Study of Adjuvant Durvalumab (MEDI4736) Plus Regorafenib vs Untreated Control in Stage IV Colorectal Cancer Patients With no Evidence of Disease (NED): VIVA Trial
Phase: PHASE2
Conditions: Colorectal Cancer Stage IV, No Evidence of Disease State
Sponsor: Ospedale Policlinico San Martino

Clinical Trial Protocol: 
Adjuvant durvalumab plus regorafenib in 
stage IV NED colorectal cancer:  
VIVA trial 
 
Study Title: 
A randomized, phase IIb study of adjuvant durvalumab (MEDI4736)  
 plus regorafenib vs untreated control in stage IV colorectal cancer 
patients with no evidence of disease (NED): VIVA trial 
Study Number: 
 
Study Phase: 
IIb 
Product Name: 
Durvalumab (MEDI4736)  
Regorafenib 
EudraCT Number: 
2020-001588-10 
Indication: 
Colorectal Cancer 
Investigators: 
Multicentre 
Sponsor: 
IRCCS Ospedale Policlinico San Martino 
 
Study Site Contact 
Fondazione GISCAD 
Gruppo Italiano per lo studio dei carcinomi dell’apparato digerente 
Contacts with Clinical Sites, Meetings, Newsletter 
Scientific 
Coordinator: 
Alberto Sobrero 
IRCCS Ospedale Policlinico San Martino 
Largo Rosanna Benzi 10, 16132 Genova, Italy 
Statistician: 
Valter Torri 
 
 
 
 
 
 
 
 
Mario Negri Institute for Pharmacological Research 
Via Mario Negri, 2, 20156 Milano MI   
Pharmaco 
vigilance 
Mario Negri Institute for Pharmacological Research 
Via Mario Negri, 2, 20156 Milano MI   
 
 
Version and Date 
1.0 del 16.09.2021 

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INDEX 
INDEX ..................................................................................................................................... 2 
LIST OF IN-TEXT TABLES ..................................................................................................... 6 
LIST OF APPENDICES .......................................................................................................... 6 
SYNOPSIS .............................................................................................................................. 7 
1 
INTRODUCTION ........................................................................................................... 21 
1.1 
Colorectal Cancer ................................................................................................ 21 
2 
BACKGROUND AND RATIONALE ............................................................................. 22 
2.1 
Pursuing the NED state in stage IV CRC ............................................................ 22 
2.1.1 
Liver limited disease .................................................................................. 22 
2.1.2 
Extra-hepatic disease ................................................................................ 23 
2.2 
Overall Rationale of the study ............................................................................. 23 
2.3 
The different ways to reach the NED state .......................................................... 24 
2.3.1 
Surgery. ..................................................................................................... 24 
2.3.2 
Radiotherapy ............................................................................................. 25 
2.3.3 
Others ........................................................................................................ 26 
2.4 
Definition of NED state ........................................................................................ 26 
2.5 
The problem of high rate of relapses dominates the stage IV NED condition. .... 26 
2.6 
Why adjuvant therapy of stage IV should work. .................................................. 27 
2.7 
But adjuvant therapy of stage IV does not work too well. .................................... 27 
2.8 
The challenge of running adjuvant trials in stage IV NED patients. ..................... 27 
2.9 
Regorafenib and immune-checkpoints inhibitors ................................................. 28 
2.9.1 
Regorafenib after curative therapy for CRC .............................................. 28 
2.9.2 
Combination of Regorafenib and immune check-points inhibitors for mCRC
 ................................................................................................................... 29 
2.9.3 
Immune checkpoints inhibitors for CRC .................................................... 29 
2.9.4 
Durvalumab ............................................................................................... 31 
2.9.5 
Overall risks ............................................................................................... 31 
2.9.5.1 
Durvalumab...................................................................................... 31 
2.9.6 
Rationale for fixed dosing .......................................................................... 32 
2.10 
Durvalumab background/non-clinical and clinical experience ............................. 33 
2.11 
Rationale for Regorafenib dose in combination with Durvalumab ....................... 34 
3 
STUDY OBJECTIVES .................................................................................................. 36 
3.1 
Primary Objective ................................................................................................ 36 
3.1.1 
Primary Endpoint ....................................................................................... 36 
3.1.2 
Treatment at progression ........................................................................... 36 
3.2 
Secondary Objectives .......................................................................................... 37 
3.2.1 
Secondary Endpoints ................................................................................. 37 
3.2.2 
Exploratory Objectives ............................................................................... 37 
3.3 
Endpoints definition ............................................................................................. 37 
3.3.1 
Disease-free survival ................................................................................. 37 

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3.3.2 
Overall survival .......................................................................................... 38 
3.3.3 
Toxicity....................................................................................................... 38 
3.3.4 
Compliance to the experimental treatment ................................................ 38 
4 
INVESTIGATIONAL PLAN ........................................................................................... 39 
4.1 
Description and Justification of the Trial Design and Plan .................................. 39 
4.1.1 
Justification of a no treatment control group .............................................. 39 
4.1.2 
Justification of an open label design .......................................................... 39 
4.1.3 
Justification of DFS as primary study endpoint .......................................... 39 
4.2 
Determination of Sample Size ............................................................................. 39 
4.3 
Study plan............................................................................................................ 40 
4.4 
Study Duration, End of Trial and Dates ............................................................... 41 
5 
PLANNED STATISTICAL METHODS .......................................................................... 42 
5.1 
Analysis populations ............................................................................................ 42 
5.2 
Statistical methods .............................................................................................. 42 
5.2.1 
Time to event endpoints ............................................................................ 42 
5.2.2 
Estimates and confidence intervals ........................................................... 42 
5.2.3 
Inference: Test statistics for comparisons ................................................. 42 
5.2.4 
Toxicity....................................................................................................... 43 
5.2.5 
Interim analyses......................................................................................... 43 
5.2.6 
Pre-planned multivariate analysis, exploratory subgroup analyses and 
analyses of DFS ........................................................................................ 43 
5.2.7 
Demographics and Baseline Characteristics ............................................. 44 
6 
SUBJECT SELECTION CRITERIA .............................................................................. 45 
6.1 
Study Population ................................................................................................. 45 
6.2 
Inclusion Criteria .................................................................................................. 45 
6.3 
Exclusion Criteria ................................................................................................. 46 
6.4 
Withdrawal of patients from study treatment and/or study .................................. 48 
6.4.1 Permanent discontinuation of Durvalumab or Regorafenib…………………..…48 
6.4.2 Lost to follow-up…………………………………………………………………......49 
6.4.3 Withdrawal of consent………………………………………………...…………….49 
7 
STUDY TREATMENT ................................................................................................... 51 
7.1 
Treatment Administered ...................................................................................... 51 
7.1.1 
Run-in phase ............................................................................................. 51 
7.2 
Dose interruption or reduction ............................................................................. 52 
7.3 
Durvalumab Dosage and Administration ............................................................. 52 
7.3.1 
Study drug preparation .............................................................................. 53 
7.3.2 
Preparation of durvalumab doses for administration with an IV bag ......... 53 
7.4 
Dose-limiting toxicities (DLTs) ............................................................................. 54 
7.4.1 
Management of toxicity .............................................................................. 55 
7.4.2 
Infusion-related reaction ............................................................................ 57 
7.4.3 
Pneumonitis ............................................................................................... 57 
7.4.4 
Hypersensitivity Reactions......................................................................... 57 

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7.4.5 
Hepatic Function Abnormalities (Hepatotoxicity) ....................................... 58 
7.5 
Administration, dose delay, reduction or interruption for Regorafenib ................. 58 
7.5.1 
Regorafenib Dose Levels .......................................................................... 59 
7.6 
Method of Assigning Patients to Treatment Groups ............................................ 62 
7.6.1 
Method of collection of Patients Data ........................................................ 62 
7.7 
Prior and Concomitant Therapies ........................................................................ 62 
7.8 
Prohibited Therapies ........................................................................................... 63 
7.9 
Treatment Compliance ........................................................................................ 63 
8 
STUDY VISITS AND PROCEDURES ........................................................................... 64 
8.1 
Study Visits .......................................................................................................... 65 
8.1.1 
Screening .................................................................................................. 65 
8.1.2 
Treatment Phase: Table 2 and 3. .............................................................. 65 
8.1.3 
End of treatment ........................................................................................ 66 
8.1.4 
Follow-up ................................................................................................... 67 
8.2 
Study Procedures ................................................................................................ 67 
8.2.1 
Enrolment Procedures ............................................................................... 68 
8.2.1.1 
Informed consent ............................................................................. 68 
8.2.1.2 
Demographics and medical history .................................................. 68 
8.2.1.3 
Pregnancy test ................................................................................. 68 
8.2.2 
Safety Assessments .................................................................................. 68 
8.2.2.1 
Physical examination ....................................................................... 68 
8.2.2.2 
Vital signs ........................................................................................ 69 
8.2.2.3 
Eastern Cooperative Oncology Group performance status ............. 69 
8.2.2.4 
Electrocardiogram ............................................................................ 69 
8.2.2.5 
Clinical chemistry, coagulation and hematology .............................. 69 
8.2.2.6 
Adverse events (AEs) ...................................................................... 70 
8.2.3 
Efficacy Assessments ................................................................................ 71 
8.2.3.1 
Relapse ............................................................................................ 71 
8.2.3.2 
Carcinoembryonic antigen and CA 19-9 .......................................... 72 
8.2.3.3 
Computed tomography and magnetic resonance imaging .............. 72 
8.3 
Appropriateness of Measurements ...................................................................... 73 
9 
ADVERSE EVENT ASSESSMENTS ............................................................................ 74 
9.1 
Definitions ............................................................................................................ 74 
9.1.1 
Adverse Events (AEs) ................................................................................ 74 
9.1.2 
Definition of adverse events of special interest (AESI) .............................. 75 
9.1.3 
Serious Adverse Event (SAEs) .................................................................. 76 
9.1.4 
Adverse Drug Reaction (ADR) ................................................................... 77 
9.1.5 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ................... 77 
9.1.6 
Classification of AEs .................................................................................. 78 
9.1.6.1 
Intensity ........................................................................................... 78 
9.1.7 
Trial Relationship to Study Drug ................................................................ 78 
9.1.8 
Follow-up of Adverse Event ....................................................................... 79 

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9.1.9 
Follow-up of Abnormal Laboratory Test Values ......................................... 79 
9.2 
Reporting of Adverse Events ............................................................................... 79 
9.3 
Hy’s Law .............................................................................................................. 80 
9.4 
New cancers ........................................................................................................ 80 
9.5 
Deaths ................................................................................................................. 80 
9.6 
Reporting of serious adverse events to Sponsor ................................................. 81 
9.7 
Other events requiring reporting .......................................................................... 82 
9.7.1 
Overdose ................................................................................................... 82 
9.7.2 
Hepatic function abnormality ..................................................................... 82 
9.7.3 
Reporting of SUSARs to the Competent Authorities / Independent Ethics 
Committees................................................................................................ 83 
9.7.4 
Immediate Reactogenicity ......................................................................... 83 
9.7.5 
Relapse of Underlying Malignancy ............................................................ 83 
9.7.6 
Laboratory Test abnormalities ................................................................... 83 
9.7.6.1 
Follow-up of Abnormal Laboratory Test Values ............................... 84 
9.8 
Pregnancy ........................................................................................................... 84 
9.9 
Review of Serious Adverse Event ....................................................................... 85 
9.10 
Protocol Deviations Due to an Emergency or an Adverse Event ........................ 85 
10 ETHICAL CONSIDERATIONS/PROTECTION OF HUMAN SUBJECTS .................... 86 
10.1 
Independent Ethics Committee Approval ............................................................ 86 
10.2 
Patient protection................................................................................................. 86 
10.3 
Informed consent process ................................................................................... 86 
10.4 
Subject Confidentiality ......................................................................................... 87 
11 ADMINISTRATIVE RESPONSIBILITIES ..................................................................... 88 
11.1 
Trial insurance ..................................................................................................... 88 
12 REFERENCE LIST ....................................................................................................... 89 
 
 
 

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LIST OF IN-TEXT TABLES 
 
Table 1. SCREENING PHASE ................................................................................ 15 
Table 2. Experimental arm ...................................................................................... 16 
Table 3. Control arm ............................................................................................... 18 
Table 4. Contribution of nine different events to the definition of six endpoints in 
adjuvant studies with cancer patients .................................................................. 36 
Table 5. Dose reduction levels ................................................................................ 52 
Table 6. Grading of AEs not listed on the CTCAE .................................................. 78 
Table 7. AEs Relatedness to the study chemotherapy ........................................... 79 
 
 
 
 
 
 
 
 
LIST OF APPENDICES 
Appendix 
1 
Eastern 
Cooperative 
Oncology 
Group 
(ECOG) 
Performace 
Status 
Scale…………………………………………………………………………….............................96 
Appendix 2 Response Evaluation Criteria In Solid Tumor………………………...…..............97 
Appendix 3 Toxicity Management Guidelines…………………………………………………….98 
Appendix 4 Run in phase…………………………………………………………..……………..125 
 
 
 
 
 
 
 

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SYNOPSIS 
Study title 
A randomized, phase IIb study of adjuvant durvalumab plus regorafenib vs 
untreated control in stage IV colorectal cancer patients with no evidence of 
disease (NED): VIVA trial 
Study phase  
Phase IIb 
Study design 
Randomized, open-label, multicenter, crossover 
Sponsor details 
IRCCS Ospedale Policlinico San Martino 
Principal 
investigator(s) 
Alberto Sobrero 
IRCCS Ospedale Policlinico San Martino 
Largo Rosanna Benzi 10, 16132 Genova, Italy  
Countries 
Italy 
Centre(s) 
35 (GISCAD) 
Planned sample 
size (N) 
182 patients  
91 patients per arm (2 arms) 
Planned study 
start/end dates 
First Patient First Visit 2020 Q4 
Last Patient Last Visit 2022 Q4 
Study end date 2025 Q4 
Recruitment 
period  
24 months 
Rational and 
Objectives 
To date, the introduction of new effective drugs, improvements in surgical 
and locoregional techniques and supportive care have led to a median 
overall survival of over 30 months in patients with metastatic colon-rectal 
cancer (CRC). Thanks to this survival prolongation, medical oncologists and 
patients are more and more attracted by the possibility to reach a non-
evidence of disease (NED) state not only under the classical favourable 
condition of a single or double liver metastases, but also under the less 
favourable conditions of multiple metastases even at different sites and even 
after 2 or 3 lines of treatment, whenever the clinical course allows. Therefore, 
this population of stage IV NED patients is growing.  
Previous studies showed that median relapse-free survival (RFS) ranges 
from 8 to 16-18 months in R0 patients, but up to 90% of these patients 
eventually relapse: hence, there is an unmet clinical need for effective 
systemic treatment to reduce the chances of recurrence in stage IV NED 
patients. 
After curative resection, international guidelines suggest regimens like 
FOLFOX, CAPOX, capecitabine or 5-FU/leucovorin alone as potential 
“adjuvant” therapy, but no standard treatments have been established and 
active surveillance with no treatment  is the standard of care, especially if 
the patient has received prior chemotherapy as it will be the case for most 
of our patient population.  
A phase Ib trial (EPOC1603) tested safety and toxicity profile of Regorafenib 
combined with an immune-checkpoint inhibitor (ICI) (Nivolumab) in gastric 
and colorectal cancer. The rather promising results of the phase Ib study has 
been presented to the ASCO 2019 Annual Meeting, suggesting the activity 
of Regorafenib in combination with ICIs.  
The combination of Durvalumab and Tremelimumab showed to prolong 
median overall survival by 2.5 months compared with best supportive care 
alone in patients with advanced treatment-refractory colorectal cancer 
(phase II Canadian Cancer Trials Group (CCTG) CO.26 study). However, 

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no data are available about the role of Durvalumab as adjuvant therapy 
together with a tyrosin-kinase inhibitor (TKI) like Regorafenib in CRC.  
Given the promising results of these drugs in the metastatic setting, the main 
objective of this study is to evaluate the efficacy (DFS) of Regorafenib plus 
Durvalumab versus untreated control in the adjuvant setting for stage IV 
NED CRC patients. 
Design 
 
 
Control arm: no treatment. Crossover to Regorafenib + Durvalumab upon 
relapse 
Experimental arm: Regorafenib 90mg d1-21 q28 + Durvalumab 1500mg  
(Q4W) up to 1 year 
Run-in phase 
The combination of an immune-checkpoint inhibitor plus TKI anti-
angiogenic agents has been extensively investigated in several trials 
(phase II and III) in different types of tumors, with no evidence of new 
safety signals. Although specific data are not available on the combination 
of durvalumab and regorafenib, we would not expect major toxicity issues. 
 
 
 
 
The run-in phase will be conducted on the first 4 patients randomized to the 
experimental arm using a starting dose of 60 mg/die of Regorafenib (and fixed 
1500 mg of Durvalumab), to be escalated after 2 months to 90 mg/die if < 2 
patients report serious adverse events (SAE). If Regorafenib 90 mg/die is well 
tolerated for other 2 months (< 2 patients with SAE) the run-in phase will be 
closed with the dose of 90 mg/die. In case of > 2 patients report SAE with 90 
mg/die, additional 4 patients will be enrolled and treated with the same dose 
of Regorafenib (90 mg/die) and if < 2 of them report SAE the run-in will be 
closed at 90 mg/die. Conversely, if > 2 patients report SAE the dose of 
Regorafenib will be reduced again to 60 mg/die and the run-in will be closed 
with Regorafenib 60 mg/die.  
If during the first part of the run-in > 2 patients report SAE with Regorafenib 
60 mg/die, additional 4 patients will be treated with Regorafenib 30 mg/die for 
2 months and, in case of > 2 patients with SAE, the trial will be revised. In 
case of good tolerance of Regorafenib 30 mg/die (< 2 patients with SAE), 
additional 4 patients will be enrolled and treated with Regorafenib 60 mg/die: 
if > 2 patients will report SAE the run-in phase will be closed with Regorafenib 
30 mg/die, instead if Regorafenib 60 mg/die will be well tolerated (< 2 SAE)  
this will be the final dose of the run-in phase. 

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Feasibility: 
need for 
crossover 
Any trial randomizing active treatments vs a no –treatment-control presents 
feasibility problems. In this setting, where the large majority of patients will 
relapse within a few months, randomizing to an inactive control vs the 
possibility of receiving entirely innovative treatments will constitute a 
prohibitive feasibility obstacle.  
This may be overcome by offering the most innovative treatment (REGO 
DURVA) to patients randomized to control whenever they relapse. This will 
also provide an opportunity for the conduct of a “satellite” phase IIa trial 
among a patient population that should present very good conditions and 
with a not too bulky disease load. Because this crossover will not affect the 
primary endpoint of the study, this part of the study will be addressed and 
better specified only if the main protocol is approved. As to the amount of 
Durvalumab to be provided for this part, we may expect that 1/3 of patients 
will not be eligible for the cross over and we may postulate that among those 
starting palliative Durvalumab + Regorafenib, patients will receive a median 
of 4 months of therapy. 
Primary 
Endpoint  
Disease-Free Survival (DFS) will be defined by Punt, JNCI 2007  
In addition to the Punt definition, the following condition will be considered 
DFS event: Two consecutive increases in CEA levels above upper limit 
level (time gap decided by the clinical investigator but no longer than 30 
days). 
Secondary 
Endpoints 
● 
18-months Disease-Free Survival (DFS) 
● 
Adverse events and Toxicity 
● 
Overall Survival (OS)  
● 
Compliance to the experimental treatment. 
 
Exploratory 
Endpoints 
● 
Association of translational research data (ctDNA, NGS) with the 
outcomes 
Main Inclusion 
criteria 
To be enrolled in this study each patient must meet all of the following criteria 
at the time of randomization: 
1. 
Signed ICF, after oral as well as written information; 
2. 
≥ 18 years; 
3.    Body weight >30 kg 
4. 
Histologically confirmed diagnosis of colorectal adenocarcinoma; 
5. 
Patients must be in NED after completion of any treatments for stage 
IV 
CRC, 
including 
resections, 
RFA; 
RT 
with 
or 
without 
neoadjuvant/adjuvant therapies or CR after chemotherapy; 
6. 
Patients must be randomized within 10 weeks since the achievement 
of the NED state. Those who have also received adjuvant therapy 
following the locoregional treatment are still eligible, provided they are 
randomized within 4 weeks since the last chemotherapy cycle; 
7. 
NED state ascertained by means of CT scan and/or PET scan and/or 
MRI scan; 

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8. 
ECOG Performance Status ≤ 1; 
9.    Must have a life expectancy of at least 12 weeks 
10.   CEA within normal limits 
11. No residual toxicity from previous chemotherapy; 
12.   Women of childbearing potential must use safe contraception. 
13.   Adequate organ and marrow function as defined below:                     
Absolute neutrophil count ≥1.5 × 109 /L  
• 
Platelet count ≥100 × 109/L 
• 
Haemoglobin ≥9.0 g/dL 
• 
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). 
This will not apply to patients 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. 
• 
Serum Creatinine ≤ 1,5 x ULN o measured creatinine clearance 
(CL) >40 mL/min or Calculated creatinine CL>40 mL/min by the 
Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-
hour urine collection for determination of creatinine clearance 
• 
AST (SGOT)/ALT (SGPT) ≤2.5 x ULN, or ≤ 5 x ULN in the 
presence of liver metastases 
Main Exclusion 
criteria 
A patient who meets any of the following criteria at the time of randomization 
will be excluded from the study: 
1. Participation in another clinical study with an investigational product 
during the last 4 weeks 
2. Concurrent enrolment in another clinical study, unless it is an 
observational (non-interventional) clinical study or the follow-up period 
of an interventional study 
3. Prior randomisation or treatment in a previous durvalumab clinical study 
regardless of treatment arm assignment.  
4. Patients with microsatellite instability (MSI) or DNA Mismatch Repair 
Deficiency (dMMR) are not allowed. 
5. Any form of systemic disease that, in the opinion of the Investigator, 
would make the subject unsuitable for the study (including autoimmunity) 
or would prevent compliance with the study protocol;  
6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer 
therapy with the exception of alopecia, vitiligo, and the laboratory values 
defined in the inclusion criteria  
a. Patients with Grade ≥2 neuropathy will be evaluated on a 
case-by-case basis after consultation with the Study 
Physician. 
b. Patients with irreversible toxicity not reasonably expected to 
be exacerbated by treatment with durvalumab may be 
included only after consultation with the Study Physician.  

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7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for 
cancer treatment. Concurrent use of hormonal therapy for non-cancer-
related conditions (e.g., hormone replacement therapy) is acceptable. 
8. Major surgical procedure (as defined by the Investigator) within 28 days 
prior to the first dose of IP. Note: Local surgery of isolated lesions for 
palliative intent is acceptable. 
9. History of allogenic organ transplantation. 
10. Active or prior documented autoimmune or inflammatory disorders 
(including inflammatory bowel disease [e.g., colitis or Crohn's disease], 
diverticulitis [with the exception of diverticulosis], systemic lupus 
erythematosus, 
Sarcoidosis 
syndrome, 
or 
Wegener 
syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc]). The following are exceptions to this criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto 
syndrome) stable on hormone replacement  
c. Any chronic skin condition that does not require systemic 
therapy 
d. Patients without active disease in the last 5 years may be 
included but only after consultation with the study physician 
e. Patients with celiac disease controlled by diet alone 
11. Uncontrolled intercurrent illness, including but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial 
lung disease, serious chronic gastrointestinal conditions associated with 
diarrhea, or psychiatric illness/social situations that would limit 
compliance with study requirement, substantially increase risk of 
incurring AEs or compromise the ability of the patient to give written 
informed consent. 
12. History of another primary malignancy except for: 
f. 
Malignancy treated with curative intent and with no known 
active disease ≥5 years before the first dose of IP and of low 
potential risk for recurrence 
g. Adequately treated non-melanoma skin cancer or lentigo 
maligna without evidence of disease 
h. Adequately treated carcinoma in situ without evidence of 
disease 
13. History of leptomeningeal carcinomatosis 
14. Mean QT interval corrected for heart rate using Fridericia's formula 
(QTcF) ≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes 
apart) 
15. History of active primary immunodeficiency  
16. Active infection including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and TB 
testing in line with local practice), hepatitis B (known positive HBV 
surface antigen (HBsAg) result), hepatitis C. Patients with a past or 
resolved HBV infection (defined as the presence of hepatitis B core 

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antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive 
for hepatitis C (HCV) antibody are eligible only if polymerase chain 
reaction is negative for HCV RNA. 
17. Current or prior use of immunosuppressive medication within 14 days 
before the first dose of durvalumab. The following are exceptions to this 
criterion: 
a. Intranasal, inhaled, topical steroids, or local steroid injections 
(e.g., intra articular injection) 
b. Systemic corticosteroids at physiologic doses not to exceed 
10 mg/day of prednisone or its equivalent 
c. Steroids as premedication for hypersensitivity reactions (e.g., 
CT scan premedication) 
18. Receipt of live attenuated vaccine within 30 days prior to the first dose 
of IP. Note: Patients, if enrolled, should not receive live vaccine whilst 
receiving IP and up to 30 days after the last dose of IP. 
19. Female patients who are pregnant or breastfeeding or male or female 
patients of reproductive potential who are not willing to employ effective 
birth control from screening to 90 days after the last dose of durvalumab 
monotherapy. 
20. Known allergy or hypersensitivity to any of the study drugs or any of the 
study drug excipients. 
21. Any condition that, in the opinion of the investigator, would interfere with 
evaluation of the study drug or interpretation of patient safety or study 
results. 
 
 

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Investigational 
Treatments 
Name - Dosage form - Dosage - Mode of administration - Schedule 
 
1. Regorafenib – film-coated tablets – 90 mg – orally – once daily for 
the first 21 days of each 28-day cycle, up to 1 year 
2. Durvalumab – solution for infusion after dilution – 1500mg – IV – 
infusion every four weeks up to 1 year 
Patients in the durvalumab+regorafenib treatment group will receive 1500 
mg durvalumab via IV infusion Q4W and 90 mg Regorafenib d1-21 q28 for 
up to a maximum of 12 months (up to 12 doses/cycles), confirmed disease 
progression, unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion.  
(N.B If a patient’s weight falls to 30kg or below (≤30 kg), then the patient 
should receive weight-based dosing equivalent to 20 mg/kg of durvalumab 
Q4W after consultation between Investigator and Study Physician, until the 
weight improves to above 30 kg (>30 kg), at which point the patient should 
start receiving the fixed dosing of durvalumab 1500 mg Q4W). 
Justification of 
Sample Size 
The study is set up as an exploratory phase 2B trial with sufficient patient 
numbers to broadly explore the differences between the experimental arm 
regimen and the control group.  
The randomization plan is 1 to 1. Patients will be stratified by center. 
The main aim of this study is to estimate the effect of the experimental arm 
relative to control group on the endpoint of interest: disease-free survival.  
In view of the treatment setting, disease-free survival is considered as the 
most sensitive clinical endpoint.  
The sample size is calculated according to a median DFS estimate of 6 
months in the control group and to a forecast of 2 years duration of uniform 
accrual and 2 years of follow-up after the end of accrual. To achieve 90% 
power at a 0.05 two-sided significance level to detect a 40% fall in DFS 
event rate (corresponding to a median increase from 6 to 10 months), 172 
patients have to be accrued and followed up for at least 2 years in order to 
achieve the requested 164 events (recurrences or deaths). Assuming an 
attrition rate of approximately 5%, a total of 182 patients (91 per arm) have 
to be randomized. 
Statistical 
considerations 
All randomized patients will be included in the primary assessment of 
efficacy (the intention-to-treat population). Safety analyses will include all 
treated patients (randomized patients receiving at least one dose of study 
drug). A log-rank test, will be used to assess disease-free survival and 
overall survival. A Cox proportional hazards model will be used to calculate 
HRs and 95% CIs). Sensitivity analysis of disease-free survival will be also 
done with a restricted mean survival time approach that does not assume 
the proportional hazards model, as outlined by Anderson and colleagues.  
For patients in the control group after progression, a cross-over is allowed. 
A descriptive summary of the duration of this crossover treatment (overall 
and from the time of initial progression) will be done. The proportions of 
patients achieving an objective response or disease control will be 
compared with a logistic regression model adjusted for relevant covariates. 
Effect on survival of regorafenib plus durvalumab regimen within this 

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crossover part of the study will be analyzed by means of proportional 
hazard time-depended analysis. Median disease-free survival will be 
calculated with the Kaplan-Meier method.  
All statistical testing is two-sided at the nominal 5% significance level, with 
no adjustment for multiplicity. All patients who receive at least one 
regorafenib plus durvalumab dose will be included in the safety analysis. 
Publication plan  - 
Timelines 2025 Q4 
- 
Target Journals: Lancet, Lancet Oncology, JCO. 

 
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Table 1. SCREENING PHASE  
 
28 to 1 day before randomization d 
 
Informed consent 
X 
 
Inclusion / Exclusion 
criteria 
X 
 
General disease medical 
history 
X 
 
Prior / Concomitant 
medications 
X 
 
Complete physical 
examination 
X 
 
ECOG PS 
X 
 
Weight 
X 
 
Vital Signsa 
X 
 
12-lead ECGb 
X 
 
Tumor imagingc 
X 
Must be performed within 10 weeks before D1C1. Tumor imaging can be accepted 
even if performed before the procedures to obtain NED status. 
Hematology, chemistry, 
coagulation and 
pregnancy testd 
X 
 
Biomarkersd 
X 
CEA and CA 19-9 must be on normal range 
Histologic Confirmation 
X 
Only if surgery performed to obtain NED state, resection of the metastases must be R0 
 
 
 

 
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Table 2. Experimental arm  
 
 
From -7 
days to 
Day 1 
Cycle 1 
Day 1 
Cycle 1 
Day 8, 
15,22 
Cycle 1 
 
 
Day 1 
Cycle 2 
Day 15 
Cycle 2 
Day 1 
Cycle 3 
and above 
up to 1-
year (12 
cycles) 
QW12 from 
C1D1 
(+/- 7 days) 
End of 
treatment visit 
Treatment 
discontinuatio
n 30-days 
from last 
treatment or 
at initiation of 
other 
anticancer 
therapy 
(whichever 
occurs first) 
Follow-up 
period g 
Prior / 
Concomitant 
medications 
 
 
 
 
 
 
 
X 
 
X 
Complete 
physical 
examination 
 
 
 
 
 
 
 
X 
 
X 
Limited 
physical 
examinationa 
 
X 
X 
X 
X 
X 
 
 
 
 
ECOG PS 
 
X 
X 
X 
X 
X 
 
X 
 
X 
Weight 
 
X 
 
X 
 
X 
 
 
 
 
Vital Signsa 
 
X 
X 
X 
X 
X 
 
X 
 
X 
12-lead ECGb 
 
 
 
 
 
 
 
X 
 
 

 
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Tumor 
imaging/ 
response 
assessmentsc 
 
 
 
 
 
 
X 
X 
 
X 
Hematologyd 
X 
 
X 
X 
X 
X 
 
X 
 
 
Coagulationd 
X 
 
 
 
 
 
 
X 
 
 
Chemistryd 
X 
 
X 
X 
X 
X 
 
X 
 
 
Biomarkersd 
 
 
 
 
 
 
X 
X 
 
X 
Durvalumab 
Administration 
 
Xe 
 
Xe 
 
Xf 
 
 
 
 
Regorafenib 
Administration 
 
Xe 
 
Xe 
 
Xf 
 
 
 
 
AEs 
assessments 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
Survival and 
anti-cancer 
therapy 
 
 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 

 
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Table 3 - Control arm  
 
 
QW12 from 
C1D1 
(+/- 7 days) 
End of treatment visit 
Treatment discontinuation 30-days from last 
treatment or at initiation of other anticancer 
therapy (whichever occurs first) 
Follow-up 
period g 
Prior / Concomitant 
medications 
X 
X 
 
X 
Complete physical 
examination 
X 
X 
 
X 
ECOG PS 
X 
X 
 
X 
Weight 
X 
X 
 
 
Vital Signsa 
X 
X 
 
X 
Tumor imaging/ response 
assessmentsc 
X 
X 
 
X 
Hematologyd 
X 
X 
 
X 
Chemistryd 
X 
X 
 
X 
Biomarkersd 
X 
X 
 
X 
AEs assessments 
X 
X 
X 
X 
Survival and anti-cancer 
therapy 
 
 
X 
X 
 
 

 
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Abbreviation: CBC: cell blood count; RBC: red blood cell; WBC: White blood cell; aPTT: activated partial thromboplastin time; PT: prothrombin 
time; INR: international normalized ratio; AST: Aspartate aminotransferase; ALT: alanine aminotransferase; LDH: Lactate dehydrogenase; β-hCG: 
beta-human chorionic gonadotropin;  Na: sodium; K: potassium; Cl: chloride; Mg: magnesium; Ca: calcium; P: phosphate; CEA: 
Carcinoembryonic antigen; Ca 19-9: Carbohydrate antigen 19-9; ECOG PS: Eastern Cooperative Oncology Group Performance Status; ECG: 
electrocardiogram; AEs: adverse events 
a) 
Vital signs and Physical examination 
Patients will have a complete physical exam to include an examination of major body systems and an assessment for emergent toxicities or changes from prior visits. 
Limited physical examination should be performed symptom-directed.  
Examinations will be conducted by a physician, trained physician’s assistant, or nurse practitioner, as acceptable according to local regulation.  
Vital signs include: blood pressure and heart rate, body temperature, respiratory rate. 
b) 
Electrocardiogram (ECG)  
Perform a 12-lead resting electrocardiogram (ECG) before the beginning of the treatment, at the end-of-treatment and if clinically indicated. Patients should be in a 
supine position for at least 10 min before recording. ECG tracings will be reviewed by a qualified physician for assessment of QT interval as well as signs of 
qualitative abnormalities, including evaluation of rhythm, ST segment morphology, T wave morphology, and presence/absence of U wave. 
The original ECG tracing will be maintained in the source documentation of each patient.  
c) 
Tumor imaging/ response assessments  
Including computed tomography (CT) scan / magnetic resonance imaging (MRI) / PET scan. The same radiographic procedure should be used throughout the study 
for each patient. 
Tumor assessment should be performed every 12 weeks ± 1 week for the first year (relative to the date of randomization), every 16 ± 1 week in the 
second year and then every 24 weeks ± 1 week thereafter until RECIST 1.1-defined radiological PD or death (whichever comes first). 
d)  Local laboratory assessments will include the following:  
• Hematology profile (CBC, including RBC count, hemoglobin, hematocrit, WBC count with differential [neutrophils, eosinophils,  
   lymphocytes, monocytes, basophils] and platelet count) 
• Coagulation profile (aPTT, PT, INR) 
• Chemistry profile includes Na, K, Cl, Mg, Ca, P, blood urea nitrogen, creatinine, glucose, total protein, albumin, AST, ALT, alkaline  
   phosphatase, total bilirubin, LDH, amylase, lipase  
• Pregnancy test (a positive urine test will be confirmed with a serum pregnancy test) during the study (for woman of childbeating  
   potential). If a patient becomes pregnant while in the study, the study treatment must be immediately discontinued. Pregnancy    
   information for a female patient or for the female partner of a male patient should be reported within 24 hours from the time the  
   Investigator first becomes aware of a pregnancy or its outcome. 
• Biomarkers: CEA, Ca19.9, backup plasma sample. 
Samples for hematology, serum chemistry, coagulation, pregnancy test and biomarkers will be analyzed at the study site’s local laboratory. Investigator may have 
additional blood tests performed for the purpose of planning treatment administration, dose modification, or following AEs. 
Procedure does not have to be repeated if performed within 72 hours prior to Cycle 1 Day 1 (i.e. first day of dosing) 
 

 
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e) 
The first administration of Regorafenib + Durvalumab must be done within 10 weeks from NED state.  Patients who are rendered NED and have received an 
adjuvant program are still eligible, provided they are randomized within 1 month since the last chemotherapy cycle 
f) 
Up to 1 year 
g) During the early follow up phase (Month 13-Month 24) all patients will undergo the following visit every 4 months. During the late follow 
up phase (Month 25 to Month 60) all patients will undergo the following visit every 6 months. 
 
 
 
 
 
 

 
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1 
INTRODUCTION 
1.1 
Colorectal Cancer 
Colorectal cancer (CRC) is the third most common cancer and the third leading 
cause of cancer mortality in the United States (US) as well as in Europe[1]. CRC 
incidence and mortality rates vary markedly around the world. Globally, CRC is the 
third most commonly diagnosed cancer in males and the second in females, with 
1.8 million new cases and almost 861,000 deaths in 2018 according to the World 
Health Organization GLOBOCAN database [2]. Liver metastases are detected in 
40-50% of patients diagnosed with CRC either as synchronous or as 
metachronous metastases[3]. Sites of metastasis in colorectal cancer patients are 
most often seen in the liver and lungs. The average median survival time after 
diagnosis for patients with metastatic colorectal cancer in the absence of treatment 
is about 6 months [4].  
To date, the introduction of new effective drugs, improvements in surgical and 
locoregional techniques and supportive care have led to a median overall survival 
of over 30 months in patients with metastatic disease [5]. Thanks to this survival 
prolongation, medical oncologists and patients are even more attracted by the 
possibility to reach a NED state and they increase the efforts to obtain it also in 
advanced stages or in further lines.  
Previous studies showed that median RFS ranges from 8 to 16-18 months in R0 
patients, but up to 80% of these patients would eventually relapse: hence, there is 
a unmet clinical need of effective systemic treatment to reduce the chances of 
recurrence in stage IV NED patients. 
After curative resection, international guidelines suggest regimens like FOLFOX, 
CAPOX, capecitabine or 5-FU/leucovorin alone as potential “adjuvant” therapy, 
but no standard treatments have been established.  
 
 

 
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2 
BACKGROUND AND RATIONALE 
2.1 
Pursuing the NED state in stage IV CRC 
2.1.1 
 
Liver limited disease  
 
Liver is the most frequent metastatic site in colorectal cancer and 95% of the whole 
literature on loco-regional approaches to stage IV CRC regards the management 
of liver metastases, mainly by surgery. The surgical approach to limited liver 
metastases has produced a 40 and 20% OS at 5 and 10 years and a DFS of 20 
and 12% at the same long terms, respectively, as stated by the international 
registry of patients operated for colorectal liver metastases[6]  
With the advent of more active combination chemotherapy than just single agent 
FU, resections of unresectable liver metastases have been reported[7],[8],[9].  
Since then, disease down-staging has become a relevant endpoint of “conversion 
therapy”. 
In nonresectable metastases the Tournigand study[10] reported higher RR for 
FOLFOX with corresponding R0 resection rate of 22% compared to 9% with 
FOLFIRI. In 2 randomized phase III trial, Falcone et al.[11],[12] demonstrated an 
increased RR and R0 resection rate for the triplet regimen FOLFOXIRI alone or 
with bevacizumab compared with FOLFIRI alone. These data were not confirmed 
in a similar randomized study from Greece[13], but were corroborated in the most 
recent Olivia study where FOLFOXIRI bevacizumab was compared to FOLFOX in 
patients with unresectable liver metastases[14]. 
At least 3 studies showed consistent improvements in RR (ranging from 59% to 
79%) with addition of Cetuximab to chemotherapy in K-RAS wild type 
tumors[15],[16],[17], and despite the New Epoc results, the contribution of this anti 
EGFR compound to enhancing resectability is highly valued (in combination with 
FOLFIRI). 
The NO16966 trial, which compared XELOX/FOLFOX with or without 
Bevacizumab, demonstrated a non-statistically significant increase in the resection 
rate with the antibody (17.1% vs 12.6% for patient with liver metastases only)[18]. 
Higher credit to bevacizumab in this setting is provided by the Olivia study 
mentioned above. 
On a separate track, the old-fashioned loco-regional treatment via HAI combined 
with systemic doublets has recently been reported extremely efficacious from a 
conversion viewpoint[19], although the limitation of this approach continues to be 
the lack of widespread experience that conditions a high complication rate of 
hepatic artery catheters.  
All this literature on conversion therapy emphasizes the possibility to pursue the 
NED state even under conditions that are initially prohibitive.  
 
 
 

 
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2.1.2 
 Extra-hepatic disease 
 
Lung, peritoneum, nodes, and other sites can be affected by metastases by CRC 
as well. Under exceptional circumstances (single lesion, very long RFS, very 
benign clinical course, sensitivity to disease control by systemic therapy) these 
disease sites could be suitable for surgery or loco-regional treatment leading to the 
NED state. For this reason, what has always been a contraindication to surgery, 
now, in an era where 50% of patients live longer than 30 months, may indeed be 
considered for a potentially radical approach. It goes without saying that under 
these conditions the chances of recurrence are extremely high; hence the need for 
efficacious systemic treatment to control disseminated microscopic metastases. 
 
Recent data report a median survival time of 16 months in patients with NED 
surgical outcome, including 50% of patients with liver metastases only[20]. The 
prognosis of R0 patients shows large variations depending on selection criteria and 
on the treatment used to achieve the R0 status, with reported median RFS ranging 
from 8 to 16-18 months[21],[22]. However, most of these estimates derive from 
uncontrolled studies in highly selected groups of patients. 
 
2.2 
Overall Rationale of the study 
 
International guidelines recommend perioperative or adjuvant chemotherapy with 
FOLFOX/CAPOX in stage IV colorectal cancer patients rendered NED by means 
of surgery or locoregional treatments. The recommendation is based on previous 
studies that show a DFS and OS trend in favour of chemotherapy versus no further 
treatment. These studies lack statistical significance mainly due to the difficulty in 
accruing patients in this setting. Our innovative design should make it possible to 
gather data on survival in this prohibitive setting. In addition, it may prove the 
efficacy of novel treatments (REGO+DURVA) in this setting, potentially 
establishing a new standard of care for these patients. 
To date, the introduction of new effective drugs, improvements in surgical and 
locoregional techniques and supportive care have led to a median overall survival 
of over 30 months in patients with metastatic disease. Thanks to this survival 
prolongation, medical oncologists and patients are more and more attracted by the 
possibility to reach a NED state not only under the classical favourable condition 
of a single or double liver metastases, but also under the less favourable conditions 
of multiple metastases even at different sites and even after 2 or 3 lines of 
treatment, whenever the clinical course allows. Therefore, this population of stage 
IV NED patients is growing.  
Previous studies showed that median RFS ranges from 8 to 16-18 months in R0 
patients, but up to 90% of these patients eventually relapse: hence, there is a 
unmet clinical need for effective systemic treatment to reduce the chances of 
recurrence in stage IV NED patients. 
After curative resection, international guidelines suggest regimens like FOLFOX, 
CAPOX, capecitabine or 5-FU/leucovorin alone as potential “adjuvant” therapy, but 

 
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Page 24 of 125 
no standard treatments have been established and active surveillance with no 
treatment is the standard of care, especially if the patient has received prior 
chemotherapy as it will be the case for most of our patient population.  
 
A phase Ib trial (EPOC1603) tested safety and toxicity profile of Regorafenib 
combined with CPI (Nivolumab) in gastric and colorectal cancer. The rather 
promising results of the phase II study has been presented to the ASCO 2019 
Annual Meeting, suggesting the activity of Regorafenib in combination with 
immune-checkpoint inhibitors.  
In addition, Regorafenib with Durvalumab has proved to be safe in a recent French 
study in neuroendocrine tumors.  
Durvalumab and Tremelimumab showed to prolong median overall survival by 
2.5 months compared with best supportive care alone in patients with advanced 
treatment-refractory colorectal cancer (phase II Canadian Cancer Trials Group 
(CCTG) CO.26 study). However, no data are available about the role of 
Durvalumab as adjuvant therapy together with a TKI like Regorafenib in CRC.  
Given the promising results of these drugs in the metastatic setting, the main 
objective of this study is to evaluate the efficacy (DFS) of Regorafenib plus 
Durvalumab versus control in the adjuvant setting for stage IV NED CRC patients. 
  
Feasibility: need for crossover 
Any trial randomizing active treatments vs a no –treatment-control arm presents 
feasibility problems. In this setting, where the large majority of patients will relapse 
within a few months, randomizing to an inactive control vs the possibility of 
receiving entirely innovative treatments will constitute a prohibitive feasibility 
obstacle.  
This may be overcome by offering the most innovative treatment (Regorafenib + 
Durvalumab) to patients randomized to control whenever they relapse. This will 
also provide an opportunity for the conduct of a “satellite” phase IIa trial among a 
patient population that should present very good conditions and with a not too bulky 
disease load.  
 
 
2.3 
The different ways to reach the NED state 
2.3.1 
 Surgery. 
 
Based on current evidence[23], a number of concepts are widely accepted: 
a. the primary aim of treatment is achieving long term RFS following 
resectability;  

 
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Page 25 of 125 
b. assessment of resectability should be performed with high quality cross-
sectional imaging, staging the liver with magnetic resonance imaging and/or 
abdominal computed tomography (CT), depending on local expertise, 
staging extrahepatic disease with thoracic and pelvic CT, and in selected 
cases fluorodeoxyglucose positron emission tomography with ultrasound 
(preferably contrast-enhanced ultrasound) for intraoperative staging;  
c. optimal first-line chemotherapy –doublet or triplet chemotherapy regimens 
combined with targeted therapy– is advisable in potentially resectable 
patients;  
d. in this situation, at least four courses of first-line chemotherapy should be 
given, with assessment of tumor response every 2 months; 
e. response assessed by RECIST criteria [24] (conventional chemotherapy) or 
non-size-based morphological changes (antiangiogenic agents) is clearly 
correlated with outcomes; no imaging technique is currently able to 
diagnose accurately complete pathological response; 
f. duration of chemotherapy should be as short as possible and resection 
achieved as soon as technically possible in the absence of tumor 
progression;  
g. number of metastases or patient age should not be an absolute 
contraindication to surgery combined with chemotherapy; 
h. for synchronous metastases, it is not advisable to undertake major hepatic 
surgery during surgery for removal of the primary CRC; the reverse surgical 
approach (liver first) produces as good an outcome as the conventional 
approach in selected cases; 
i. for patients with resectable CRC liver metastases, perioperative 
chemotherapy may be associated with modest improved RFS; 
j. whether initially resectable or unresectable, cure is possible after complete 
resection of the metastases and MDT treatment is essential for improved 
clinical outcome and survival [23]. 
 
The surgical approach to limited liver metastases has produced a 40 and 20 % OS 
at 5 and 10 years and a DFS of 20 and 12% at the same long terms, respectively[6].  
 
2.3.2 
 Radiotherapy 
 
Radiofrequency and liver-directed treatment could be listed among other non-
conventional approaches to obtain NED status. Nonetheless, numerical data about 
complete response are so far unavailable with these techniques despite growing 
evidence for their efficacy[25],[26],[27],[28]. A retrospective analysis from the MD 
Anderson indicated that the RFS and OS of resected stage IV are better than the 
figures obtained through RFA[29],[30],[31]. 
 

 
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2.3.3 
 Others  
 
In most patients with colorectal metastases chemotherapy is the primary option 
with progression delaying or tumor shrinking intent. The achievement of NED 
status by means of complete response to chemotherapy has become more and 
more frequent recently thanks to the use of new antineoplastic agents. Recent 
clinical trials in metastatic colorectal cancer have shown complete response rates 
ranging from 4 to 7%[20]. 
 
2.4 
Definition of NED state 
For the purpose of this trial, NED state is defined as follows: 
  
1 NED following surgery: complete resection of all visible lesions (R-0 or R-
1) and no evidence of disease elsewhere. In case of uncertain lesions, 
potentially related to the colorectal neoplastic disease, PET scan can be used 
and, if used, it should be negative. Postoperative CEA must be within normal 
limits.  
2 NED following RFA (radio frequency ablation): there is no formal definition 
of complete ablation (technically effective ablation). The literature refers to 
the concept of an ablation defect completely covering the target lesion 
assessed by CT scan within 4 to 8 weeks since the procedure[32],[33]. From 
a pragmatic point of view, RFA is accepted as a procedure with radical intent 
when at the baseline CT scan done after the procedure and before 
randomization, no living tissue is detected in the ablated area (less than 6% 
chances of local relapses with this method in case of lesions below 4 cm in 
diameter and less than 3% chances of relapses for lesions smaller than 3 
cm[34]. CEA level post procedure must be within normal limits.  
3 NED following stereotactic RT: no formal definition of potentially radical 
outcome on imaging is available following this procedure. However, one, two 
and three years LC rate is reported to be 97%, 92% and 83% for doses higher 
than 60cGy[35]. Patients receiving 60 or more cGy and no other signs of 
disease, including CEA level post stereotactic RT must be within normal 
limits. 
4 NED following chemotherapy: this is the case of complete response 
defined as the complete disappearance of any lesion and the normalization 
of tumor markers. 
 
 
 
2.5 
The problem of high rate of relapses dominates the stage IV NED 
condition.  
Despite the improved possibility of reaching the NED state in metastatic CRC, it 
must be remembered that more than 80% of these patients eventually recur and 
die of their disease. Therefore, any systemic treatment aimed at reducing the 

 
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chances of recurrence of stage IV patients who reached the NED state should be 
considered. 
  
2.6 
Why adjuvant therapy of stage IV should work. 
  
The classical paradigm of cancer treatment is that whatever works in the advanced 
setting (useful clinical responses, prolonged PFS or OS) should work with curative 
intent when used as adjuvant therapy. This paradigm has held up in CRC: 
Fluoropyrimidines affording a 6 month gain in the advanced setting, produce an 
additional cure rate of about 10% when used adjuvantly in stage III. Based upon 
this paradigm the benefit of adjuvant chemotherapy in the setting of stage IV NED 
is expected to be even higher, considering the 90% chances of relapsing of these 
patients.  
 
2.7 
But adjuvant therapy of stage IV does not work too well. 
 
The efficacy of pure adjuvant CT is debatable: FU affords a borderline significant 
benefit in OS compared to surgery alone [36] (absolute delta 7% at 5 years) and 
FOLFIRI produced a numerically better OS that was not statistically significant 
compared to FU alone [37]. FOLFOX has not been studied (the NSABP trial C09 
was discontinued for lack of accrual), although FOLFOX/CAPOX remain the most 
commonly employed regimen in clinical practice around the world. In the light of 
these marginal results obtained by the adjuvant strategies, “neoadjuvant CT” of 
resectable metastases has been investigated within the frame of a “perioperative 
strategy” i.e, preoperative CT, then surgery, then CT after surgery. The EORTC 
produced the only randomized phase III study available (BOS study), that failed to 
demonstrate a OS advantage of the interventional strategy as compared to surgery 
alone[38].  
 
 
2.8 
The challenge of running adjuvant trials in stage IV NED patients. 
 
No prospective randomized adjuvant trial of systemic therapy has ever been 
completed in this setting. The failure in conducting and completing this kind of trial 
can be ascribed to different causes. First, a randomized trial with experimental 
treatments versus a control arm with no treatment at all is usually less attractive to 
patients. However, the possibility to crossover to REGODURVA in the control arm 
upon progression will improve the feasibility. Second, patients can achieve the 
NED state by different therapeutic approaches (surgery upfront or after induction 
chemotherapy, radiofrequency, chemotherapy alone). Thus, the definition of clear 
and simple eligibility criteria is prohibitive. In this perspective, the trial internal 
consistency is opposed to its feasibility and conducting. 
 
 

 
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2.9 
Regorafenib and immune-checkpoints inhibitors 
 
Regorafenib is approved treatments for previously treated mCRC patients. It is an 
oral multi-kinase inhibitor which targets angiogenic, stromal and oncogenic 
receptor tyrosine kinase (RTK) administered in numerous countries worldwide, 
including the United States and European Union. 
It was found to exhibit potent inhibitory activity against angiogenic and stromal 
receptor 
tyrosine 
kinases 
(RTKs) 
VEGFR 
1–3, 
tyrosine 
kinase 
with 
immunoglobulin and epidermal growth factor homology domain 2 (TIE2), fibroblast 
growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor beta 
(PDGFR-β), in addition to oncogenic RTKs RET and KIT, and intracellular signaling 
kinases c-RAF/RAF-1 and BRAF. 
 
It was approved based on a Phase III trial (CORRECT trial) that showed an 
improvement of OS compared to best supportive care of 1.4 months (6.4 versus 5 
months, hazard ratio [HR] 0.77, 95% CI 0.64-0.94) and a PFS of 0.2 months (HR 
0.49, mPFS 1.9 versus 1.7 months) (Grothey et al. 2013). These results were later 
confirmed by a smaller Phase III, randomized, double-blind, placebo-controlled trial 
conducted in Asia (CONCUR) (Li et al. 2015). 
As the approved dose of regorafenib (160 mg daily for 21 days of every 28-day 
cycle) may be too high for many patients it was conducted the phase II ReDOS 
trail. It demonstrated that a weekly dose escalating strategy (starting with 80 mg 
daily, escalating weekly in the absence of treatment-related toxicity to a target of 
160 mg daily) allows more patients to continue therapy beyond the first response 
assessment compared with starting at 160 mg per day. In a preliminary report, 
presented at the 2018 American Society of Clinical Oncology (ASCO) 
Gastrointestinal Cancers Symposium, median overall survival also trended better 
in the dose escalation cohort (9 versus 5.9 months), and toxicity was more 
favorable. (Bekali-Saab T et al. 2018) 
 
2.9.1 
Regorafenib after curative therapy for CRC 
 
Regorafenib have been largely studied in clinical trials as a palliative treatment for 
metastatic colorectal cancer, showing a good efficacy and safety profile.  
To date, a few studies have been conducted for the adjuvant or NED settings and 
unfortunately no data are available. 
All the following trials withdraw for low accrual: a trial for stage IIIC adjuvant CRC 
(NCT02425683) randomized patients to Regorafenib or placebo after FOLFOX; 
the COAST trial (NCT01939223) randomized patients to Regorafenib or placebo 
after obtaining NED status; patients who have received peri-operative multimodal 
treatment for locally advanced rectal cancer were randomized to Regorafenib 
versus observation (NCT02287727). 

 
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2.9.2 
Combination of Regorafenib and immune check-points 
inhibitors for mCRC 
 
Interesting preliminal results of the REGONIVO trial have been presented in the 
poster session of the 2019 ASCO annual meeting. Fifty heavely pre-treated pts (25 
Gastric Cancer; 25 CRC) were given the combination of nivolumab and 
regorafenib. An objective tumor response was observed in 19 patients (38%), 
including 7 MSS CRC and 1 MSI-H CRC. A response rates of 29% was observed 
in patients with MSS CRC.  
We are now waiting for results of two ongoing trials which combine Pembrolizumab 
+ Regorafenib (ongoing NCT03657641) and Nivolumab + Regorafenib 
(NCT03712943). 
 
2.9.3 
 Immune checkpoints inhibitors for CRC 
 
Immune checkpoint blockade has been an area of active investigation in 
gastrointestinal cancers. 
Initial trials lead to disappointing results of PD-1 and PD-L1 blockade in unselected 
patients with colorectal cancer. Some results are here reported in the table. 
 
 
The approved use of immune checkpoints for CRC are currently restricted to a 
specific subgroup of patients (i.e. Microsatellite instability (MSI) or Mismatch Repair 
deficient (dMMR). This subtype, observed in approximately in 5% of mCRC, is 
characterized by dense immune cell infiltration, probably due to the accumulation 
of somatic mutations as a result from inactivation of the DNA mismatch repair 
system. 

 
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In the study of Le DT et al. (NEJM, 2015), which lead to the FDA approval of 
Pembrolizumab for agnostic dMMR tumors, there were 10 patients with dMMR 
mCRC. Four (40 %) patients achieved objective responses and 5 (50 %) patients 
had stable disease. In contrast, no patient with pMMR colorectal cancer had an 
objective response and only 2 patients (11 %) experienced disease stabilization. 
PFS at 20 weeks was 78 % in the dMMR colorectal cancer cohort and 11% in the 
pMMR colorectal cancer group. 
Based on these results, the clinical activity of pembrolizumab is currently being 
evaluated in a larger, single arm phase II (NCT02460198) and a randomized phase 
III trial (NCT02563002) for patients with metastatic dMMR colorectal cancer as first 
line treatment versus standards of care. In addition, a phase II trial of durvalumab 
in dMMR colorectal cancer is currently enrolling patients (NCT02227667). 
The interim analysis of CheckMate-132 included 56 patients with dMMR metastatic 
colorectal cancer, treated with nivolumab or nivolumab and ipilimumab. The ORR 
was 27 % for the Nivolumab group and 15 % for the combination group. Despite 
the higher response rate in the monotherapy group, the combination was superior 
with regard to PFS and OS. The 4-month PFS was 55 % for the Nivolumab group 
and 80 % for the Nivolumab+Ipilimumab group, while the 5-month OS was 75 % 
and 100 % respectively. 
The Canadian Cancer Clinical Trials Group (CCCTG) evaluate in the CO.26 trial 
the addition of the immune checkpoint doublet durvalumab + tremelimumab to best 
supportive care in unselected refractory mCRC. The study was presented at the 
ASCO GI 2019 symposium and demonstrated a median OS of 6.6 months 
compared with 4.1 months with supportive care alone (hazard ratio [HR], 0.72; 90% 
CI, 0.54-0.97; P = .07). However, median progression-free survival (PFS) did not 
significantly differ between arms (1.8 months vs. 1.9 months; HR, 1.01; 90% CI, 
0.76-1.34; P = .97). 
An ongoing Phase Ib/II trial (NCT03202758) will evaluate the safety, tolerability and 
immunological activity of durvalumab (MEDI4736) (anti-PD-L1) plus tremelimumab 
(anti-CTLA-4) combined with FOLFOX in patients with metastatic colorectal 
cancer. 
Little is known for early stage disease. In the first neoadjuvant study (Chalabi M et 
al., presented at ESMO 2018 annual meeting) to test ipilimumab plus nivolumab in 
early-stage dMMR and pMMR colon cancers, 19 patients with resectable, early-
stage colon cancer were treated with ipilimumab at 1 mg/kg on day 1 and 
nivolumab at 3 mg/kg on days 1 and 15. Patients then underwent surgery within a 
planned maximum of 6 weeks. Seven patients had dMMR tumors (1 patient had a 
double tumor) and major pathological responses (<10% residual vital tumor) were 
observed in 100% (7/7) of them, with 4 (57%) complete responses. 
As far as we know, no trials have been conducted with Durvalumab or any other 
immune check point in the adjuvant setting. 
 

 
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2.9.4 
 Durvalumab 
 
Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody 
that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-
1 and CD80. It is composed of 2 identical heavy chains and 2 identical light chains, 
with an overall molecular weight of approximately 149 kDa. Durvalumab contains 
a triple mutation in the constant domain of the Ig G1 heavy chain that reduces 
binding to complement protein C1q and the fragment crystallizable gamma 
receptors involved in triggering effector function. 
It works as a checkpoint inhibitor, blocking a signal that would have prevented 
activated T cells from attacking the cancer, thus allowing the immune system to 
clear the cancer. 
 
It is indicated as monotherapy for the treatment of locally advanced, unresectable 
non-small cell lung cancer (NSCLC) in adults whose tumors express PD-L1 on ≥ 
1% of tumor cells and whose disease has not progressed following platinum-based 
chemoradiation therapy. 
 
2.9.5 
 Overall risks 
 
Monoclonal antibodies directed against immune checkpoint proteins, such as 
programmed cell death ligand 1 (PD-L1) as well as those directed against 
programmed cell death-1 (PD-1) or cytotoxic T-lymphocyte antigen-4 (CTLA-4), 
aim to boost endogenous immune responses directed against tumor cells. By 
stimulating the immune system however, there is the potential for adverse effects 
on other tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of 
agents are thought to be due to the effects of inflammatory cells on specific tissues. 
These risks are generally events with a potential inflammatory or immune mediated 
mechanism and which may require more frequent monitoring and/or unique 
interventions such as immunosuppressants and/or endocrine therapy. These 
immune mediated effects can occur in nearly any organ system, and are most 
commonly seen as gastrointestinal AEs such as colitis and diarrhoea, 
pneumonitis/interstitial lung disease (ILD),, hepatic AEs such as hepatitis and liver 
enzyme elevations, skin events such as rash and dermatitis and endocrinopathies 
including hypo- and hyper-thyroidism. 
 
2.9.5.1 Durvalumab 
 
Risks with durvalumab include, but are not limited to, diarrhea/colitis 
pneumonitis/ILD, endocrinopathies (hypo- and hyper-thyroidism, type I diabetes 
mellitus, 
hypophysitis 
and 
adrenal 
insufficiency) 
hepatitis/increases 
in 

 
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transaminases, nephritis/increases in creatinine, pancreatitis/increases in amylase 
and lipase, rash/pruritus/dermatitis, myocarditis, myositis/polymyositis, other rare 
or less frequent inflammatory events including neurotoxicities, infusion-related 
reactions, hypersensitivity reactions, and infections/serious infections.  
For information on all identified and potential risks with durvalumab please always 
refer to the current version of the durvalumab IB. 
Further information on these risks can be found in the current version of the 
durvalumab IB. 
In monotherapy clinical studies AEs (all grades) reported very commonly (≥ 15% 
of patients) are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, 
diarrhea, vomiting, back pain, pyrexia, asthenia, anemia, arthralgia, peripheral 
edema, headache, rash, and pruritus. Approximately 9.4% of patients experienced 
an AE that resulted in permanent discontinuation of durvalumab and approximately 
6.5 % of patients experienced an SAE that was considered to be related to 
durvalumab by the study investigator. 
The majority of treatment-related AEs were manageable with dose delays, 
symptomatic treatment, and in the case of events suspected to have an immune 
basis, the use of established treatment guidelines for immune-mediated (Appendix  
A detailed summary of durvalumab monotherapy AE data can be found in the 
current version of the durvalumab IB. 
 
2.9.6 
 Rationale for fixed dosing 
 
A population PK model was developed for durvalumab using monotherapy data 
from a Phase I study (study 1108; N=292; doses= 0.1 to 10 mg/kg Q2W or 15 
mg/kg Q3W; solid tumors). Population PK analysis indicated only minor impact of 
body weight (WT) on the PK of durvalumab (coefficient of ≤0.5). The impact of body 
WT-based (10 mg/kg Q2W) and fixed dosing (750 mg Q2W) of durvalumab was 
evaluated by comparing predicted steady state PK concentrations (5th, median 
and 95th percentiles) using the population PK model. A fixed dose of 750 mg was 
selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total 
of 1000 patients were simulated using body WT distribution of 40–120 kg. 
Simulation results demonstrate that body WT-based and fixed dosing regimens 
yield similar median steady state PK concentrations with slightly less overall 
between-patient variability with fixed dosing regimen.  
Similar findings have been reported by others (Ng et al 2006, Wang et al 2009, 
Zhang et al 2012, Narwal et al 2013) Wang and colleagues investigated 12 
monoclonal antibodies and found that fixed and body size-based dosing perform 
similarly, with fixed dosing being better for 7 of 12 antibodies (Wang et al 2009) . 
In addition, they investigated 18 therapeutic proteins and peptides and showed that 
fixed dosing performed better for 12 of 18 in terms of reducing the between-patient 
variability in pharmacokinetic/pharmacodynamics parameters (Zhang et al 2012).  

 
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A fixed dosing approach is preferred by the prescribing community due to ease of 
use and reduced dosing errors. Given expectation of similar pharmacokinetic 
exposure and variability, we considered it feasible to switch to fixed dosing 
regimens. Based on average body WT of 75 kg, a fixed dose of 1500 mg Q4W 
durvalumab (equivalent to 20 mg/kg Q4W) is included in the current study.  
 
To date durvalumab has been given to more than 8000 patients as part of ongoing 
studies either as monotherapy or in combination with other anti-cancer agents.  
Details on the safety profile of durvalumab monotherapy refer to the current 
durvalumab Investigator’s Brochure for a complete summary of non-clinical and 
clinical information including safety, efficacy and pharmacokinetics 
 
Durvalumab has recently been approved by FDA for the treatment of patients with 
locally advanced or metastatic urothelial carcinoma who either have disease 
progression during or following platinum-containing chemotherapy or have disease 
progression within 12 months of neoadjuvant or adjuvant treatment with platinum-
containing chemotherapy 
As regards colorectal cancer a monotherapy with CPI have not demonstrated 
clinically meaningful efficacy in the majority of mCRC, the MSS mCRC cohort, 
which are cold tumors with a low mutational burden. 
However, in the small percentage of MSI mCRC (5%) they are proving outstanding 
results. In fact, two works were published recently by Overman et al, the first one 
with Nivolumab (Overman et al) and the second one with Nivolumab and 
Ipilimumab in combination (Overman et al). These studies showed an ORR of 31% 
and 55% and a 1y-PFS of 50% and 71%, respectively. 
 
 
2.10 Durvalumab background/non-clinical and clinical experience 
 
The non-clinical and clinical experience is fully described in the most current 
version of the durvalumab Investigator’s Brochure.  
Durvalumab is a human monoclonal antibody (mAb) of the immunoglobulin G (IgG) 
1 kappa subclass that inhibits binding of PD-L1 and is being developed by 
AstraZeneca/MedImmune for use in the treatment of cancer (MedImmune is a 
wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune will be 
referred to as AstraZeneca throughout this document.)). The proposed mechanism 
of action (MOA) for durvalumab is interference in the interaction of PD-L1 with PD-1 
and CD80 (B7.1).  Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases 
the inhibition of immune responses, including those that may result in tumor 
elimination.  In vitro studies demonstrate that durvalumab antagonizes the 
inhibitory effect of PD-L1 on primary human T cells resulting in the restored 
proliferation of IFN-γ (Stewart et al 2015).  In vivo studies have shown that 
durvalumab inhibits tumor growth in xenograft models via a T-cell-dependent 
mechanism (Stewart et al 2015).  Based on these data, durvalumab is expected to 
stimulate the patient’s antitumor immune response by binding to PD-L1 and shifting 

 
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the balance toward an antitumor response. Durvalumab has been engineered to 
reduce antibody-dependent cellular cytotoxicity and complement-dependent 
cytotoxicity.  
To date durvalumab has been given to more than 8000 patients as part of 
ongoing studies either as monotherapy or in combination with other anti-cancer 
agents.  Details on the safety profile of durvalumab monotherapy are summarized 
in Section 0. Refer to the current durvalumab Investigator’s Brochure for a 
complete summary of non-clinical and clinical information including safety, 
efficacy and pharmacokinetics. 
  
 
2.11 Rationale for Regorafenib dose in combination with Durvalumab   
Regorafenib will be administered at a dose of 90 mg orally, once daily (q.d.) for 3 
weeks in a 4-week cycle. Durvalumab will be administered intravenously (i.v.) at a 
dose of 1500 mg every 4 weeks (Q4W).  
The dose of regorafenib is lower than the dose currently approved in CRC and 
other indications. The selection of this dose is based on the recently published 
REGONIVO trial as well as data from other ongoing trials, as explained below. 
REGONIVO was a phase Ib trial that enrolled 50 patients with pre-treated 
metastatic gastric and colorectal cancer. Patients received (during the dose 
expansion phase), 80-120 mg of regorafenib in combination with nivolumab. The 
80 mg dose had a manageable safety profile and encouraging antitumor activity 
(objective tumor response 40%) in patients with heavily pretreated disease. Based 
on these promising results, the Rego-Nivo combination is being tested in a number 
of ongoing clinical trials, including an industry-sponsored phase II trial in patients 
with mismatch repair-proficient advanced colorectal cancer and two phase II trials 
in unresectable HCC. 
Based on data from the combination of regorafenib and nivolumab in the 
REGONIVO trial, the combination of regorafenib and pembrolizumab in an ongoing 
HCC trial, as well as ongoing data from a phase II regorafenib + nivolumab trial in 
colorectal cancer (Bayer - data on file), a few observations are noted: 
• 
A starting dose of 120 mg of regorafenib cannot be sustained in the majority 
of patients, predominantly due to rash. 
• 
A starting dose of 80 mg is more tolerable and certain patients can maintain 
therapy at this dose as well as escalate to 120 mg; however approximately 25% of 
Western patients require further dose reduction. 
It is therefore not clear whether additional efficacy beyond that seen with an 80 mg 
starting dose could be observed, this suggests that the optimal dose of regorafenib 
in combination with a PD-(L)1 inhibitor may lie between 80 and 120 mg. 
Since there is no pharmacodynamic marker for the regorafenib activity in 
combination with a PD-(L)1 inhibitor, empirically one can conclude that an 
intermediate dose closer to 80 mg would have a lower likelihood of eliciting toxicity. 
However, concerns regarding unrealized efficacy may remain. Conversely, a dose 
closer to 120 mg may elicit toxicity, leading to higher rates of discontinuation. 

 
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A further consideration is that some patients treated with 80 mg of regorafenib still 
require dose reductions and with 40 mg tablets, a 50% dose reduction is drastic 
and not considered usual practice.  
Based on PK and PD data from the phase I dose escalation trial (11650), 
regorafenib exposure in the range expected for a dose of 40 mg had less of an 
impact on levels of sVEGFR2 as compared to exposure associated with doses ≥ 
60 mg. Since VEGFR inhibition is one of the proposed mechanisms for the 
beneficial effect of regorafenib and PD-(L)1 inhibitor combination therapy, this is 
relevant to consider.  
Dosing regorafenib in combination using a lower strength tablet would allow 
flexibility to achieve a starting dose between 80 and 120 mg and have a more 
gradual dose reduction if needed. 
In order to provide maximum flexibility to attain an optimal dose, with the current 
information, 30 mg tablets are optimal. A starting dose of 90 mg (3 tabs) in 
combination therapy is recommended. Should an initial dose reduction be required, 
the first dose reduction would be to 60 mg (2 tablets), which is a more conventional 
30% reduction and is also expected to provide regorafenib exposure in a 
pharmacologically active range. 
 
 
 

 
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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The primary objective of this study is: 
● To investigate the efficacy of Regorafenib plus Durvalumab versus control 
arm as adjuvant treatment in stage IV CRC patients rendered Disease-Free 
after completion of standard treatment according to local practices. 
3.1.1 
Primary Endpoint 
 
The primary endpoint is Disease-Free Survival (DFS) defined according to Punt, 
2007 (Table 4)[60]. In addition to the Punt definition, one the following will be 
considered DFS event as well : 
a) Appearance of any imaging or clinical new sign of disease 
b) Two consecutive (time gap will be decided by the clinical investigator but it 
should not be longer than 30 days) increases in CEA levels above upper 
limit level.  
3.1.2 
 Treatment at progression 
 
Since progression marks the achievement of the primary endpoint, the treatment 
upon progression is left to investigator clinical judgment.  
In the control arm (observation) crossover to regorafenib plus durvalumab is 
allowed. 
 
Table 4. Contribution of nine different events to the definition of six endpoints in 
adjuvant studies with cancer patients  
 
Endpoint a 
Event 
DFS 
RFS 
TTR 
TTF 
CSS 
OS 
Loco-regional recurrence  
E 
E 
E 
E 
I 
I 
Distant metastases 
E 
E 
E 
E 
I 
I 
Second primary, same cancer 
E 
I 
I 
E 
I 
I 
Second primary, other cancer 
E 
I 
I 
E 
I 
I 
Death from same cancer 
E 
E 
E 
E 
E 
E 
Death from other cancer 
E 
E 
C 
E 
C 
E 
Non-cancer-related death 
E 
E 
C 
C 
C 
E 
Treatment-related death 
E 
E 
C 
E 
C 
E 
Loss to follow-up 
C 
C 
C 
C 
C 
C 
(Consensus agreement, from: Punt, 2007). 
 
a DFS = disease-free survival; RFS = relapse-free survival; TTR = time to recurrence; TTF 
= time to treatment failure; CSS = cancer specific survival; OS = overall survival; 
E = event; C = censor; I = ignore  
 

 
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To the purpose of this trial a loco-regional recurrence or systemic recurrence 
is defined as follows: 
CT positive or CT uncertain with elevated CEA and positive PET scan.  
 
3.2 
Secondary Objectives 
The secondary objectives of this study are: 
● to assess the short-term effects of adjuvant regorafenib plus durvalumab 
on DFS 
● to assess the effect of adjuvant regorafenib plus durvalumab on all causes 
mortality. 
● to investigate potential  correlation between molecular and biological 
markers and survival outcomes( progression and death) in patients treated 
with adjuvant regorafenib plus durvalumab. 
● to assess toxicity correlated to study treatment 
● to assess the treatment compliance 
 
3.2.1 
Secondary Endpoints 
 
The secondary endpoints are: 
● 18 months Disease-Free Survival (DFS) 
● Overall Survival (OS) 
● Compliance to the experimental treatment. 
 
3.2.2 
 Exploratory Objectives 
 
- 
Correlation between ctDNA and survival outcomes (progression and death) 
in patients treated with adjuvant regorafenib plus durvalumab. 
- 
Explore the potential prognostic and predictive value of Next-generation 
sequencing analyses, Tumour DNA methylation analyses, Gene expression 
analyses, CMS subgrouping analyses, Immune signature analyses and the 
correlation with the survival outcomes in mCRC NED patients enrolled in 
this trial. 
 
 
3.3 
Endpoints definition 
3.3.1 
 Disease-free survival 
 
The primary study endpoint is DFS as defined in Section 3.1.1 and computed for 
each patient from the day of randomization to the day of occurrence of first event 

 
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of interest or last follow up clinical examination. If no event (relapse or death) has 
been observed, the patient is censored at the date of the last follow up. 
Patients who discontinue treatment prior to documented disease relapse including 
those who initiate non-protocol therapy prior to relapse, will be followed up for 
disease progression and death  and will be censored at the time of therapy change. 
 
3.3.2 
 Overall survival 
 
Defined as time from the date of randomization until death from any cause. If no 
event (death) has been observed, the patient is censored at the date of last follow 
up.  
 
3.3.3 
 Toxicity 
 
Toxicity / adverse events classified according to NCI CTCAE version 5.0 [61] . 
 
3.3.4 
 Compliance to the experimental treatment 
 
Defined as the ratio between the actual and expected number of 
Durvalumab+Regorafenib administrations in each patient. 

 
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4 
INVESTIGATIONAL PLAN 
4.1 
Description and Justification of the Trial Design and Plan 
This project is a randomized, open-label, multicenter study. All eligible patients, 
after completion of locoregional treatment to render them disease free, will be 
randomized to experimental treatment (adjuvant regorafenib plus durvalumab) or 
no further treatment (observation).  Randomization is 1:1. Patients randomized to 
the experimental arm will receive up to 1 year of regorafenib + durvalumab. 
Patients randomized to the control arm will receive no further treatment. Patients 
in the control arm will be offered the possibility to crossover to regorafenib plus 
durvalumab upon relapse. 
 
4.1.1 
 Justification of a no treatment control group 
 
The use of an untreated control group (i.e., no further treatment) is acceptable 
when patients in the control group are managed as per SoC, and patients are 
informed of the possibility of being randomized to no further treatment. 
Standard of care “treatment” for CRC patients after resection surgery and 
chemotherapy is observation. The possibility of randomization to no further 
treatment will be clearly documented in the Informed Consent Form (ICF). 
 
4.1.2 
Justification of an open label design 
 
The primary study endpoint is Disease-Free Survival (DFS) (Section 3.1). The 
open label design (lack of masking) is justified by the need of up to 1-year placebo 
injections and placebo pills, which are not felt ethically justifiable. 
 
4.1.3 
 Justification of DFS as primary study endpoint 
 
The choice of DFS as the primary study endpoint is justified by  
a) the intrinsic clinical relevance of living without relapse and,  
b) the demonstration of its validity as a surrogate endpoint of overall survival 
(OS)[62]. 
 
4.2 
Determination of Sample Size  
The study is set up as an exploratory phase 2B trial with sufficient patient numbers 
to broadly explore the differences between the experimental arm regimen and the 
control group.  
The randomization plan is 1 to 1. Patients will be stratified by centre. 

 
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The main aim of this study is to estimate the effect of the experimental arm relative 
to control group on the endpoint of interest: disease-free survival.  
In view of the treatment setting, disease-free survival is considered as the most 
sensitive clinical endpoint.  
To achieve 90% power at a 0.05 two-sided significance level to detect a 40% fall 
in DFS event rate (corresponding to a median increase from 6 to 10 months), 172 
patients have to be accrued and followed up for at least 2 years in order to achieve 
the requested 164 events (recurrences or deaths). Assuming an attrition rate of 
approximately 5%, a total of 182 patients (91 per arm) have to be randomized. The 
primary efficacy endpoint will be evaluated on the ITT population. 
A log-rank test will be used to assess disease-free survival and overall survival. A 
Cox proportional hazards model will be used to calculate HRs and 95% CIs). 
Sensitivity analysis of disease-free survival will be also done with a restricted mean 
survival time approach that does not assume the proportional hazards model, as 
outlined by Anderson and colleagues.  
For patients in the control group after progression, a cross-over is allowed. A 
descriptive summary of the duration of this crossover treatment (overall and from 
the time of initial progression) will be done. The proportions of patients achieving 
an objective response or disease control will be compared with a logistic regression 
model adjusted for relevant covariates. Effect on survival of regorafenib plus 
durvalumab regimen within this crossover part of the study will be analysed by 
means of proportional hazard time dependent analysis. Median progression-free 
survival will be calculated with the reverse Kaplan-Meier method.  
All statistical testing is two-sided at the nominal 5% significance level, with no 
adjustment for multiplicity. All patients who receive at least one regorafenib plus 
durvalumab dose will be included in the safety analysis.  
 
A data-monitoring committee will be appointed to assess the trial data periodically 
to ensure patient safety and the integrity of the trial. 
 
4.3 
Study plan  
 
Approximately 182 patients, >18 years of age, with Stage IV CRC and no evidence 
of disease (NED) will be enrolled. Randomization will be 1:1.  
 
Prior to enrolment, all patients will have received standard of care (SoC) treatment 
for Stage IV CRC (locoregional), and will have to be NED. 
Treatment schedules and safety and efficacy assessments will be the same for all 
patients, regardless of treatment group. 

 
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All patients will undergo assessments (Section 6.2) to confirm compliance with 
inclusion and exclusion criteria, after that they will sign informed consent. Patients 
who will be randomized to the experimental treatment group will receive up to 1 year 
of regorafenib plus durvalumab.  
 
Run-in phase: The combination of an immune-checkpoint inhibitor plus TKI anti-
angiogenic agents has been extensively investigated in several trials (phase II and 
III) in different types of tumors, with no evidence of new safety signals. Although 
specific data are not available on the combination of durvalumab and regorafenib, 
we would not expect major toxicity issues.  
 
Therefore, a run-in phase will be conducted on the first 4 patients randomized to the 
experimental arm using a starting dose of 60 mg/die of Regorafenib (and fixed 1500 
mg of Durvalumab), to be escalated after 2 months to 90 mg/die if < 2 patients report 
serious adverse events (SAE). If Regorafenib 90 mg/die is well tolerated for other 2 
months (< 2 patients with SAE) the run-in phase will be closed with the dose of 90 
mg/die. In case of > 2 patients report SAE with 90 mg/die, additional 4 patients will 
be enrolled and treated with the same dose of Regorafenib (90 mg/die) and if < 2 of 
them report SAE the run-in will be closed at 90 mg/die. Conversely, if > 2 patients 
report SAE the dose of Regorafenib will be reduced again to 60 mg/die and the run-
in will be closed with Regorafenib 60 mg/die.  
If during the first part of the run-in > 2 patients report SAE with Regorafenib 60 
mg/die, additional 4 patients will be treated with Regorafenib 30 mg/die for 2 months 
and, in case of > 2 patients with SAE, the trial will be revised. In case of good 
tolerance of Regorafenib 30 mg/die (< 2 patients with SAE), additional 4 patients will 
be enrolled and treated with Regorafenib 60 mg/die: if > 2 patients will report SAE 
the run-in phase will be closed with Regorafenib 30 mg/die, instead if Regorafenib 
60 mg/die will be well tolerated (< 2 SAE)  this will be the final dose of the run-in 
phase. 
(see Flowchart in Appendix 4) 
 
The first regorafenib plus durvalumab cycle will be administered on Day 1.  
 
The timing of visits, assessments and procedures is detailed in Section 8 and in 
Table 1, Table 2, and Table 3, respectively. 
 
 
4.4 
Study Duration, End of Trial and Dates 
 
The study duration for each patient will be dependent on patient survival and/or on 
the occurrence of unacceptable toxicities. Given that the accrual period is 2 years 
and follow-up is 2 year, the maximum active study period for each patient range 
from 24 months to 48 months after randomization. 
 

 
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5 
PLANNED STATISTICAL METHODS 
All trial data must be recorded in the eCRF. The data will be recorded as soon as 
possible after they are generated. All sections of each eCRF must be completed. 
Only the Investigator can electronically sign the eCRF for assurance of exactitude 
and completeness of each page.  
 
5.1  Analysis populations 
• Intention-to-treat population (ITT): The ITT population will include all 
randomized patients. Patients will be analyzed in the arm they were allocated 
by randomization. 
• Per protocol population (PP): All patients of the ITT population who do not 
have any major deviation from eligibility criteria and have started their 
allocated treatment (at least one dose of the study drug). 
• Safety population (SP): All patients of the ITT population, who have received 
at least one dose of the study drug. Patients will be analyzed in the treatment 
they actually received. 
 
5.2 
Statistical methods 
5.2.1 
Time to event endpoints 
 
The analyses of the primary and secondary time to event endpoints (DFS and OS) 
will be performed on all patients according to the intention to treat principle. 
5.2.2 
Estimates and confidence intervals 
 
Estimates of the event-free rates at a fixed time points, namely 1, 3 and 5 years 
will be obtained using the Kaplan Meier technique and (1- α) CI will be calculated 
by Greenwood’s estimation of the standard deviation. Estimates of hazard ratios 
and their (1-α) CI will be obtained by Cox regression.  
Kaplan Meier Curves will be drawn for both the experimental and control arms on 
the same plot. 
Follow-up time will be estimated based on the reverse Kaplan Meier method for 
both groups 
5.2.3 
Inference: Test statistics for comparisons 
 
A log-rank test will be used to compare the experimental versus the control arms 
for the time to event endpoints.  
 

 
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5.2.4 
Toxicity 
 
Analyses for toxicity will be based on the safety population. For each patient and 
for each type of toxicity, the worst grade of toxicity/adverse events observed over 
the whole treatment period according to CTCAE version 5 will be presented and 
used for the analyses. Two sets of statistical analyses will be performed to compare 
toxicity in the two treatment groups. In the first set the whole pattern of toxicity (all 
grades) will be considered for each item; analysis will be done by a linear rank test. 
In the second set toxicity will be defined as severe (mostly including grade 3 or 
higher) and not severe (mostly including grades up to 2) and analysis will be 
performed by chi-square or the Fisher’s exact test, as appropriate. 
 
5.2.5 
Interim analyses 
 
For the primary endpoint of efficacy an interim analysis for futility is planned when 
approximately 40% of patients will be accrued and evaluated for endpoint. A 
conditional power analysis will be considered and trial will be stopped if, under the 
assumption that the results distribution of future data under the current trend and 
under alternative hypothesis, the probability of detect a statistically significant result 
will be <20%. 
 
5.2.6 
Pre-planned multivariate analysis, exploratory subgroup 
analyses and analyses of DFS 
 
 
As a sensitivity analysis aimed at confirming the results of the primary analysis 
while adjusting for any imbalance in baseline factor, a multivariate Cox PH model 
will be fitted to the data with treatment assigned at random, routine prognostic 
factors including gender, age and CEA at randomization, number of metastatic 
lesions (1vs >1, or as continuous), size of metastatic lesions, number of metastatic 
sites (1vs >1, or as continuous), time from primary resection to metastatic detection 
(<6 mos vs >=6 mos, or as continuous), R0 vs R1 resections, RFS since removal 
of primary, molecular determinants such as RAS, BRAF status and therapy used 
to achieve the NED status, as covariates. The results of this analysis will be used 
to confirm those of the primary analysis, and any difference in the results of the two 
analyses will be mentioned in the presentation of the trial results, but in no case 
they will be used to overrule the conclusions drawn based on the results of the 
primary analysis.  
Subgroup analyses will be carried out for all prognostic factors considered in the 
Cox model by including in the model the appropriate treatment-by-factor interaction 
terms, one at a time, and evaluating the change in the log-likelihood. The results 
of these analyses will be presented with the standard Forrest plots with stratum-
specific hazard ratios and p-values for interaction, but they will be considered and 
presented as merely exploratory, hypothesis-generating, analyses. Proportional 
hazards assumption will be checked using the method described by Grambsch & 
Therneau [64]. If the data clearly do not follow proportional hazards, medical 

 
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explanations should be identified and alternative statistical methods will be 
explored. 
The same univariate and multivariate analyses will be replicated for Overall 
Survival. 
 
5.2.7 
Demographics and Baseline Characteristics 
 
Demographic and baseline characteristics will be summarised by treatment group 
and overall. These assessments will include other relevant parameters such as 
blood pressure measurements and medical history. By-treatment summaries will 
serve to identify any imbalances between the treatment groups at baseline. 
Summary tables will be provided for the ITT and the PP populations by means of 
descriptive statistics and frequency tables where appropriate. 
 
 

 
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6 
SUBJECT SELECTION CRITERIA 
6.1 
Study Population 
This study plans to enrol 182 patients, > 18 years of age, with Stage IV CRC and 
no evidence of disease (NED state, see Section 2.4 for the definition of NED), who 
comply with all inclusion and exclusion criteria and who provide written consent to 
participate in the study.  
The patients will be enrolled at approximately 25-40 study facilities in Italy. 
 
6.2 
Inclusion Criteria 
 
To be enrolled in this study each patient must meet all of the following criteria at 
the time of randomization: 
1. Signed ICF, after oral as well as written information. Capable of giving signed 
informed consent which includes compliance with the requirements and 
restrictions listed in the informed consent form (ICF) and in this protocol. Written 
informed consent obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening evaluations 
2. Age ≥ 18 years at time of study entry 
3. Body weight >30 kg 
4. Histologically confirmed diagnosis of colorectal adenocarcinoma; 
5. Patients must be in NED after completion of any treatments for stage IV CRC, 
including resections, RFA; RT with or without neoadjuvant/adjuvant therapies 
or CR after chemotherapy; 
6. Patients must be randomized within 10 weeks since the achievement of the 
NED state. Those who have also received adjuvant therapy following the 
locoregional treatment are still eligible, provided they are randomized within 4 
weeks since the last chemotherapy cycle; 
7. NED state ascertained by means of CT scan and/or PET scan and/or MRI scan; 
8. ECOG Performance Status ≤ 1; 
9. Life expectancy of at least 12 weeks 
10. CEA within normal limits; 
11. No residual toxicity from previous chemotherapy; 
12. Women of childbearing potential must use safe contraception. 
13.  Adequate normal organ and marrow function as defined below: 
Haemoglobin ≥9.0 g/dL 
Absolute neutrophil count (ANC) ≥1.5 × 109 /L  
• 
Platelet count ≥100 × 109/L 
Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).  
This will not apply to patients with confirmed Gilbert’s syndrome 
(persistent or recurrent hyperbilirubinemia that is predominantly 
unconjugated in the absence of haemolysis or hepatic pathology), 
who will be allowed only in consultation with their physician.  

 
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Serum Creatinine ≤ 1.5 x ULN o measured creatinine clearance (CL) >40 mL/min 
or Calculated creatinine CL>40 mL/min by the Cockcroft-Gault formula (Cockcroft 
and Gault 1976) or by 24-hour urine collection for determination of creatinine 
clearance: 
Males: 
 
 
Creatinine 
CL (mL/min) 
= Weight 
(kg) 
x 
(140 
– 
Age)  
72 x serum creatinine (mg/dL) 
Females: 
 
 
Creatinine 
CL (mL/min) 
= Weight (kg) x (140 – Age)    x 
0.85 
72 x serum creatinine (mg/dL) 
 
AST (SGOT)/ALT (SGPT) ≤2.5 x ULN, o ≤ 5 x ULN in the presence of liver 
metastases 
 
14. Patient is willing and able to comply with the protocol for the duration of the 
study including undergoing treatment and scheduled visits and examinations 
including follow up. 
 
6.3 
Exclusion Criteria 
1. Participation in another clinical study with an investigational product during 
the last 4 weeks. 
2. Concurrent enrolment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an 
interventional study 
3. Prior randomisation or treatment in a previous durvalumab clinical study 
regardless of treatment arm assignment.  
4. Patients with microsatellite instability (MSI) or DNA Mismatch Repair 
Deficiency (dMMR) are not allowed. 
5. Any form of systemic disease that, in the opinion of the Investigator, would 
make the subject unsuitable for the study (including autoimmunity) or would 
prevent compliance with the study protocol;  
6. Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer 
therapy with the exception of alopecia, vitiligo, and the laboratory values 
defined in the inclusion criteria  
a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-
case basis after consultation with the Study Physician. 
b. Patients with irreversible toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab may be included only 
after consultation with the Study Physician.  

 
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7. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 
treatment. Concurrent use of hormonal therapy for non-cancer-related 
conditions (e.g., hormone replacement therapy) is acceptable. 
8. Major surgical procedure (as defined by the Investigator) within 28 days 
prior to the first dose of IP. Note: Local surgery of isolated lesions for 
palliative intent is acceptable. 
9. History of allogenic organ transplantation. 
10. Active or prior documented autoimmune or inflammatory disorders 
(including inflammatory bowel disease [e.g., colitis or Crohn's disease], 
diverticulitis [with the exception of diverticulosis], systemic lupus 
erythematosus, 
Sarcoidosis 
syndrome, 
or 
Wegener 
syndrome 
[granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, 
hypophysitis, uveitis, etc]). The following are exceptions to this criterion: 
a. Patients with vitiligo or alopecia 
b. Patients with hypothyroidism (e.g., following Hashimoto syndrome) 
stable on hormone replacement  
c. Any chronic skin condition that does not require systemic therapy 
d. Patients without active disease in the last 5 years may be included 
but only after consultation with the study physician 
e. Patients with celiac disease controlled by diet alone 
11. Uncontrolled intercurrent illness, including but not limited to, ongoing or 
active infection, symptomatic congestive heart failure, uncontrolled 
hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung 
disease, serious chronic gastrointestinal conditions associated with 
diarrhea, or psychiatric illness/social situations that would limit compliance 
with study requirement, substantially increase risk of incurring AEs or 
compromise the ability of the patient to give written informed consent 
12. History of another primary malignancy except for 
f. Malignancy treated with curative intent and with no known active 
disease ≥5 years before the first dose of IP and of low potential risk 
for recurrence 
g. Adequately treated non-melanoma skin cancer or lentigo maligna 
without evidence of disease 
h. Adequately treated carcinoma in situ without evidence of disease 
13. History of leptomeningeal carcinomatosis 
14.  Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) 
≥470 ms calculated from 3 ECGs (within 15 minutes at 5 minutes apart) 
15. History of active primary immunodeficiency  
16. Active infection including tuberculosis (clinical evaluation that includes 
clinical history, physical examination and radiographic findings, and TB 
testing in line with local practice), hepatitis B (known positive HBV surface 
antigen (HBsAg) result), hepatitis C. Patients with a past or resolved HBV 
infection (defined as the presence of hepatitis B core antibody [anti-HBc] 
and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) 
antibody are eligible only if polymerase chain reaction is negative for HCV 
RNA. 

 
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17. Current or prior use of immunosuppressive medication within 14 days before 
the first dose of durvalumab. The following are exceptions to this criterion: 
d. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., 
intra articular injection) 
e. Systemic corticosteroids at physiologic doses not to exceed 10 
mg/day of prednisone or its equivalent 
f. Steroids as premedication for hypersensitivity reactions (e.g., CT 
scan premedication) 
18. Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. 
Note: Patients, if enrolled, should not receive live vaccine whilst receiving 
IP and up to 30 days after the last dose of IP. 
19. Female patients who are pregnant or breastfeeding or male or female 
patients of reproductive potential who are not willing to employ effective birth 
control from screening to 90 days after the last dose of durvalumab 
monotherapy. 
20. Known allergy or hypersensitivity to any of the study drugs or any of the 
study drug excipients. 
21. Any condition that, in the opinion of the investigator, would interfere with 
evaluation of the study drug or interpretation of patient safety or study 
results. 
 
 
6.4 
Withdrawal of patients from study treatment and/or study 
 
6.4.1 Permanent discontinuation of Durvalumab or Regorafenib 
Discontinuation of study treatment, for any reason, does not impact the 
patient’s participation in the study. A patient who decides to discontinue IP will 
always be asked about the reason(s) for discontinuation and the presence of 
any AE. The patient should continue attending subsequent study visits, and 
data collection should continue according to the study protocol. If the patient 
does not agree to continue in-person study visits, a modified follow-up must be 
arranged to ensure the collection of endpoints and safety information. This 
follow-up could be a telephone contact with the patient, a contact with a relative 
or treating physician, or information from medical records. The approach taken 
should be recorded in the medical records. A patient that agrees to modify 
follow-up is not considered to have withdrawn consent or to have withdrawn 
from the study. 
Patients who are permanently discontinued from further receipt of IP, 
regardless of the reason, will be identified as having permanently discontinued 
treatment. Patients who are permanently discontinued will enter follow-up (see 
the SoAs).  
Patients who permanently discontinue drug for reasons other than objective 
RECIST disease progression should continue to have RECIST scans 
performed every 12 weeks ± 1 week for the first year (relative to the date of 
randomization), and then every 16 weeks ± 1 week in the second year and 
then every 24 weeks ± 1 week thereafter until RECIST 1.1-defined radiological 
PD or death (whichever comes first) as defined the SoAs. 

 
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If a patient is discontinued for RECIST 1.1-defined progression, then the 
patient should have 1 additional follow-up scan performed preferably at the 
next (and no later than the next) scheduled imaging visit, and no less than 4 
weeks after the prior assessment of PD. 
All patients will be followed for survival until the end of the study.  
Patients who decline to return to the site for evaluations should be contacted 
by telephone as indicated in the SoAs as an alternative.  
Patients who have permanently discontinued from further receipt of IP will need 
to be discontinued from the IVRS/IWRS. 
 
 
6.4.2   Lost to follow-up 
 
Patients will be considered lost to follow-up only if no contact has been 
established by the time the study is completed, such that there is insufficient 
information to determine the patient’s status at that time. Patients who refuse 
to continue participation in the study, including telephone contact, should be 
documented as “withdrawal of consent” rather than “lost to follow-up.”   
Investigators should document attempts to re-establish contact with missing 
patients throughout the study period. If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and 
evaluations should resume according to the protocol. In order to support key 
end points of DFS and OS analyses, the survival status of all patients in the 
full analysis and the safety analysis sets should be re-checked, this includes 
those patients who withdrew consent or are classified as “lost to follow up.” 
 
• Lost to Follow up – site personnel should check hospital records, the 
patients’ current physician, and a publicly available death registry (if 
available) to obtain a current survival status. (The applicable CRF 
modules will be updated.) 
 
• In the event that the patient has actively withdrawn consent to the 
processing of their personal data, the survival status of the patient can be 
obtained by site personnel from publicly available death registries (if 
available) where it is possible to do so under applicable local laws to 
obtain a current survival status. (The applicable CRF modules will be 
updated.)    
 
 
6.4.3   Withdrawal of consent 
 
Patients are free to withdraw from the study at any time (IP and assessments) 
without prejudice to further treatment. Patients who withdraw consent for 
further participation in the study will not receive any further IP or further study 
observation, with the exception of follow-up for survival, which will continue 
until the end of the study unless the patient has expressly withdrawn their 
consent to survival follow-up. Note that the patient may be offered additional 
tests or tapering of treatment to withdraw safely.  

 
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A patient who withdraws consent will always be asked about the reason(s) for 
withdrawal and the presence of any AE. The Investigator will follow up AEs 
outside of the clinical study. If a patient withdraws consent, they will be 
specifically asked if they are withdrawing consent to: 
 
• 
All further participation in the study including any further follow up (eg, survival 
contact telephone calls) 
• 
Withdrawal to the use of any samples  

 
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7 
STUDY TREATMENT 
 
Control arm 
Patients in the control arm upon relapse will be treated with either standard 
treatment or regorafenib + durvalumab.  
 
7.1 
Treatment Administered 
Patients randomized and assigned to experimental arm will receive Regorafenib + 
durvalumab. Treatment will begin only after the patient has been randomized to 
the Treatment Group. Regorafenib 90 mg will be administered orally once daily for 
the first 21 days of each 28-day cycle, up to 1 year. Durvalumab (1500mg q4W IV 
infusion) will be administered every four weeks up to 1 year. 
 
7.1.1 
Run-in phase 
Run-in phase: The combination of an immune-checkpoint inhibitor plus TKI anti-
angiogenic agents has been extensively investigated in several trials (phase II and 
III) in different types of tumors, with no evidence of new safety signals. Although 
specific data are not available on the combination of durvalumab and regorafenib, 
we would not expect major toxicity issues.  
 
Therefore, a run-in phase will be conducted on the first 4 patients randomized to the 
experimental arm using a starting dose of 60 mg/die of Regorafenib (and fixed 1500 
mg of Durvalumab), to be escalated after 2 months to 90 mg/die if < 2 patients report 
serious adverse events (SAE). If Regorafenib 90 mg/die is well tolerated for other 2 
months (< 2 patients with SAE) the run-in phase will be closed with the dose of 90 
mg/die. In case of > 2 patients report SAE with 90 mg/die, additional 4 patients will 
be enrolled and treated with the same dose of Regorafenib (90 mg/die) and if < 2 of 
them report SAE the run-in will be closed at 90 mg/die. Conversely, if > 2 patients 
report SAE the dose of Regorafenib will be reduced again to 60 mg/die and the run-
in will be closed with Regorafenib 60 mg/die.  
If during the first part of the run-in > 2 patients report SAE with Regorafenib 60 
mg/die, additional 4 patients will be treated with Regorafenib 30 mg/die for 2 months 
and, in case of > 2 patients with SAE, the trial will be revised. In case of good 
tolerance of Regorafenib 30 mg/die (< 2 patients with SAE), additional 4 patients will 
be enrolled and treated with Regorafenib 60 mg/die: if > 2 patients will report SAE 
the run-in phase will be closed with Regorafenib 30 mg/die, instead if Regorafenib 
60 mg/die will be well tolerated (< 2 SAE)  this will be the final dose of the run-in 
phase. 
(see Flowchart in Appendix 4) 
 

 
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7.2 
Dose interruption or reduction 
In case of adverse events, dose interruption or reduction are at the investigator’s 
discretion based on local clinical practice. 
If an adverse event is attributed to only one drug (i.e., regorafenib or durvalumab), 
the investigator’s discretion will be used to determine what drug dose should be 
reduced or withheld.  
 
Table 5. Dose reduction levels 
 
Drug 
Dose levels 
Starting dose 
-1 
-2 
Durvalumab 
1500mg 
- 
- 
Regorafenib 
90mg 
60 mg 
30 mg 
7.3 
Durvalumab Dosage and Administration 
Durvalumab will be used in the commercially available formulation. 
Patients randomized to REGO-DURVA arm will receive Durvalumab at the dose 
level of 1500mg (60 minutes intravenous injection infusion) every 4 weeks. 
 
Premedications are not recommended for the first dose of Durvalumab. 
 
The study investigator may interrupt or delay Durvalumab administration according 
to adverse events to ensure patient safety and tolerability. Guidelines for treatment 
delay or discontinuation are provided in Appendix 3.  
Durvalumab will be supplied by AstraZeneca as a 500 mg vial solution for infusion 
after dilution.  The solution contains 50 mg/mL durvalumab, 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% 
weight/volume (w/v) polysorbate 80; it has a pH of 6.0 and density of 1.054 
g/mL.  The nominal fill label-claim volume is 10.0 mL.  
 
Durvalumab is a sterile, clear to opalescent, colorless to slightly yellow solution, 
free from visible particles.  
 
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not 
be frozen. Drug Investigational product should must be kept in original packaging 
until use to prevent prolonged light exposure.  
 
Any overdose or incorrect administration of Durvalumab should be noted on the 
Durvalumab Administration eCRF. Adverse events associated with an overdose or 

 
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incorrect administration of Durvalumab should be recorded on the Adverse Event 
eCRF. 
 
7.3.1 Study drug preparation 
 
Patients in the durvalumab treatment group will receive 1500 mg durvalumab via 
IV infusion Q4W for up to a maximum of 12 months (up to 12 doses/cycles), 
confirmed disease progression, unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion. If a patient’s weight falls to 30 kg or below (≤30 
kg) the patient should receive weight-based dosing equivalent to 20 mg/kg of 
durvalumab Q4W until the weight improves to >30 kg, at which point the patient 
should start receiving the fixed dosing of durvalumab 1500 mg Q4W. 
 
7.3.2 
Preparation of durvalumab doses for administration with an IV bag 
 
The dose of durvalumab for administration must be prepared by the Investigator’s 
or site’s designated IP manager using aseptic technique.  Total time from needle 
puncture of the durvalumab (MEDI4736) vial to the start of administration should 
must not exceed:  
 
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
If the final product is stored at both refrigerated and ambient temperatures, the total 
time must not exceed 24 hrs 
 
A dose of 1500 mg (for patients >30 kg in weight) will be administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab 
concentration ranging from 1 to 15 mg/mL, and delivered through an IV 
administration set with a 0.2- or 0.22-μm filter.  Add 30.0 mL (i.e. 1500 mg) of 
durvalumab  (i.e., 1500 mg of durvalumab) to the IV bag. The IV bag size should 
be selected such that the final concentration is within 1 to 15 mg/mL. Mix the bag 
by gently inverting to ensure homogeneity of the dose in the bag. 
If patient weight falls to ≤30 kg weight-based dosing at 20 mg/kg will be 
administered using an IV bag size selected such that the final concentration is 
within 1 to 15 mg/mL. 
    
Standard infusion time is 1 hour, however if there are interruptions,   In the event 
that there are interruptions during infusion, the total allowed infusion time should 
must not exceed 8 hours at room temperature.  
 
Do not co-administer other drugs through the same infusion line. 
 
The IV line will be flushed with a volume of IV diluent equal to the priming volume 
of the infusion set used after the contents of the IV bag are fully administered or 

 
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complete the infusion according to institutional policy to ensure the full dose is 
administered.  
The IV line will be flushed according to local practices to ensure the full dose is 
administered. Infusion time does not include the final flush time. 
 
 If either preparation time or infusion time exceeds the time limits a new dose must 
be prepared from new vials.  Durvalumab does not contain preservatives, and any 
unused portion must be discarded.  
 
Figure 1. Durvalumab Dosing Schedule 
 
 
7.4 
Dose-limiting toxicities (DLTs) 
A DLT is defined as the occurrence of an adverse event (AE) that is at least 
possibly related to the investigational product (IP) or investigational regimen (IR), 
with two exceptions: any grade of vitiligo or alopecia will not qualify as a DLT. AEs 
that are at least possibly related to durvalumab- and/or tremelimumab-containing 
regimens shall be assessed as DLTs if they meet any of the following criteria: 
 
Hematologic toxicity: 
• Grade ≥3 neutropenia complicated by fever >38.3°C 
• Grade 4 neutropenia (lasting more than 7 days) 
• Grade ≥3 thrombocytopenia with significant bleeding 
• Grade 4 thrombocytopenia (regardless of duration) 
• Grade 4 anemia (regardless of duration) 
 
Non-hematologic toxicity: 
• Any Grade 4 non-immune-mediated AE 
• Any Grade 4 immune-mediated AE, excluding endocrinopathies 
• Any Grade 3 non-immune mediated AE that does not resolve to ≤Grade 1 or 
baseline within 30 days with optimal medical management 
• Any Grade 3 immune-mediated AE – excluding diarrhea/colitis, pneumonitis, 
hepatitis, 
rash, 
neurotoxicity, 
myocarditis, 
myositis/polymyositis, 
endocrinopathies and nephritis – that does not resolve to ≤Grade 1 or baseline 
within 30 days after onset of the event despite optimal medical management 
including systemic corticosteroids 

 
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• Grade 3 diarrhea or colitis that does not resolve to ≤Grade 1 within 14 days 
[both immune- and non-immune-mediated indicated here; the same is the case 
if not specified in remaining bullet points below] 
• Grade 3 non-infectious pneumonitis 
• Grade 2 noninfectious pneumonitis that does not resolve to ≤Grade 1 within 3 
days of the initiation of maximal supportive care 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) ≥3×ULN 
with concurrent increase in total bilirubin (TBL) ≥2×ULN without evidence of 
cholestasis or alternative explanations (e.g., viral hepatitis, disease progression 
in the liver; i.e., “Hy’s Law”) 
• ALT or AST >8×ULN or TBL>5×ULN 
• Grade 3 immune-mediated rash that does not resolve to ≤Grade 1 or baseline 
within 30 days 
• Grade 2 rash covering > 30% BSA that does not resolve to ≤Grade 1 or baseline 
within 30 days  
• Any grade of immune-mediated rash with bullous formation 
• Grade 3 immune-mediated neurotoxicity (excluding Guillain-Barre and 
myasthenia gravis) that does not resolve to ≤Grade 1 within 30 days 
• Grade 2 or 3 immune-mediated peripheral neuromotor syndrome (such as 
Guillain-Barre and myasthenia gravis) that does not resolve to ≤Grade 1 within 
30 days or that exhibits signs of respiratory insufficiency or autonomic instability 
• Grade 3 immune-mediated myocarditis 
• Any symptomatic immune-mediated myocarditis that does not become 
asymptomatic within 3 days of initiating optimal medical management including 
systemic corticosteroids 
• Grade 2 or 3 immune-mediated myositis/polymyositis that does not resolve to 
Grade ≤1 within 30 days of initiating optimal medical management including 
systemic corticosteroids or that exhibits signs of respiratory insufficiency 
regardless of optimal medical management 
• Immune-mediated increase in creatinine >3×ULN, or >3×baseline for patients 
with a baseline creatinine elevated above ULN 
 
 
The period for evaluating DLTs will be from the time of first administration of 
durvalumab until the complete resolution of the treatment-related toxicity. 
 
 
 
 
7.4.1 
  Management of toxicity 
 
The following general guidance should be followed for management of toxicities:   
1. Treat each of the toxicities with maximum supportive care (including holding 
the agent suspected of causing the toxicity where required).  
2. If the symptoms promptly resolve with supportive care, consideration should 
be given to continuing study drug along with appropriate continuing 

 
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supportive care. If medically appropriate, dose modifications are permitted 
(see below).  
3. All dose modifications should be documented with clear reasoning and 
documentation of the approach taken.  
In addition, there are certain circumstances in which study drug should be 
permanently discontinued (see Appendix 3). Following the first infusion of study 
drug, subsequent administration of study drug can be modified based on toxicities 
observed as described in Appendix 3. All toxicities will be graded according to NCI 
CTCAE Version 5.0.  
Dose reductions are not permitted for durvalumab.  
Guidelines for the management of immune-mediated reactions, infusion-related 
reactions, and non-immune-mediated reactions for durvalumab are provided in the 
Toxicity Management Guidelines (TMGs) (see Appendix 3). 
 
Dose modifications will not be required for AEs that are clearly not attributed to 
study drug (such as an accident) or for laboratory abnormalities that are not 
deemed to be clinically significant. Dosing may continue despite concurrent vitiligo 
of any AE grade. Based on the mechanism of action of Durvalumab leading to T 
cell activation and proliferation, there is the possibility of observing irAEs during the 
conduct of this study. Potential irAEs may be similar to those seen with the use of 
ipilimumab and nivolumab including immune-mediated enterocolitis, dermatitis, 
hepatitis, and endocrinopathies (Brahmer et al 2010, Hodi et al 2010). Patients 
should be monitored for signs and symptoms of irAEs. In the absence of an 
alternate aetiology (eg, infection or PD) signs or symptoms of enterocolitis, 
dermatitis, hepatitis, and endocrinopathy should be considered to be immune-
related. 
 
- 
Management of irAEs may require administration of immunosuppressive 
medications (and/or hormone replacement therapy for endocrinopathies). 
Resolution of irAEs managed in this manner in the timeframes specified is 
acceptable. 
- 
Pneumonitis may be immune-related or as a result of late toxicity to 
radiotherapy. Either way study drug modifications detailed in this table 
should be followed.  
 
AE Adverse event; irAE Immune-related adverse event; ULN Upper limit of 
normal. 
 
 
 

 
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7.4.2 
 Infusion-related reaction 
 
In the event of a ≤Grade 2 infusion-related reaction, the infusion rate of study drug 
may be decreased by 50% or interrupted until resolution of the event (up to 4 hours) 
and re-initiated at 50% of the initial rate until completion of the infusion. For patients 
with a ≤Grade 2 infusion-related reaction, subsequent infusions may be 
administered at 50% of the initial rate. Acetaminophen and/or an antihistamine (eg, 
diphenhydramine) or equivalent medications per institutional standard may be 
administered at the discretion of the investigator. If the infusion-related reaction is 
≥Grade 3 or higher in severity, study drug will be discontinued. As with any 
antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately 
available, and study personnel must be trained to recognize and treat anaphylaxis. 
The study site must have immediate access to emergency resuscitation teams and 
equipment in addition to the ability to admit patients to an intensive care unit if 
necessary. 
 
7.4.3 
 Pneumonitis 
 
Pneumonitis has been reported in association with use of anti-PD-L1/anti-PD-1 
antibodies (Brahmer et al 2012). It is also seen in 5% to 15% of patients irradiated 
for breast, lung, and mediastinal tumours. The risk of developing radiation 
pneumonitis is directly related to the volume of irradiated lung, the amount of 
radiation given, and the use of concurrent chemotherapy. Additional risk factors 
include co-morbid lung disease, poor baseline pulmonary function testing, and low 
performance status. Symptoms of radiation pneumonitis, including low-grade 
fever, congestion, dry cough, pleuritic chest pain, and a sensation of chest fullness, 
usually develop 1 to 3 months after completion of radiation therapy. Diagnosis is 
difficult, often complicated by co-morbid conditions and radiation injury to adjacent 
structures (eg, oesophagus, pericardium). Prednisone, in dosages of at least 50 to 
60 mg per day for 1 week followed by an extended taper, has been shown to abate 
symptoms and improve lung function. Bronchodilators and supplemental oxygen 
may be necessary. 
 
 
7.4.4 
 Hypersensitivity Reactions 
 
Hypersensitivity reactions as well as infusion-related reactions have been reported 
with anti-PD-L1 and anti-PD-1 use (Brahmer et al 2012). As with the administration 
of any foreign protein and/or other biologic agents, reactions following the infusion 
of monoclonal antibodies can be caused by various mechanisms, including acute 

 
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anaphylactic (IgE-mediated) and anaphylactoid reactions against the monoclonal 
antibody, and serum sickness. Acute allergic reactions may occur, may be severe, 
and may result in death. Acute allergic reactions may include hypotension, 
dyspnoea, cyanosis, respiratory failure, urticaria, pruritis, angioedema, hypotonia, 
urticaria, arthralgia, bronchospasm, wheeze, cough, dizziness, fatigue, headache, 
hypertension, myalgia, vomiting and unresponsiveness. 
7.4.5 
 Hepatic Function Abnormalities (Hepatotoxicity) 
 
Increased transaminases have been reported during treatment with anti-PD-L1 
(Brahmer et al 2012). Inflammatory hepatitis has been reported in 3% to 9% of 
patients treated with anti-CTLA-4 monoclonal antibodies (eg, ipilimumab). The 
clinical manifestations of ipilimumab-treated patients included general weakness, 
fatigue, nausea and/or mild fever and increased liver function tests such as AST, 
ALT, alkaline phosphatase, and/or total bilirubin. Cases where a patient shows 
AST or ALT ≥3 x ULN or total bilirubin ≥2 x ULN may need to be reported as SAEs. 
 
7.5 
Administration, dose delay, reduction or interruption for 
Regorafenib 
 
 Regorafenib tablets should be taken as follows: 
• 
Once a day, approximately at the same time every day (the recommendation is to 
have at least a 20 hour interval between doses). 
• 
With approximately 240 mL (8 fluid ounces) of water, after a light meal that contains 
less than 30% fat. Some examples of low-fat meals are: 
o Two slices of white toast with 1 tablespoon of low-fat margarine and 1 
tablespoon of jelly and 8 ounces (240 mL) of skim milk (approximately 319 
calories and 8.2 g of fat). 
o One cup of cereal (i.e. Special K), 8 ounces (240 mL) of skim milk, one 
piece of toast with jam (no butter or marmalade), apple juice and one cup 
of coffee or tea (2 g fat, 17 g protein, 93 g of carbohydrate, 520 calories). 
•      Tablets must not be chewed 
• 
If a dose of regorafenib is missed, the missed dose should be skipped (vomited 
tablets cannot be made up), and the next dose should be taken at the regular time. 
The subsequent dose of regorafenib should not be doubled. The Investigator 
should be informed if the dose of regorafenib taken exceeded the scheduled dose. 
 
 
 
 
 
 
 
 

 
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7.5.1 
Regorafenib Dose Levels 
 
Dose Level 
Daily Dose 
Daily Dose 
Daily Dose 
Dose level patient is currently 
receiving 
90 mg 
60 mg 
30 mg 
Dose level -1 
60 mg 
30 mg 
Not permitted* 
Dose level -2 
30 mg 
Not permitted* 
Not permitted* 
* If a dose reduction is required to manage a regorafenib-related AE, then regorafenib must 
be discontinued. 
 
 
Recommended dose modification for toxicities except hand-foot-skin reaction, 
hypertension and ALT/AST/bilirubin 
NCI-CTCAE 
v5.0a 
Dose interruption 
Dose Modification b Dose for Subsequent Cycles 
Grade 0-2 
Treat on time 
No change 
Grade 3 
Delay until ≤ Grade 2c Reduce by 1 dose level 
If toxicity remains < Grade 2, 
dose re-escalation can be 
considered at the discretion of 
the treating investigator. If dose 
is re-escalated and toxicity(  
Grade 3) recurs,  institute 
permanent dose reduction. 
Grade 4 
Delay until ≤ Grade 2c 
Reduce by 1 dose level. 
Permanent 
discontinuation can be 
considered at treating 
investigator’s discretion. 
a. NCI-CTCAE = National Cancer Institute - Common Terminology Criteria for Adverse Events, 
version 5.0 
b. Excludes alopecia, non-refractory nausea/vomiting, lymphocyte count decreased, non-
refractory hypersensitivity and nonclinical and asymptomatic laboratory abnormalities. 
c. If no recovery after a 4 week delay*, treatment should be permanently discontinued unless 
subject is deriving clinical benefit. 
 
  
If greater than 2 dose level reductions are required, regorafenib will be discontinued and 
the rest of the study follow up may be continued. The following tables outline dose 
adjustments for toxicities related to regorafenib except hand-foot skin reaction, 
hypertension and liver function test abnormalities. 
 
The table above outlines dose adjustments for hematologic and non-hematologic 
toxicities related to regorafenib except PPES and hypertension. In addition to these 
recommended dose modifications, subjects who develop diarrhea, mucositis, anorexia 
or other events predisposing to fluid loss or inadequate fluid intake should be carefully 
monitored and rehydrated as clinically necessary. This is in order to minimize the risk of 
postural hypotension and renal failure. 

 
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Regorafenib Dose Modification Guidance, Non-Immune Toxicities: Hand-Foot Skin 
Reaction Related to Regorafenib Only 
 
CTCAE 
v5.0 
Grade 
Occurrence 
Recommended Management 
G1 
Any 
• 
Maintain dose level and immediately institute 
supportive measures for symptomatic relief. 
G2 
1st occurrence 
• 
Consider decreasing dose by 1 dose level and 
immediately institute supportive measures.  
• 
If no improvement, interrupt therapy for a minimum of 
7 days, until toxicity resolves to G0-1.a, b 
No improvement 
within 7 days or 2nd 
occurrence 
• 
Interrupt therapy until toxicity resolves to G0-1.b 
• 
When resuming treatment, treat at reduced dose 
level.a 
3rd occurrence 
• 
Interrupt therapy until toxicity resolves to G0-1.b 
• 
When resuming treatment, decrease dose by 1 dose 
level. 
4th occurrence 
• 
Discontinue permanently. 
G3 
1st occurrence 
• 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to G0-1. 
• 
When resuming treatment, decrease dose by 1 dose 
level. 
2nd occurrence 
• 
Institute supportive measures immediately. Interrupt 
therapy for a minimum of 7 days until toxicity resolves 
to G0-1. 
• 
When resuming treatment, decrease dose by 1 
additional dose level.  
3rd occurrence 
Discontinue permanently. 
Abbreviations: CTCAE=common terminology criteria for adverse events; G=Grade 
If reductions are required resulting in a daily dose of less than 30 mg of regorafenib, 
regorafenib will be permanently discontinued. 
Footnotes: 
a) If toxicity returns to G0-1 after dose reduction, dose re-escalation is not permitted. 
b) If there is no recovery after a 4-week delay (28 days) (including the 1 week drug 
holiday), treatment with regorafenib will be discontinued permanently. 
 
 
 
 
 
 
 

 
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Regorafenib Dose Modification Guidance, Non-Immune Toxicities: Hypertension 
 
CTCAE v5.0 
Grade 
Suggested regorafenib dose modification  
Specific guidance for Hypertension 
G1 
• 
No change. Consider increased BP monitoring. 
G2 
• 
If symptomatic, hold until symptoms resolve. At restart, continue at 
the same dose level. 
G3 
• 
Hold until diastolic BP < 100 mm Hg, and if symptomatic, until 
symptoms resolve. At restart, continue at the same dose level. 
• 
If BP is not controlled with the addition of new or more intensive 
therapy, reduce by 1 dose level. 
• 
If 
G3 
hypertension 
recurs 
despite 
dose 
reduction 
and 
antihypertensive therapy, reduce another dose level.  
G4 
• 
Discontinue permanently. 
Abbreviations: BP=blood pressure; CTCAE=common terminology criteria for adverse 
events; G=Grade; Hg=mercury  
If reductions are required resulting in a daily dose of less than 30 mg of regorafenib, 
regorafenib will be permanently discontinued. If BP remains controlled for at least one full 
cycle, dose re-escalation is permitted at the Investigator’s discretion. Patients requiring a 
delay of > 4 weeks (28 days) (including the 1 week drug holiday) should discontinue 
regorafenib treatment. However, continuation of regorafenib may be considered if, in the 
Investigator's opinion, the patient may continue to benefit from the regorafenib treatment, 
and after consultation with the Medical Monitor. 
 
Regorafenib Dose Modification Guidance, Non-Immune Toxicities: Liver Function 
Test Abnormalitiesa 
 
Increases in 
AST/ALT and/or 
bilirubin 
1st occurrence 
Restart 
Recurrence 
AST and/or ALT 
≤ to 5 x ULN, 
with normal AST 
and/or ALT at 
baseline  
Continue dosing, with weekly 
monitoring of liver function until 
transaminases return to < 3 x 
ULN (< or equal to G1) or 
baseline. 
  
  
AST and/or ALT 
> 5 x ULN  
Interrupt dosing, with weekly 
monitoring of liver function until 
transaminases return to < 3 x 
ULN or baseline. 
If the potential to reinitiate 
regorafenib is considered to 
outweigh the risk of 
hepatotoxicity: reduce 1 
dose level and measures 
serum transaminases 
weekly for at least 4 weeks. 
Discontinue 
permanently 
AST and/or ALT 
> 20 x ULN  
Discontinue permanently  and 
measure serum transaminases 
weekly until resolution. 
  
  

 
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AST and/or ALT 
> 3 x ULN with 
concurrent total 
bilirubin > 2 x 
ULN 
Discontinue permanently and 
measure serum transaminases 
weekly until resolution. 
Exception: participants with 
Gilbert’s syndrome who develop 
elevated transaminases should 
be managed as per the above 
outlined recommendations for 
the respective observed 
elevation of ALT and/or AST. 
  
  
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper 
limit of normal; G=Grade 
If reductions are required resulting in a daily dose of less than 30 mg of regorafenib, 
regorafenib will be permanently discontinued. 
Footnote: 
a) If all values remain stable for 2 full cycles, dose re-escalation may be considered at the 
discretion of the Investigator. After re-escalation AST, ALT, bilirubin should be checked 
2×/week for 2 weeks, followed by weekly assessments for at least 4 weeks.  
 
 
 
7.6 
Method of Assigning Patients to Treatment Groups 
Randomization, according to a 1:1 ratio, will be performed using centre as 
stratification variable. 
7.6.1 
Method of collection of Patients Data 
 
Data collection will be granted electronically through the internet (remote data 
entry, RDE) to data managers and clinical investigators at each clinical site using 
a safe internet based procedure, providing the best and most secure on line data 
entry process and a daily backup of all collected data. RDE will be done via 
connection only after the identification via individual user name and password. 
For each clinical site, individual user names and passwords will be granted to the 
principal investigator and to qualified delegated staff members by GISCAD upon 
reception of a delegation log form dated and signed by all the staff members 
involved in the trial and the documentation of the affirmative decision of the IEC 
that the clinical trial has been reviewed and may be conducted at the institution site 
within the constraints set by the IEC, the institution, GCP, and the applicable 
regulatory requirements (ICH E6). 
 
7.7 
Prior and Concomitant Therapies 
All relevant medications administered within 4 weeks prior to the randomization 
visit are to be recorded as prior medications; medications administered from the 
time of signing the ICF are to be recorded as concomitant medications. Both prior 
and concomitant medications are to be documented in the eCRF. 
 

 
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7.8 
Prohibited Therapies 
Prohibited medication/class of drug: Usage: 
Any investigational anticancer therapy 
other than those under investigation in 
this study 
Should not be given concomitantly whilst the 
patient is on study treatment 
mAbs against CTLA-4, PD-1, or PD-L1 
other than those under investigation in 
this study 
Should not be given concomitantly whilst the 
patient is on study treatment 
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or 
biologic or hormonal therapy for cancer 
treatment other than those under 
investigation in this study 
Should not be given concomitantly whilst the 
patient is on study treatment. (Concurrent 
use of hormones for non-cancer-related 
conditions [e.g., insulin for diabetes and 
hormone replacement therapy] is 
acceptable. Local treatment of isolated 
lesions, excluding target lesions, for 
palliative intent is acceptable [e.g., by local 
surgery or radiotherapy]) 
Immunosuppressive medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding 10 
mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers 
Should not be given concomitantly, or used 
for premedication prior to the I-O infusions. 
The following are allowed exceptions: 
• Use of immunosuppressive 
medications for the management of 
IP-related AEs. 
• Use in patients with contrast allergies.  
• Use of inhaled, topical, and intranasal 
corticosteroids is permitted. 
 
A temporary period of steroids will be 
allowed if clinically indicated and considered 
to be essential for the management of non-
immunotherapy related events experienced 
by the patient (e.g., chronic obstructive 
pulmonary disease, radiation, nausea, etc.). 
Live attenuated vaccines 
Should not be given through 30 days after 
the last dose of IP (including SoC) 
Herbal and natural remedies which 
may have immune-modulating effects 
Should not be given concomitantly unless 
agreed by the sponsor 
Patients in any arm who take prohibited medications will be considered protocol 
violators and thus excluded from the present study. 
7.9 
Treatment Compliance 
The details of each administration of study treatment will be documented in the 
eCRF. 

 
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8 
STUDY VISITS AND PROCEDURES 
The timing of all assessments and procedures is detailed in Section 8.1; details of 
procedures and assessments to be done are provided in Section 8.2; Schedules 
of Events for pre-randomization, treatment periods and long term follow-up are 
provided in Table 1, Table 2 and Table 3.  
Any procedures other than those indicated will be considered SoC of the facility, 
and not part of the study. Data from any CEA/CA 19-9 analyses or CT scans done 
as part of SoC procedures should be collected and recorded in the eCRF. 
 
For all treatment arms 
 Tumor efficacy (RECIST) assessment dates are not affected by dose delays and 
remain as originally scheduled, as they are based on the date of randomization 
(not the date of therapy). 
All other scheduled assessments must be performed relative to the start of the 
dosing cycle such that all laboratory procedures, etc. required for dosing should be 
performed within 3 days prior to dosing. 
 
For durvalumab + regorafenib combination arms 
Patients may delay dosing under certain circumstances.  
• Dosing may be delayed per Toxicity Management Guidelines, due to either 
an immune or a non-immune-related AE. 
• If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible 
• Dosing intervals of subsequent cycles may be shortened as clinically 
feasible in order to gradually align treatment cycles with the schedule of 
tumor efficacy (RECIST). Subsequent time between 2 consecutive doses 
cannot be less than 22 days, based on the half-lives of durvalumab (see 
current Investigator Brochure for durvalumab).  
 
Standard of Care Arm: 
Patients may delay and subsequently resume dosing per local standard clinical 
practice. 
If dosing must be delayed for reasons other than treatment-related toxicity, dosing 
will occur as soon as feasible. 
 
 
 
 
 

 
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8.1 
Study Visits 
8.1.1 
Screening 
 
Screening, to verify inclusion and exclusion criteria, will include: 
1. 
obtaining written informed consent from patient or legally authorised 
representative (Section 8.2.1.1) 
2.    Review of eligibility criteria 
3. 
documentation of demographics and medical history (Section 8.2.1.2)  
4. 
Complete physical examination (Section 8.2.2.1) 
5. 
vital signs (Section 8.2.2.2) 
6. 
ECOG performance status (Section 8.2.2.3) 
7. 
12-lead electrocardiogram (ECG; Section 8.2.2.4) 
8. 
clinical chemistry, coagulation profile and haematology (Section 8.2.2.45) 
9. 
CEA and CA 19-9 analysis, backup plasma sample (Section 8.2.3.2) 
10. pregnancy test (serum or urine) for female patients of child-bearing 
potential (Section 8.2.1.3); patients with positive results will be 
discontinued from the study with no further study procedures performed 
11. CT/MRI/PET scan of chest and abdomen with tumor measurement and 
evaluation by RECIST 1.1 criteria (Section 8.2.3.3) 
12. documentation of prior and concomitant medications (Section 7.7) 
13. Histological confirmation 
 
Patients who meet the inclusion/exclusion criteria (Section 6) will be randomized to 
one of the following: 
1. 
Treatment arm (Regorafenib + Durvalumab) 
2. 
Control arm 
 
8.1.2 
 Treatment Phase: Table 2 and 3.   
 
Patients allocated to regorafenib + durvalumab arm will undergo visits every week 
for the first cycle, every 2 weeks for the second cycle, and monthly thereafter.  
Patients allocated to the control group will undergo visits every 12 weeks.  
If at any time a relapse is confirmed, the patient will discontinue treatment. Patients 
in the control arm will be offered to crossover to regorafenib plus durvalumab.  
 
All visits have a window of ± 7 days. 
 
• Patients allocated to Treatment arms will undergo the following procedures 
and assessments: 
At each visit:  

 
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1. Limited physical examination  
2. vital signs  
3. ECOG performance status  
4. Weight 
5. Clinical chemistry and haematology (CBC + differential platelet count; 
creatinine; total bilirubin; AST; ALT; alkaline phosphatase; LDH; albumin; 
glucose; potassium; sodium; calcium) 
6. administration of therapy (regorafenib plus durvalumab at Day 1 of every 
cycle) 
7. documentation of AEs/SAEs  
8. documentation of concomitant medications and procedures (at Day 1 of 
every cycle) 
9. CEA and CA19-9 analysis and CT/MRI/PET scan as per baseline 
assessment: every 12 weeks. From day 1 (± 7 days). 
 
• Patients allocated to no further treatment (Control Group) will undergo the 
following procedures and assessments: 
at each visit (every 12 weeks.) 
1. 
physical examination  
2. 
vital signs  
3. 
ECOG performance status  
4. 
Weight 
5. 
pregnancy test (serum or urine) for female patients of child-bearing 
potential 
6. 
Clinical chemistry and haematology (CBC + differential platelet count; 
creatinine; total bilirubin; AST; ALT; alkaline phosphatase; LDH; 
albumin; glucose; potassium; sodium; calcium) 
7. 
documentation of AEs/SAEs  
8. 
documentation of concomitant medications and procedures 
9. 
CEA and CA 19-9 analysis 
10. CT/MRI/PET scan as per baseline assessment 
 
8.1.3 
 End of treatment 
 
End of treatment is defined as the last planned dosing visit within the 12-month 
dosing period. For patients who discontinue durvalumab prior to 12 months, end of 
treatment is considered the last visit where the decision is made to discontinue 
treatment. All required procedures may be completed within ±7 days of the end of 

 
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treatment visit. Repeat disease assessment is not required if performed within 28 
days prior to the end of treatment visit. 
Assessments for patients who have completed the treatment and achieved disease 
control, or have discontinued durvalumab due to toxicity in the absence of 
confirmed progressive disease: 
1. Prior/concomitant medications 
2. Complete physical examination  
3. Vital signs  
4. ECOG performance status  
5. 12 - lead ECG 
6. Tumor imaging/response assessment  
7. Clinical chemistry and haematology (CBC + differential platelet count; 
creatinine; total bilirubin; AST; ALT; alkaline phosphatase; LDH; albumin; 
glucose; potassium; sodium; calcium) 
8. Documentation of AEs/SAEs 
 
8.1.4 
 Follow-up 
 
During the early follow-up phase (Month 13-Month 24, Table 2 and 3) all patients 
will undergo the following visits every 3 months.  
During the late follow-up phase (Month 25 to Month 60) all patients will undergo 
the following visits every 4-6 months.  
1. 
Safety assessments 
2. 
Physical examination 
3. 
Vital signs 
4. 
Eastern Cooperative Oncology Group [ECOG] performance status 
5. 
CT/MRI/PET scan as per Investigator’s choice 
6. 
CEA and CA 19-9 analysis 
7. 
Clinical chemistry and haematology (CBC + differential platelet count; 
creatinine; total bilirubin; AST; ALT; alkaline phosphatase; LDH; albumin; 
glucose; potassium; sodium; calcium; amylase; lipase) 
8. 
Concomitant medications 
9. 
For patients with documented relapse: visit (according to SoC) or telephone 
contact to document OS. 
 
8.2 
Study Procedures 
All study related investigations are to be performed by the Investigator or medically 
qualified study personnel delegated by the Investigator. The Investigator is 
considered responsible for the overall treatment of the patient. 
All procedures will be carried out at the times indicated in Table 1, Table 2, and 
Table 3 and in Section 8.1. 

 
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8.2.1 
 Enrolment Procedures 
8.2.1.1 
Informed consent 
 
Before inclusion into the study, each patient will be informed, both verbally and in 
writing, about the nature of the study, the anticipated risks and discomfort 
associated with the study and also about the right to discontinue participation in 
the study at any time. 
Prior to participation in the study, each patient will have signed the written ICF 
which has been approved by the Independent Ethics Committee (IEC). 
No study activities may take place until the informed consent documents have been 
signed. 
 
8.2.1.2 
Demographics and medical history 
 
All relevant hospital records are to be made available to the Investigator prior to 
randomization. Medical history includes details of: any neoadjuvant or adjuvant 
chemotherapy; surgical or other procedure; tissue samples and documentation 
relating to tumour assessment; and prior antitumoral drugs.  
 
8.2.1.3 
Pregnancy test 
 
A serum or urine pregnancy test will be administered to all female patients of 
childbearing potential, defined as follows:  
- Premenopausal women capable of becoming pregnant, including women on 
oral, injectable or mechanical contraception. 
 
If the result of the pregnancy test is positive, the patient will be withdrawn from the 
study prior to administration of study treatment. 
Female patients who become pregnant during the study or within 6 months after 
receiving the last administration of study treatment will be followed through birth or 
termination of the pregnancy. The Investigator or designee must report all 
pregnancies to the Study Contact for Reporting Serious Adverse Events (Section 
9.2) immediately after becoming aware of the event. 
8.2.2 
 Safety Assessments 
8.2.2.1 
Physical examination 
 
Physical examinations will include height (at screening), weight, and a general 
assessment of overall body systems (cardiovascular, respiratory, gastrointestinal, 
etc.). 

 
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8.2.2.2 
Vital signs 
 
Assessment of vital signs includes systolic and diastolic blood pressure, heart rate, 
body temperature and respiratory rate. Body temperature should be measured 
using the same methodology at each assessment and it should be measured in 
decimals. 
 
8.2.2.3 
Eastern Cooperative Oncology Group performance 
status 
 
The ECOG performance status is a standardised set of scales and criteria used to 
assess how a patient's disease is progressing, how the disease affects the daily 
living abilities of the patient and to determine appropriate treatment and prognosis. 
The assessment is provided in Appendix 1. 
 
8.2.2.4 
Electrocardiogram 
 
Perform a 12-lead resting electrocardiogram (ECG) before the begin of the 
treatment, at the end-of-treatment and if clinically indicated. Patients should be in 
a supine position for at least 10 min before recording. ECG tracings will be 
reviewed by a qualified physician for assessment of QT interval as well as signs of 
qualitative abnormalities, including evaluation of rhythm, ST segment morphology, 
T wave morphology, and presence/absence of U wave. 
The original ECG tracing will be maintained in the source documentation of each 
patient. 
 
8.2.2.5 
Clinical chemistry, coagulation and hematology 
 
The Investigator must review the laboratory assessments (initialled and dated) 
within 24 hours after the receipt of results. Out of range values will be interpreted 
by the Investigator with a comment of “not clinically significant” (NCS) or “clinically 
significant” (CS). Clinically significant abnormal laboratory values must be repeated 
at the appropriate clinical follow-up arranged by the Investigator and documented 
on the lab report until the lab value has stabilised or has returned to a clinically 
acceptable range (regardless of relationship to study treatment). Any laboratory 
value that remains abnormal and is judged to be clinically significant will be 
followed according to accepted medical standards for 30 days or until resolution of 
the abnormality. 
Procedure does not have to be repeated if performed within 72 hours prior to Cycle 
1 Day 1 (i.e. first day of dosing). 

 
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All haematology, coagulation and blood chemistry samples will be processed at 
the local laboratory according to institutional procedures. Blood samples will be 
collected for the following analyses: 
Chemistry  
o albumin 
o total bilirubin 
o alkaline phosphatase (ALP) 
o alanine aminotransferase (ALT) 
o aspartate aminotransferase (AST) 
o LDH 
o glucose 
o sodium 
o potassium 
o chloride 
o magnesium 
o urea 
o calcium 
o creatinine 
o total protein 
o amylase 
o lipase 
 
Coagulation Profile  
o aPTT 
o PT 
o INR 
  
 
 
Haematology profile (complete blood count [CBC]) 
o red blood cell (RBC) count  
o white blood cell (WBC) count and differential (neutrophils, eosinophils, 
limphocytes, monocytes, basophils) 
o haemoglobin (Hgb) 
o haematocrit (Hct) 
o platelet count 
 
A Plasma sample will be stored for potential future research for which specific 
experimental plan and informed consent form will be developed 
 
 
8.2.2.6 
Adverse events (AEs) 
 
After informed consent is obtained, AEs will be recorded continuously through the 
study conduct, and managed as outlined in Section 9 and according to the Safety 
Management Plan developed for this study. Events that occur prior to initiation of 
study treatment will be assessed as “not related” to study medication; AEs that 
occur after the first administration of study medication will be assessed as 
treatment-emergent AEs (TEAEs).  

 
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Adverse events will be categorised based on severity; relationship to study 
treatment and seriousness and according to National Cancer Institute’s Common 
Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0. 
 
8.2.3 
 Efficacy Assessments 
 
8.2.3.1 
Relapse 
 
Any of the following events will be considered as relapse: loco-regional recurrence 
(as defined in Section 3.3.1), distant metastases, death from same cancer or death 
from other cancer, non-cancer-related death, and treatment-related death. 
 
A positive CT/MRI/PET scan (appearance of a lesion) will be considered evidence 
of relapse. Two consecutive increases in CEA levels above upper limit level (time 
gap decided by the clinical investigator). 
 
Confirmation of progression guidelines are set for the following reasons:  
• 
for patient management and treatment decisions 
• 
in the absence of significant clinical deterioration, to promote the collection 
of additional scans after the first radiologic RECIST 1.1 assessment of 
progressive disease (PD) in order to distinguish pseudoprogression from 
true radiologic progression, also known as RECIST 1.1 modified for 
confirmation of progression 
• 
when scans are evaluated by Investigator and by BICR, to reduce 
informative censoring by Investigator assessments (Investigator assesses 
PD at a time-point earlier than does BICR). 
Confirmed objective disease progression refers to either of the following 
scenarios: 1. clinical progression/deterioration followed by a radiologic verification 
scan (PD by RECIST 1.1); or 2. in the absence of significant clinical deterioration, 
radiologic PD by RECIST 1.1 followed by a second radiologic confirmation scan 
with PD assessed according to the specific confirmation of progression criteria 
listed below. RECIST 1.1 modified for confirmation of progression refers to the 
second scenario above. The confirmatory scan should occur preferably at the 
next scheduled imaging visit and no earlier than 4 weeks following the date of the 
immediate prior assessment of RECIST 1.1 PD. 
Immediate prior radiologic progression would be considered confirmed if any the 
following criteria are met in the confirmatory scan: 
• 
≥20% increase in the sum diameters of target lesions (TLs) compared with 
the nadir at 2 consecutive visits, with an absolute increase of at least 5 mm 
in sum of diameters compared to nadir, 
• 
and/or significant progression (worsening) of non-target lesions (NTLs) 
and/or of pre-existing new lesions at the confirmatory scan time-point 

 
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compared with the immediate prior time-point (Note: Pre-existing new 
lesions are evaluated as NTLs at the confirmatory scan time-point), 
• 
and/or additional new unequivocal lesions at the confirmatory scan time-
point. 
NOTE: In order to have confirmed objective disease progression, there should be 
two consecutive assessments meeting the PD definition:  the first PD by RECIST 
1.1 and the second PD using the confirmation of progression criteria (above). If 
the first assessment fulfilling the PD definition by RECIST 1.1 is not confirmed, 
continue with assessments until the next PD by RECIST 1.1, which in turn will 
need its own immediate subsequent confirmation scan. In the absence of 
significant clinical deterioration, treatment with study drug may continue between 
the initial assessment of progression and the scan to confirm progression. 
If the confirmation scan confirms progression, then the date of the prior scan with 
PD should be declared as the date of progression. 
If progression is not confirmed, in the absence of significant clinical deterioration, 
then the patient should continue study drug and on-treatment assessments until 
the next PD which will also require a follow-up confirmation scan. If the first PD is 
not confirmed by the immediate next scan, then the Investigator should not 
change the PD assessment of the first scan. 
If a patient discontinues treatment (and/or receives a subsequent anticancer 
therapy) prior to radiologic progression, then the patient should still continue to be 
followed until confirmed objective disease progression. 
 
8.2.3.2 
Carcinoembryonic antigen and CA 19-9 
 
Blood will be collected for assessment of CEA and CA 19-9 as markers of potential 
relapse of CRC. Samples will be analysed at the local laboratory. 
Data from CEA and CA 19-9 analyses done at any times other than those specified 
for this study, i.e., done as part of SoC of the facility, will be collected for the eCRF. 
 
8.2.3.3 
Computed 
tomography 
and 
magnetic 
resonance 
imaging 
 
CT/MRI/PET scans will be done to detect relapse, as specified by the objectives 
and endpoints of the study, and to confirm a diagnosis of relapse at any time during 
the study (Section 3.3.1). 
While scans will be done as per SoC of the facility, minimal standards for 
CT/MRI/PET procedures will be provided. Data from CT/MRI/PET scans done at 
any times other than those specified for this study, i.e., done as part of SoC of the 
facility, will be collected for the eCRF. 
 

 
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8.3 
Appropriateness of Measurements 
All measurements will be carried out according to standard methodologies and to 
ensure patient safety. The methods used in this study are commonly regarded as 
reliable and valid, and relevant to the indication. The design of this study is a design 
for the assessment of efficacy, safety, and tolerability in a Phase IIb study, including 
use of the ECOG Performance Scale. CT/MRI/PET scans and CEA/CA 19-9 have 
been included for the purposes of this study and the timing is that patients would 
be undergoing CT/MRI/PET scans and CEA/CA 19-9 as part of SoC treatment and 
follow-up of NED CRC patients. 
 
 
 

 
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9 
ADVERSE EVENT ASSESSMENTS 
The criteria outlined in this section will be used to evaluate each patient before, 
during, and after treatment to determine the safety associated with the patient’s 
treatment and study procedures. The safety of the investigational treatments will 
be assessed by evaluating the nature and frequency of Adverse Events (AEs). 
Details of the management of Serious Adverse Events (SAEs) will be further 
documented in the Safety Management Plan developed for this study.  
 
Clinical laboratory tests 
Clinical laboratory safety tests, including serum pregnancy tests, will be performed 
in a licensed clinical laboratory according to local standard procedures. Sample 
tubes and sample sizes may vary depending on the laboratory method used and 
routine practice at the site. Pregnancy tests may be performed at the site using a 
licensed test (urine or serum pregnancy test). Abnormal clinically significant 
laboratory results should be repeated as soon as possible (preferably within 24 to 
48 hours). 
 
Other safety assessments 
If new or worsening pulmonary symptoms (e.g., dyspnea) or radiological 
abnormality suggestive of pneumonitis/ILD is observed, toxicity management as 
described in detail in the Dosing Modification and Toxicity Management 
Guidelines (see Appendix 1) will be applied. The results of the full diagnostic 
workup (including high-resolution computed tomography [HRCT], blood and 
sputum culture, hematological parameters, etc.) will be captured in the eCRF. It is 
strongly recommended to perform a full diagnostic workup, to exclude alternative 
causes such as lymphangitic carcinomatosis, infection, allergy, cardiogenic 
edema, or pulmonary hemorrhage. In the presence of confirmatory HRCT scans 
where other causes of respiratory symptoms have been excluded, a diagnosis of 
pneumonitis (ILD) should be considered and the Dosing Modification and Toxicity 
Management Guidelines should be followed.  
The Principal Investigator is responsible for ensuring that all staff involved in the 
study is familiar with the content of this section. 
 
9.1 
Definitions 
9.1.1 
 Adverse Events (AEs) 
 
According to the International Conference of Harmonization (ICH), an AE is any 
untoward medical occurrence in a clinical investigation subject (patient) 
administered a pharmaceutical product and which does not necessarily have a 
causal relationship with this 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 considered related to the investigational product. Pre-existing 
conditions which worsen during a study are to be considered as AEs. 

 
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An AE that occurs after signing informed consent but prior to the first administration 
of study treatment will be considered not related to study treatment. 
 
9.1.2 
  Definition of adverse events of special interest (AESI) 
 
An adverse event of special interest (AESI) is one of scientific and medical 
interest specific to understanding of the Investigational Product and may require 
close monitoring. An AESI may be serious or non-serious.  
If the Investigator has any questions in regards to an event being an imAE, the 
Investigator should promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
• 
Diarrhea / Colitis and intestinal perforation 
• 
Pneumonitis / ILD 
• 
Hepatitis / transaminase increases 
• 
Endocrinopathies (i.e. events of hypophysitis/hypopituitarism, adrenal 
insufficiency, hyper- and hypothyroidism and type I diabetes mellitus) 
• 
Rash / Dermatitis 
• 
Nephritis / Blood creatinine increases 
• 
Pancreatitis / serum lipase and amylase increases   
• 
Myocarditis 
• 
Myositis / Polymyositis 
• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia 
gravis) 
• 
Intestinal Perforations 
 
Other inflammatory responses that are rare/less frequent with a potential 
immune-mediated etiology include, but are not limited to: 
• 
Pericarditis 
• 
Sarcoidosis 
• 
Uveitis 
• 
Other events involving the eye and skin 
• 
Hematological events 
• 
Rheumatological events 
• 
Vasculitis 
• 
Non-infectious meningitis 
• 
Non-infectious encephalitis.  

 
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It is possible that events with an inflammatory or immune mediated mechanism 
could occur in nearly all organs. 
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions 
with a different underlying pharmacological aetiology are also considered AESIs. 
Further information on these risks (e.g. presenting symptoms) can be found in the 
current version of the durvalumab Investigator’s Brochure. More specific guidelines 
for their evaluation and treatment are described in detail in the Dosing Modification 
and Toxicity Management Guidelines (please see Appendix 1). These guidelines 
have been prepared by the Sponsor to assist the Investigator in the exercise of 
his/her clinical judgment in treating these types of toxicities.  These guidelines 
apply to AEs considered causally related to the study drug/study regimen by the 
reporting investigator. 
 
9.1.3 Serious Adverse Event (SAEs) 
 
A SAE is any experience that suggests a significant hazard, contraindication, 
side effect or precaution. It is any AE that at any dose fulfils at least one of the 
following criteria: 
 is fatal (results in death)1 ; 
 is Life-Threatening2 ; 
 required in-patient hospitalization or prolongation of existing hospitalization; 
 results in persistent or significant disability/incapacity; 
 is a congenital anomaly/birth defect; 
 is medically significant or requires intervention to prevent one or other of the 
outcomes listed above. Medical or scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in this situation. 
Examples of medically important events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or 
convulsions that do not result in hospitalizations; or development of drug 
dependency or drug abuse. 
Adverse Events (AEs) for malignant tumours reported during a study should 
generally be assessed as Serious AEs. If no other seriousness criteria apply, the 
‘Important Medical Event’ criterion should be used. In certain situations, however, 
medical judgement on an individual event basis should be applied to clarify that 
the malignant tumour event should be assessed and reported as a Non-Serious 
AE. For example, if the tumour is included as medical history and progression 
                                                 
1 Death is an outcome, not an event. The term sudden death should be used only when the cause 
is of a cardiac origin as per standard definition. The terms death and sudden death are clearly 
distinct and must not be used interchangeably. 
 
2 the term "Life-Threatening" refers to an event in which the patient was at immediate risk of death 
at the time of the event; it does not refer to an event which could hypothetically have caused a 
death if had it been more severe 

 
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occurs during the study, but the progression does not change treatment and/or 
prognosis of the malignant tumour, the AE may not fulfill the attributes for being 
assessed as Serious, although reporting of the progression of the malignant tumor 
as an AE is valid and should occur. Also, some types of malignant tumours, which 
do not spread remotely after a routine treatment that does not require 
hospitalization, may be assessed as Non-Serious; examples include Stage 1 basal 
cell carcinoma and Stage 1A1 cervical cancer removed via cone biopsy. 
The above instruction applies only when the malignant tumour event in question 
is a new malignant tumour (i.e., it is not the tumour for which entry into the study 
is a criterion and that is being treated by the IP under study and is not the 
development of new or progression of existing metastasis to the tumour under 
study). Malignant tumours that – as part of normal, if rare, progression – undergo 
transformation (e.g., Richter's transformation of B cell chronic lymphocytic 
leukemia into diffuse large B cell lymphoma) should not be considered a new 
malignant tumour. 
Hospitalisation will not be considered a SAE for the following cases: 
- 
hospitalisation or prolongation of hospitalisation for a procedure required by 
the study Protocol 
- 
hospitalisation or prolongation of hospitalisation is part of a routine procedure 
followed by the study site 
- 
hospitalisations or prolongation of hospitalisation due to merely diagnostic 
reasons, planned surgery, planned chemotherapy. 
 
Merely the introduction of a patient in the emergency room does not fulfil the criteria 
“hospitalisation” without subsequent admission. 
Medical and scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations, such as important medical events that 
are not immediately life-threatening or do not result in death or hospitalisation. 
 
9.1.4     Adverse Drug Reaction (ADR) 
 
All AE related to the medicinal (investigational) product at any dose should be an 
ADR.  
An ADR, the nature or severity of which is not consistent with the applicable product 
information is an Unexpected adverse drug reaction. 
9.1.5     Suspected Unexpected Serious Adverse Reaction (SUSAR) 
 
When an SAE is recognized as unexpected and its correlation with the 
investigational product cannot reasonably be excluded, it is classified as 
Suspected Unexpected Serious Adverse Reaction (SUSAR). 
 

 
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9.1.6 
 Classification of AEs 
 
ALL AE will be classified on the basis of its intensity and relatedness to study 
treatments. The relationship between an AE and the study treatments will be 
determined by the Investigator on the basis of his or her clinical judgment and the 
following definitions: 
 
9.1.6.1 Intensity 
 
Intensity of all AEs will be graded according to the NCI Common Terminology 
Criteria for Adverse Events v 5.0 (CTCAE v 5.0; most recent sub-version), on a 
five-point scale (Grade 1 to 5) and reported in detail on the CRF. 
AEs not listed on the CTCAE should be graded as follows:  
Table 6.  
Grading of AEs not listed on the CTCAE  
CTC Grade Equivalent to: 
Grade 1 (Mild) 
Mild Discomfort noticed but no disruption of normal daily 
activity 
Grade 2 (Moderate) 
 
Moderate Discomfort sufficient to reduce or affect daily 
activity; no treatment or medical intervention is indicated 
although this could improve the overall well-being or 
symptoms of the patient 
Grade 3 (Severe) 
Severe Inability to work or perform normal daily activity; 
treatment or medical intervention is indicated in order to 
improve the overall wellbeing or symptoms; delaying the 
onset of treatment is not putting the survival of the patient 
at direct risk 
Grade 4 (Life 
threatening) 
Life threatening/disabling. An immediate threat to life or 
leading to a permanent mental or physical conditions that 
prevents work or performing normal daily activities; 
treatment or medical intervention is required in order to 
maintain survival 
Grade 5 (Death) 
AE resulting in death 
 
 
9.1.7 Trial Relationship to Study Drug  
 
The investigator will evaluate the relationship of the adverse events to the study 
product based on the following definitions:  
 
 

 
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Table 7.  
AEs Relatedness to the study chemotherapy 
Definite/Certain (yes) are terms applied to an adverse events which have a timely 
relationship to the study drug and no alternative etiology is 
present. The adverse event must have occurred within a 
reasonable 
temporal 
sequence 
of 
the 
chemotherapy 
administration, must not be reasonably explained, and must 
follow a known pattern of response 
Probable         (yes) 
means that the adverse event has a timely relation to the study 
drug and a potential alternative etiology is not apparent (i.e., 
fever or malaise when no other symptoms suggestive of an 
illness are present) 
Possible          (yes) 
means that the adverse event has a timely relation to the study 
drug; however, a potential alternative etiology exists, which 
may be responsible for the symptom (i.e., fever or malaise 
when other symptoms are present that suggest another 
etiology such as upper respiratory infection) 
Unrelated/Unlikely     
(No) 
means that the adverse event is applied to those adverse 
events for which evidence exists that the symptom is definitely 
related to an etiology other than the study drug (i.e., car 
accident, or a symptom suggestive of another illness that is not 
accepted to have a possible relatedness to chemotherapy). 
 
9.1.8 
 Follow-up of Adverse Event 
 
The Investigator must continue to monitor the following events until they resolve or 
until the Investigator assesses them as chronic or stable: 1) all SAEs; 2) any 
non-serious events assessed as possibly, probably, or definitely related to the 
study treatment; and 3) any SAEs or AEs that lead to study withdrawal. This follow 
up will be extended through the end of the study. 
 
9.1.9 
 Follow-up of Abnormal Laboratory Test Values 
 
In the event of medically significant unexplained abnormal laboratory test values, 
the tests should be repeated and followed up until they have returned to the normal 
range and/or an adequate explanation of the abnormality is found. If a clear 
explanation is established it should be recorded on the CRF. 
 
9.2 
Reporting of Adverse Events 
AEs: At each study visit the Investigator, will determine whether any AEs have 
occurred. Any AEs will be reported in the patient’s medical record and on the AE 
eCRF page and each will be classified according to the criteria above. Adverse 
event reporting for each patient starts when the patient signs the Informed Consent 

 
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Form (ICF). Any pre-existing conditions that are detected as part of the initial pre-
randomization procedures will need to be reported in the medical history and not 
as an AE. However, pre-existing conditions that worsen after enrolment should be 
reported as an AE. 
SAEs: AEs and SAEs will be collected from the time of the patient signing the 
informed consent form until the follow-up period is completed (90 days after the 
last dose of durvalumab). If an event that starts post the defined safety follow up 
period noted above is considered to be due to a late onset toxicity to study drug 
then it should be reported as an AE or SAE as applicable. 
During the course of the study, all AEs and SAEs should be proactively followed 
up for each patient for as long as the event is ongoing.  Every effort should be 
made to obtain a resolution for all events, even if the events continue after the 
patient has discontinued study drug or the study has completed. 
The Sponsor retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
9.3 
Hy’s Law 
Cases where a patient shows elevations in liver biochemistry may require further 
evaluation and occurrences of AST or ALT ≥3 × ULN together with total bilirubin 
≥2 × ULN may need to be reported as SAEs. Please refer to Appendix 1 for further 
instruction on cases of increases in liver biochemistry and evaluation of Hy’s law. 
 
9.4 
New cancers 
The development of a new cancer should be regarded as an SAE. New primary 
cancers are those that are not the primary reason for the administration of the IP 
and have been identified after the patient’s inclusion in this study. 
 
9.5 
Deaths 
All deaths that occur during the study treatment period, or within the protocol-
defined follow-up period after the administration of the last dose of study drug, 
must be reported as follows: 
• 
Death clearly resulting from disease progression should be reported to the 
Study Monitor/Physician at the next monitoring visit and should be 
documented in the eCRF in the Statement of Death page. It should not be 
reported as an SAE. 
• 
Where death is not due (or not clearly due) to progression of the disease 
under study, the AE causing the death must be reported to the Study 
Monitor/Physician as an SAE within 24 hours. It should also be documented 
in the Statement of Death page of eCRF. 
• 
The report should contain a comment regarding the co involvement of PD, 
if appropriate, and should assign main and contributory causes of death. 
• 
Deaths with an unknown cause should always be reported as an SAE. It 
should also be documented in the Statement of Death page in the eCRF. 

 
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• 
A post mortem may be helpful in the assessment of the cause of death, and 
if performed, a copy of the post-mortem results should be forwarded to 
Sponsor Safety Desk  
Deaths occurring after the protocol defined safety follow up period after the 
administration of the last dose of study drug should be documented in the 
Statement of Death page. If the death occurred as a result of an event that started 
after the defined safety follow up period and the event is considered to be due to 
a late onset toxicity to study drug, then it should also be reported as an SAE. 
Death should be considered an outcome and not a distinct event.  The event or 
condition that caused or contributed to the fatal outcome should be reported as 
the single medical concept. If the cause of death is unknown and cannot be 
ascertained at the time of reporting, "unexplained death" should be reported as 
SAE term.  If the cause of death later becomes available (e.g., after autopsy), 
"unexplained death" should be replaced by the established cause of death.  The 
term “sudden death” should only be used for the occurrence of an abrupt and 
unexpected death due to presumed cardiac causes in a patient with or without pre-
existing heart disease, within 1 hour of the onset of acute symptoms or, in the case 
of an unwitnessed death, within 24 hours after the patient was last seen alive and 
stable. If the cause of death later becomes available (e.g. after autopsy), “sudden 
death” should be replaced by the established cause of death. 
 
9.6 
Reporting of serious adverse events to Sponsor 
To ensure patient safety, all SAEs, regardless of suspected causality, occurring 
from the time of enrolment must be immediately reported to Sponsor, and always 
within 24 hours of learning of its occurrence.   
All identified SAEs must be recorded and described on the appropriate SAE form 
of the eCRF. All forms must be dated and signed by the responsible investigator 
or sub-investigator and sent by email or fax within 24 hours of the initial 
observation of the event to the Sponsor safety desk:  
Laboratory of Methodology for Clinical Research 
Istituto di Ricerche Farmacologiche Mario Negri IRCCS 
Study Safety Desk   
Email: safetydesk.rc@marionegri.it 
Fax: + 39 02 3571800 
Any new or additional significant information regarding an SAE must be reported 
as follow-up to the original episode within 24 hours of the investigator receiving the 
follow-up information.  
New significant information includes the following: 
• New signs or symptoms or a change in the diagnosis 
• A new serious criterion met or worsening of severity 
• Significant new diagnostic test results 

 
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• Change in causality based on new information 
• Change in the event's outcome, including recovery 
• Additional narrative information on the clinical course of the event 
Once an SAE is detected, it should be followed until its resolution or until it is judged 
to be permanent. Follow-up information is sent to the same contact(s) to whom the 
initial SAE report form was sent, accessing the original SAE report form and 
completing the section dedicated to follow-up reporting.  
The repetition of the same SAE after its resolution should be reported as a second 
separate event.   
 
9.7 
Other events requiring reporting 
9.7.1 
 Overdose 
 
An overdose is defined as a patient receiving a dose of durvalumab in excess of 
that specified in the Investigator’s Brochure, unless otherwise specified in this 
protocol. 
Any overdose of a study patient with durvalumab, with or without associated 
AEs/SAEs, is required to be reported within 24 hours of knowledge of the event to 
the sponsor. 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. There is 
currently no specific treatment in the event of an overdose of durvalumab.  
The investigator will use clinical judgment to treat any overdose. 
 
9.7.2 
 Hepatic function abnormality 
 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s 
Law case in a study patient, 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. The criteria for a potential Hy’s Law case 
is Aspartate Aminotransferase (AST) or Alanine Aminotransferase (ALT) ≥3x 
Upper Limit of Normal (ULN) together with Total Bilirubin (TBL) ≥2xULN at any 
point during the study following the start of study medication irrespective of an 
increase in Alkaline Phosphatase (ALP). 
• 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 patient will be based on the clinical judgment 
of the investigator. 
• If no definitive underlying diagnosis for the abnormality is established, 
dosing of the study patient must be interrupted immediately. Follow-up 

 
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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.  
 
9.7.3 
 Reporting of SUSARs to the Competent Authorities / 
Independent Ethics Committees 
 
All SUSAR will be notified by Sponsor or its delegated to Competent Authority, 
investigators and Ethics Committees in the manner and time provided by law. 
In accordance with Community Legislation, Regulation 726/2004 and Directive 
2001/83/EC (and subsequent amendments) and Agenzia Italiana del Farmaco 
(AIFA) determination 20/09/2012:“Adozione delle linee guida CT-3 (giugno 2011 
della C.E. di attuazione della Direttiva 2001/20/CE, delle linee guida ICH E2F 
(settembre 2011)”, all SUSAR will be sent electronically to EudraVigilance by the 
Sponsor or designee. Competent Authority (AIFA) will be aware of the SUSAR 
through EudraVigilance. 
 
9.7.4 
Immediate Reactogenicity  
 
Immediate reactions occurring within the first 15 minutes after administration of the 
study drug and treatment of the reactions will be reported in the patient’s medical 
record and on the treatment eCRF page (i.e., hives, difficulty breathing, 
anaphylaxis and other severe reactions) and observations and treatment recorded. 
Reactions fulfilling the criteria for a SAE should be reported as such. 
 
9.7.5 
Relapse of Underlying Malignancy 
 
Loco-regional and distant metastasis of the underlying malignancy and death from 
same malignancy (see RFS definition, Table 4) are not reported as AE/SAEs. 
Second primary, other cancer; death from other cancer; non-cancer-related death; 
treatment-related death are reported as AE/SAEs. 
 
9.7.6 
Laboratory Test abnormalities 
 
Laboratory test results will be recorded on the laboratory results form of the eCRF. 
Any laboratory result abnormality fulfilling the criteria for an SAE should be reported 
as such, in addition to being recorded as an AE in the eCRF. 
Any treatment-emergent abnormal laboratory result which is clinically significant, 
i.e., meeting one or more of the following conditions, should be recorded as a single 
diagnosis on the AE page in the eCRF: 

 
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• Accompanied by clinical symptoms 
• Leading to a change in study medication (e.g. dose modification, interruption 
or permanent discontinuation) 
• Requiring a change in concomitant therapy (e.g. addition of, interruption of, 
discontinuation of, or any other change in a concomitant medication, therapy 
or treatment). 
This applies to any protocol and non-protocol specified safety and efficacy 
laboratory result from tests performed after the first dose of study medication, 
which falls outside the laboratory reference range and meets the clinical 
significance criteria. 
 
9.7.6.1 Follow-up of Abnormal Laboratory Test Values 
 
In the event of medically significant unexplained abnormal laboratory test values, 
the tests should be repeated and followed up until they have returned to the normal 
range and/or an adequate explanation of the abnormality is found. If a clear 
explanation is established it should be recorded on the CRF. 
 
9.8 
Pregnancy 
A female patient must immediately inform the investigator and must stop taking 
study product if she becomes pregnant during the study. 
If any pregnancy occurs in the course of the study, then the Investigator or other 
site personnel should inform the sponsor 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.    
The same timelines apply when outcome information is available.  
The investigator should counsel the patient, discuss the risks of continuing with the 
pregnancy and the possible effects on the fetus. Monitoring of the patient should 
continue until conclusion of the pregnancy. Pregnancy will not be considered an 
SAE. 
Pregnancies occurring up to 6 months after the completion of the study medication 
must also be reported to the investigator. 
Pregnancy occurring in the partner of a male patient participating in the study 
should be reported to the investigator and the Sponsor. The partner should be 
counseled, the risks of continuing the pregnancy discussed, as well as the possible 
effects on the fetus. Monitoring of the patient should continue until conclusion of 
the pregnancy. 
Where a report of pregnancy is received, prior to obtaining information about the 
pregnancy, the Investigator must obtain the consent of the patient’s partner. 
Therefore, the local study team should adopt the generic ICF template in line with 

 
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local 
procedures 
and 
submit 
it 
to 
the 
relevant 
Ethics 
Committees 
(ECs)/Institutional Review Boards (IRBs) prior to use.  
 
9.9 
Review of Serious Adverse Event 
The Investigator, the Data Safety Manager, and Ospedale Policlinico S. Martino 
IRCCS will review each SAE report and evaluate the relationship of the SAE to 
study treatment. Based on the assessment of the SAE, a decision will be made 
concerning the need for further action (e.g., report single SAEs to the IDMSC). The 
primary consideration governing further action is whether new findings affect the 
safety of patients participating in the clinical study.  
Further actions that may be required includes the following: 
• modification of the Protocol  
• discontinuation or suspension of the study  
• modification of the existing consent form and informing current study 
participants of new findings (Section 10.3) 
• updating of the IB. 
 
 
9.10 Protocol Deviations Due to an Emergency or an Adverse Event 
In the case of a clinical emergency or medically important AE, significant departure 
from the Protocol procedures may be necessary in the judgment of the Investigator. 
Such Protocol deviations will be determined as allowable on a case-by-case basis. 
The Investigator or designee must contact the Sponsor as soon as possible to 
discuss the circumstances of Protocol deviation and the Sponsor will decide 
whether the patient should continue to participate in the study. All Protocol 
deviations and the reasons for such deviations must be noted in the site's 
regulatory documents and monitoring reports. 
 
 
 

 
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10 ETHICAL 
CONSIDERATIONS/PROTECTION 
OF 
HUMAN 
SUBJECTS 
 
10.1 Independent Ethics Committee Approval  
The study will be performed in accordance with ethical principles that have their 
origin in the Declaration of Helsinki and are consistent with ICH/Good Clinical 
Practice, and applicable regulatory requirements Patient data protection. 
This protocol and the informed consent document will be reviewed and approved 
by the IRB or IEC responsible for oversight of the study. Any patient materials or 
advertisements used during the trial also be reviewed and approved by the 
IEC/IRB.  
The approval letter, signed by the Chair of the IEC/IRB, must specify name, 
location and composition of the committee, the date of the approval, the documents 
approved, the Investigator's name, the Protocol version, date and title. 
Approval of both the protocol and the informed consent form (ICF) must be 
obtained before any subject is enrolled.   
Any amendment to the protocol and the ICF will require review and approval by the 
IRB before the changes are implemented in the study except where necessary to 
eliminate apparent immediate hazards to participants. 
 
10.2 Patient protection 
 
The trial will be conducted in accordance with the latest version of the Declaration 
of Helsinki[67], ICH Guideline on Good Clinical Practice (ICH-GCP (E6)[68] and in 
accordance with the protocol and applicable European and local regulatory 
requirements regarding ethical committee review, informed consent, and other 
statutes and regulations regarding the protection of the rights and welfare 
participants participating in the study. 
 
10.3 Informed consent process 
 
Patients will sign the informed consent document prior to any study-related 
assessments or procedures.   
Extensive discussion of risks and possible benefits of study participation will be 
provided to patients. The investigator or designee will explain the research study 
to the patients and how personal health information may be used and disclosed in 
research. A consent form describing in detail the study procedures and risks will 
be given to the patient. Patients will be given the opportunity to think about it prior 
to agreeing to participate and to discuss the study with their families and their family 
physician. The rights and welfare of the subjects will be protected by emphasizing 
to them that the quality of their clinical care will not be adversely affected if they 
decline to participate in this study. 

 
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Patients will be encouraged and will have the opportunity to have their questions 
answered before and after consenting to participate. They may withdraw consent 
at any time throughout the course of the study without giving a reason.  
The consent process will be documented in the clinical or research record.   
Consent forms will be provided in duplicate (the original will be kept by the 
investigator and a copy given to the trial participant). 
 
10.4 Subject Confidentiality 
 
Trial participant confidentiality will be strictly protected by the trial investigators, 
involved staff, the sponsor(s) and associates following the protocol. This pertains 
to all personal information relating to participants including clinical information and 
results of laboratory testing of biological samples. A unique trial participant ID 
number will be assigned to participant to be used through the trial. This number will 
identify the patient and must be included on all case report forms. In order to avoid 
identification errors, the patient’s ID will also be reported on all case report forms. 
Identifiable information of trial participants will not be disclosed without prior written 
consent of the participant. However, in the case of safety and quality monitoring, 
the trial monitor or other authorized representatives of Ospedale Policlinico S. 
Martino IRCCS may access all documents and records maintained by the 
investigator at the trial sites.  
In case of data transfer, Ospedale Policlinico S. Martino IRCCS will maintain high 
standards of confidentiality and protection of patient personal data. 

 
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11 ADMINISTRATIVE RESPONSIBILITIES 
11.1 Trial insurance 
A clinical trial insurance has been taken out according to the Italian laws. An 
insurance certificate will be made available to the participating sites at the time of 
study initiation. 
 
 
 
 

 
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12 REFERENCE LIST 
[1] 
F. Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, Rebelo 
M, Parkin DM, Forman D, Bray, “GLOBOCAN 2012 v1.0, Cancer Incidence 
and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: 
International 
Agency 
for 
Research 
on 
Cancer. 
Available 
from 
http://globocan.iarc.fr.” 2013. 
[2] 
Bray F, Ferlay J, Soerjomataram I, et al. Global Cancer Statistics 2018: 
GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers 
in 185 Countries. CA Cancer J Clin, 68 (6), 394-424 Nov 2018 
[3] 
R. Adam, D. G. Haller, G. Poston, J.-L. Raoul, J.-P. Spano, J. Tabernero, 
and E. Van Cutsem, “Toward optimized front-line therapeutic strategies in 
patients with metastatic colorectal cancer--an expert review from the 
International Congress on Anti-Cancer Treatment (ICACT) 2009.,” Ann. 
Oncol., vol. 21, no. 8, pp. 1579–84, Aug. 2010. 
[4] 
R. Giacchi, M. Sebastiani, and F. Lungarotti, “[Natural history of synchronous 
hepatic metastases from a non-treated colorectal cancer].,” J. Chir. (Paris)., 
vol. 125, no. 6–7, pp. 419–23. 
[5] 
Lenz H, Niedzwiecki D, Innocenti F, Blanke C, Mahony MR, et al 
“CALGB/SWOG 80405: Phase III trial of irinotecan/5-FU/leucovorin 
(FOLFIRI) or oxaliplatin/5-FU/leucovorin (MFOLFOX6) with bevacizumab 
(BV) or cetuximab (CET) for patients with expanded RAS analyses untreated 
metastatic adenocarcinoma of the colon or rectum.” 2014. 
[6] 
“LiverMetSurvey 
Sanofi-Aventis.” 
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Appendix 1 
Eastern Cooperative Oncology Group (ECOG) Performace 
Status Scale 
 
Grade 
Description 
0 
Fully active, able to carry all predisease performance 
without restriction 
1 
Restricted in phisically strenous activity but 
ambulatory and able to carry out work of a light or 
sedentary nature; e.g., light housework or office work 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities; up and about > 50% of 
waking hours 
3 
Capable of only limited self-care, confined to a bed or 
a chair > 50% of waking hours 
4 
Completely disabled; cannot carry on any self-care; 
totally confined to bed or chair 
5 
Dead 
 
 
 
 

 
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Appendix 2 
Response Evaluation Criteria In Solid Tumors 
 
 
RECIST 1.1 
Lesion measurement  
Imaging modality 
CT, PET/CT, MRI and chest radiography  
Definition of measurable 
lesions 
CT: 10 mm 
Clinical: 10 mm (must be measurable with calipers) 
Lymph node 
CT: 
>= 15 mm short axis for target 
>= 10 or < 15 mm for non-taget 
< 10 mm is non-pathological 
Method of measurement 
Longest diameter in the axial plane 
No. lesions to be 
measured 
5 lesions (2 per organ) 
Response evaluation 
Complete response (CR) Disappearance of all lesions and pathological lymph 
nodes 
Partial response (PR) 
>= 30% decrease in the sum of the longest diameter 
Stable disease (SD) 
Neither PR nor PD 
Progressive Disease 
(PD) 
>= 20% increase smallest sum on study (including 
baseline if that is smallest) and at least 5 mm increase 
or new lesions 
 
 
 
 
 
 

 
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APPENDIX 3. DOSING MODIFICATION AND TOXICITY MANAGEMENT 
GUIDELINES FOR DURVALUMAB (V. 17 OCT 2019, CTCAE V5.0) 
 
17 October 2019, CTCAE version 5.0 
 
 
The Toxicity Management Guidelines (TMGs) have been developed to assist investigators with 
the recognition and management of toxicities associated with use of the immune-checkpoint 
inhibitors durvalumab [MEDI4736] (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor). 
Given the similar underlying mechanism of toxicities observed with these two compounds, these 
TMGs are applicable to the management of patients receiving either drug as monotherapy or 
both drugs in combination. Additionally, these guidelines are applicable when either drug is used 
alone or both drugs are used in combination and, also, other anti-cancer drugs (i.e., antineoplastic 
chemotherapy, targeted agents) are administered concurrently or sequentially as part of a 
protocol-specific treatment regimen.  The TMGs provide information for the management of 
immune-mediated reactions, infusion-related reactions, and non-immune-mediated reactions that 
may be observed with monotherapy or combination checkpoint inhibitor regimens, with specific 
instructions for checkpoint inhibitor-specific dose modifications (including discontinuation) and 
treatment interventions.  Investigators are advised however to use local practice guidelines and 
consult local references for the management of toxicities observed with other anti-cancer 
treatment. 
Dosing modification and toxicity management for immune-mediated, infusion-related, and non-
immune–mediated reactions associated with the use of a checkpoint inhibitor or checkpoint 
inhibitors in this protocol – whether that is MEDI4736 alone, tremelimumab alone, or 
MEDI4736 + tremelimumab in combination, or MEDI4736 +/- tremelimumab in combination 
with other anti-cancer drugs (i.e., antineoplastic chemotherapy, targeted agents) administered 
concurrently or sequentially – should therefore be performed in accordance with this Annex to 
Protocol, which for the purposes of submission and approval of substantial updates is maintained 
as a standalone document. 
TMG updates are iterated by date, and issued in CTCAE version as specified in the clinical study 
protocol. This Annex to Protocol presents the dated version of the TMGs issued in CTCAE 
version 5.0. 
Although the TMG versioning is independent of the protocol, the TMG Annex to Protocol 
should be read in conjunction with the Clinical Study Protocol, where if applicable additional 
references for the management of toxicities observed with other anti-cancer treatment are 
included in the specific section of the Clinical Study Protocol.  
 
 

 
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions  17 October 2019 Version (CTCAE v5.0) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Drug administration modifications of study drug/study regimen will be made to 
manage potential immune-related AEs based on severity of treatment-emergent 
toxicities graded per NCI CTCAE v5.0. 
In addition to the criteria for permanent discontinuation of study drug/study 
regimen based on CTC grade/severity (table below), permanently discontinue 
study drug/study regimen for the following conditions: 
• 
Inability to reduce corticosteroid to a dose of ≤10 mg of prednisone per 
day (or equivalent) within 12 weeks of the start of the immune-mediated 
adverse event (imAE) 
• 
Grade 3 recurrence of a previously experienced treatment-related imAE 
following resumption of dosing 
Grade 1 
No dose modification 
Grade 2 
Hold study drug/study regimen dose until Grade 2 resolution 
toGrade ≤1. 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
Study drug/study regimen can be resumed once event stabilizes to 
Grade ≤1 after completion of steroid taper. 
Patients with endocrinopathies who may require prolonged or 
continued steroid replacement can be retreated with study 
drug/study regimen on the following conditions: 
1. 
The event stabilizes and is controlled. 
2. 
The patient is clinically stable as per Investigator or treating 
physician’s clinical judgement. 
3. 
Doses of prednisone are at ≤10 mg/day or equivalent. 
Grade 3 
Depending on the individual toxicity, study drug/study regimen 
may be permanently discontinued. Please refer to guidelines below. 
Grade 4 
Permanently discontinue study drug/study regimen. 
It is recommended that management of immune-mediated adverse events (imAEs) 
follows the guidelines presented in this table: 
− 
It is possible that events with an inflammatory or immune mediated 
mechanism could occur in nearly all organs, some of them not noted 
specifically in these guidelines. 
− 
Whether specific immune-mediated events (and/or laboratory indicators of 
such events) are noted in these guidelines or not, patients should be 
thoroughly evaluated to rule out any alternative etiology (e.g., disease 
progression, concomitant medications, and infections) to a possible immune-
mediated event. In the absence of a clear alternative etiology, all such events 
should be managed as if they were immune related. General 
recommendations follow. 
− 
Symptomatic and topical therapy should be considered for low-grade (Grade 
1 or 2, unless otherwise specified) events.  
− 
For persistent (>3 to 5 days) low-grade (Grade 2) or severe (Grade ≥3) 
events, promptly start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
Some events with high likelihood for morbidity and/or mortality – e.g., 
myocarditis, or other similar events even if they are not currently noted in 
the guidelines – should progress rapidly to high dose IV corticosteroids 
(methylprednisolone at 2 to 4 mg/kg/day) even if the event is Grade 2, and if 
clinical suspicion is high and/or there has been clinical confirmation. 
Consider, as necessary, discussing with the study physician, and promptly 
pursue specialist consultation. 
− 
If symptoms recur or worsen during corticosteroid tapering (28 days of 
taper), increase the corticosteroid dose (prednisone dose [e.g., up to 2 to 
4 mg/kg/day PO or IV equivalent]) until stabilization or improvement of 
symptoms, then resume corticosteroid tapering at a slower rate (>28 days of 
taper). 
− 
More potent immunosuppressives such as TNF inhibitors (e.g., infliximab; 
also refer to the individual sections of the imAEs for specific type of 
immunosuppressive) should be considered for events not responding to 
systemic steroids. Progression to use of more potent immunosuppressives 
should proceed more rapidly in events with high likelihood for morbidity 
and/or mortality – e.g., myocarditis, or other similar events even if they are 
not currently noted in the guidelines – when these events are not responding 
to systemic steroids. 

 
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Dosing Modification and Toxicity Management Guidelines for Immune-Mediated, Infusion-Related, and  
Non-Immune–Mediated Reactions  17 October 2019 Version (CTCAE v5.0) 
General Considerations regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
Note: For asymptomatic amylase or lipase levels of >2X ULN, hold study 
drug/study regimen, and if complete work up shows no evidence of pancreatitis, 
study drug/study regimen may be continued or resumed. 
Note: Study drug/study regimen should be permanently discontinued in Grade 3 
events with high likelihood for morbidity and/or mortality – e.g., myocarditis, or 
other similar events even if they are not currently noted in the guidelines. 
Similarly, consider whether study drug/study regimen should be permanently 
discontinued in Grade 2 events with high likelihood for morbidity and/or mortality 
– e.g., myocarditis, or other similar events even if they are not currently noted in 
the guidelines – when they do not rapidly improve to Grade <1 upon treatment 
with systemic steroids and following full taper 
Note: There are some exceptions to permanent discontinuation of study drug for 
Grade 4 events (i.e., hyperthyroidism, hypothyroidism, Type 1 diabetes mellitus).  
 
− 
With long-term steroid and other immunosuppressive use, consider need for 
Pneumocystis jirovecii pneumonia (PJP, formerly known as Pneumocystis 
carinii pneumonia) prophylaxis, gastrointestinal protection, and glucose 
monitoring. 
− 
Discontinuation of study drug/study regimen is not mandated for  
Grade 3/Grade 4 inflammatory reactions attributed to local tumor response 
(e.g., inflammatory reaction at sites of metastatic disease and lymph nodes). 
Continuation of study drug/study regimen in this situation should be based 
upon a benefit-risk analysis for that patient. 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE immune-mediated adverse event; IV intravenous; NCI 
National Cancer Institute; PO By mouth. 
 
 
 

 
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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial 
Lung Disease (ILD) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of pneumonitis or 
ILD (new onset or worsening shortness of breath or cough). 
Patients should be evaluated with imaging and pulmonary 
function tests, including other diagnostic procedures as 
described below. 
− 
Initial work-up may include clinical evaluation, monitoring of 
oxygenation via pulse oximetry (resting and exertion), 
laboratory work-up, and high- resolution CT scan. 
Grade 1 
(asymptomatic, clinical 
or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications required. However, 
consider holding study drug/study 
regimen dose as clinically appropriate and 
during diagnostic work-up for other 
etiologies. 
For Grade 1 (radiographic changes only): 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, pulse oximetry (resting and exertion), and 
laboratory work-up and then as clinically indicated. 
− 
Consider Pulmonary and Infectious Disease consults. 
Grade 2 
(symptomatic; medical 
intervention indicated; 
limiting instrumental 
ADL) 
Hold study drug/study regimen dose until 
Grade 2 resolution to Grade ≤1. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then the decision to reinitiate study 
drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. 
For Grade 2 (mild to moderate new symptoms): 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Promptly start systemic steroids (e.g., prednisone 1 to 
2 mg/kg/day PO or IV equivalent). 
− 
Reimage as clinically indicated. 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started 
− 
If still no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 

 
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anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections)a 
− 
Consider Pulmonary and Infectious Disease consults. 
− 
Consider, as necessary, discussing with study physician. 
Grade 3 or 4 
(Grade 3: severe 
symptoms; limiting 
self-care ADL; oxygen 
indicated) 
 
(Grade 4: life-
threatening respiratory 
compromise; urgent 
intervention indicated 
[e.g., tracheostomy or 
intubation]) 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4 (severe or new symptoms, new/worsening hypoxia, 
life-threatening): 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Obtain Pulmonary and Infectious Disease consults; consider, as 
necessary, discussing with study physician. 
− 
Hospitalize the patient. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days, additional workup 
should be considered and prompt treatment with additional 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks’ dose) started. 
Caution: rule out sepsis and refer to infliximab label for general 
guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, 
and, in particular, anti-PJP treatment (refer to current NCCN 
guidelines for treatment of cancer-related infections).a 
Diarrhea/Colitis 
Large intestine 
perforation/Intestine 
perforation 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, cramping, or changes in 
bowel habits such as increased frequency over baseline or 
blood in stool) or related to bowel perforation (such as sepsis, 
peritoneal signs, and ileus). 
- 
When symptoms or evaluation indicate a perforation is 
suspected, consult a surgeon experienced in abdominal surgery 
immediately without any delay.  
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections), including testing for clostridium 
difficile toxin, etc. 
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in order to 

 
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prevent potential progression to higher grade event, including 
perforation.  
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
(Diarrhea: stool 
frequency of <4 over 
baseline per day) 
(Colitis: asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not 
indicated) 
No dose modifications. 
For Grade 1: 
− 
Monitor closely for worsening symptoms. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide. Use 
probiotics as per treating physician’s clinical judgment. 
Grade 2 
(Diarrhea: stool 
frequency of 4 to 6 over 
baseline per day; 
limiting instrumental 
ADL)  
(Colitis: abdominal 
pain; mucus or blood in 
stool) 
(Perforation: invasive 
intervention not 
indicated) 
Hold study drug/study regimen until 
resolution to Grade ≤1 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
• 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
resumed after completion of steroid 
taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, dietary changes (e.g., American 
Dietetic Association colitis diet), and loperamide and/or 
budesonide. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, GI consult 
should be obtained for consideration of further workup, such as 
imaging and/or colonoscopy, to confirm colitis and rule out 
perforation, and prompt treatment with IV methylprednisolone 
2 to 4 mg/kg/day started. 
− 
If still no improvement within 3 to 5 days despite 2 to 4 mg/kg 
IV methylprednisolone, promptly start immunosuppressives 
such as infliximab at 5 mg/kg once every 2 weeksa. Caution: it 
is important to rule out bowel perforation and refer to 
infliximab label for general guidance before using infliximab. 
− 
Consider, as necessary, discussing with study physician if no 
resolution to Grade ≤1 in 3 to 4 days. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 

 
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Grade 3 or 4 
(Grade 3 Diarrhea: 
stool frequency of ≥7 
over baseline per day; 
limiting self care ADL; 
Grade 4 Diarrhea: life 
threatening 
consequences) 
(Grade 3 Colitis: severe 
abdominal pain, fever; 
ileus; peritoneal signs; 
Grade 4 Colitis: life-
threatening 
consequences, urgent 
intervention indicated) 
(Grade 3 Perforation:   
invasive intervention 
indicated;  
Grade 4 Perforation: 
life-threatening 
consequences; urgent 
intervention indicated) 
 
Grade 3 
Permanently discontinue study drug/study 
regimen for Grade 3 if toxicity does not 
improve to Grade ≤1 within 14 days; 
study drug/study regimen can be resumed 
after completion of steroid taper. 
 
Grade 4 
Permanently discontinue  
study drug/study regimen.  
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone 2 to 
4 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain hydration. 
− 
Urgent GI consult and imaging and/or colonoscopy as 
appropriate. 
− 
If still no improvement within 3 to 5 days of IV 
methylprednisolone 2 to 4 mg/kg/day or equivalent, promptly 
start further immunosuppressives (e.g., infliximab at 5 mg/kg 
once every 2 weeks). Caution: Ensure GI consult to rule out 
bowel perforation and refer to infliximab label for general 
guidance before using infliximab. If perforation is suspected,  
consult a surgeon experienced in abdominal surgery 
immediately without any delay . 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 

 
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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis. 
Any  Grade 
 
General Guidance 
For Any Grade 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications). 
Grade 1 
(AST or ALT >ULN 
and ≤3.0×ULN if 
baseline normal, 1.5-
3.0×baseline if baseline 
abnormal; and/or TB 
>ULN and ≤1.5×ULN 
if baseline normal, 
>1.0-1.5×baseline if 
baseline abnormal) 
• 
No dose modifications. 
• 
If it worsens, then treat as  Grade 2.  
− 
Continue LFT monitoring per protocol. 
Grade 2  
(AST or  
ALT >3.0×ULN and 
≤5.0×ULN if baseline 
normal, >3-5×baseline 
if baseline abnormal; 
and/or  
TB >1.5×ULN and 
≤3.0×ULN if baseline 
normal, >1.5- 
3.0×baseline if baseline 
abnormal) 
• 
Hold study drug/study regimen dose 
until resolution to  Grade≤1. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to  Grade≤1, 
resume study drug/study regimen 
after completion of steroid taper. 
For Grade 2: 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 2 days) 
until elevations of these are improving or resolved. 
− 
If no resolution to ≤Grade 1 in 1 to 2 days, consider, as 
necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional work up and start prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, promptly start 
immunosuppressives (i.e., mycophenolate mofetil).a Discuss 
with study physician if mycophenolate mofetil is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
PLEASE SEE 
shaded area 
immediately below 
this section to find 
guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in HCC 
patients 

 
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Grade 3 
 (AST or  
ALT >5.0×ULN and 
≤20×ULN if baseline 
normal, >5-20× 
baseline if baseline 
abnormal; and/or  
TB >3.0×ULN  and  
≤10.0×ULN if baseline 
normal, >3.0-10.0× 
baseline if baseline 
abnormal) 
 
 
Grade 4 
(AST or ALT 
>20×ULN if baseline 
normal, >20×baseline if 
baseline abnormal; 
and/or  
TB >10×ULN if 
baseline normal, 
>10.0×baseline if 
baseline abnormal)   
For elevations in transaminases ≤8×ULN, 
or elevations in TB ≤5×ULN: 
• Hold study drug/study regimen dose 
until resolution to Grade≤1 
• Resume study drug/study regimen if 
elevations downgrade to  Grade≤1 
within 14 days and after completion 
of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to Grade≤1 within 
14 days. 
For elevations in transaminases >8×ULN 
or elevations in bilirubin >5×ULN, 
permanently discontinue study drug/study 
regimen. 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria (AST and/or ALT >3×ULN + 
bilirubin >2×ULN without initial findings 
of cholestasis [i.e., elevated alkaline P04] 
and in the absence of any alternative 
cause).b 
For Grade 3 or 4: 
− 
Promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
4 mg/kg/day methylprednisolone IV or equivalent, promptly 
start treatment with immunosuppressive therapy (i.e., 
mycophenolate mofetil). Discuss with study physician if 
mycophenolate is not available. Infliximab should NOT be 
used. 
− 
Request Hepatology consult, and perform abdominal workup 
and imaging as appropriate. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Hepatitis  
(elevated LFTs) 
Infliximab should not be 
used for management of 
immune-related hepatitis.  
See instructions at  
bottom of shaded area  
if transaminase rise is  
not isolated but (at any 
time) occurs in setting  
of either increasing 
bilirubin or signs of 
DILI/liver 
decompensation 
Any Elevations of 
AST, ALT, or TB as 
Described Below 
General Guidance 
 
For Any Elevations Described: 
− 
Monitor and evaluate liver function test: AST, ALT, ALP, and 
TB. 
− 
Evaluate for alternative etiologies (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of liver 
cirrhosis [e.g., portal vein thrombosis]). 
− 
For HBV+ patients: evaluate quantitative HBV viral load, 
quantitative HBsAg, or HBeAg 
− 
For HCV+ patients: evaluate quantitative HCV viral load 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral medications 
for any patient with an elevated HBV viral load >2000 IU/ml 
− 
Consider consulting hepatologist/Infectious Disease specialist 
regarding change/implementation in/of antiviral HCV 
medications if HCV viral load increased by ≥2-fold 
− 
For HCV+ with HBcAB+: Evaluate for both HBV and HCV as 
above 
 Isolated AST or ALT 
>ULN and ≤5.0×ULN, 
whether normal or 
elevated at baseline  
• 
No dose modifications. 
• 
If ALT/AST elevations represents 
significant worsening based on 
investigator assessment, then treat as 
described for elevations in the row 
below. 
For all transaminase elevations, see 
instructions at bottom of shaded area if 
transaminase rise is not isolated but (at 
any time) occurs in setting of either 
increasing bilirubin or signs of 
DILI/liver decompensation 
 
 
THIS shaded area 
is guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients  

 
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Isolated AST or ALT 
>5.0×ULN and 
≤8.0×ULN, if normal 
at baseline 
 
Isolated AST or ALT 
>2.0×baseline and 
≤12.5×ULN, if 
elevated >ULN at 
baseline 
 
• 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤5.0×ULN. 
• 
If toxicity worsens, then treat as 
described for elevations in the rows 
below. 
If toxicity improves to AST or ALT 
≤5.0×ULN, resume study drug/study 
regimen after completion of steroid taper. 
− 
Regular and frequent checking of LFTs (e.g., every 1 to 3 days) 
until elevations of these are improving or resolved. 
− 
Recommend consult hepatologist; consider abdominal 
ultrasound, including Doppler assessment of liver perfusion. 
− 
Consider, as necessary, discussing with study physician. 
− 
If event is persistent (>3 to 5 days) or worsens, and investigator 
suspects toxicity to be immune-mediated AE, recommend to 
start prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 3 to 5 days despite 1 to 
2 mg/kg/day of prednisone PO or IV equivalent, consider 
additional workup and treatment with IV methylprednisolone 2 
to 4 mg/kg/day. 
− 
If still no improvement within 3 to 5 days despite 2 to 
4 mg/kg/day of IV methylprednisolone, consider additional 
abdominal workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting immunosuppressives 
(i.e., mycophenolate mofetil).a Discuss with study physician if 
mycophenolate mofetil is not available. Infliximab should 
NOT be used. 
 
 
Isolated AST or ALT 
>8.0×ULN and 
≤20.0×ULN, if normal 
at baseline 
 
Isolated AST or ALT 
>12.5×ULN and 
≤20.0×ULN, if 
elevated >ULN at 
baseline 
 
• 
Hold study drug/study regimen dose 
until resolution to AST or ALT 
≤5.0×ULN.  
• Resume study drug/study regimen if 
elevations downgrade to AST or ALT 
≤5.0×ULN within 14 days and after 
completion of steroid taper. 
• Permanently discontinue study 
drug/study regimen if the elevations 
do not downgrade to AST or ALT 
≤5.0×ULN within 14 days 
Permanently discontinue study drug/study 
regimen for any case meeting Hy’s law 
criteria, in the absence of any alternative 
cause.b 
− 
Regular and frequent checking of LFTs (e.g., every 1-2 days) 
until elevations of these are improving or resolved. 
− 
Consult hepatologist (unless investigator is hepatologist); 
obtain abdominal ultrasound, including Doppler assessment of 
liver perfusion; and consider liver biopsy. 
− 
Consider, as necessary, discussing with study physician. 
− 
If investigator suspects toxicity to be immune-mediated, 
promptly initiate empiric IV methylprednisolone at 1 to 
4 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 4 mg/kg/day 
methylprednisolone IV or equivalent, obtain liver biopsy (if it 
has not been done already) and promptly start treatment with 
immunosuppressive therapy (mycophenolate mofetil). Discuss 
with study physician if mycophenolate is not available. 
Infliximab should NOT be used. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PCP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 

 
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Isolated AST or ALT 
>20×ULN, whether 
normal or elevated at 
baseline 
 
Permanently discontinue study drug/study 
regimen. 
 
Same as above  
(except would recommend obtaining liver biopsy early) 
 
 
If transaminase rise is not isolated but (at any time) occurs in setting of either increasing total/direct bilirubin (≥1.5×ULN, if normal at baseline; or 2×baseline, if 
>ULN at baseline) or signs of DILI/liver decompensation (e.g., fever, elevated INR): 
- 
Manage dosing for each level of transaminase rise as instructed for the next highest level of transaminase rise 
- 
For example, manage dosing for second level of transaminase rise (i.e., AST or ALT >5.0×ULN and ≤8.0×ULN, if normal at baseline, or AST or ALT 
>2.0×baseline and ≤12.5×ULN, if elevated >ULN at baseline) as instructed for the third level of transaminase rise (i.e., AST or ALT >8.0×ULN and 
≤20.0×ULN, if normal at baseline, or AST or ALT >12.5×ULN and ≤20.0×ULN, if  elevated >ULN at baseline) 
- 
For the third and fourth levels of transaminase rises, permanently discontinue study drug/study regimen 
 
Nephritis or renal 
dysfunction 
(elevated serum 
creatinine) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Consult with nephrologist. 
− 
Monitor 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, or proteinuria). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression or infections). 
− 
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. 
 
 

 
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Grade 1 
(serum creatinine  
>ULN to 1.5×ULN) 
No dose modifications. 
For Grade 1: 
− 
Monitor serum creatinine weekly and any accompanying 
symptoms. 
• 
If creatinine returns to baseline, resume its regular 
monitoring per study protocol. 
• 
If creatinine worsens, depending on the severity, treat 
as Grade 2, 3, or 4. 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
If baseline serum creatinine is elevated above normal, and there 
is a rise to > 1 to 1.5 × baseline, consider following 
recommendations in this row.  
Grade 2 
(serum creatinine >1.5 
to 3.0×baseline; >1.5 to 
3.0×ULN) 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline.  
• 
If toxicity worsens, then treat as 
Grade 3 or 4. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper. 
For Grade 2: 
− 
Consider symptomatic treatment, including hydration, 
electrolyte replacement, and diuretics. 
− 
Carefully monitor serum creatinine every 2 to 3 days and as 
clinically warranted. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 
− 
If event is persistent (>3 to 5 days) or worsens, promptly start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone at 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
− 
When event returns to baseline, resume study drug/study 
regimen and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
(Grade 3: serum 
creatinine 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Carefully monitor serum creatinine on daily basis. 
− 
Consult nephrologist and consider renal biopsy if clinically 
indicated. 

 
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>3.0×baseline; >3.0 to 
6.0×ULN) 
 
(Grade 4: serum 
creatinine >6.0×ULN) 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days or worsens despite 
prednisone at 1 to 2 mg/kg/day PO or IV equivalent, additional 
workup should be considered and prompt treatment with IV 
methylprednisolone 2 to 4 mg/kg/day started. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
Rash or Dermatitis 
(including Pemphigoid) 
Any Grade 
(refer to NCI CTCAE 
v 5.0 for definition of 
severity/grade 
depending on type of 
skin rash) 
General Guidance 
For Any Grade: 
− 
Monitor for signs and symptoms of dermatitis (rash and 
pruritus). 
− 
IF THERE IS ANY BULLOUS FORMATION, THE STUDY 
PHYSICIAN SHOULD BE CONTACTED AND STUDY 
DRUG DISCONTINUED IF SUSPECT STEVENS-
JOHNSON SYNDROME OR TOXIC EPIDERMAL 
NECROLYSIS. 
Grade 1 
No dose modifications. 
For Grade 1: 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
Grade 2 
For persistent (>1 to 2 weeks) Grade 2 
events, hold scheduled study drug/study 
regimen until resolution to Grade ≤1 or 
baseline. 
• 
If toxicity worsens, then treat as 
Grade 3. 
• 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper. 
For Grade 2: 
− 
Obtain Dermatology consult. 
− 
Consider symptomatic treatment, including oral antipruritics 
(e.g., diphenhydramine or hydroxyzine) and topical therapy 
(e.g., urea cream). 
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 3 to 
5 days or is worsening despite symptomatic treatment and/or 
use of moderate strength topical steroid, consider, as necessary, 
discussing with study physician and promptly start systemic 
steroids such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. If > 30% body surface area is involved, consider 
initiation of systemic steroids promptly. 
− 
Consider skin biopsy if the event is persistent for >1 to 2 weeks 
or recurs. 

 
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Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
If temporarily holding the study 
drug/study regimen does not provide 
improvement of the Grade 3 skin rash to 
Grade ≤1 or baseline within 30 days, then 
permanently discontinue study drug/study 
regimen. 
 
For Grade 4 (or life-threatening): 
Permanently discontinue study drug/study 
regimen. 
 
For Grade 3 or 4 (or life-threatening): 
− 
Consult Dermatology. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor extent of rash [Rule of Nines]. 
− 
Consider skin biopsy (preferably more than 1) as clinically 
feasible. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, and 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
− 
Consider, as necessary, discussing with study physician. 
Endocrinopathy 
(e.g., hyperthyroidism, 
thyroiditis, 
hypothyroidism, Type 1 
diabetes mellitus, 
hypophysitis, 
hypopituitarism, and 
adrenal insufficiency; 
exocrine event of 
amylase/lipase increased 
also included in this 
section) 
 
Any Grade 
(depending on the type 
of endocrinopathy, 
refer to NCI CTCAE 
v5.0 for defining the 
CTC grade/severity) 
General Guidance 
For Any Grade: 
− 
Consider consulting an endocrinologist for endocrine events. 
− 
Consider, as necessary, discussing with study physician. 
− 
Monitor patients for signs and symptoms of endocrinopathies. 
Non-specific symptoms include headache, fatigue, behavior 
changes, changed mental status, vertigo, abdominal pain, 
unusual bowel habits, polydipsia, polyuria, hypotension, and 
weakness. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression including brain 
metastases, or infections). 
− 
Depending on the suspected endocrinopathy, monitor and 
evaluate thyroid function tests: TSH, free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood glucose 
and ketone levels, HgA1c). 
− 
For asymptomatic elevations in serum amylase and lipase 
>ULN and <3×ULN, corticosteroid treatment is not indicated 
as long as there are no other signs or symptoms of pancreatic 
inflammation. 
− 
If a patient experiences an AE that is thought to be possibly of 
autoimmune nature (e.g., thyroiditis, pancreatitis, hypophysitis, 

 
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or diabetes insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
 
Grade 1 
No dose modifications. 
For Grade 1 (including those with asymptomatic TSH elevation): 
− 
Monitor patient with appropriate endocrine function tests. 
− 
For suspected hypophysitis/hypopituitarism, consider 
consultation of an endocrinologist to guide assessment of early-
morning ACTH, cortisol, TSH and free T4; also consider 
gonadotropins, sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not be useful in 
diagnosing early secondary adrenal insufficiency). 
− 
If TSH < 0.5 × LLN, or TSH >2 × ULN, or consistently out of 
range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated and consider 
consultation of an endocrinologist. 
Grade 2 
For Grade 2 endocrinopathy other than 
hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until patient is clinically stable. 
• 
If toxicity worsens, then treat as 
Grade 3 or Grade 4. 
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
For Grade 2 (including those with symptomatic endocrinopathy): 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an endocrinologist, consider short-term corticosteroids (e.g., 1 
to 2 mg/kg/day methylprednisolone or IV equivalent) and 
prompt initiation of treatment with relevant hormone 
replacement (e.g., hydrocortisone, sex hormones). 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus (DM) may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections).a 
− 
For patients with normal endocrine workup (laboratory 
assessment or MRI scans), repeat laboratory assessments/MRI 
as clinically indicated. 

 
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Grade 3 or 4 
For Grade 3 or 4 endocrinopathy other 
than hypothyroidism and Type 1 diabetes 
mellitus, hold study drug/study regimen 
dose until endocrinopathy symptom(s) are 
controlled.  
Study drug/study regimen can be resumed 
once event stabilizes and after completion 
of steroid taper. 
Patients with endocrinopathies who may 
require prolonged or continued steroid 
replacement (e.g., adrenal insufficiency) 
can be retreated with study drug/study 
regimen on the following conditions: 
1. 
The event stabilizes and is 
controlled. 
2. 
The patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
3. 
Doses of prednisone are ≤10 mg/day 
or equivalent. 
For Grade 3 or 4: 
− 
Consult endocrinologist to guide evaluation of endocrine 
function and, as indicated by suspected endocrinopathy and as 
clinically indicated, consider pituitary scan. Hospitalization 
recommended. 
− 
For all patients with abnormal endocrine work up, except those 
with isolated hypothyroidism or Type 1 DM, and as guided by 
an endocrinologist, promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or equivalent, as well as 
relevant hormone replacement (e.g., hydrocortisone, sex 
hormones). 
− 
For adrenal crisis, severe dehydration, hypotension, or shock, 
immediately initiate IV corticosteroids with mineralocorticoid 
activity. 
− 
Isolated hypothyroidism may be treated with replacement 
therapy, without study drug/study regimen interruption, and 
without corticosteroids. 
− 
Isolated Type 1 diabetes mellitus may be treated with 
appropriate diabetic therapy, without study drug/study regimen 
interruption, and without corticosteroids. 
− 
Once patients on steroids are improving, gradually taper 
immunosuppressive steroids (as appropriate and with guidance 
of endocrinologist) over ≥28 days and consider prophylactic 
antibiotics, antifungals, and anti-PJP treatment (refer to current 
NCCN guidelines for treatment of cancer-related infections).a 
 
Neurotoxicity 
(to include but not be 
limited to limbic 
encephalitis and 
autonomic neuropathy, 
excluding Myasthenia 
Gravis and Guillain-
Barre) 
Any Grade 
(depending on the type 
of neurotoxicity, refer 
to NCI CTCAE v5.0 
for defining the CTC 
grade/severity) 
General Guidance 
For Any Grade: 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes, or 
medications). 
− 
Monitor patient for general symptoms (headache, nausea, 
vertigo, behavior change, or weakness). 
− 
Consider appropriate diagnostic testing (e.g., electromyogram 
and nerve conduction investigations). 
− 
Perform symptomatic treatment with Neurology consult as 
appropriate. 
− 
 

 
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Grade 1 
No dose modifications. 
For Grade 1: 
− 
See “Any Grade” recommendations above. 
− 
Treat mild signs/symptoms as Grade 1 (e.g.  loss of deep 
tendon reflexes or paresthesia) 
Grade 2 
For acute motor neuropathies or 
neurotoxicity, hold study drug/study 
regimen dose until resolution to Grade ≤1. 
For sensory neuropathy/neuropathic pain, 
consider holding study drug/study 
regimen dose until resolution to Grade ≤1. 
If toxicity worsens, then treat as 
Grade 3 or 4. 
Study drug/study regimen can be resumed 
once event improves to Grade ≤1 and 
after completion of steroid taper. 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Obtain Neurology consult. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
− 
Promptly start systemic steroids prednisone 1 to 2 mg/kg/day 
PO or IV equivalent. 
− 
If no improvement within 3 to 5 days despite 1 to 2 mg/kg/day 
prednisone PO or IV equivalent, consider additional workup 
and promptly treat with additional immunosuppressive therapy 
(e.g., IV IG). 
Grade 3 or 4 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days. 
 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
For Grade 3 or 4: 
− 
Consider, as necessary, discussing with study physician. 
− 
Obtain Neurology consult. 
− 
Consider hospitalization. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
If no improvement within 3 to 5 days despite IV 
corticosteroids, consider additional workup and promptly treat 
with additional immunosuppressants (e.g., IV IG). 
− 
Once stable, gradually taper steroids over ≥28 days. 
Peripheral neuromotor 
syndromes 
(such as Guillain-Barre 
and myasthenia gravis) 
Any Grade 
General Guidance 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated peripheral 
neuromotor syndromes is important, since certain patients may 
unpredictably experience acute decompensations that can result 
in substantial morbidity or in the worst case, death. Special care 
should be taken for certain sentinel symptoms that may predict 

 
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a more severe outcome, such as prominent dysphagia, rapidly 
progressive weakness, and signs of respiratory insufficiency or 
autonomic instability. 
− 
Patients should be evaluated to rule out any alternative etiology 
(e.g., disease progression, infections, metabolic syndromes or 
medications). It should be noted that the diagnosis of immune-
mediated peripheral neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, due to the 
multiple potential confounding effects of cancer (and its 
treatments) throughout the neuraxis. Given the importance of 
prompt and accurate diagnosis, it is essential to have a low 
threshold to obtain a Neurology consult. 
− 
Neurophysiologic diagnostic testing (e.g., electromyogram and 
nerve conduction investigations, and “repetitive stimulation” if 
myasthenia is suspected) are routinely indicated upon suspicion 
of such conditions and may be best facilitated by means of a 
Neurology consultation. 
− 
It is important to consider that the use of steroids as the primary 
treatment of Guillain-Barre is not typically considered 
effective. Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive to IV IG. 
 
Grade 1 
(Guillain-Barre [GB]:  
mild symptoms) 
(Myasthenia gravis 
[MG]: asymptomatic or 
mild symptoms; 
clinical or diagnostic 
observations only; 
intervention not 
indicated)    
No dose modifications. 
For Grade 1: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a Neurology consult. 
Grade 2 
(GB: moderate 
symptoms; limiting 
instrumental ADL) 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if it does not resolve to Grade ≤1 
For Grade 2: 
− 
Consider, as necessary, discussing with the study physician. 
− 
Care should be taken to monitor patients for sentinel symptoms 
of a potential decompensation as described above. 
− 
Obtain a Neurology consult 

 
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(MG: moderate; 
minimal, local or 
noninvasive 
intervention indicated; 
limiting age-
appropriate 
instrumental ADL) 
within 30 days or if there are signs of 
respiratory insufficiency or autonomic 
instability. 
− 
Sensory neuropathy/neuropathic pain may be managed by 
appropriate medications (e.g., gabapentin or duloxetine). 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. It is important to consider that steroid therapy 
(especially with high doses) may result in transient 
worsening of myasthenia and should typically be 
administered in a monitored setting under supervision 
of a consulting neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. Such 
decisions are best made in consultation with a 
neurologist, taking into account the unique needs of 
each patient. 
o 
If myasthenia gravis-like neurotoxicity is present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Grade 3 or 4 
(Grade 3 GB: severe 
symptoms; limiting self 
care ADL;  
Grade 4 GB: life-
threatening 
consequences; urgent 
intervention indicated; 
intubation) 
(Grade 3 MG: severe or 
medically significant 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency or 
autonomic instability. 
 
 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Consider, as necessary, discussing with study physician. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and obtain Neurology consult. 
MYASTHENIA GRAVIS: 
o 
Steroids may be successfully used to treat myasthenia 
gravis. They should typically be administered in a 
monitored setting under supervision of a consulting 
neurologist. 
o 
Patients unable to tolerate steroids may be candidates 
for treatment with plasmapheresis or IV IG. 

 
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but not immediately 
life-threatening; 
hospitalization or 
prolongation of existing 
hospitalization 
indicated; limiting self 
care ADL;  
Grade 4 MG: life-
threatening 
consequences; urgent 
intervention indicated) 
For Grade 4: 
Permanently discontinue study drug/study 
regimen. 
o 
If myasthenia gravis-like neurotoxicity present, 
consider starting AChE inhibitor therapy in addition 
to steroids. Such therapy, if successful, can also serve 
to reinforce the diagnosis. 
GUILLAIN-BARRE: 
o 
It is important to consider here that the use of steroids 
as the primary treatment of Guillain-Barre is not 
typically considered effective. 
o 
Patients requiring treatment should be started with IV 
IG and followed by plasmapheresis if not responsive 
to IV IG. 
 
Myocarditis 
Any Grade 
General Guidance 
Discontinue drug permanently if biopsy-
proven immune-mediated myocarditis. 
For Any Grade: 
− 
The prompt diagnosis of immune-mediated myocarditis is 
important, particularly in patients with baseline 
cardiopulmonary disease and reduced cardiac function.  
− 
Consider, as necessary, discussing with the study physician. 
− 
Monitor patients for signs and symptoms of myocarditis (new 
onset or worsening chest pain, arrhythmia, shortness of breath, 
peripheral edema). As some symptoms can overlap with lung 
toxicities, simultaneously evaluate for and rule out pulmonary 
toxicity as well as other causes (e.g., pulmonary embolism, 
congestive heart failure, malignant pericardial effusion). A 
Cardiology consultation should be obtained early, with prompt 
assessment of whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
− 
Initial work-up should include clinical evaluation, BNP, 
cardiac enzymes, ECG, echocardiogram (ECHO), monitoring 
of oxygenation via pulse oximetry (resting and exertion), and 
additional laboratory work-up as indicated. Spiral CT or 
cardiac MRI can complement ECHO to assess wall motion 
abnormalities when needed. 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections) 

 
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Grade 1 
(asymptomatic or mild 
symptoms*; clinical or 
diagnostic observations 
only; intervention not 
indicated) 
*Treat myocarditis with 
mild symptoms as 
Grade 2. 
No dose modifications required unless 
clinical suspicion is high, in which case 
hold study drug/study regimen dose 
during diagnostic work-up for other 
etiologies. If study drug/study regimen is 
held, resume after complete resolution to 
Grade 0. 
 
For Grade 1 (no definitive findings): 
- 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms, BNP, cardiac enzymes, ECG, ECHO, pulse 
oximetry (resting and exertion), and laboratory work-up as 
clinically indicated. 
- 
Consider using steroids if clinical suspicion is high. 
 
Grade 2, 3 or 4 
(Grade 2: Symptoms 
with moderate activity 
or exertion) 
 (Grade 3: Severe with 
symptoms at rest or 
with minimal activity 
or exertion; inter-
vention indicated; new 
onset of symptoms*) 
(Grade 4: Life-
threatening conse-
quences; urgent 
intervention indicated 
(e.g., continuous IV 
therapy or mechanical 
hemodynamic support)) 
 
* Consider “new onset 
of symptoms” as 
referring to patients 
with prior episode of 
myocarditis. 
- If Grade 2 -- Hold study drug/study 
regimen dose until resolution to 
Grade 0. If toxicity rapidly improves to 
Grade 0, then the decision to reinitiate 
study drug/study regimen will be based 
upon treating physician’s clinical 
judgment and after completion of 
steroid taper. If toxicity does not 
rapidly improve, permanently. 
discontinue study drug/study regimen. 
If Grade 3-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4: 
− 
Monitor symptoms daily, hospitalize. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day or 
equivalent after Cardiology consultation has determined 
whether and when to complete diagnostic procedures including 
a cardiac biopsy. 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 3 to 5 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly start 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 

 
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Myositis/Polymyositis 
(“Poly/myositis”) 
Any Grade 
General Guidance 
For Any Grade: 
− 
Monitor patients for signs and symptoms of poly/myositis. 
Typically, muscle weakness/pain occurs in proximal muscles 
including upper arms, thighs, shoulders, hips, neck and back, 
but rarely affects the extremities including hands and fingers; 
also difficulty breathing and/or trouble swallowing can occur 
and progress rapidly. Increased general feelings of tiredness 
and fatigue may occur, and there can be new-onset falling, 
difficulty getting up from a fall, and trouble climbing stairs, 
standing up from a seated position, and/or reaching up. 
− 
If poly/myositis is suspected, a Neurology consultation should 
be obtained early, with prompt guidance on diagnostic 
procedures. Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given breathing 
complications, refer to guidance under Pneumonitis/ILD.  
Given possibility of an existent (but previously unknown) 
autoimmune disorder, consider Rheumatology consultation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Initial work-up should include clinical evaluation, creatine 
kinase, aldolase, LDH, BUN/creatinine, erythrocyte 
sedimentation rate or C-reactive protein level, urine myoglobin, 
and additional laboratory work-up as indicated, including a 
number of possible rheumatological/antibody tests (i.e., 
consider whether a rheumatologist consultation is indicated and 
could guide need for rheumatoid factor, antinuclear antibody, 
anti-smooth muscle, antisynthetase [such as anti-Jo-1], and/or 
signal-recognition particle antibodies). Confirmatory testing 
may include electromyography, nerve conduction studies, MRI 
of the muscles, and/or a muscle biopsy. Consider Barium 
swallow for evaluation of dysphagia or dysphonia. 
Patients should be thoroughly evaluated to rule out any alternative 
etiology (e.g., disease progression, other medications, or infections). 
 
Grade 1 
(mild pain) 
- No dose modifications. 
For Grade 1: 
− 
Monitor and closely follow up in 2 to 4 days for clinical 
symptoms and initiate evaluation as clinically indicated. 
− 
Consider Neurology consult. 
− 
Consider, as necessary, discussing with the study physician. 

 
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Grade 2 
(moderate pain 
associated with 
weakness; pain limiting 
instrumental activities 
of daily living [ADLs]) 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
- Permanently discontinue study 
drug/study regimen if it does not 
resolve to Grade ≤1 within 30 days or 
if there are signs of respiratory 
insufficiency. 
For Grade 2: 
− 
Monitor symptoms daily and consider hospitalization. 
− 
Obtain Neurology consult, and initiate evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
If clinical course is rapidly progressive (particularly if 
difficulty breathing and/or trouble swallowing), promptly start 
IV methylprednisolone 2 to 4 mg/kg/day systemic steroids 
along with receiving input from Neurology consultant  
− 
If clinical course is not rapidly progressive, start systemic 
steroids (e.g., prednisone 1 to 2 mg/kg/day PO or IV 
equivalent); if no improvement within 3 to 5 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 
 
Grade 3 or 4 
(Grade 3: pain 
associated with severe 
weakness; limiting self-
care ADLs 
 
Grade 4:  life-
threatening 
consequences; urgent 
intervention indicated) 
For Grade 3: 
Hold study drug/study regimen dose until 
resolution to Grade ≤1. 
Permanently discontinue study drug/study 
regimen if Grade 3 imAE does not resolve 
to Grade ≤1 within 30 days or if there are 
signs of respiratory insufficiency. 
 
For Grade 4: 
- Permanently discontinue study 
drug/study regimen. 
For Grade 3 or 4 (severe or life-threatening events): 
− 
Monitor symptoms closely; recommend hospitalization. 
− 
Obtain Neurology consult, and complete full evaluation. 
− 
Consider, as necessary, discussing with the study physician. 
− 
Promptly start IV methylprednisolone 2 to 4 mg/kg/day 
systemic steroids along with receiving input from Neurology 
consultant. 
− 
If after start of IV methylprednisolone at 2 to 4 mg/kg/day 
there is no improvement within 3 to 5 days, consider start of 
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab at 5 mg/kg every 2 weeks). Caution: It is 
important to rule out sepsis and refer to infliximab label for 
general guidance before using infliximab. 
− 
Consider whether patient may require IV IG, plasmapheresis. 
− 
Once the patient is improving, gradually taper steroids over 
≥28 days and consider prophylactic antibiotics, antifungals, or 
anti-PJP treatment (refer to current NCCN guidelines for 
treatment of cancer-related infections).a 

 
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aASCO Educational Book 2015 “Managing Immune Checkpoint Blocking Antibody Side Effects” by Michael Postow MD. 
bFDA Liver Guidance Document 2009 Guidance for Industry: Drug Induced Liver Injury – Premarketing Clinical Evaluation. 
AChE Acetylcholine esterase; ADL Activities of daily living; AE Adverse event; ALP Alkaline phosphatase test; ALT Alanine aminotransferase; AST Aspartate aminotransferase; 
BUN Blood urea nitrogen; CT Computed tomography; CTCAE Common Terminology Criteria for Adverse Events; ILD Interstitial lung disease; imAE immune-mediated 
adverse event; IG Immunoglobulin; IV Intravenous; GI Gastrointestinal; LFT Liver function tests; LLN Lower limit of normal; MRI  Magnetic resonance imaging; NCI  
National Cancer Institute; NCCN  National Comprehensive Cancer Network; PJP Pneumocystis jirovecii pneumonia (formerly known as Pneumocystis carinii pneumonia); 
PO  By mouth; T3  Triiodothyronine; T4 Thyroxine; TB Total bilirubin; TNF Tumor necrosis factor; TSH Thyroid-stimulating hormone; ULN Upper limit of normal. 
 
 

 
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Infusion-Related Reactions 
Severity Grade of the 
Event (NCI CTCAE 
version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance 
For Any Grade: 
− 
Manage per institutional standard at the discretion of investigator. 
− 
Monitor patients for signs and symptoms of infusion-related 
reactions (e.g., fever and/or shaking chills, flushing and/or itching, 
alterations in heart rate and blood pressure, dyspnea or chest 
discomfort, or skin rashes) and anaphylaxis (e.g., generalized 
urticaria, angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1: 
The infusion rate of study drug/study regimen may be decreased 
by 50% or temporarily interrupted until resolution of the event. 
 
For Grade 2: 
The infusion rate of study drug/study regimen may be decreased 
50% or temporarily interrupted until resolution of the event. 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2: 
− 
Acetaminophen and/or antihistamines may be administered per 
institutional standard at the discretion of the investigator. 
− 
Consider premedication per institutional standard prior to 
subsequent doses. 
− 
Steroids should not be used for routine premedication of Grade ≤2 
infusion reactions. 
Grade 3 or 4 
For Grade 3 or 4: 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4: 
− 
Manage severe infusion-related reactions per institutional 
standards (e.g., IM epinephrine, followed by IV diphenhydramine 
and ranitidine, and IV glucocorticoid). 
CTCAE Common Terminology Criteria for Adverse Events; IM intramuscular; IV intravenous; NCI National Cancer Institute. 
 
 
 

 
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Non–Immune-Mediated Reactions 
Severity Grade of the Event 
(NCI CTCAE version 5.0) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard. 
Grade 3 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
For AEs that downgrade to ≤Grade 2 within 7 days or resolve to 
≤Grade 1 or baseline within 14 days, resume study drug/study 
regimen administration. Otherwise, discontinue study drug/study 
regimen. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, and 
consultation with the Sponsor.). 
Treat accordingly, as per institutional standard. 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Study Physician.” 
AE Adverse event; CTCAE Common Terminology Criteria for Adverse Events; NCI National Cancer Institute. 
 
 
 
 
 

 
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Appendix 4. Run in phase