g., drug, radiation or immunotherapy). 
Wash-out period: 4 weeks or 5 half-lives (whichever is shorter) prior to Day 1; 6 weeks 
for nitrosoureas).”  This was changed for clarification and to update to standard protocol 
language. 
• 
Sections 5.3.1(Non-permitted Concomitant Therapies) and 5.3.2 (Permitted Concomitant 
Therapies): Paclitaxel and carboplatin were added to the statement: “For oxaliplatin, 
capecitabine, paclitaxel, and carboplatin, refer to the prescribing information… “  
• 
Section 5.3.2 (Permitted Concomitant Therapies): a correction was made to the following 
sentence (changes in bold): “All non-drug therapies must be recorded in the respective 
sections of the case report form or as AEs. 
• 
Section 6 (Study Drug Preparation and Administration): The following paragraph was changed 
FROM: “On days with concurrent tremelimumab and durvalumab dosing, durvalumab 
administration will start 60 (± 10) minutes after the end of the tremelimumab infusion.  On 
days with concurrent durvalumab and oxaliplatin dosing, oxaliplatin administration will start 
60 (± 10) minutes after the end of the durvalumab infusion.  The morning dose of 
capecitabine is taken after the oxaliplatin infusion. 
TO: “On days with concurrent tremelimumab and durvalumab dosing, durvalumab 
administration will start at least 60 minutes after the end of the tremelimumab infusion.   
On days with concurrent durvalumab and oxaliplatin dosing, oxaliplatin administration will 
start at least 60 minutes after the end of the durvalumab infusion.  The morning dose of 
capecitabine is taken after the oxaliplatin infusion. On days with concurrent paclitaxel and 
carboplatin dosing, paclitaxel will be infused over 1 hour followed by carboplatin infusion 
over 1 hour according to local standards.” 
• 
Section 6.3 (Paclitaxel) and Section 6.4 (Carboplatin) were added. 
• 
Section 6.5 (Tremelimumab) and Section 6.6 (Durvalumab):  
o The entire sections were updated and reorganized according to current language from 
AstraZeneca. 
o Dextrose was added as an option to be used as a diluent.   
o The following statement was added “See Section 8.5.1 for guidelines for infusion-related 
reactions.” 
o The following statement was clarified:  “After the contents of the IV bag are fully 
administered, the IV line will be flushed with a volume of IV diluent equal to the priming 
volume of the infusion set used.  Alternatively, the infusion will be completed according 
to institutional policy to ensure the full dose is administered; documentation is required 
if the line was not flushed.” 


 
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o The following statement was clarified: “The total time from needle puncture of the 
tremelimumab vial to the start of administration should not exceed 4 hours at room 
temperature or 24 hours at 2 to 8°C (36°F to 46°F). Standard infusion time is 60 ± 5 
minutes. However, if there are interruptions during infusion (total infusion time not to 
exceed 4 hours), the total allowed time for preparation and administration should not 
exceed 8 hours at room temperature.  In the event that either preparation time or 
infusion time exceeds the time limits, a new dose must be prepared from new vials.” 
o The following statement was added for tremelimumab: “No incompatibilities between 
tremelimumab and polyvinylchloride or polyolefin have been observed. However, 
administration sets containing cellulose-based filters should not be used with 
tremelimumab. 
• 
Section 6.7 (Estimated Study Drug Requirements): Paclitaxel and carboplatin were added. 
• 
Section 6.8 (Monitoring): The following was added: “ 
Note: When durvalumab and tremelimumab are to be administered on the same day, 
durvalumab infusion will start at least 60 minutes after the end of tremelimumab infusion 
even though vital signs assessment is not required during the entire 60-minute period post 
tremelimumab. 
If a subject tolerates treatment well for the first 4 doses of durvalumab (i.e., no infusion 
reactions), subsequent infusions for that subject can be monitored according to the table 
below.  A longer duration of observation after the end of infusion can be used if the 
Investigator deems it clinically necessary. 
Vital Signs Assessment on Study Drug Administration Days (after first 4 doses) 
Drug 
Pre Dose 
During Infusion 
End of Infusion  
(± 5 minutes) 
15 (± 5) Minutes 
Post Infusion 
Durvalumab 
X 
Every 30 (± 5) 
minutes 
X 
X 
• 
Section 6.9 (Drug Overdose Management): Paclitaxel and Carboplatin were added. 
• 
Section 7.1.2 (Additional Expedited Reporting Requirements): The following paragraph was 
changed FROM: “For the purpose of this study, the following events are considered medically 
important conditions and must be reported in an expedited manner (See Section 7.1.6 for 
Sponsor contact information):” 
TO: “For the purpose of this study, the following events must be reported by phone or email 
to the Sponsor within 24 hours of knowledge of the event (See Section 7.1.6 for Sponsor 
contact information) and may result in submission of an SAE based on certain criteria 
outlined below:” This was updated to provide clarification and consistency with other 
protocols. 
• 
Section 7.1.2.1.1 (Maternal Exposure): The following paragraph was added: “Female subjects 
should avoid becoming pregnant and breastfeeding during the study and for 90 days after the 
last dose of durvalumab or for 6 months after the last dose of tremelimumab (whichever is 
longer)” 
• 
Section 7.1.2.1.2 (Paternal Exposure): The following paragraph was changed FROM: “Male 
subjects should refrain from fathering a child or donating sperm during the study and for 6 
months after the final dose of investigational product.” TO: “Male subjects should refrain 


 
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from fathering a child or donating sperm during the study and for 90 days after the last dose 
of durvalumab or for 6 months after the last dose of tremelimumab (whichever is longer).   
• 
Section 7.1.5 (General Reporting Requirements): The section was updated to be consistent 
with current reporting language. FROM: “Documentation of serious and non-serious adverse 
events includes: dates of onset and resolution, severity, seriousness, study drug intervention, 
treatment and outcome, as well as the causal relationship between the event and the study 
drug in accordance with Section 7.1.4. All serious and non-serious adverse events occurring 
between the date of signing the informed consent and the off-study date must be 
documented in the source records and on the respective section of the CRF, regardless of the 
assumption of a causal relationship.   During the On Study Follow-up period, all AEs will 
continue to be documented for 110 days after the last dose of study drug for all subjects.  
NOTE:  For subjects in Cohorts C and D, there may be 2 On Study Follow-up periods. (1) All 
AEs will be collected for 110 days after the last dose of durvalumab in Cycle 2, with the 
exception of those AEs that are related to the protocol-defined surgical procedure(s). (2) If 
any subjects in Cohorts C and D continue durvalumab treatment after the planned surgical 
procedure, there will be another On Study Follow-up period, and all AEs will be collected for 
110 days after the last dose of durvalumab.” TO: All serious and non-serious adverse events 
must be documented in the source records and on the respective section of the CRF, 
regardless of the assumption of a causal relationship.  The documentation includes: dates of 
onset and resolution, severity, seriousness, study drug intervention, treatment and outcome, 
as well as, the causal relationship between the event and the study drug in accordance with 
Section 7.1.4  This documentation is required for all AEs that occur:  (a).from the date of 
signing the informed consent, and (b)until the off-study date or 110 days after the last 
administration of study drug, whichever is longer, or until a new treatment is initiated (see 
Section 3.1.10 for subjects who begin other anti-cancer treatment).  Immune Related Adverse 
Events (irAEs) will be collected from the time of informed consent through 110 days after the 
last dose of the last study treatment (regardless of initiation of another therapy). NOTE:  For 
subjects in Cohorts C and D, there may be 2 On Study Follow-up periods: (1) All AEs will be 
collected for 110 days after the last dose of pre-surgery durvalumab, with the exception of 
those AEs that are related to the protocol-defined surgical procedure(s). (2) If any subjects in 
Cohorts C and D continue durvalumab treatment after the planned surgical procedure, there 
will be another On Study Follow-up period, and all AEs will be collected for 110 days after the 
last dose of durvalumab. 
• 
Section 7.1.6: The following statement was added; “Serious adverse event reporting to 
AstraZeneca/Medimmune is described in a separate agreement.” 
• 
Section 7.1.8 (AESIs). Additional information was added to the description of the AESIs per 
the updated guidelines provided by AstraZeneca/Medimmune. 
• 
Section 7.2.3 (CRF Data Collection): The following statement was added: “All subjects who 
sign an informed consent form, regardless of study procedures performed, will be assigned a 
screening number and have their data entered into the eCRF.” 
• 
Sections 8.5, 8.6, 8.7 (Dose Modifications and Management Guidelines): The following 
paragraph was added: “If a toxicity occurs that requires toxicity management in accordance 
with Sections 8.5, 8.6, and 8.7,and the toxicity causing agent can be clearly identified, then 
the respective guideline should be followed. If the toxicity causing agent cannot be identified, 
then the more conservative guideline should be followed.” 
• 
Section 8.5.1 (Durvalumab and Tremelimumab Dose Modification Due to Toxicity): 


 
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o The paragraph, which referenced Yervoy, Opdivo, and Keytruda was deleted. 
o The statement that referenced tremelimumab guidelines was deleted, as these are 
included in the combined guidelines from Medimmune. 
o Modifications were made to the table based on updated recommendations from 
Medimmune dated 19Aug2016. 
• 
Section 8.5.2 (Durvalumab and Tremelimumab Dose Modifications not due to Toxicity): The 
following updated language was added and the previous criteria were deleted (this was done 
to provide clarification and consistency with other protocols): 
1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may be 
made only for individual dosing days, whereby the interval between any two doses shall 
be no less than 10 days. All resulting protocol deviations should be documented.  
2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned 
dose should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary.  
4. If the dosing interruption is greater than half the planned dosing interval, the dose 
should be skipped and the next dose(s) should be adjusted in accordance with #1, if 
necessary 
• 
Section 8.7 was added:  Dose Modification and Management Guidelines for 
Paclitaxel/Carboplatin. 
• 
Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable.  Sections were numbered as appropriate when 
additional sections were added. Abbreviations were updated. Modified signature box on 
Synopsis page to allow space for Local Sponsor Signature. 
 
Amendment 2.1 (Administrative Change) 
Issue date: 28-FEB-2017 
Summary of Changes: 
• 
Synopsis page: Removed additional space for local sponsor signature, as the additional 
signature is not required. 
 
Amendment 3  
Issue date: 14-JUL-2017 
NOTE: Amendment 2 was previously approved by the study team and AstraZeneca; however, it 
was not submitted to MHRA and Ethics Committee. The changes for Amendment 3 are 
documented below. For the purposes of MHRA/Ethics submissions, all changes from 
Amendments 2 and 3 will be combined into one tracked changes document. 
Summary of Changes: 
• 
Section 3.1 (Study Design): the next to last paragraph was modified to provide clarity for the 
durvalumab dose post CRT for Cohort D (changes in bold): “For Cohorts A1, A2, B and C, the 
immunotherapy will be given for a 4-week period before starting the chemotherapy, 
continuing durvalumab treatment once the chemotherapy starts.  For Cohort D, the 
immunotherapy will be given for a 4-week period before starting chemoradiotherapy, but 
the durvalumab dosing will not continue during the chemoradiotherapy. A dose of 


 
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durvalumab will be given following chemoradiotherapy on Day 64 (±3 days).  If the subject 
has not completely recovered (per Investigator assessment) by Day 64 (±3 days), the 
durvalumab dose may be delayed until Day 71 (±3 days).” 
• 
Section 3.1.4 (Subject Population): the last sentence was changed as follows (changes in 
bold): “The radiotherapy offered in Cohort D will be standard of care provided per Section 
6.13 for these subjects, as already determined by MDT. 
• 
Section 3.1.5 (No. of Sites/Subjects): The following sentence was updated to present the 
possibility of additional sites (changes in bold): “Two (2) Up to 4 sites; and 75 evaluable 
subjects are estimated for this study.” 
• 
Section 3.1.7 (Treatment Arms and Treatment Schema):  
o The following paragraph for Cohort D was updated to reflect changes that were 
requested by the study team (i.e., 4 weekly doses of Chemotherapy was changed to 5 
weekly doses; and the timing of the post-CRT dose of durvalumab was clarified). The 5 
week dose regimen for the chemotherapy in Cohort D aligns with the standard for 
paclitaxel/carboplatin. Changes are shown in bold: “For Cohort D, chemoradiotherapy 
will start after the 4-week durvalumab immunotherapy period, i.e., on Cycle 1, Day 1 
(Study Week 5, Study Day 29).  Subjects will receive (4) 5 weekly doses of paclitaxel (50 
mg/m2) and carboplatin (AUC 2) concurrent with radiotherapy (41.4 Gy in 23 fractions), 
but without durvalumab.  Radiotherapy will be given over 23 fractions over a period 5 
weeks.  A dose of durvalumab will be given following chemoradiotherapy on Day 64 (±3 
days).  If the subject has not completely recovered (per Investigator assessment) by 
Day 64 (±3 days), the durvalumab dose may be delayed until Day 71 (±3 days).” 
o In the Phase 2 section, similar changes were made for the Cohort D description.  In the 
table, paclitaxel and carboplatin schedules were changed from Weeks 5-8 to Study 
Weeks 5-9.  
o Phases 1 and 2 sections: clarifications and formatting consistency were added for the 
Cohort tables. 
• 
Section 3.1.16 (On Study and Post Study Follow-up): Paragraph 2 was clarified (changes in 
bold): “For all subjects who complete study treatment or who discontinue treatment 
prematurely according to Section 3.1.10, there will be an On Study Follow-up period for 110 
days after the last durvalumab or durvalumab + tremelimumab study drug treatment, 
which will include collection of AE data.  NOTE:  For subjects in Cohorts C and D, there may 
be 2 On Study Follow-up periods, as described in Section 7.1.5. 
• 
Section 3.2 (Flowchart): 
o Paclitaxel and carboplatin doses were added to Week 9 for Cohort D to align with the 
changes implemented in Section 3.1.7. 
o For Cohort D, Lab assessments and pregnancy test were added for Day 64. Footnote L 
was added to the durvalumab dose and the added assessments on Day 64: “For Cohort 
D, a dose of durvalumab will be given following chemoradiotherapy on Day 64 (±3 days).  
If the subject has not completely recovered (per Investigator assessment) by Day 64 (±3 
days), the durvalumab dose may be delayed until Day 71 (±3 days). Lab assessments and 
pregnancy test should be done on the day (64 or 71) the durvalumab dose is given. 
o Hematology assessments were added to Days 36, 50, 92, and 134 to align with 
chemotherapy dosing days.  
o Chemistry assessments were added to Days 36 and 50 for Coh D only (weekly 
assessments are standard practice during CRT).  


 
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o Footnote a. The following clarification was added: “For each on-treatment cohort, 
hematology, chem, urine and pregnancy safety assessments should coincide with drug 
administration study visits. With the exception of On Study Follow-up, Lab assessments 
are not applicable if there is no drug administration visit for a particular cohort. End of 
study pregnancy test for women of child-bearing potential must be done on serum.” 
o Physical exam assessments were added to Days 36, 50, 64, 92, 134, and Post surgery 
durvalumab dosing days. 
o Footnote b. The following clarification was added: ”For each on-treatment cohort, 
physical exams should coincide with drug administration study visits. With the exception 
of On Study Follow-up, physical exams are not applicable if there is no drug 
administration visit for a particular cohort.” 
o Footnote e was re-written to provide clarification: “For each on-treatment cohort, vital 
signs assessments should coincide with drug administration study visits. With the 
exception of On Study Follow-up, vital sign assessments are not applicable if there is no 
drug administration visit for a particular cohort. For durva and treme, vital signs are 
measured before, during and after infusions according to Section 6.8. 
o Previous Footnote g was deleted; lab assessments, physical exams, and vital sign 
assessments were clarified in Footnotes a, b, and, e respectively. 
o New Footnote g was added: “Concomitant med and AE information may be collected by 
telephone if there is no study drug administration/lab test/scan/procedure visit 
scheduled.” 
o Footnote m was added for ECG assessment: “12 Lead ECG - baseline and abnormal ECG 
at any time will be done in triplicate (2-5 minutes apart); others may be single 
measurements. 
• 
Section 4.2.1 (Endpoints and Assessment Methods): Last paragraph was clarified (changes in 
bold):  “Evaluation according to irRECIST using CT scanning will be performed every 6 weeks 
for Cohorts A and B.  Subjects in Cohorts C and D, will undergo PET/CT scanning before and 
after treatment per standard of care the Study Flowchart in Section 3.2.  Metabolic 
response will be assessed according to PERCIST.38  
• 
Section 6: Heading was changed to (changes in bold): Study Drug Preparation and 
Administration and Radiotherapy Delivery. 
• 
Section 6.5.4 (Tremelimumab administration): the following bullet was updated to provide 
clarity based on current Medimmune/Astrazeneca recommendations. Changed FROM: “The 
total time from needle puncture of the tremelimumab vial to the start of administration 
should not exceed 4 hours at room temperature or 24 hours at 2 to 8°C (36°F to 46°F). 
Standard infusion time is 60 ± 5 minutes. However, if there are interruptions during infusion 
(total infusion time not to exceed 4 hours), the total allowed time for preparation and 
administration should not exceed 8 hours at room temperature.  In the event that either 
preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials.”  TO:  “The total time from needle puncture of the tremelimumab vial to the 
start of administration should not exceed 4 hours at room temperature or 24 hours at 2 to 
8°C (36°F to 46°F). Standard infusion time is 60 ± 5 minutes. However, if there are 
interruptions during infusion, the total allowed infusion time should not exceed 8 hours.  In 
the event that either preparation time or infusion time exceeds the time limits, a new dose 
must be prepared from new vials.” 


 
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• 
Section 6.6.4 (Durvalumab administration): similar change as the one described for 
tremelimumab in the previous bullet  
• 
Section 6.10 (Radiotherapy Delivery) was added. 
• 
Section 7.1.5 (General Reporting Requirements): the following statement was added: “See 
Section 8.7.3 for Reference Safety Information (RSI) on radiotherapy; see Sections 8.6.3 and 
8.7.4 for RSI on surgery.” 
• 
Section 7.1.8 (AESIs): Based on updated information from Astrazeneca, the following 
changes were made: 1) diabetes insipidus was added to endocrine disorders; 2) bullet was 
added: “Other inflammatory responses that are rare with a potential immune-mediated 
aetiology include, but are not limited to, myocarditis, pericarditis, and uveitis.” 
• 
Section 8.5.1 (Durvalumab and Tremelimumab Dose Modification due to Toxicity): for 
Infusion-related Reactions Grades 1 and 2, the phrase “total infusion time not to exceed 4 
hours” was deleted in order to align with the updates in Sections 6.5.4 and 6.6.4.  
• 
Section 8.6: Heading was changed to (changes in bold): ” Dose Modification and 
Management Guidelines for Oxaliplatin/Capecitabine and Surgery.” 
• 
Section 8.6.3 (Surgery) was added to provide additional study information that was 
previously not included in the protocol. 
• 
Section 8.7: Heading was changed to (changes in bold): ” Dose Modification and 
Management Guidelines for Paclitaxel/Carboplatin, Radiotherapy and Surgery.” 
• 
Section 8.7.1 (Haematologic Related Toxicity): 
o “Delay chemotherapy” was changed to “omit chemotherapy” to account for the weekly 
dosing schedule. 
o Table was added for monitoring neutrophils and platelets 
• 
Section 8.7.2 (Non-Haematologic Toxicity):  
o Table was updated based on input from team and NEOSCOPE protocol. 
o Other Non-haematologic Toxicities table was added. 
• 
Section 8.7.3 (Heading was updated from Radiation Toxicity to Radiotherapy Toxicity): The 
following paragraphs were added to provide additional study information that was previously 
not included in the protocol: “The following list provides the expected events in relation to 
radiotherapy (and its possible effect following surgery). This should be used as the Reference 
Safety Information (RSI) when assessing the expectedness of SAEs causally related to 
radiotherapy: Mucositis, oesophagitis, dysphagia, lethargy, pain, anaemia, nausea and 
vomiting, weight loss, poor oral intake, tinnitus, infection, pneumonitis, pericarditis, wound 
infection, anastomotic leak, chest infection, pleural effusion, thrombo-embolism. In the event 
of a chemotherapy toxicity or dose modification, the decision to continue radiotherapy rests 
with the treating clinician. “ 
• 
Section 8.7.4 (Surgery) was added to provide additional study information that was previously 
not included in the protocol.  
• 
Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable.  Sections were numbered as appropriate when 
additional sections were added. Abbreviations were updated. 
 
 


 
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Amendment 4  
Issue date: 08-SEP-2017 
NOTE: MHRA review of Amendment 3 resulted in a request for the clarifications/additions, which 
are included in Amendment 4 and documented below.  
• 
Section 5.2 (Exclusion Criteria), #18. The following Note was added to provide additional 
requirements for contraception/breastfeeding/fertility with respect to carboplatin and 
paclitaxel:  “NOTE: additional requirements for carboplatin and paclitaxel treatment. 
Women of childbearing potential should avoid becoming pregnant while taking carboplatin 
and paclitaxel; they should notify the treating physician immediately if pregnancy occurs. 
Female and male subjects of fertile age and/or their partners should use contraceptives 
during and for at least 6 months after treatment with these drugs. Male subjects should 
also avoid sperm donation during and for at least 6 months after treatment with these 
drugs. Breastfeeding should be discontinued for the duration of treatment with these 
drugs. Male subjects should be advised regarding cryoconservation of sperm prior to 
treatment because of the possibility of irreversible infertility due to the treatment.” 
• 
Section 5.3.1 (Non-permitted Concomitant Therapies): the following paragraphs were 
added to provide additional information regarding non-permitted concomitant medications 
for carboplatin and paclitaxel: 
“Nephrotoxic/ototoxic drugs: Auditory defects have been reported during carboplatin 
therapy. Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as 
aminoglycosides, vancomycin, capreomycin and diuretics is not recommended as they may 
increase or exacerbate toxicity, particularly in renal failure patients, due to carboplatin 
induced changes in renal clearance.” 
“CYP2C8 or CYP3A4 inhibitors/inducers: Caution should be exercised when administering 
paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g., 
ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, 
clopidogrel, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of 
paclitaxel may be increased due to higher paclitaxel exposure. Administering paclitaxel 
concomitantly with medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, 
carbamazepine, phenytoin, efavirenz, nevirapine) is not recommended because efficacy 
may be compromised because of lower paclitaxel exposures.” 
 
Amendment 5 
Issue date: 10-MAR-2018 
Summary of Changes: 
• 
Section 3.1.7 (Treatment Arms and Treatment Schema). Clarification was added to indicate 
that surgery timing would be according to institutional policies; changes in bold: 
Subjects in Cohorts C and D will undergo surgery 6 to 8 weeks after completing 
chemo(radio)therapy or according to institutional policies for surgery; and they will be 
eligible to resume durvalumab dosing (to a maximum of 12 infusions) once recovered from 
surgery, provided that this is within 3 months of surgery 
• 
Section 3.1.9 (DLT and MTD/RCD for the Combination Therapy): The following exception 
bullet was added to Point #3: “Grade 3 or 4 asymptomatic increases in amylase or lipase 
levels for which appropriate evaluation shows no clinical evidence of pancreatitis.” This was 
done to align with the amylase/lipase information in Section 8.5.1 dose modifications. 


 
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• 
Section 3.1.10 (Subject Withdrawal). The following paragraph was moved within the section 
to allow for better clarity: “Discontinuation from receiving study treatment does not mean 
that the subject is withdrawn from the study. Subjects who are withdrawn from the study 
treatment should enter the On Study Follow-up (see Section 3.1.16), if feasible.  Subjects 
who begin other anti-cancer therapy should immediately be considered off-study and 
proceed to the Post Study Follow-up (Section 3.1.16).” 
• 
Section 3.1.16 (On Study and Post Study Follow-up).  The following paragraph was added to 
provide clarification and to align with the directions in the flowchart: “Refer to Flowchart in 
Section 3.2 for post treatment biopsies.  If the subject discontinues from treatment early, 
the biopsy specimen should be collected at the last study visit or the first On Study Follow-
up visit.” 
• 
Section 3.1.16 (On Study and Post Study Follow-up). The Note was clarified to indicate that 
“For subjects in Cohorts C and D, additional details regarding the On Study Follow-up period 
are provided in Section 7.1.5.” (The note originally indicated there may be 2 On Study 
Follow-up periods for these 2 cohorts). 
• 
Section 3.2 (Flowchart).  
o The following clarification was added to the surgery lines (changes in bold): “Surgery - 6 
to 8 weeks after completion of therapy or according to institutional policies for 
surgery” 
o Footnote c-1 was changed to n and updated as follows: 
PET/CT scan for Cohorts C and D: Scan scheduled after completion of therapy/before 
surgery may be combined as part of the surgery workup or per local institutional 
standards. Post surgery scan may be done at first post surgery durvalumab dosing visit. 
PET scan at the post-surgery and On-Study Follow-Up timepoints may be replaced with a 
CT scan. 
o Footnote o was added for CT and PET/CT lines 
o Footnotes h and i were updated to reflect change in Section 3.1.16: the phrase “or the 
first On Study Follow-up visit” was added.  
o Footnote p was added to provide clarification for the collection of AEs for Cohorts C and 
D during the period after the last dose of pre-surgery durvalumab. 
• 
Section 4.2.1 (Clinical Efficacy, Endpoints and Assessment Methods).  The last paragraph was 
modified to provide clarification (changes in bold): “Evaluation according to irRECIST using 
CT scanning will be performed every 6 weeks for Cohorts A and B.  Subjects in Cohorts C and 
D, will undergo PET/CT scanning before and after treatment per the Study Flowchart in 
Section 3.2. The scans should be carried out according to local institutional standards and 
reported according to irRECIST and RECIST1.1 (see the guidelines in Section 8.8). The 
information to be captured at each scan is outlined in the eCRF.  Scanning protocols and 
modalities should remain consistent throughout the study. Metabolic response will be 
assessed according to PERCIST.38” 
• 
Section 5.1 (Inclusion Criteria). Criterion #1 was updated to include the following: “Have not 
received full dose systemic chemotherapy.” Rationale: this intention was previously included 
with other criteria, but was inadvertently deleted during previous updates. 
• 
Section 5.2 (Exclusion Criteria). Criterion #13 was updated for clarification (changes in bold): 
“Peripheral sensitive neuropathy with functional impairment prior to first course.” 
• 
Section 5.3.2 (Permitted Concomitant Therapies). Item #7 was added: “Subjects may 
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with the LICR medical monitor.” Rationale:  This was added to provide clarification, as it 
was previously inadvertently omitted based on other changes. 
• 
Section 7.1.5 (General Reporting Requirements). The Note for Cohorts C and D was edited to 
provide clarification. The changes implemented are shown in bold:  
“NOTE:  For subjects in Cohorts C and D, there may be 2 On Study Follow-up periods is 
defined as follows:  1. All AEs will be collected for 110 days after the last dose of pre-surgery 
durvalumab, with the exception of those AEs that are related to the protocol-defined 
surgical procedure(s). If the decision is made that a subject will not receive continued 
durvalumab, the subject must start On Study Follow-up and have at least one On Study 
Follow-up visit at 110 days (+30 days) after last dose of durvalumab or at the point of the 
decision (+30 days), whichever is later. See Flowchart in Section 3.2 for details.  
2. If any subjects in Cohorts C and D continue durvalumab treatment after the planned 
surgical procedure, therey will follow the On Study Follow-up period according to the 
Flowchart in Section 3.2, and all AEs will be collected for 110 days after the last dose of 
durvalumab. 
• 
Section 7.1.8 (AESIs):  
The section was updated and reorganized based on updated recommendations from 
Medimmune in the updated IB. Specifically: 
o Endocrine disorders-deleted diabetes insipidus. 
o Myocarditis and myositis/polymyositis were added 
o Other inflammatory responses was updated (changes in bold):  
“Other inflammatory responses that are rare / less frequent with a potential 
immune-mediated aetiology include, but are not limited to, myocarditis, 
pericarditis, sarcoidosis, uveitis, and other events involving the eye, skin, 
hematological and rheumatological events. 
• 
Section 8.3 (Participating Laboratories): The table that listed participating laboratories was 
deleted and replaced with “Information regarding participating laboratories is provided in 
the Clinical Study File.”  Rationale: additional sites have been added and the table no longer 
provides current information. 
• 
Section 8.5 (Dose Adjustment and Delays for Durvalumab).  The following note was added: 
“Note: the Medimmune guideline refers to dose modifications for durvalumab (MEDI4736) 
and tremelimumab. For this protocol, however, only 1 dose of tremelimumab is given to 
certain cohorts, and no dose modification is possible.  Therefore, this section has been 
modified to refer to dose modifications for durvalumab only.” References to tremelimumab 
dose modifications throughout the section were deleted, as appropriate. 
• 
Section 8.5.1 (Durvalumab and Tremelimumab dose modification due to toxicity): Immune-
related AEs were updated based on updated Toxicity Mgt Guidelines from Medimmune 
(Dated 01Nov2017). Specifically, myocarditis, myositis/polymyositis were added; 
Diarrhea/colitis and endocrinopathies were updated.  
• 
Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 


 
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Amendment 6 
Issue date: 18-MAY-2018 
Summary of Changes: 
• 
Per rationale in Section 2.2, Cohort C-FLOT was added. 
• 
Updates related to Cohort C-FLOT were added to the following sections, as appropriate: 
o Synopsis 
o Section 2.2 (Rationale for Amendment 6) was added. 
o Section 3.1 (Study Design) 
o Section 3.1.2 (Enrollment/Randomization) 
o Section 3.1.4 (Subject Population) 
o Section 3.1.5 (No. of Sites/Subjects) 
o Section 3.1.6 (Sample Size and Statistical Considerations) 
o Section 3.1.7 (Treatment Arms and Treatment Schema) 
o Figure 1 – Treatment Schema 
o Section 3.1.7.2 (Phase 2 – Expansion Phase 
o Section 3.1.8 (Dosing Adjustments, Delays, and Discontinuations) 
o Section 3.1.9 (DLT) 
o Section 3.1.12 (Optional Study Treatment Extension) 
o Section 3.1.14 (Safety Monitoring and Study Stopping Rules) 
o Section 3.1.15 (Duration of Study) 
o Section 3.1.16 (On Study and Post Study Follow-up) 
o Section 3.2 (Study Flowcharts). A clarification was added to footnotes “a and f” to 
record times as well as dates. 
o Section 3.2.1 (Study Flowchart for all Cohorts except Cohort C-FLOT) – new section was 
added 
o Section 3.2.2 (Study Flowchart for Cohort C-FLOT) – new flowchart and new section 
were added. 
o Section 4 (Study Objectives and Endpoints) 
o Section 4.1.1 (Safety Endpoints and Assessment Methods) 
o Section 4.2 (Clinical Efficacy) and sub sections 
o Section 4.3 (Immune Monitoring) 
o Section 5.1 (Inclusion Criteria): C-FLOT was added to #1 
o Section 5.2 (Exclusion Criteria) 
 
FLOT was added to the NOTE in #18 (contraception) 
 
FLOT was added to Criteria #20 and 21  
o Section 5.3.1 (Non-permitted Concomitant Therapies) was updated. See details below. 
o Section 5.3.2 (Permitted Concomitant Therapies). Last row was updated as follows 
(changes in bold): “For oxaliplatin, capecitabine, paclitaxel, carboplatin, and FLOT (5-
fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel), refer to prescribing 
information for additional information.” 
o Section 6 (Study Drug Preparation). The following paragraph was added: “On days with 
concurrent durvalumab and FLOT dosing, the cytotoxic chemotherapy drugs should be 
administered at least 60 minutes after the end of the durvalumab infusion. Local 
standard procedures for the administration of 5-fluorouracil, leucovorin, oxaliplatin and 
docetaxel will apply. Note that leucovorin should not be mixed in the same infusion as 
5-fluorouracil because a precipitate may form.” 


 
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o Sections 6.5 (Fluorouracil), 6.6 (Leucovorin), and 6.7 (Docetaxel) were added. 
Subsequent Sections were re-numbered, as appropriate. 
o Newly numbered Section 6.10 (Estimated Study Drug Requirements) was updated to 
include FLOT drugs 
o Newly numbered Section 6.12 (Drug Overdose Management) was updated to include 
FLOT drugs 
o Section 7.1.5 (General Reporting Requirements): Note in last paragraph was updated 
for addition of Cohort C-FLOT. 
o Section 8.6 (Dose Modification and Management Guidelines for 
Oxaliplatin/Capecitabine and Surgery) was updated to include FLOT and/or specific 
elements of FLOT, as appropriate. 
o Section 8.7.4 (Surgery) 
o Section 8.10 (List of Abbreviations) 
o Section 9 (References) – Al-Batran et al. 2017 was added 
o Section 5.3.1 (Non-permitted Concomitant Therapies) was updated as follows (changes 
in bold): 
“For oxaliplatin, capecitabine, paclitaxel, carboplatin, and FLOT (5-fluorouracil (5-FU), 
leucovorin, oxaliplatin, and docetaxel) refer to the prescribing information and the additional 
information below: 
Warfarin:  INR (International normalised ratio) control may be affected by capecitabine. If a 
subject requiring coumarin-derived anticoagulants such as warfarin is taking capecitabine, more 
frequent INR monitoring is required.  The use of low molecular weight heparin instead of 
warfarin is at the discretion of the Investigator. 
Phenytoin:  Blood phenytoin levels may increase with capecitabine or 5-fluorouracil.  If a subject 
is taking phenytoin concomitantly with capecitabine these drugs, they should be monitored 
regularly for increased phenytoin plasma concentrations and associated clinical symptoms.  
Other anti-epileptic substances: Leucovorin may diminish the effect of anti-epileptic 
substances: phenobarbital, primidone, phenytoin and succinimides, and may increase the 
frequency of seizures (a decrease of plasma levels of enzymatic inductor anticonvulsant drugs 
may be observed). 
Allopurinol: Interactions with allopurinol have been observed for 5-fluorouracil; with possible 
decreased efficacy of 5-fluorouracil. Concomitant use of allopurinol with capecitabine or 5-
fluorouracil should be avoided.  
Antivirals:  Brivudine and sorivudine must not be prescribed with capecitabine as they may 
produce a life-threatening interaction. 
Brivudin, sorivudin and analogues: 5-fluorouracil must not be given in combination with 
brivudin, sorivudin and analogues. Brivudin, sorivudin and analogues are potent inhibitors of 
the 5-fluorouracil metabolising enzyme dihydropyrimidine dehydrogenase (DPD). 
5-Fluorouracil must not be given to subjects known to be homozygotic for dihydropyrimidine 
dehydrogenase (DPD). 
Vaccination with a live vaccine should be avoided in subjects receiving 5-fluorouracil due to the 
potential for serious or fatal infections. Contact should be avoided with people who have 
recently been treated with polio virus vaccine. 
Photosensitivity: It is not advisable to have prolonged exposure to sunlight because of the risk 
of photosensitivity with 5-fluorouracil. 


 
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Nephrotoxic/ototoxic drugs: Auditory defects have been reported during carboplatin therapy. 
Concurrent therapy with nephrotoxic drugs or ototoxic drugs such as aminoglycosides, 
vancomycin, capreomycin and diuretics is not recommended as they may increase or exacerbate 
toxicity, particularly in renal failure patients, due to carboplatin induced changes in renal 
clearance. 
CYP2C8 or CYP3A4 inhibitors/inducers: Caution should be exercised when administering 
paclitaxel concomitantly with medicines known to inhibit either CYP2C8 or CYP3A4 (e.g., 
ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, clopidogrel, 
cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) because toxicity of paclitaxel may be 
increased due to higher paclitaxel exposure. Administering paclitaxel concomitantly with 
medicines known to induce either CYP2C8 or CYP3A4 (e.g. rifampicin, carbamazepine, 
phenytoin, efavirenz, nevirapine) is not recommended because efficacy may be compromised 
because of lower paclitaxel exposures. 
The concomitant use of docetaxel with strong CYP3A4 inhibitors (e.g., ketoconazole, 
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, 
telithromycin and voriconazole) should be avoided.   
Cytochrome P450-3A: The metabolism of docetaxel may be modified by the concomitant 
administration of compounds which induce, inhibit or are metabolised by (and thus may inhibit 
the enzyme competitively) cytochrome P450-3A such as ciclosporine, ketoconazole and 
erythromycin.” 
• 
Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 
Amendment 6.1 
Issue date: 10-JUL-2018 
Summary of Changes: 
Per Investigator request, the following changes/clarifications were made to the flowchart: 
• 
Footnote “i” in both flowcharts was updated to indicate that blood draw for correlatives 
may be up to 3 days before surgery. 
o This clarification was also added to Section 4.3, Immune Monitoring. 
• 
Footnote “q” in Flowchart 3.2.1 (all cohorts except C-FLOT) and footnote “m” in Flowchart 
3.2.2 (C-FLOT) were added to indicate that “Saliva samples may be collected at each biopsy 
collection time point; photographs at endoscopy may be taken.” 
• 
For Flowchart 3.2.2 (Cohort C-FLOT), the following corrections were incorporated: the 
collection of the full chemistry panel and urinalysis samples were added to Cycle 2 Day 1 and 
the urine pregnancy test was moved from Cycle 2 Day 15 to Cycle 2 Day 1. 
 
Amendment 6.2 (Administrative Change) 
Issue date: 20-JUL-2018 
Summary of Changes: 
• 
For Flowchart 3.2.2 (Cohort C-FLOT), the following assessments, which were inadvertently 
included in the surgery column, were deleted: physical exam, vital signs, and hematology, 
chemistry, urinalysis, and pregnancy labs. According to the footnotes, these assessments are 
only done on drug administration days. 
 


 
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Amendment 7 
Issue date: 03-MAR-2019 
Summary of Changes: 
• 
Cohort D2, a subset of Cohort D, was added. Rationale for Cohort D2 is provided in Section 
2.3 (which was added for Amendment 7). 
• 
Changes related to the addition of Cohort D2 were made in the following sections: 
o Synopsis 
o Section 2.3, Rationale for Amendment 7 
o Section 3.1, Study Design 
o Section 3.1.2, Enrollment/Randomization 
o Section 3.1.4, Subject Population 
o Section 3.1.5, No. of Sites/Subjects 
o Section 3.1.6, Sample Size and Statistical Considerations 
o Section 3.1.7, Treatment Arms and Treatment Schema 
o Figure 1, Treatment Schema 
o Section 3.1.7.2, Phase 2 -Expansion Phase 
o Section 3.1.12, Optional Treatment Study Extension 
o Section 3.1.14, Safety Monitoring and Study Stopping Rules 
o Section 3.1.15, Duration of Study 
o Section 3.2.1 Flowchart was re-named as Flowchart for all Cohorts except C-FLOT and D2 
o Section 3.2.3 Study Flowchart for Cohort D2 was added. 
o Section 4.1.1, Safety Endpoints and Assessment Methods 
o Section 4.2, Clinical Efficacy 
o Section 4.2.1, Efficacy Endpoints and Assessment Methods 
o Section 4.2.1.2, Progression-free Survival Rate 
o Section 5.1, Inclusion Criteria 
o Section 7.1.5, General Reporting Requirements 
• 
The following was added: “The option to approach subjects with long-term survival (PFS > 1 
year, still in remission) from the metastatic cohorts (A and B) of the trial to request blood (up 
to 300 mL, acquired in aliquots of 100 mL at a time) for additional testing.” 
o The rationale for this addition was provided in Section 2.3, Rationale for Amendment 7. 
o The change was added to Section 4.3, Immune Monitoring 
o The change was also added to Section 3.2.1 (Flowchart for all Cohorts except C-FLOT and 
D2), Footnote r 
• 
Section 3.1.2 (Enrollment/Randomization). In addition to the changes listed above, the 
following notes were added: 
“See note in Section 3.1 regarding enrollment to Cohort D2. 
See notes in Section 3.1.7 (Cohort D), for information regarding safety assessment of subjects 
in Cohort D and prior to enrollment into Cohort D2.” 
• 
Section 3.1.7 (Treatment Arms and Treatment Schema). In addition to the changes listed 
above, the following note was added: 
“Note: The Cohort D subset, Cohort D2, will start enrollment after several Cohort D subjects 
have been treated with the non-concurrent immunotherapy/ chemoradiotherapy schedules; 
ongoing safety review of those Cohort D subjects will inform enrollment into Cohort D2.” 
• 
Section 3.1.16 (On Study and Post Study Follow-up). 


 
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The Note was changed FROM: “NOTE:  For subjects in Cohorts C/C-FLOT and D, additional 
details regarding the On Study Follow-up period are provided in Section 7.1.5.”  TO: “NOTE:  
For each of the cohorts, additional details regarding the On Study Follow-up period are 
provided in Section 7.1.5.” 
• 
Section 3.2.1 (Flowchart for all Cohorts except C-FLOT and D2).  In addition to the changes 
listed above, the following change was made: 
o For footnote a, the following clarification was added: “Day 1 lab assessments may be 
performed within 3 days prior to Day 1.” 
o Footnote L was clarified, and the footnote was added to Day 64 safety assessments 
(physical exam, vitals, AEs, Con meds). 
o Footnote p – “See Section 7.1.5 for details on Cohorts A and B” was added. 
• 
Section 6 (Study Drug Preparation and Administration). The following statement was added: 
“For chemotherapy, banded doses may be used according to institutional guidelines.” 
• 
Section 6.10 (Estimated Drug Requirements). Durvalumab estimate was updated: 
 
• 
Section 7.1.1 (General AE/SAE Definitions per ICH Guidelines). The following statement was 
added: “NOTE: If a subject is hospitalized for a planned standard of care procedure that is not 
related to an AE, the hospitalization does not require an SAE report.  However, if there is an 
additional AE or complication during the hospitalization, or if the hospitalization is prolonged, 
the SAE procedures described in Section 7.1 must be followed.” 
• 
Section 7.1.5 (General Reporting Requirements for AEs). The following note was added for 
clarification: 
NOTE:  For subjects in Cohorts A and B: 1) If durvalumab is discontinued early, subjects will 
follow the On Study Follow-up period according to the Flowchart in Section 3.2, and all AEs 
will be collected for 110 days after the last dose of durvalumab.  2) If any subjects continue 
chemotherapy treatment alone (no durvalumab), they will complete the first On Study 
Follow-up at Day 28 (+14 days) post last dose of chemotherapy. All AEs will be collected for at 
least 28 (+14) days after the last dose of chemotherapy; however, per point #1, subjects must 
still be followed for On Study Follow-up post last dose of durvalumab for 110 days. 
• 
Section 8.6 (Dose Modification and Management Guidelines for Oxaliplatin/Capecitabine, 
FLOT, and Surgery). The last sentence was clarified as follows (changes in bold): “The 
following outlines provide guidance for the management of toxicities for subjects treated 
with oxaliplatin/capecitabine or the FLOT regimen.” 
• 
Administrative: Spelling, grammar and typographical errors were corrected; formatting 
changes were implemented, as applicable. 
 


 
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Amendment 7.1 (Administrative Change) 
Issue date: 26-APR-2019 
Summary of Changes: 
In Sections 2.3 (Rationale for Amendment 7) and Section 4.3 (immune Monitoring), the following 
change was made (changes in bold): 
The Investigator(s) will have the option to approach subjects with long-term survival (PFS > 1 
year, still in remission) from the metastatic cohorts (A and B) of the trial to request blood (up to 
300 mL, acquired in aliquots of 100 mL at a time) for additional testing.   
 
This change was also applied to Section 3.2.1 (Study Flowchart for all cohorts except C-FLOT and 
D2) in footnote “r”. 
 
Amendment 8  
Issue date: 11-JAN-2022 
Summary of Changes: 
1. All subjects have completed treatment and On Study Follow-up. This amendment provides 
that the Post Study Follow-up for the collection of survival data will be discontinued as of 30 June 
2022, and the study will be completed. As of 30 June 2022, all but up to 8 subjects will have 
completed the 3-year Post Study Follow-up, which would have occurred by December 2022 for 
the remaining subjects. (The preceding paragraph was added to the synopsis). 
a. The following note was added to Sections 3.1.15 (Duration of Study), 3.1.16 (On Study and 
Post Study Follow-up), and 4.2.1.4 (Overall Survival): “NOTE: Per Amendment 8, all post 
study follow-up for the collection of survival data will be discontinued as of 30 June 2022 
(see rationale in Section 8.1, Amendment 8 on Page 96)” 
b. Section 3.2 (Study Flowchart). The following footnote was added to each of the 3 
flowcharts: “Per Amendment 8, all post study follow-up for the collection of survival data 
will be discontinued as of 30Jun2022 (see Section 8.1, Amendment 8). 
2. Section 7.1.6 (Expedited SAE Reporting Requirements): updated address for Drug Safety 
Contact and Primary Sponsor Contact due to office move. 
 
3. Administrative edit: In Section 7.1.6, the title of Primary Sponsor Contact was changed from 
Director to Senior Director. 
 
8.2 
Participating Study Sites, Investigators and Staff 
Site and Investigator information is provided in the Clinical Study File. 
8.3 
Participating Laboratories 
Information regarding participating laboratories is provided in the Clinical Study File. 
8.4 
Sponsor Information 
Sponsor Information is provided in the Clinical Study File. 
 


 
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8.5 
Dose Adjustments and Delays for Durvalumab 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.5, 8.6, and 
8.7, and the toxicity causing agent can be clearly identified, then the respective guideline should 
be followed. If the toxicity causing agent cannot be identified, then the more conservative 
guideline should be followed. 
8.5.1 Durvalumab Dose Modification Due to Toxicity 
Durvalumab (MEDI4736) administration may be modified or discontinued as a result of toxicities 
as described the table below.  
Additional information and guidance regarding dose modification due to toxicity are provided 
from Medimmune in the following guidelines: 
“Medimmune’s Dosing Modification and Toxicity Management Guidelines for Immune-
mediated, Infusion Related, and Non Immune-mediated Reactions (MEDI4736 Monotherapy or 
Combination therapy with Tremelimumab or Tremelimumab monotherapy).” 
Note: the Medimmune guideline refers to dose modifications for durvalumab (MEDI4736) and 
tremelimumab. For this protocol, however, only 1 dose of tremelimumab is given to certain 
cohorts, and no dose modification is possible.  Therefore, this section has been modified to refer 
to dose modifications for durvalumab only. 
Dose modifications will not be required for AEs that are clearly not attributed to durvalumab or 
tremelimumab (such as an accident) or for laboratory abnormalities that are not deemed to be 
clinically significant. 
MEDI4736 (M) Dose Modification Due to Toxicity 
Note: If M dosing is held temporarily until resolution of the event as per instructions below, 
treatment should resume at the next scheduled treatment date. 
Immune-related Adverse Events (irAEs) 
Immune-related adverse events are defined as AEs of immune nature (i.e., inflammatory) in 
the absence of a clear alternative etiology.  Maximum supportive care, including 
immunosuppressive medications, such as high dose steroids, is allowed to induce resolution of 
the event.  However, infliximab should not be used for management of immune-related 
hepatitis. 
In addition to the criteria for permanent discontinuation of M depicted below, permanently 
discontinue M also for:  
• Any Grade rash with bullous skin formations. 
• Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per day (or 
equivalent) within 12 weeks after last dose of study drug/regimen. 
• Recurrence of a previously experienced Grade 3 treatment-related AE following 
resumption of dosing. 
• Any Grade biopsy-proven immune-mediated myocarditis. 


 
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Grade 1 
• 
In general, no dose modification required. 
• 
For pneumonitis/interstitial lung disease and myocarditis, consider holding M dosing as clinically 
appropriate and during diagnostic work-up for other etiologies. 
Grade 2 
• 
In general, hold M until resolution to ≤ Grade 1 and after the end of any steroid taper, and 
discontinue M permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities).  Criteria for temporary hold or permanent discontinuation of M may differ by event 
as detailed below. 
• 
For myositis/polymyositis, hold M until resolution to ≤ Grade 1; permanently discontinue M if it 
does not resolve to ≤ Grade 1 within 30 days or if there are signs of respiratory insufficiency. 
• 
For pneumonitis/interstitial lung disease and myocarditis, the decision to reinitiate M upon 
resolution shall be based upon treating physician’s clinical judgment (as long as the event does not 
meet DLT criteria). 
• 
For peripheral neuromotor syndromes, such as Guillain-Barre and Myasthenia Gravis, follow general 
instructions above, but always discontinue M permanently if there are signs of respiratory 
insufficiency or autonomic instability. 
• 
For endocrinopathies, other than isolated hypothyroidism and isolated Type 1 diabetes mellitus, 
follow general instructions above, but patients may be retreated if the endocrinopathy is controlled 
and the patient is clinically stable while requiring steroid doses of ≤ 10 mg/day prednisone 
equivalent. 
• 
For isolated hypothyroidism managed with hormone replacement therapy, isolated Type 1 diabetes 
mellitus treated with appropriate diabetic therapy, and for sensory neuropathy/neuropathic pain, 
holding M is at the discretion of the investigator. 
• 
For elevated creatinine or rash, M should be held until resolution to ≤ Grade 1 or baseline and after 
completion of steroid taper. 
• 
For vitiligo, no dose modification required. 
Grade 3 
• 
In general, hold M until resolution to ≤ Grade 1, and after the end of any steroid taper, and 
discontinue M permanently if such resolution does not occur within 60 days (30 days for 
neurotoxicities and rash).  Criteria for permanent discontinuation of M may differ by event as 
detailed below. 
• 
For myositis/polymyositis, follow Grade 2 instructions above. 
• 
For peripheral neuromotor syndromes (such as Guillain-Barre and Myasthenia Gravis), apply 
respective Grade 2 rules. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For diarrhea/colitis, permanently discontinue M if toxicity does not improve to ≤ Grade 1 within 
14 days. 
• 
For pneumonitis/interstitial lung disease, myocarditis, and elevated serum creatinine (e.g., nephritis 
or renal dysfunction), always discontinue M permanently. 
• 
For asymptomatic increases of amylase or lipase levels, hold M, and if complete work up shows no 
evidence of pancreatitis, M may be continued. 
• 
For hepatitis, discontinue M permanently for (1) transaminases or bilirubin not resolving to ≤ Grade 
1 or baseline within 14 days, (2) transaminases > 8 × the upper limit of normal (ULN) or bilirubin > 5 


 
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MEDI4736 (M) Dose Modification Due to Toxicity 
× ULN, or (3) any case meeting Hy’s law criteria (as defined in FDA Guidance Document “Drug-
Induced Liver Injury”). 
• 
For rash, M should be held until resolution to ≤ Grade 1 or baseline. 
Grade 4 
• 
In general, discontinue M permanently. 
• 
For endocrinopathies, follow Grade 2 instructions above. 
• 
For asymptomatic increases of amylase or lipase levels, hold M , and if complete work up shows no 
evidence of pancreatitis, M may be continued.  
Infusion-related Reactions 
Grade 1 
• 
The infusion rate of M and T may be decreased 50% or temporarily interrupted until resolution of 
the event. 
• 
Acetaminophen and/or antihistamines may be administered per institutional standards at the 
discretion of the Investigator. 
• 
Premedication for subsequent doses should be considered. 
• 
Steroids should not be used for routine premedication of ≤ Grade 2 infusion reactions. 
Grade 2: 
• 
Same as Grade 1, but consider giving subsequent infusions at 50% of the initial infusion rate. 
Grade 3 and 4: 
• 
The infusion must be stopped immediately and treatment permanently discontinued. 
• 
Manage severe infusion-related reactions per institutional standards (e.g., IM epinephrine, followed 
by IV diphenhydramine and ranitidine, and IV glucocorticoid). 
All other Adverse Events 
Grade 1 
• 
No dose modification required. 
Grade 2  
• 
Hold M until resolution to ≤ Grade 1 or baseline, and discontinue M permanently if such resolution 
does not occur within 60 days. 
Grade 3 
• 
Hold M. If AEs downgrade to ≤ Grade 2 within 7 days or resolve to ≤ Grade 1 or baseline within 14 
days, resume M administration at next scheduled dose. Otherwise, discontinue M permanently. 
Grade 4 
• 
In general, discontinue M permanently. 
• 
For isolated lab results, decision to discontinue should be based on accompanying clinical 
signs/symptoms and per Investigator’s clinical judgment and in consultation with the Sponsor 
 


 
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8.5.2 Durvalumab Dose Modification Not Due to Toxicities 
Durvalumab administration may be modified or discontinued as a result of events other than 
toxicity, e.g., intercurrent illness or logistical/administrative reasons, whereby the following rules 
should apply: 
1. The originally planned visit/treatment schedule should be maintained in general, i.e., 
dosing interruptions should not reset the original treatment schedule. Exceptions may be 
made only for individual dosing days, whereby the interval between any two doses shall 
be no less than 10 days. All resulting protocol deviations should be documented.  
2. If the dosing interruption causes 2 consecutive planned doses to be missed, the 
treatment should be discontinued. 
3. If the dosing interruption is ≤ half the planned dosing interval, the originally planned dose 
should be given and the next dose(s) should be adjusted in accordance with #1, if 
necessary.  
4. If the dosing interruption is greater than half the planned dosing interval, the dose should 
be skipped and the next dose(s) should be adjusted in accordance with #1, if necessary 
 
 


 
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8.6 
Dose Modification and Management Guidelines for 
Oxaliplatin/Capecitabine, FLOT, and Surgery  
If a toxicity occurs that requires toxicity management in accordance with Sections 8.5, 8.6, and 
8.7, and the toxicity causing agent can be clearly identified, then the respective guideline should 
be followed. If the toxicity causing agent cannot be identified, then the more conservative 
guideline should be followed. 
Every effort should be made to administer trial treatment on the planned schedule.  The toxicity 
of each cycle of chemotherapy must be recorded before the administration of the next one and 
graded according to the current version of the Common Terminology Criteria for Adverse Events 
(CTCAE Version 4.03).  If individual subjects experience treatment related toxicity, subsequent trial 
treatment may be delayed, omitted and/or dose modified according to the worst toxicity observed 
during the previous cycle as described below.  Dose reductions are permanent (no dose re-
escalation permitted).  The following outlines provide guidance for the management of toxicities 
for subjects treated with oxaliplatin/capecitabine or the FLOT regimen. 
8.6.1 Non Haematological Toxicity 
If a DLT occurs during Cycle 1, then oxaliplatin/capecitabine or FLOT can be reduced to 75% and 
then to 50% of the starting dose, at the discretion of Investigator, if this is felt to be the basis for 
toxicity.  No dose modifications for tremelimumab or durvalumab (MEDI4736) will be made if, in 
the Investigator's opinion, the toxicity is specifically exclusively related to oxaliplatin, 
capecitabine or FLOT (e.g., neuropathy or hand foot syndrome). 
For Grade 3, Grade 4 or intolerable Grade 2 toxicity, the treatment will be interrupted until 
recovery to < Grade 2 or baseline (in the judgement of the Investigator).  If the subject fails to 
recover to this extent within 3 weeks of treatment will be discontinued.  If a subject cannot 
tolerate treatment after two successive dose reductions trial treatment will be discontinued. 
8.6.1.1 
Rash 
In the event of a rash, unless the Investigator is of the opinion that oxaliplatin/capecitabine or 
FLOT is causative, chemotherapy should be continued as planned.  (Note: Hand/foot syndrome is 
considered below.)  For Grades 1 and 2 rash, treatment should be continued.  Consider using 
alcohol free emollient cream/moisturiser and/or topical 1-2.5% hydrocortisone cream to the 
affected areas. If the rash persists or worsens, oral antibiotics (doxicycline 100 mg b.d. or 
minocycline 100 mg b.d.) or topical clindamycin 1% should be added.  
8.6.1.2 
Diarrhoea 
Supportive care should be provided according to local clinical practices (e.g., loperamide).  In the 
event of Grade 2 or higher symptoms, capecitabine or FLOT dosing should be interrupted.  Once 
symptoms have resolved to Grade 1 or better, capecitabine/all elements of FLOT may be 
resumed at a reduced dose (75% of starting dose).  If diarrhoea was Grade 3 or 4, then the 
capecitabine/all elements of FLOT dose(s) should be reduced by 50%. 


 
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8.6.1.3 
Mucositis/Stomatitis 
Supportive care should be provided according to local clinical practices (e.g., mouth wash, topical 
anesthetics or systemic analgesics).  In the event of Grade 2 or higher symptoms, capecitabine or 
FLOT dosing should be interrupted.  Once symptoms have resolved to Grade 1 or better, 
capecitabine/all elements of FLOT may be resumed at a reduced dose (75% of starting dose if 
Grade 2 toxicity, 50% of starting dose if Grade 3 or 4).  If there is no improvement to Grade 1 or 
better within 3 weeks of stopping, capecitabine or FLOT should be discontinued permanently. 
8.6.1.4 
Neuropathy 
Oxaliplatin commonly causes peripheral sensory symptoms.  Many subjects experience transient 
paraesthesia of hands and feet, and some experience dysaesthesia in the throat.  These 
symptoms are precipitated by cold and last from a few hours to a few days after each oxaliplatin 
administration.  They do not require treatment or dose reduction.  In the case of Laryngeal Spasm 
Syndrome, increase the oxaliplatin infusion time from 2 to 6 hours.  
Asymptomatic (Grade 1) neuropathy requires no dose adjustment.  Where there are moderate 
symptoms limiting day to day activity persisting for more than 7 days, subsequent oxaliplatin 
doses should be reduced by 25%.  If symptoms persist despite this, a further reduction to 50% of 
the starting dose can be performed.  In the event of Grade 3 and 4 toxicity, or Grade 2 toxicity 
despite 2 dose reductions, discontinue oxaliplatin. Where subjects are on the FLOT regimen, the 
docetaxel dose should be reduced by the same percentage as for oxaliplatin. 
8.6.1.5 
Hand/Foot Syndrome 
Supportive care should be provided according to local clinical practices (e.g., topical therapy and 
oral pyridoxine).  In the event of Grade 2 or higher symptoms, capecitabine/5-fluorouracil and 
leucovorin dosing should be interrupted.  Once symptoms have resolved to Grade 1 or better, 
capecitabine/5-fluorouracil and leucovorin may be resumed at a reduced dose (75% of starting 
dose if grade 2 toxicity, 50% of starting dose if Grade 3).  If there is no improvement to Grade 1 or 
better within 3 weeks of stopping, capecitabine/5-fluorouracil and leucovorin should be 
discontinued permanently. 
8.6.1.6 
Allergic Reactions to Oxaliplatin 
The occasional subject (approximately 0.5% of subjects) develops acute hypersensitivity to 
oxaliplatin, usually after more than 6 cycles have been administered.  During drug administration, 
the subject may develop rash, fever, swollen mouth or tongue, hypo- or hypertension and other 
signs/symptoms of hypersensitivity.  This rarely develops to full-blown anaphylaxis, even with 
repeated treatment. 
1. If acute hypersensitivity occurs, discontinue the infusion and treat with IV corticosteroid 
and antihistamine. 
2. After full recovery, the subject may continue with capecitabine. 
3. At the Investigator’s discretion, the subject may be rechallenged with oxaliplatin at the 
next cycle. In this case, premedication is recommended with hydrocortisone 100 mg IV or 
Dexamethasone 8mg IV 30 minutes pre dose + Chlorphenamine 10mg (or equivalent) + 
ranitidine 50 mg (or equivalent) IV.  


 
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8.6.1.7 
Dose Modification for Other Non-haematological Toxicity 
8.6.1.7.1 Renal Toxicity 
If serum creatinine ≥ 2 x ULN has been demonstrated, this parameter must be repeated at least 
twice a week until resolution to ≤ CTCAE Grade 1, and then at least weekly until either resolution 
to allow for initiation of re-treatment or until stabilization. 
Oxaliplatin is not nephrotoxic but is renally cleared.  Check serum creatinine at each cycle.  If this 
rises to >25%, re-check serum creatinine clearance or EDTA clearance or 24-hour urinary 
creatinine, and adjust oxaliplatin and capecitabine doses according to the Table 8.6-1 below.  If 
the glomerular filtration rate (GFR) drops to between 30ml/min to 50ml/min, reduce 
capecitabine dose by 25% until recovery.  If GFR drops to below 30ml/min, omit oxaliplatin and 
capecitabine until recovery. 
8.6.1.7.2 Hepatic Toxicity 
If bilirubin ≥ 2 x ULN or ≥ CTCAE Grade 3 AST/ALT has been demonstrated, these parameters 
must be repeated at least twice a week until resolution to ≤ CTCAE Grade 1 (or ≤ Grade 2 if liver 
metastasis were present at baseline), and then at least weekly until either resolution to allow for 
initiation of re-treatment or until stabilization. 
Table 8.6-1 Adverse Event Management for other Non-haematological Toxicity  
Serum Creatinine  
Grade 1 (< 2 x ULN) (GFR > 50ml/min) 
Maintain full dose oxaliplatin/capecitabine or FLOT 
Grade 2 (2 - 3 x ULN) (GFR 30 - 50ml/min) 
Oxaliplatin: full dose; Capecitabine or 5-fluorouracil: 
reduce by 25% 
Grade 3 (> 3.0 - 6.0 x ULN) (GFR < 30ml/min) or  
Grade 4 (> 6.0 x ULN) 
Oxaliplatin:  do not give; Capecitabine or 5-fluorouracil: 
do not give 
Bilirubin 
Grade 1 or 2 (<2 - 3 x ULN) 
Oxaliplatin and Capecitabine: full dose 
Docetaxel: do not give 
Grade 3 (> 3.0 - 10.0 x ULN) 
Oxaliplatin: withhold until to ≤ Grade 1, reduced by 50%;  
Capecitabine: withhold until to ≤ Grade 1, then ↓ 50% 
Grade 4 (> 10.0 x ULN) 
discontinue treatment 
AST or ALT 
Grade 1 (>ULN - 3.0 x ULN) 
Maintain full dose oxaliplatin/capecitabine 
Grade 2 (Asymptomatic with ALT >3.0 - 5.0 x 
ULN) 
Oxaliplatin: full dose 
Capecitabine and 5-fluorouracil: reduce by 25% 
Docetaxel: do not give 
Grade 3 (>5.0 - 20.0 x ULN ) 
Oxaliplatin: withhold until to ≤ Grade 1, ↓ by 25%;  
Capecitabine and 5-fluorouracil: withhold until to ≤ Grade 
1, then ↓ by 25% 


 
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Grade 4 (> 20.0 x ULN) 
Oxaliplatin: withhold until to ≤ Grade 1, then ↓ by 50% 
Capecitabine and 5-fluorouracil: withhold until to ≤ Grade 
1, then ↓ by 50% 
ULN = upper limit of normal; GFR = glomerular filtration rate 
8.6.2 Haematological Toxicity 
The complete blood count is analyzed on (or up to 3 days before) Day 1 of each cycle. The 
following guidelines are applied (also see Table 8.6-2, below): 
1. Treatment should only be given when neutrophils ≥ 1.5 x 109/L and platelets ≥ 75 x 109/L.   
2.  If these criteria are not met, delay oxaliplatin/capecitabine for 1 week and restart with 
the full dose on recovery.  
3. If a delay of 2 weeks occurs, reduce the doses of capecitabine and oxaliplatin 25% upon 
recovery and continue at the lower dose for subsequent cycles unless further toxicity 
occurs. 
4. If more than 2 weeks delay or further delay(s) for myelotoxicity occur despite a 25% 
reduction, a further dose reduction may be made, at the discretion of the treating 
Investigator. 
Table 8.6-2 Dose Modification Guidance for Haematological Toxicity  
ANC = absolute neutrophil count; LLN = lower limit of normal; PLT = platelets 
* at second occurrence reduce to 50% dose 
8.6.3 Surgery 
See Section 8.7.4 for details regarding events related to surgery for applicable cohort. 
 
 
Neutropaenia or Thrombocytopaenia 
Grade 1 (ANC < LLN - 1.5 x 109/L or  PLT < LLN - 
75 x 109/L) and  
Grade 2 (ANC < 1.5 - 1.0 x 109/L, or PLT < 75 - 50 
x 109/L) 
Maintain dose of oxaliplatin/capecitabine or 
FLOT 
Grade 3 (ANC < 1.0 - 0.5 x109/L or PLT < 50-25 x 
109/L, febrile neutropenia) 
Oxaliplatin: withhold until to ≤ Grade 1, then 
↓ 25%* 
Capecitabine: withhold until to ≤ Grade 1, 
then full dose 
FLOT:  withhold until to ≤ Grade 1, then ↓ 
25%* 
Grade 4 (ANC < 0.5 x 109/L or PLT < 25 x 109/L) 
Oxaliplatin: withhold until to ≤ Grade 1, then 
↓ 25%* 
Capecitabine: withhold until to ≤ Grade 1, 
then ↓ 25%* 


 
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8.7 
Dose Modification and Management Guidelines for 
Paclitaxel/Carboplatin, Radiotherapy, and Surgery 
If a toxicity occurs that requires toxicity management in accordance with Sections 8.5, 8.6, and 
8.7, and the toxicity causing agent can be clearly identified, then the respective guideline should 
be followed. If the toxicity causing agent cannot be identified, then the more conservative 
guideline should be followed. 
8.7.1 Haematologic Related Toxicity 
On each dosing day for paclitaxel and carboplatin, if the white blood cell count (WBC) is < 1.0 x 
109/L and/or platelet count is < 50 x 109/L, omit chemotherapy for that week. 
In case of febrile neutropenia (granulocytes < 0.5 x 109/L and fever > 38.5 °C) or in case of severe 
bleeding or requiring ≥ 2 platelet transfusions, further chemotherapy will be withheld. 
Additional management guidelines are provided in the following table: 
Neutrophil count 
once weekly during 
CRT 
 
Platelet count once 
weekly during CRT 
Action 
≥1.0 x 109/L 
AND 
≥75 x 109/L 
Full dose paclitaxel and carboplatin 
<1.0 x 109/L 
OR 
<75 x 109/L 
Omit both drugs that week and omit 
chemotherapy weekly until recovery 
(N≥1.0 x 109/L and platelets ≥75 x 
109/L). Dose reduce by 25% for 
subsequent doses 
ANY 
AND 
<25 x 109/L 
Omit both drugs that week and omit 
chemotherapy weekly until recovery 
(N≥1.0 x 109/L and platelets ≥75 x 
109/L). Dose reduce by 50% for 
subsequent doses 
 


 
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8.7.2 Non-Haematologic Toxicity 
These effects will be graded according to CTCAE recommendations for grading of acute and sub-
acute toxicity. 
Hypersensitivity Reactions 
Hypersensitivity reactions will be classified as mild, moderate or severe. Definitions and 
management guidelines are outlined below: 
Classification of Reactions 
Management of reactions 
Mild symptoms 
(e.g. mild flushing, rash, pruritis) 
Complete infusion. Supervise at bedside. No 
treatment required. 
Moderate symptoms (e.g. moderate rash, 
flushing mild dyspnea, chest discomfort, mild 
hypotension) 
Stop infusion; give IV antihistamine 
(Clemastine 2 mg IV and Dexamethasone 
10 mg IV) →  
After recovery of symptoms, resume infusion 
at a rate of 20 mL/h for 15 minutes then 50 
mL/h for 15 minutes then, if no further 
symptoms, at full dose rate until infusion is 
complete. 
Severe symptoms (e.g. one or more of the 
following): respiratory distress requiring 
treatment, generalized urticaria, angioedema, 
hypotension requiring therapy) 
Stop infusion; give IV antihistamine and 
steroid as above. Add epinephrine or 
bronchodilators if indicated; report as an 
adverse event; the subject will go off protocol 
therapy. 
 
Other toxic reactions and the prescribed management of these reactions are outlined in the 
following table: 
 
Reaction 
Management of Reaction 
Renal 
GFR < 20 mL/min 
Carboplatin is contraindicated 
Paclitaxel- no dose modification 
Hepatic 
Carboplatin – no dose modification required 
Bilirubin <1.25 x ULN and ALT <10 x ULN,  
 
Paclitaxel - continue full intended dose. If these 
parameters are exceeded, further treatment 
should be discussed with the study team. 
Cardiac 
Asymptomatic bradycardia or isolated and 
asymptomatic ventricular extrasystoles. 
Continue therapy under continuous cardiac 
monitoring. 
First degree AV block. 
Continue therapy under continuous cardiac 
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Symptomatic arrhythmia or AV block 
(except1st degree) or other heart blocks. 
Stop chemotherapy, manage arrhythmia 
according to standard practice; subject goes off 
therapy. 
 
Other Non-haematologic toxicities: 
INCIDENCE  
CTCAE Grade 2 
CTCAE Grade 3 
CTCAE Grade 4 
1st occurrence 
Interrupt until 
resolved to Grade 0-
1, then resume at 
original dose 
Interrupt until 
resolved to Grade 0-
1, then resume at 
75% dose 
Discontinue 
treatment unless 
investigator 
continues this is in 
best interest for 
patient, in which case 
interrupt until 
resolved to Grade 0-
1, then resume at 
50% dose 
2nd occurrence of 
same toxicity 
Interrupt until 
resolved to Grade 0-
1, then resume at 
75% dose 
Interrupt until 
resolved to Grade 0-
1, then resume at 
50% dose 
N/A 
3rd occurrence of 
same toxicity 
Interrupt until 
resolved to Grade 0-
1, then resume at 
50% dose 
Discontinue 
treatment 
N/A 
4th occurrence of 
same toxicity 
Discontinue 
treatment 
N/A 
N/A 
 


 
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8.7.3 Radiotherapy Toxicity 
Radiotherapy, especially concurrent with chemotherapy can lead to acute esophagitis. In some 
cases, medical support and/or a feeding tube will be necessary. In the event of Grade 4 radiation 
induced esophagitis, both chemotherapy and radiotherapy will be withheld until the esophagitis 
recovered to Grade 3. 
Other acute complications of the radiation therapy are erythema, cough, nausea, fatigue and 
weight loss. In the first weeks to six months after the irradiation radiation pneumonitis or fistula 
formation can occur. 
The following list provides the expected events in relation to radiotherapy (and its possible effect 
following surgery); this should be used as the Reference Safety Information (RSI) when assessing 
the expectedness of SAEs causally related to radiotherapy: 
• 
Mucositis 
• 
Oesophagitis 
• 
Dysphagia 
• 
Lethargy 
• 
Pain 
• 
Anaemia 
• 
Nausea and vomiting 
• 
Weight loss 
• 
Poor oral intake 
• 
Tinnitus 
• 
Infection 
• 
Pneumonitis 
• 
Pericarditis 
• 
Wound infection 
• 
Anastomotic leak 
• 
Chest infection 
• 
Pleural effusion 
• 
Thrombo-embolism 
In the event of a chemotherapy toxicity or dose modification, the decision to continue radiotherapy 
rests with the treating clinician.  


 
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8.7.4 Surgery 
Hospitalizations for surgical procedures, which are planned for Cohorts C/C-FLOT and D per this 
protocol, should not be considered SAEs. 
The table below provides the expected events in relation to surgery. This should be used as the 
RSI when assessing the expectedness of SAEs causally related to surgery. 
Bleeding  
Genitourinary 
Neurological 
Anaemia requiring transfusion 
Post-operative bleed other than 
gastrointestinal 
Wound haematoma 
Renal failure 
Urinary retention 
Delirium / agitation 
Loss of consciousness 
Vertigo 
Cardiac 
Infectious 
Pulmonary 
Angina 
Arrythmia 
Congestive heart failure 
Hypertension 
Hypotension 
Myocardial Infarction 
Abscess 
Fever of unknown origin (FUO) 
Systemic sepsis 
Urinary tract infection 
Atelectasis 
Pleural effusion 
Pneumonia 
Pneumothorax 
Respiratory distress 
Gastrointestinal 
Wound Infection 
Surgical 
Clostridium difficile colitis 
Constipation (inability to have a 
bowel movement postoperative 
Day 5 with no signs of ileus or 
SBO) 
Diarrhoea 
Emesis 
Deep or superficial wound 
dehiscence 
Wound infection 
Wound seroma 
Bowel injury 
Incisional hernia 
Retained foreign body 
Vascular injury 
Thoracic duct injury 
Cranial nerve and/or 
sympathetic chain injury 
Brachial plexus injury 
Miscellaneous 
Thromboembolic 
 
Acidosis 
Decubitis ulcer 
Dehydration 
Lymphocele 
Peripheral arterial ischemia 
Psychological illness 
Thrombocytopenia 
Deep vein thrombosis (DVT) 
Superficial phlebitis 
Pulmonary embolism 
 
Note: Many of the side effects to surgery can be exacerbated by chemoradiotherapy 
 
 


 
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8.8 
RECIST 1.1 and irRECIST Guidelines  
The Response Evaluation Criteria in Solid Tumors (RECIST) guidelines were revised in 2009 as 
RECIST 1.1.41 These guidelines have been the widely accepted criteria to assess response and 
progression in solid tumors; however, limitations have been noted in the use of RECIST 1.1 for 
immunotherapy trials. With immunotherapeutic agents, clinical trials have shown that complete 
response, partial response, or stable disease status can still be achieved after an initial increase in 
overall tumor burden, and regression of initial lesions may occur despite development of new 
lesions. The Immune-related Response Criteria (irRC) were developed to address the need for 
response criteria in an immunotherapy setting.42  The main difference with irRC was that it 
considered the subject's total tumor burden at each subsequent assessment and required 
confirmation of suspected disease progression with subsequent imaging, approximately four 
weeks later.  In addition, a greater number of lesions (10 vs. 5) were measured in a bidimensional 
manner instead of unidimensionally as in RECIST 1.1.  In 2013, Nishino et al. demonstrated that 
immune-related response criteria using unidimensional measurements were highly concordant 
with the bidimensional results of irRC, but with less measurement variability.43  Based on these 
findings and in order to utilize both the established criteria of irRC and RECIST 1.1, the two 
systems have been adapted, modified, and combined into the Immune-related Response 
Evaluation Criteria in Solid Tumors (irRECIST).44  The adapted irRECIST criteria are modifications 
to the irRC, incorporating the findings of Nishino et al. and the advantages of RECIST 1.1 while 
overcoming the shortcomings of each of the other guidelines.   
The guidelines for RECIST 1.1 are summarized below, followed by a summary for irRECIST. 
RECIST 1.1 
The following section outlines the RECIST 1.1 guidelines as published41 and as summarized by 
National Cancer Institute for CTEP-involved clinical trials.   
I. 
Disease Parameters for RECIST 1.1 
Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the 
shortest diameter in the case of malignant lymph nodes are used in the RECIST 1.1 criteria. 
Measurable disease.  Measurable lesions are defined as those that can be accurately measured in 
at least one dimension (longest diameter to be recorded) as >20 mm by chest x-ray, as >10 mm 
with CT scan, or >10 mm with calipers by clinical exam.  All tumor measurements must be 
recorded in millimeters (or decimal fractions of centimeters). 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not be 
considered measurable.  If the investigator thinks it appropriate to include them, the conditions 
under which such lesions should be considered must be defined in the protocol. 
NOTE for irRECIST: During target lesion selection the radiologist will consider information on 
the anatomical sites of previous intervention (e.g. previous irradiation, RF-ablation, TACE, 
surgery, etc.). Lesions undergoing prior intervention will not be selected as target lesions 
unless there has been a demonstration of progress in the lesion. 


 
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Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a lymph 
node must be >15 mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm).  At baseline and in follow-up, only the short axis will 
be measured and followed. 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 to <15 mm short axis), are considered 
non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial 
effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, and abdominal masses 
(not followed by CT or MRI), are considered as non-measurable. 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.  ‘Cystic lesions’ thought to represent cystic metastases can be considered 
as measurable lesions, if they meet the definition of measurability described above. However, if 
non-cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
NOTE for irRECIST:  
Lesions that are partially cystic or necrotic can be selected as target lesions. The longest 
diameter of such a lesion will be added to the Total Measured Tumor Burden (TMTB) of all 
target lesions at baseline. If other lesions with a non-liquid/non-necrotic component are 
present, those should be preferred. 
Brain lesions detected on brain scans can be considered as both target or non-target lesions 
depending on the protocol definition. 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in 
total, representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size (lesions 
with the longest diameter), be representative of all involved organs, but in addition should be 
those that lend themselves to reproducible repeated measurements.  It may be the case that, on 
occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected.  A 
sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters.  If lymph nodes are to be 
included in the sum, then only the short axis is added into the sum.  The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the 
measurable dimension of the disease. 
Non-target lesions.  All other lesions (or sites of disease) including any non-measureable as well 
as measurable lesions over and above the 5 target lesions should be identified as non-target 
lesions and should also be recorded at baseline.  Measurements of these lesions are not 
required, but the presence, absence, or in rare cases unequivocal progression of each should be 
noted throughout follow-up.  


 
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II. 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment 
and never more than 4 weeks before the beginning of the treatment. 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
Chest x-ray:  Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
Conventional CT and MRI:  This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness greater 
than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  MRI is 
also acceptable in certain situations (e.g. for body scans).   
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of MRI 
is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
PET-CT:  At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if the 
site can document that the CT performed as part of a PET-CT is of identical diagnostic quality to a 
diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be used for 
RECIST measurements and can be used interchangeably with conventional CT in accurately 
measuring cancer lesions over time.  Note, however, that the PET portion of the CT introduces 
additional data which may bias an investigator if it is not routinely or serially performed.   
Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to 


 
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the next.  If new lesions are identified by ultrasound in the course of the study, confirmation by 
CT or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used 
instead of CT in selected instances. 
Endoscopy, Laparoscopy:  The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence 
following complete response (CR) or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete 
clinical response.  Specific guidelines for both CA-125 response (in recurrent ovarian cancer) and 
PSA response (in recurrent prostate cancer) have been published.45-47  In addition, the 
Gynecologic Cancer Intergroup has developed CA-125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line trials in ovarian cancer.48  
Cytology, Histology:  These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as germ 
cell tumors, where known residual benign tumors can remain). 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect 
of the treatment) and progressive disease. 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of FDG-
PET imaging can be identified according to the following algorithm:  
a) Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based 
on a new lesion. 
b) No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-PET at 
follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the positive 
FDG-PET at follow-up is not confirmed as a new site of disease on CT, additional follow-
up CT scans are needed to determine if there is truly progression occurring at that site (if 
so, the date of PD will be the date of the initial abnormal FDG-PET scan).  If the positive 
FDG-PET at follow-up corresponds to a pre-existing site of disease on CT that is not 
progressing on the basis of the anatomic images, this is not PD. 
c) FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than 
twice that of the surrounding tissue on the attenuation corrected image. 


 
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III. 
Response Criteria for RECIST 1.1 
A. Evaluation of Target Lesions 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm.   
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target lesions, 
taking as reference the baseline sum diameters 
Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study).  In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm.  (Note:  the appearance of one or more new lesions is also 
considered progressions). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study 
B. Evaluation of Non-Target Lesions 
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor 
marker level.  All lymph nodes must be non-pathological in size (<10 mm short axis) 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits 
Progressive Disease (PD):  Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal progression should not normally trump 
target lesion status.  It must be representative of overall disease status change, not a single lesion 
increase.   
Although a clear progression of “non-target” lesions only is exceptional, the opinion of the 
treating physician should prevail in such circumstances, and the progression status should be 
confirmed at a later time by the review panel (or Principal Investigator). 
C. Evaluation of Best Overall Response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the treatment started).  The patient's best response assignment 
will depend on the achievement of both measurement and confirmation criteria. 


 
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1. For Patients with Measurable Disease (i.e., Target Disease) 
Target 
Lesions 
Non-Target Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation** 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation** 
CR 
Not evaluated 
No 
PR 
PR 
Non-CR/Non-PD/not evaluated 
No 
PR 
SD 
Non-CR/Non-PD/not evaluated 
No 
SD 
documented at least once >4 
wks. from baseline** 
PD 
Any 
Yes or No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
*      See RECIST 1.1 manuscript for further details on what is evidence of a new lesion. 
**    Only for non-randomized trials with response as primary endpoint. 
***  In exceptional circumstances, unequivocal progression in non-target lesions may be accepted as disease 
progression. 
Note: 
Patients with a global deterioration of health status requiring discontinuation of treatment without 
objective evidence of disease progression at that time should be reported as “symptomatic deterioration.”  
Every effort should be made to document the objective progression even after discontinuation of 
treatment. 
 
2. For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
* ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as an end-
point for assessment of efficacy in some trials so to assign this category when no lesions can be measured is not 
advised. 
D. Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first date that 
recurrent or progressive disease is objectively documented (taking as reference for progressive 
disease the smallest measurements recorded since the treatment started). 
The duration of overall CR is measured from the time measurement criteria are first met for CR 
until the first date that progressive disease is objectively documented. 
Duration of stable disease:  Stable disease is measured from the start of the treatment until the 
criteria for progression are met, taking as reference the smallest measurements recorded since 
the treatment started, including the baseline measurements.  
 


 
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irRECIST 
Immune-related RECIST (irRECIST) guidelines according to Bohnsack et al.44 are presented below. 
I. 
Baseline Assessments in irRECIST 
In irRECIST, baseline assessment and measurement of measurable/non-measurable and 
target/non-target lesions and lymph nodes are in line with RECIST 1.1.  One new definition is 
added: If a subject has no measurable and no non-measurable disease at baseline the radiologist 
will assign ‘No Disease’ (irND) as the overall tumor assessment for any available follow-up time 
points unless new measurable lesions are identified and contribute to the total measured tumor 
burden (TMTB).  irND is a valid assessment in studies with adjuvant setting where the protocol 
and study design allow the inclusion of subjects with no visible disease 
II 
Follow-up Assessments in irRECIST 
A. Follow-up recording of target and new measurable lesions 
A key difference in irRECIST is that the appearance new lesions does not automatically indicate 
progression.  Instead, all measured lesions (baseline-selected target lesions and new 
measurable lesions) are combined into the total measured tumor burden (TMTB) at follow up.  
Baseline-selected target lesions and new measurable lesions are NOT assessed separately. 
Measurements of those lesions are combined into the TMTB, and one combined assessment 
provided. 
In order to be selected as new measurable lesions (≤ 2 lesions per organ, ≤ 5 lesions total, per 
time point), new lesions must meet criteria as defined for baseline target lesion selection and 
meet the same minimum size requirements of 10 mm in long diameter and minimum 15 mm in 
short axis for new measurable lymph nodes. New measurable lesions should be prioritized 
according to size, and the largest lesions elected as new measured lesions.  
B. Follow-up non-target assessment 
RECIST 1.1 definitions for assessment of non-target lesions apply.  The response of non-target 
lesions primarily contributes to the overall response assessments of irCR and irNon-CR/Non-PD 
(irNN). Non-target lesions do not affect irPR and irSD assessments. Only a massive and 
unequivocal worsening of non-target lesions alone, even without progress in the TMTB is 
indicative of irPD.  In alignment with RECIST 1.1, baseline selected non-target lesions can never 
convert to measurable lesions, not even if they increase in size at subsequent time points and 
become measurable. Only true new lesions can be measured and contribute to the TMTB. 
C. Follow-up for New Non-Measurable Lesions  
All new lesions not selected as new measurable lesions are considered new non-measurable 
lesions and are followed qualitatively. Only a massive and unequivocal progression of new non-
measurable lesions leads to an overall assessment of irPD for the time point. Persisting new non-
measurable lesions prevent irCR.  
III 
Overall Assessments for irRECIST 


 
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The irRECIST overall tumor assessment is based on TMTB of measured target and new lesions, 
non-target lesion assessment and new non-measurable lesions. 
At baseline, the sum of the longest diameters (SumD) of all target lesions (up to 2 lesions per 
organ, up to total 5 lesions) is measured.  At each subsequent tumor assessment, the SumD of 
the target lesions and of new, measurable lesions (up to 2 new lesions per organ, total 5 new 
lesions) are added together to provide the total measurable tumor burden (TMTB). 
Overall Assessments by irRECIST 
Complete Response 
(irCR) 
Complete disappearance of all measurable and non-measurable lesions. Lymph 
nodes must decrease to < 10 mm in short axis. 
Partial Response 
(irPR) 
Decrease of ≥ 30% in TMTB relative to baseline, non-target lesions are irNN, and 
no unequivocal progression of new non-measurable lesions 
• 
If new measurable lesions appear in subjects with no target lesions at 
baseline, irPD will be assessed. That irPD time point will be considered a new 
baseline, and all subsequent time points will be compared to it for response 
assessment. irPR is possible if the TMTB of new measurable lesions 
decreases by ≥ 30% compared to the first irPD documentation 
• 
irRECIST can be used in the adjuvant setting, in subjects with no visible 
disease on CT/MRI scans. The appearance of new measurable lesion(s) 
automatically leads to an increase in TMTB by 100% and leads to irPD. These 
subjects can achieve a response if the TMTB decreases at follow-up, as a sign 
of delayed response. 
• 
Based on the above, sponsors may consider enrolling subjects with no 
measurable disease and/or no visible disease in studies with response 
related endpoints. 
Stable Disease 
(irSD) 
Failure to meet criteria for irCR or irPR in the absence of irPD 
Progressive Disease 
(irPD) 
Minimum 20% increase and minimum 5 mm absolute increase in TMTB 
compared to nadir, or irPD for non-target or new non-measurable lesions. 
Confirmation of progression is recommended minimum 4 weeks after the first 
irPD assessment. An irPD confirmation scan may be recommended for subjects 
with a minimal TMTB %-increase over 20% and especially during the flare time-
window of the first 12 weeks of treatment, depending on the compound efficacy 
expectations, to account for expected delayed response. 
• 
In irRECIST a substantial and unequivocal increase of non-target lesions is 
indicative of progression. 
• 
IrPD may be assigned for a subject with multiple new non-measurable 
lesions if they are considered to be a sign of unequivocal massive worsening 
Other 
irNE: used in exceptional cases where insufficient data exist.  
irND: in adjuvant setting when no disease is detected 
irNN: no target disease was identified at baseline, and at follow-up the subject 
fails to meet criteria for irCR or irPD 
 
 


 
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8.9 
Laboratory Procedures 
Peripheral blood and biopsy samples will be collected at the time points designated in Section 
3.2, and the assays described in Section 4.3 and Section 4.4 will be performed.  Please refer to 
the Laboratory Manual for this study to obtain additional instructions and information on lab 
specimen handling and logistics. 
8.9.1 Additional Translational and Exploratory Studies 
Optional research studies may only be performed for subjects who voluntarily gave their consent 
for additional correlative research on the informed consent document.  Subjects who declined 
consent to participate in additional translational studies will have their samples destroyed at the 
end of the study.  Refusal to participate in this optional research will involve no penalty or loss of 
benefits to which the subject would otherwise be entitled.  Based on the data generated during 
the study and/or in other studies, not all samples from subjects consenting to this optional 
research may be utilized. 
 
 


 
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8.10 List of Abbreviations 
ADA 
Anti-drug antibodies 
AE 
Adverse event 
b.d. 
Twice a day 
CBC 
Complete Blood Count 
CRT 
Chemoradiotherapy 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTLA-4 
Cytotoxic T-Lymphocyte Antigen 4 
DACH 
1,2-diaminocyclohexane 
DLT 
Dose-limiting Toxicity 
eCRF 
Electronic Case Report Form 
FFPE 
Formalin-fixed paraffin-embedded 
FLOT 
5-fluorouracil (5-FU), leucovorin, oxaliplatin, and docetaxel 
GCP 
Good Clinical Practice 
GFR 
Glomerular filtration rate 
HLA 
Human Leukocyte Antigen 
IB 
Investigator's Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
ICT 
induction chemotherapy  
IgG2 
immunoglobulin G2  
IHC 
Immunohistochemistry 
irAE 
Immune-related Adverse Events 
irCR 
Immune-related Complete Response 
irPD 
Immune-related Progressive Disease 
irPR 
Immune-related Partial Response 
irRECIST 
Immune-related Response Evaluation Criteria In Solid Tumors 
irSD 
Immune-related Stable Disease 
IV 
intravenous 
LICR 
Ludwig Institute for Cancer Research 
LLN 
Lower limit of normal 
mAb 
Monoclonal antibody 
MDSC 
Myeloid derived suppressor cells  
MDT 
multidisciplinary team 
OAC 
Oesophageal adenocarcinoma 
OC 
Oesophageal cancer 
OSCC 
Oesophageal squamous cell carcinoma 
OS 
Overall survival 
PD-1 
programmed cell death-1  
PFS 
Progression-free survival 


 
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Q2W 
Every 2 weeks 
RCD 
Recommended combination dose 
REC 
Research Ethics Committee 
RSI 
Reference Safety Information 
RT 
Radiotherapy 
SAE 
Serious Adverse Event 
SCCHN 
Squamous cell carcinoma of the head and neck  
SD 
Standard Deviation 
ULN 
Upper limit of normal 
 


 
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