Conditions: Metastatic Colorectal Cancer
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 33
Healthy volunteers: no

Brief summary:
The POLE mutations represent high somatic mutation loads in patients with colorectal cancer, especially in those with MMR proficient or MSS, therefore, tumors harbouring POLE mutations might be susceptible to immune checkpoint blockade.

Based on these reasons, the investigators planned a phase II study of durvalumab monotherapy in patients with previously treated, metastatic, MMR deficient (MSI-H) or POLE mutated colorectal cancer.

Detailed description:
Later-line therapies after failure of standard treatments for metastatic colorectal cancer patients are limited; regorafenib and TAS-102 have shown clinical activity for these patients, however, efficacy outcomes seemed not to be sufficient although there have been rather higher frequencies of adverse events.

Mismatch repair (MMR) deficiency or microsatellite instability-high (MSI-H) played a role of negative predictive factor for adjuvant fluorouracil-based chemotherapy in patients with resected colorectal cancer. In the metastatic setting, deficient MMR or MSI-H represented poor prognosis; however, their predictive role has been documented after the pembrolizumab trial was reported. The results of the pembrolizumab trial demonstrated that the PD-1 blockade with pembrolizumab monotherapy showed 40% of confirmed immune-related objective response rates in patients with MMR deficient metastatic colorectal cancers; hence there was no objective response in those with MMR proficient tumors. The progression-free rates at 20 weeks were 78% versus 11%, respectively, also favouring those with MMR deficient tumors. However, the MMR deficiency of MSI-H is found in only about 5% in patients with metastatic colorectal cancer, which is too small to expand potential candidate of immunotherapy.

One of the proposed mechanism of promising efficacy from pembrolizumab for MMR deficient colorectal cancer is that MMR deficient or MSI-H colorectal cancers harbour higher somatic mutation loads than MMR proficient colorectal cancer (a mean of 1782 somatic mutations per tumor in the MMR deficient tumors versus 73 in the MMR proficient tumors in the results of pembrolizumab trial); somatic mutations have the potential to encode non-self immunogenic antigens; therefore, immunotherapy enhancing immune surveillance produced promising treatment efficacy in the MMR deficient tumors.

The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, and it involves DNA repair and chromosomal replication. The POLE mutations are located in the exonuclease domain, and their presence has already been reported in the various cancers including colorectal and endometrial cancer.

Arms:
arm 1: The mismatch repair deficient or microsatellite instable, or POLE mutated metastatic colorectal cancer patients who were refractory to fluoropyrimidines, irinotecan and oxaliplatin with or without targeted agents will be accrued.

After checking the eligibility for the study entry, patients will be entered into the study treatment with durvalumab monotherapy.

Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: Study treatment consists of durvalumab 1500 mg Q4W for patients \> 30 kg, and will be repeated every 4 weeks. For patients ≤ 30 kg, weight based dosing of 20 mg/kg durvalumab Q4W will be used.

Response evaluation will be performed every 8 weeks (± 1-week window period). Treatment will be continued until disease progression, unacceptable adverse events or the patient's refusal.

Treatment through progression is at the investigator's discretion, and the investigator should ensure that patients do not have any significant, unacceptable, or irreversible toxicity that indicate that continuing treatment will not further benefit the patient. The Investigator should ensure that patients still meet all of the inclusion criteria and none of the exclusion criteria for this study.

Protocol document:
Prot_SAP_000.pdf: 
A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  1 
 
 
Clinical Trial Protocol 
 
 
A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated 
metastatic colorectal cancer 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 
효능을 평가하는 2상 연구 
 
 
Chief Principal Investigator: Tae Won Kim 
Asan Medical Center, University of Ulsan 
College of Medicine, Seoul 
Co-investigator: Yong Sang Hong 
 Sun Young Kim 
 Jeong Eun Kim 
  
 
 
 
 
 
Current Version: English_version_1.7 
Current Date:  12/Apr/2022 
 
 
 
Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 
Korea 
 
 
 
 
 
 
 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  2 
 
CONTENTS 
Version History ......................................................................................................................................................... 6 
Protocol Synopsis ................................................................................................................................................. 7 
연구 계획 요약 ..................................................................................................................................................... 14 
1. 
TITLE OF THE STUDY............................................................................................................................... 20 
2. 
PARTICIPATING CENTERS AND INVESTIGATORS ................................................................... 20 
3. 
INTRODUCTION AND STUDY RATIONALE.................................................................................. 21 
3.1. 
INTRODUCTION ........................................................................................................................ 21 
3.2. 
DURVALUMAB (MEDI4736) ............................................................................................... 24 
3.3. 
FIXED DOSING ........................................................................................................................... 25 
3.4. 
RATIONALE OF THE STUDY ............................................................................................... 26 
4. 
STUDY OBJECTIVES .................................................................................................................................. 27 
4.1. 
PRIMARY OBJECTIVE ............................................................................................................. 27 
4.2. 
SECONDARY OBJECTIVES .................................................................................................... 27 
5. 
STUDY DESIGN ........................................................................................................................................... 27 
5.1. 
DESIGN OVERVIEW ................................................................................................................. 27 
5.2. 
JUSTIFICATION OF THE DESIGN ..................................................................................... 28 
6. 
STUDY POPULATION............................................................................................................................... 28 
6.1. 
ELIGIBILITY .................................................................................................................................. 28 
6.1.1. 
INCLUSION CRITERIA ............................................................................................................... 28 
6.1.2. 
EXCLUSION CRITERIA .............................................................................................................. 29 
6.2. 
WITHDRAWAL OF SUBJECTS ............................................................................................ 31 
6.3. 
REPLACEMENT........................................................................................................................... 31 
7. 
STUDY TREATMENT ................................................................................................................................. 31 
7.1. 
DURVALUMAB ........................................................................................................................... 32 
7.2. 
DOSE AND TREATMENT REGIMEN ................................................................................ 33 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  3 
 
7.3. 
DOSE MODIFICATION AND DELAYS ............................................................................. 33 
7.3.1. 
GENERAL RULES FOR DOSE MODIFICATION AND DELAYS .................................. 33 
7.4. 
LABELING ..................................................................................................................................... 34 
7.5. 
STORAGE ...................................................................................................................................... 34 
7.6. 
COMPLIANCE ............................................................................................................................. 34 
7.7. 
CONCOMITANT THERAPY .................................................................................................. 34 
7.7.1. 
PROHIBITED CONCOMITANT MEDICATIONS ............................................................... 34 
7.7.2. 
PERMITTED CONCOMITANT MEDICATIONS ................................................................ 35 
7.8. 
RESTRICTIONS ........................................................................................................................... 35 
7.8.1. 
FEMALE PATIENT OF CHILD-BEARING POTENTIAL .................................................... 35 
7.8.2. 
MALE PATIENT WITH A FEMALE PARTNER OF CHILDBEARING POTENTIAL . 36 
7.8.3. 
BLOOD DONATION .................................................................................................................. 37 
8. 
STUDY PROCEDURE AND SCHEDULE ............................................................................................ 38 
8.1. 
TABULATED OVERVIEW ....................................................................................................... 38 
8.2. 
EVALUATION BEFORE STUDY TREATMENT (WITHIN 2 WEEKS) ................... 39 
8.3. 
EVALUATION DURING STUDY TREATMENT (EVERY CYCLES OF STUDY 
TREATMENT) .................................................................................................................................................... 39 
8.4. 
RESPONSE EVALUATION (EVERY 8 WEEKS ± 1 WEEK WINDOW PERIOD)
 
40 
8.5. 
POST-TREATMENT FOLLOW-UP (EVERY 3 MONTHS) ......................................... 40 
9. 
ADVERSE EVENTS ...................................................................................................................................... 40 
9.1. 
DEFINITIONS .............................................................................................................................. 40 
9.1.1. 
ADVERSE EVENT......................................................................................................................... 40 
9.1.2. 
SERIOUR ADVERSE EVENTS .................................................................................................. 41 
9.1.3. 
DEFINITION OF ADVERSE EVENTS OF SPECIAL INTEREST (AESI) ........................ 42 
9.1.4. 
RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS .............. 43 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  4 
 
9.2. 
DOCUMENTATION AND REPORTING OF ADVERSE EVENTS BY 
INVESTIGATOR ................................................................................................................................................ 44 
9.3. 
IMMEDIATE REPORTING BY INVESTIGATOR TO IRB AND MONITORING 
COMMITTEE ...................................................................................................................................................... 45 
9.4. 
OTHER EVENTS REQUIRING REPORTING ................................................................... 46 
9.4.1. 
Timeline .......................................................................................................................................... 46 
9.4.2. 
Medication Error ........................................................................................................................ 46 
9.4.3. 
Drug Abuse .................................................................................................................................. 46 
9.4.4. 
Drug Misuse ................................................................................................................................. 47 
9.4.5. 
HEPATIC FUNCTION ABNOMALITY ................................................................................... 47 
9.4.6. 
PREGNANCY ................................................................................................................................ 47 
10. 
STATISTICAL CONSIDERATION ........................................................................................ 48 
10.1. 
ANALYSIS SET.............................................................................................................................. 48 
10.1.1. EFFICACY ANALYSIS SET ........................................................................................................ 48 
10.1.2. SAFETY ANALYSIS SET ............................................................................................................. 48 
10.2. 
SAMPLE SIZE AND RATIONALE ....................................................................................... 49 
10.3. 
STATISTICAL PARAMETERS AND STATISTICAL ANALYSIS PLAN ................. 49 
10.4. 
FINAL ANALYSIS ...................................................................................................................... 49 
11. 
ETHICAL AND LEGAL ASPECTS ........................................................................................ 50 
11.1. 
GOOD CLINICAL PRACTICE (GCP) .................................................................................. 50 
11.2. 
DELEGATION OF INVESTIGATOR DUTIES ................................................................... 50 
11.3. 
SUBJECT INFORMATION AND INFORMED CONSENT ........................................ 50 
11.4. 
CONFIDENTIALITY ................................................................................................................... 51 
11.5. 
PROTOCOL AMENDMENTS ................................................................................................ 51 
11.6. 
APPROVAL OF THE CLINICAL STUDY PROTOCOLS AND AMMENDMENTS
 
51 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  5 
 
11.7. 
CLOSURE OF THE STUDY .................................................................................................... 52 
11.8. 
FINANCIAL DISCLOSURE ..................................................................................................... 52 
12. 
Exploratory biomarker studies ......................................................................................... 52 
13. 
REFERENCES................................................................................................................................ 53 
Appendix A. ........................................................................................................................................................... 56 
APPENDIX B. ......................................................................................................................................................... 84 
APPENDIX C. ......................................................................................................................................................... 85 
  
 
 
 
 
 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  6 
 
Version History 
Version 
Number 
Version date 
Summary/Reason for changes 
1.11 
27Oct2017 
Appendix C ( Add POLE mutation method) 
1.12 
08Feb2018 
Add sites 
1.13 
14Mar2018 
Delete KCSG, contraception period modification 
Amended Appendix A 
1.2 
14Jun2018 
IC #3 & EC #24, Study period 
1.3 
21May2019 
Amended section 9.4.2 ,change sites & investigators. 
1.4 
01Dec2020 
Amended Appendix A 
1.5 
11Nov2021 
Amended Appendix A (TMG amendment) 
1.6 
12Apr2022 
Added the maximum number of Durvalumab administrations 
allowed 
1.7 
12Dec2022 
Amended Table 1.Highly effective methods of contraception  
Added section 9.4.1 to 9.4.4 (Other events requiring 
reporting; Timeline, Medication error, Drug Abuse, Drug 
misuse)  
Amended Appendix A (TMG amendment) 
 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  7 
 
Protocol Synopsis 
Title 
A phase II study of durvalumab in patients with mismatch repair deficient or POLE 
mutated metastatic colorectal cancer 
Duration 
IRB approval ~ Dec 2023 
Investigators Principal Investigator: Tae Won Kim, Department of Oncology, Asan Medical Center 
Objectives 
 
Primary Objective 
 
Objective response rates (RECIST 1.1) 
 
 
Secondary Objectives 
 
Response rates by irRECIST 
 
Disease control rates 
 
Progression-free survival 
 
Overall survival  
 
Safety and toxicity assessments 
 
Exploratory biomarker studies 
- Opal Multiplex Tissue Staining with OpalTM including PD-1 and PD-L1 
 
Design 
Prospective, open-label, multicenter phase II study 
Background 
Later-line therapies after failure of standard treatments for metastatic colorectal 
cancer patients are limited; regorafenib and TAS-102 have shown clinical activity for 
these patients, however, efficacy outcomes seemed not to be sufficient although 
there have been rather higher frequencies of adverse events.  
Mismatch repair (MMR) deficiency or microsatellite instability-high (MSI-H) played a 
role of negative predictive factor for adjuvant fluorouracil-based chemotherapy in 
patients with resected colorectal cancer. In the metastatic setting, deficient MMR or 
MSI-H represented poor prognosis; however, their predictive role has been 
documented after the pembrolizumab trial was reported. The results of the 
pembrolizumab trial demonstrated that the PD-1 blockade with pembrolizumab 
monotherapy showed 40% of confirmed immune-related objective response rates 
in patients with MMR deficient metastatic colorectal cancers; hence there was no 
objective response in those with MMR proficient tumors. The progression-free rates 
at 20 weeks were 78% versus 11%, respectively, also favouring those with MMR 
deficient tumors. However, the MMR deficiency of MSI-H is found in only about 5% 
in patients with metastatic colorectal cancer, which is too small to expand potential 
candidate of immunotherapy. 
One of the proposed mechanism of promising efficacy from pembrolizumab for 
MMR deficient colorectal cancer is that MMR deficient or MSI-H colorectal cancers 
harbour higher somatic mutation loads than MMR proficient colorectal cancer (a 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  8 
 
mean of 1782 somatic mutations per tumor in the MMR deficient tumors versus 73 
in the MMR proficient tumors in the results of pembrolizumab trial); somatic 
mutations have the potential to encode non-self immunogenic antigens; therefore, 
immunotherapy enhancing immune surveillance produced promising treatment 
efficacy in the MMR deficient tumors. 
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, and it 
involves DNA repair and chromosomal replication. The POLE mutations are located 
in the exonuclease domain, and their presence has already been reported in the 
various cancers including colorectal and endometrial cancer. 
The POLE mutations represent high somatic mutation loads in patients with 
colorectal cancer, especially in those with MMR proficient or MSS, therefore, tumors 
harbouring POLE mutations might be susceptible to immune checkpoint blockade. 
Based on these reasons, we planned a phase II study of durvalumab monotherapy 
in patients with previously treated, metastatic, MMR deficient (MSI-H) or POLE 
mutated colorectal cancer. 
Patients 
number 
The primary endpoint is objective response rate of durvalumab in mismatch repair 
deficient (microsatellite instable) or POLE mutated metastatic colorectal cancer 
patients who have progressed after standard therapies. 
Assuming the target of response rate was set to 30% and a rate of 10% or below 
was considered futile. A 2-stage optimal design, as proposed by Simon, was used 
to allow early termination of any ineffective treatment early in the study. With a 1-
sided, type I error of 5% and power of 0.8, the planned study was to proceed in 2 
steps. In the first step, 10 patients were required, and if complete or partial response 
was observed in 2 or more patients, the study was to proceed to the second step 
with 19 additional patients (29 patients as a total). If this condition was not met, the 
study would be stopped for futility. In the second step, if complete or partial 
response was observed in 6 or more patients, the treatment will be considered 
effective. Assuming a dropout rate of 10%, 33 patients were required. 
Inclusion 
criteria 
1. Histologically or cytologically confirmed adenocarcinoma of the colon or the 
rectum. 
2. Mismatch repair deficient or microsatellite instable (defined below), or POLE 
mutated tumors 
A. 
Mismatch repair deficient: loss of expression by immunohistochemical 
stains ≥ 1 out of 4 markers (MLH1, MSH2, MSH6, PMS2) 
B. 
Microsatellite instable: loss of stability ≥2 out of 5 gene panels (BAT-
25, BAT-26, D2S123, D5S346, D17S250) 
C. 
POLE gene: P286R mutation or other mutation 
3. 
Refractory to at least one agent of prior treatments(fluoropyrimidines, irinotecan 
or oxaliplatin) Progressed after at least first-line systemic chemotherapy for 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  9 
 
metastatic setting (progressed within 6 months after completion of adjuvant 
chemotherapy is also considered as first-line failure) 
4. ≥ 1 measurable lesion(s) by RECIST 1.1. 
5. Unresectable advanced or metastatic disease. 
6. Age over 20 years old. 
7. ECOG performance status of 0-1 or lower. 
8. Adequate organ functions. 
A. Bone marrow function: Hemoglobin  9.0 g/dL, ANC  1,500/mm3, platelet 
 100,000/mm3 
B. Hepatic functions: bilirubin ≤ 1.5 X ULN, AST/ALT ≤ 2.5 X ULN (≤ 5 X ULN 
in cases of liver metastasis) 
C. Renal functions: serum Cr ≤ 1.5 X ULN or calculated CCr (Cockroft) > 40 
ml/min 
9. Be willing and able to comply with the protocol for the duration of the study. 
10. Give written informed consent prior to study-specific screening procedures, with 
the understanding that the patient has the right to withdraw the study at any 
time, without prejudice. 
11. Female subjects must either be of non-reproductive potential ( 60 years old and 
no menses for  1 year without an alternative medical cause, or history of 
hysterectomy, or history of bilateral tubal ligation, or history of bilateral 
oophorectomy) or must have a negative serum pregnancy test upon study entry. 
12. Women of childbearing potential and men must agree to use adequate 
contraception since signing of the IC form until at least 90days after the last 
study drug administration. 
Exclusion 
criteria 
1. Any prior treatment with PD-1 or PD-L1 inhibitor, including durvalumab. 
2. Involvement in the planning and/or conduct of the study. 
3. Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of 
study drugs. 
4. Mean QT interval corrected for heart rate (QTc)  470 msec calculated from 3 
electrocardiograms (ECGs) using Frediricia’s Correction. 
5. 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  
6. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis 
after consultation with the Study Physician. 
7. Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the 
Study Physician. 
8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  10 
 
treatment. Concurrent use of hormonal therapy for non-cancer-related conditions 
(eg, hormone replacement therapy) is acceptable. 
9. Current or prior use of immunosuppressive medication within 14 days before the 
first dose of durvalumab, with the exceptions of intranasal and inhaled 
corticosteroids or systemic corticosteroids at physiologic doses, which are not to 
exceed 10 mg/day of prednisolone, or an equivalent corticosteroid. 
10. Concurrent or previous history of another primary cancer within 3 years prior to 
randomisation except for curatively treated cervical cancer in situ, non-
melanomatous skin cancer, superficial bladder cancer (pTis and pT1) and 
curatively treated thyroid cancer of any stage. Concurrent, histologically 
confirmed, unresected thyroid cancer without distant metastasis could be 
allowed with the agreement of the chief principal investigator. 
11. Uncontrolled CNS metastases; permitted if asymptomatic or neurologically 
stable. 
12. Prior radiation therapy would be permitted, but non-radiated evaluable lesions 
should be present at study entry. 
13. Radiation therapy during study treatment is not permitted, but if the local 
investigator decides that radiation therapy should be given during study 
treatments, he should be convinced that there is no evidence of disease 
progression with agreement of the chief principal investigator.  
14. Congestive heart failure ≥ New York Heart Association (NYHA) class 2. 
15. Unstable angina, new-onset angina within 3 months, or history of myocardial 
infarction within 6 months before the study entry. 
16. Active or prior documented autoimmune disease within the past 2 years; 
subjects with vitiligo, Grave’s disease, or psoriasis not requiring systemic 
treatment (within the past 2 years) are not excluded. 
17. Active or prior documented inflammatory bowel disease. 
18. History of prior immunodeficiency. 
19. History of allogeneic organ transplantation. 
20. History of hypersensitivity to durvalumab or any excipient. 
21. Clinical diagnosis of active tuberculosis. 
22. Receipt of live attenuated vaccination within 30 days prior to study entry. 
23. Known history of testing positive for HIV 
24. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive) 
Except, resolved HBV infection (as evidenced by detectable HBV surface 
antibody, detectable HBV core antibody, undetectable HBV DNA, and 
undetectable HBV surface antigen) or Chronic HBV infection (as evidenced by 
detectable HBV surface antigen or HBV DNA). Subjects with chronic HBV 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  11 
 
infection must have HBV DNA < 100 IU/mL and must be on antiviral therapy. 
25. Major surgery or significant traumatic injury within 28 days prior to study 
treatment. 
26. Non-healing wound, ulcer, or bone fracture. 
27. Current evidence of significant gastrointestinal bleeding or (impending) 
obstruction. 
28. Concomitant participation in another interventional clinical trial. 
29. Pregnant of breast-feeding subjects. Women of child-bearing potential must 
have pregnancy test within 7 days and a negative result must be documented 
before start of study treatment. 
30. Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 
Treatment 
plan 
The mismatch repair deficient or microsatellite instable, or POLE mutated metastatic 
colorectal cancer patients who were refractory to fluoropyrimidines, irinotecan and 
oxaliplatin with or without targeted agents will be accrued. 
 
After checking the eligibility for the study entry, patients will be entered into the 
study treatment with durvalumab monotherapy. 
 
Study treatment consists of durvalumab 1500 mg Q4W for patients > 30 kg, and 
will be repeated every 4 weeks.  For patients ≤ 30 kg, weight based dosing of 20 
mg/kg durvalumab Q4W will be used.  
 
Response evaluation will be performed every 8 weeks (± 1-week window period). 
Treatment will be continued until disease progression, unacceptable adverse events 
or the patient’s refusal.  
 
Treatment through progression is at the investigator’s discretion, and the 
investigator should ensure that patients do not have any significant, unacceptable, 
or irreversible toxicity that indicate that continuing treatment will not further benefit 
the patient. The Investigator should ensure that patients still meet all of the inclusion 
criteria and none of the exclusion criteria for this study. 
Statistical 
consideration 
All patients who entered into the study will be included for response rates and 
survival estimation and who received at least 1 cycle of study treatment will be 
considered as eligible for safety assessment. Descriptive statistics were reported as 
proportions and medians. Progression-free survival (PFS) and overall survival (OS) 
were assessed by the Kaplan-Meier method and the 95% confidence interval (95% 
CI) for the median time to event was computed. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  12 
 
Evaluation 
Evaluation before study entry (within 2 weeks) 
1. Complete medical history. 
2. Physical examination including ECOG performance status. 
3. Radiologic assessments using RECIST 1.1. (permitted to be assessed within 28 
days from the study treatment) 
4. CBC with differentials. 
5. Serum chemistry: calcium, phosphorus, glucose, BUN, creatinine, total protein, 
albumin, AST/ALT, alkaline phosphatase, total bilirubin, uric acid and 
electrolytes. 
6. Routine urinalysis  
7. Serum CEA 
8. Serum TSH, free T4, T3 
9. Serum amylase/lipase 
10. EKG (3 consecutive EKG for eligibility check) 
11. Chest X-rays  
12. Urine β-hCG will be performed in women with child-bearing potential. 
13. Other tests (i.e. bone scans) if clinically indicated. 
 
Evaluation during study treatment (every cycle) 
1. Physical examination including ECOG performance status and drug-related 
side effects. 
2. CBC with differentials. 
3. Serum chemistry: calcium, phosphorus, glucose, BUN, creatinine, total protein, 
albumin, AST/ALT, alkaline phosphatase, total bilirubin, uric acid and 
electrolytes. 
4. Serum amylase/lipase. 
5. Toxicity assessments (NCI-CTC version 4.0) 
 
Response evaluation (every 8 weeks ± 1 week window period) 
1. Serum CEA, TSH, T3 and free T4 
2. CT (or MRI) scans of evaluable/measurable lesions by RECIST 1.1. 
3. Other test (i.e. bone scans) if clinically indicated 
4. Response evaluation will be performed every 8 weeks without regard to the 
schedules of study treatment. 
 
Post-treatment follow-up (every 3 months) 
1. Subsequent treatments (chemotherapy, immunotherapy or radiotherapy) and 
their responses 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  13 
 
2. Survival information on subject 
3. Status of disease and date of progression (in patients who stopped study 
treatment without documentation of disease progression) 
4. Date and cause of death 
 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  14 
 
연구 계획 요약 
연구 제목 DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 
durvalumab의 효능을 평가하는 2상 연구 
연구 기간 IRB 심의일 ~ 2023년 12월 
연구자 
책임연구자: 김태원, 서울아산병원 종양내과 
연구 목표 
 
일차 목표 
 
종양 반응율 (RECIST 1.1 기준) 
 
 
이차 목표 
 
irRECIST 에 의한 종양 반응율 
 
종양 조절율 (disease control rates) 
 
무진행 생존 기간 (progression-free survival) 
 
전체 생존 기간 (overall survival) 
 
안전성 및 독성 평가 
 
탐색적 생체 표지자 연구 
- 
Opal Multiplex Tissue Staining with OpalTM including PD-1 and PD-L1 
 
연구 설계 전향적, 공개, 다기관 2상 연구 
연구 배경 표준 치료에 진행한 전이성 대장암의 후기 치료는 제한되어 있다. 후기 치료로 
regorafenib과 TAS-102 임상연구 결과가 일부 생존 기간 향상에 도움이 되는 것으로 
보고되었으나 그 효과는 아직 불충분하고 일부 심한 독성도 보고되고 있다. 
DNA 복구 유전자 결핍 (mismatch repair deficiency, dMMR) 또는 현미부수체불안정 
(microsatellite 
instability-high, 
MSI-H)는 
수술적 
절제가 
시행된 
대장암에서 
플루오로피리미딘 기반 화학요법의 효과가 없는 음성 예측인자로 알려져 있으며, 
전이성 대장암에서는 그 자체가 나쁜 예후를 반영하는 것으로 되어 있다. 그러나 
최근 전이성 대장암에서 dMMR 또는 MSI-H가 pembrolizumab의 치료 예측인자로써 
역할을 
하는 
연구 
결과가 
발표되었다. 
dMMR/MSI-H 
전이성 
대장암에서 
pembrolizumab을 이용하여 PD-1을 억제하였을 때 종양 반응율이 40%에 달하였다. 
반면 DNA 복구 유전자가 정상적으로 발현되는 경우 (mismatch repair proficiency, 
pMMR)에는 종양 반응율이 0% 였다. 20주 째에 종양이 진행하지 않은 환자의 비율도 
78% 대 11%로 dMMR/MSI-H 대장암에서 높았다. 
dMMR/MSI-H 전이성 대장암이 pembrolizumab 등 면역치료에 반응하는 이론적인 
근거 중 하나는, dMMR/MSI-H 전이성 대장암에서 종양 유전자 돌연변이가 매우 많이 
발생한다는 것이다. 유전자 돌연변이가 많은 경우 항원에 대한 노출이 많아지기 
때문에 면역치료의 역할이 커진다는 이론이다. 실제로 pembrolizumab에 반응하였던 
dMMR/MSI-H 대장암 환자의 유전자 돌연변이 개수를 보았을 때 평균 1782개의 종양 
유전자 돌연변이가 발견되었다. 
POLE 유전자 역시 DNA 복구와 염색체 복제 과정에 관여하는 유전자로 알려져 
있으며, POLE 유전자 돌연변이가 있는 경우 다른 종양 유전체 돌연변이가 많이 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  15 
 
발생하는 것으로 보고되어 있다. 즉, pMMR/MSS 대장암에서 POLE 유전자 돌연변이가 
있는 경우 dMMR/MSI-H 대장암과 마찬가지로 종양 유전자 돌연변이가 많이 
존재하는 것으로 간주할 수 있으며, 이 역시 면역치료의 좋은 대상이 될 수 있다. 
위와 같은 배경으로 표준 치료에 진행한 전이성 대장암 중에서 dMMR/MSI-H 또는 
POLE 유전자 돌연변이가 있는 환자에서 durvalumab 단독치료의 2상 연구를 
계획하였다. 
환자 수 
본 연구의 일차 목표는 dMMR/MSI-H 또는 POLE 유전자 돌연변이가 있는 전이성 
대장암 환자에서 durvalumab 단독 치료를 하였을 때의 종양 반응율이다. 목표 종양 
반응율을 30%, 10% 미만의 반응율을 보이는 경우 실패하는 것으로 가정하였을 때, 
Simon 2-stage optimal design에 의하면 1단계에서 10명의 환자 등재 후 2명 이상에서 
종양 반응을 보이는 경우 2단계로 진입하고, 2단계에서 추가적으로 19명의 환자를 
등재하게 된다 (type I error 5%, power 0.8). 총 29명의 평가 가능 환자가 필요하고, 
10%의 탈락율을 고려할 때 총 33명의 환자가 등재된다. 
선정 기준 1. 조직학적/세포학적으로 증명된 대장의 선암 
2. DNA 복구 유전자 결핍 (dMMR) 또는 현미부수체 불안정 (MSI-H) 또는 POLE 
유전자 돌연변이가 있는 경우 
A. 
dMMR: 면역조직화학염색 기법으로 MLH1, MSH2, MSH6, PMS2 중 1개 
이상 면역단백표현이 없는 경우 (loss of expression) 
B. 
MSI-H: PCR 기법으로 5개 유전자 중 (BAT-25, BAT-26, D2S123, D5S346, 
D17S250) 2개 이상에서 불안정성이 보이는 경우 
C. 
POLE gene: P286R mutation or other mutation 
3. 플루오로피리미딘, 옥살리플라틴 또는이리노테칸 중 최소 1가지 이상의 약제에 
내성. 전이성 대장암의 치료로 최소한 1차 요법 이상 시행하여 진행한 
경우(보조화학요법 종료 후 6개월 이내 임상적 또는 영상학적으로 진행한 
경우에도 1차요법 이상에 실패한 것으로 간주) 
4. RECIST 1.1. 기준에 따른 계측 가능 (measurable) 병변의 존재. 
5. 수술적인 치료가 불가능한 경우 
6. 만 20세 이상 
7. ECOG 활동도 0-1 
8. 적절한 장기 기능 
A. 골수기능: 혈색소 (Hb)  9.0 g/dL, 호중구 (ANC)  1,500/mm3, 혈소판 (PLT)  
100,000/mm3 
B. 간기능: bilirubin ≤ 정상 상한치의 1.5배, AST/ALT ≤ 정상 상한치의 2.5배 (간 
전이가 있는 경우 ≤ 정상 상한치의 5배) 
C. 신기능: 혈청 크레아티닌 ≤ 정상 상한치의 1.5배 또는 calculated CCr 
(Cockroft) > 40 ml/min 
9. 연구 기간 동안 연구 계획서에 순응하고 치료 계획에 준수할 의지가 있는 환자. 
10. 연구 동의서에 자발적으로 서명하고, 자발적으로 연구에 참여하고 언제든지 
참여를 철회할 수 있음을 이해하는 환자. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  16 
 
11. 대상자가 여성인 경우 임신 가능성이 없어야 함 (60세 이상이면서 1년 이상 
생리가 없었던 경우 또는 자궁적출술 또는 양측난소절제수술을 시행한 경우). 그 
외 임신 가능성이 있다면 연구 참여 전에 임신 반응 검사를 시행하여 임신이 
아님을 증명하여야 한다. 
12. 가임기의 남녀 환자의 경우, 연구약 투여 기간 동안과 최종 투여 후 최소한 90일 
까지 적절한 피임법을 준수할 수 있는 환자. 
제외 기준 1. 
이전에 durvalumab을 포함한 PD-1 또는 PD-L1 억제제를 사용한 적이 있는 경우. 
2. 
연구 계획 또는 수행에 관계된 종사자 
3. 
마지막 화학요법 시행 후 28일이 지나지 않은 경우 
4. 
QTc  470 msec 이상인 경우 (3회의 EKG 시행 후 평균 값, Frediricia’s Correction) 
5. 
이전 항암요법으로부터 해결되지 않은 CTCAE 2등급 이상인 독성 (탈모, 백반증, 
선정기준에 적합하지 않은 실험실검사 결과 제외) 
6. 
2등급 이상의 신경병증 환자의 경우 대상자 질환에 대한 평가는 연구자의 의학적 
자문 이후 진행한다.  
7. 
비가역성 독성 환자에서 durvalumab 치료가 증상을 더 악화하지 않을 경우에는 
연구자의 의학적 판단을 기준으로 한다. 
8. 
항암 치료를 위해 화학요법, 시험약, 생물학적 제제, 또는 호르몬 요법을 현재 
사용하는 환자. 암과 무관한 상태에 대한 호르몬 요법의 동시 사용(예: 호르몬 
대체 요법)은 허용된다. 
9. 
14일 이내의 면역 억제제 사용, 단 흡입성 스테로이드나 생리적 용량의 
스테로이드는 허용한다 (10 mg/day of prednisolone 또는 equivalent dose의 다른 
스테로이드 제제). 
10. 3년 이내에 다른 원발암의 병력이 있는 경우, 단 수술적으로 완치된 표재성 자궁 
경부암, 표재성 피부암 (흑색종 제외), 표재성 방광암 (pTis, pT1)과 4기를 제외한 
갑상샘암은 허용된다. 갑상샘암의 경우 수술적인 제거가 되지 않았더라도 
연구자의 판단 하에, 전이성 대장암의 치료 경과와 예후에 영향을 주지 않는다는 
연구자의 판단이 있다면, 총 책임 연구자와 상의 후 환자를 연구에 참여시킬 수 
있다.  
11. 조절되지 않은 중추신경계 전이. 
12. 이전의 방사선 치료 병력은 허용된다. 그러나 방사선 조사 범위에 들어가지 않는 
평가 가능 병변의 존재가 있어야 한다. 
13. 원칙적으로 연구 치료 기간 동안의 방사선 치료는 허용되지 않는다. 그러나 
연구자가 질병진행의 증거가 없는 치료병변 외의 부위에 방사선 치료가 
필요하다고 판단되는 경우 총 책임연구자와 상의 후 진행 할 수 있다. 
14.  New York Heart Association (NYHA) class 2 이상의 심부전. 
15.  3개월 이내의 불안정성 협심증 병력, 또는 최근의 새로 생긴 심근 허혈 증상,    
또는 6개월 이내의 심근 경색 병력이 있는 경우. 
16.  2년 이내의 활동성 자가면역질환, 단 전신 치료가 필요하지 않는 vitiligo, 
그레이브스씨 병, 건선은 허용된다. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  17 
 
17.  염증성 장질환의 병력 
18.  면역억제의 병력 
19.  장기 이식 환자 
20.  Durvalumab 또는 비슷한 약제에 대한 과민반응 
21.  연구 참여 시 활동성 결핵이 있는 경우 
22.  생백신 (live attenuated vaccine) 투여 후 30일 이내 
23.  HIV 감염 병력 또는 알려진 면역결핍 신드롬. 
24. 스크리닝 단계에서 활동성HBV/HCV 감염(HBV 표면항원양성 또는 HCV RNA 
양성). 단, 회복된B형간염(anti HBs 와 anti HBc가확인되고, HBsAg, HBV DNA가 
검출되지 않는 경우) 또는 HBsAg, HBV DNA로 확인된 만성 B형 간염의 경우 
제외. 만성 B형 간염의 경우 항바이러스제 치료 중이며, HBV DNA <100IU/mL 
임을 반드시 확인해야 한다. 
25. 연구 시작 28일 이내의 주요 수술 또는 심각한 외상 병력. 
26. 치유되지 않은 창상, 궤양 또는 골절.  
27. 위장관 출혈이 지속되거나, 장 폐색이 의심되는 경우.  
28. 현재 다른 약물이 투여되는 임상 연구에 참여 중인 경우. 
29. 임산부 또는 모유 수유 중인 환자. 가임기의 여성은 연구 참여 7일 이내에 임신 
반응 검사를 시행하여야 하며 음성임이 확인되어야 한다. 
30. 연구 참여와 연구 결과 해석에 지장을 줄 수 있다고 판단되는 약물 남용자, 
내과적/정신과적/사회적 질환을 가진 자. 
치료 계획 이전의 표준 치료 (플루오로피리미딘, 옥살리플라틴, 이리노테칸)에 불응하며, DNA 
복구 유전자 결핍 (mismatch repair deficiency) 또는 현미부수체불안정 (microsatellite 
instability) 또는 POLE 유전자 돌연변이가 있는 전이성 대장암 환자를 대상으로 한다. 
 
선정/제외 기준에 만족하는 경우만 연구에 참여할 수 있으며, durvalumab은 1500 
mg의 용량으로 매 4주 마다 반복한다. 
 
반응 평가는 매 8주 마다 (± 1주) 시행되며, 질병의 진행, 감내할 수 없는 독성 또는 
동의 철회가 있을 때 중지한다. 반응 평가는 연구 치료의 주기와 상관 없이 매 8주 
마다 시행한다. 
 
질병의 진행 이후에도 연구자의 판단 하에 durvalumab을 지속할 수 있으며, 이때는 
감내할 만한 부작용이 없는지, 환자에게 이득이 되는지, 그리고 그 시점에서의 환자 
상태가 선정/제외 기준에 부합하는지 평가 후 진행하여야 한다. 
통계학적 
고려 
연구에 참여한 모든 환자는 유효성 (반응율) 분석에 포함될 것이며, 안전성 평가에는 
1차 이상 연구 약제를 투여 받은 환자가 포함될 것이다. 통계 기술은 %와 
중간값으로 기술되며, 생존 기간 (PFS, OS)은 Kaplan-Meier 기법을 이용하여 
분석/비교될 것이다. 
연구 절차 연구 참여 전 절차 (연구 치료 시작 2주 이내) 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  18 
 
1. 병력 확인. 
2. ECOG 활동도를 포함한 신체 검진. 
3. RECIST 1.1 기준에 따른 계측 가능 병변 확인 
4. 일반혈액검사 (CBC) 
5. 혈청 일반화학검사 (Chemistry): calcium, phosphorus, glucose, BUN, creatinine, 
total protein, albumin, AST/ALT, alkaline phosphatase, total bilirubin, uric acid and 
electrolytes. 
6. 요검사 
7. 혈중 CEA 
8. 갑상선 기능 검사 (TSH, T3, free T4) 
9. 혈중 amylase/lipase 
10. 심전도 (3회 시행) 
11. 흉부 X-선 검사 
12. 가임기 여성의 경우 임신 반응 검사 (소변 beta-hCG) 
13. CT, MRI 등의 영상학적 검사 외에 연구자가 반응 평가에 필요하다고 판단하는 
다른 검사 
 
연구 치료 기간 동안의 절차 (매 연구 치료 시작 전) 
1. 신체 검진, ECOG 활동도 검사, 약제 복용 확인 
2. 일반혈액검사 (CBC). 
3. 혈청 일반화학검사 (Chemistry): calcium, phosphorus, glucose, BUN, creatinine, 
total protein, albumin, AST/ALT, alkaline phosphatase, total bilirubin, uric acid and 
electrolytes. 
4. 혈중 amylase/lipase 
5. 독성 및 안전성 평가 (NCI-CTC version 4.0) 
 
반응 평가 (매 8주 마다 ± 1 week window period) 
1. 혈중 CEA, 갑상선 기능 검사 (TSH, T3, free T4),  
2. 영상의학적 검사를 통한 종양 계측/반응 평가 (RECIST 1.1) 
3. 그 외 연구자가 반응 평가를 위해 필요하다고 판단하는 검사 
4. 반응 평가는, 연구 치료의 주기와 상관없이 매 8주 (± 1주)마다 시행되어야 
한다. 
 
치료 종료 후 절차 (매 3개월 마다) 
1. 이후 치료에 대한 정보 (항암화학요법, 면역요법, 방사선치료): 기간, 반응, 약제 
종류 등 
2. 생존에 대한 정보 
3. 질병의 확인 없이 연구 치료가 종료된 경우, 질병의 진행을 확인할 수 있는 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  19 
 
정보 
4. 사망한 경우, 사망일과 사망 원인 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  20 
 
1. TITLE OF THE STUDY 
 
A phase II study of durvalumab (MEDI4736) in patients with mismatch repair deficient or POLE 
mutated metastatic colorectal cancer 
 
2. PARTICIPATING CENTERS AND INVESTIGATORS 
 
Chief Principal Investigator: 
 
Tae Won Kim 
Asan Medical Center, University of Ulsan College of Medicine, Seoul, 
Korea 
 
Participating Principal Investigators: 
 
Myung-Ah Lee 
Seoul St.Maryt. Hospital 
 
Hye Sook Han 
Chungbuk National University Hospital 
 
Joong Bae Ahn 
Severance Hospital 
 
Jiyeon Baek 
National Cancer Center 
 
Myoung-joo Kang 
Inje University Haeundae Paik Hospital 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  21 
 
3. INTRODUCTION AND STUDY RATIONALE 
 
3.1. INTRODUCTION 
 
Recent advances have made survival advances of patients with metastatic colorectal cancer 
(mCRC) upto median 30 months after upfront targeted agents plus doublet chemotherapy 
(Figure 1).1,2  
 
Figure 1. Survival advances of metastatic colorectal cancer patients after optimized first-
line systemic chemotherapy. 
 
 
 
Later-line treatments after failure to standard treatments, however, are limited; regorafenib 
and TAS-102 showed mild improvement of survival without significant response rates 
although those agents had rather higher frequencies of significant adverse events (Figure 
2).3-5 
 
Figure 2. Limited survival advantages in the later-line setting; roughly 2 months of overall 
survival benefit with higher cost and higher frequencies of adverse events. 
 
 
 
Mismatch repair (MMR) deficiency or microsatellite instability-high (MSI-H) itself is better 
prognostic factor in the resected stage II or III colorectal cancer; however, they played a 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  22 
 
role of negative predictive factor for adjuvant fluorouracil-based chemotherapy in patients 
with resected colorectal cancer.6-8 In the adjuvant setting, fluoropyrimidine based adjuvant 
chemotherapy did not benefit or did even harm for patient with resected stage II colorectal 
cancer with MSI-H or MMR deficiency. Adjuvant fluoropyrimidines even did not any benefit 
in those with resected stage III colorectal cancer with MSI-H or MMR deficiency. 
 
In the metastatic setting, MMR deficiency or MSI-H represented poor prognosis and 
predictive of poor treatment responses from systemic treatments.9 However, their positive 
predictive role has been documented from the results of the KEYNOTE-016 trial.10 
 
The KEYNOTE-016 trial studied pembrolizumab monotherapy in the 3 parallel groups; 
MMR deficient mCRC, MMR proficient mCRC, and MMR deficient non-colorectal cancers.  
The study results were very promising; pembrolizumab monotherapy showed 40% of 
confirmed immune-related objective response rates in patients with MMR deficient mCRC; 
hence there was no objective response in those with MMR proficient tumors (Figure 3).10 
The progression-free rates at 20 weeks were 78% versus 11%, respectively, also favouring 
those with MMR deficient tumors. We can say that the KEYNOTE-016 trial has opened the 
new era of immunotherapy for colorectal cancer treatment, and also has an impact on 
finding novel positive predictive factor for better response in this field. However, the MMR 
deficiency of MSI-H is found in only about 5% in patients with metastatic colorectal cancer, 
which is too small to expand potential candidate of immunotherapy. On the bases of these 
results, the confirmatory phase II study of pembrolizumab monotherapy in the second- or 
third-line setting (KEYNOTE-164, NCT02460198) and a phase III study of pembrolizumab 
versus standard therapies (KEYNOTE-177, NCT02563002) for MSI-H mCRC patients are 
ongoing. 
 
Figure 3. Promising activity of pembrolizumab monotherapy in MMR deficient or MSI-H 
mCRC patients. 
 
 
One of the proposed mechanism of promising efficacy from pembrolizumab for MMR 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  23 
 
deficient colorectal cancer is that MMR deficient or MSI-H colorectal cancers harbour 
higher somatic mutation loads than MMR proficient colorectal cancer (a mean of 1,782 
somatic mutations per tumor in the MMR deficient tumors versus 73 in the MMR proficient 
tumors in the results of KEYNOTE-016 trial); somatic mutations have the potential to 
encode non-self immunogenic antigens; therefore, immunotherapy enhancing immune 
surveillance produced promising treatment efficacy in the MMR deficient tumors. 
 
CheckMate 142 is evaluating nivolumab (3 mg/kg) with and without ipilimumab (Yervoy; 
1 mg/ kg) in patients with metastatic MMR-deficient/MSI-H colorectal cancer. The 
objective response rate was 31.1%, and 68.9% of patients demonstrated disease control 
for at least 12 weeks. Responses occurred early, at a median of 2.8 months, and the median 
duration of response has not been reached.11 
 
 
The POLE gene encodes the catalytic subunit of DNA polymerase epsilon, and it involves 
DNA repair and chromosomal replication. The POLE mutations are located in the 
exonuclease domain, and their presence has already been reported in the various cancers 
including colorectal and endometrial cancer; however, its role as a prognostic or predictive 
factor has not been studied yet..12-14 Our recent study demonstrated that the POLE 
mutations were found in 6 out of 28 colorectal cancer patients, characterized as younger 
age (< 40 years) and mismatch repair proficient (or MSS) tumors. More interestingly, 6 
patients harbouring POLE mutations had higher somatic mutation loads in their tumors 
(ranged 2000 to 12,000) by whole-exom sequencing, compared to 50 to 150 mutation 
loads in those without POLE mutations (Figure 4).15  
 
Figure 4. POLE mutation represents higher somatic mutation loads (recent published 
internal data). 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  24 
 
 
 
The POLE mutations represent high somatic mutation loads in patients with colorectal 
cancer, especially in those with MMR proficient or MSS (microsatellite stable), therefore, 
tumors harbouring POLE mutations might be susceptible to immune checkpoint blockade. 
 
 
3.2. DURVALUMAB (MEDI4736) 
 
Durvalumab is a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-
L1 binding to PD-1 and CD80 but does not bind to PD-L2, avoiding potential immune-
related toxic effects due to PD-L2 inhibition, which has been noted in susceptible animal 
models. 
 
Recent studies demonstrated that durvalumab is safe and active in patients with non-small 
cell lung cancer and bladder cancer.  
 
For non-small cell lung cancer patients, 102 patients were enrolled into the dose-escalation 
phase and received durvalumab plus tremelimumab. The maximum tolerated dose was 
exceeded in the cohort receiving durvalumab 20 mg/kg every 4 weeks plus tremelimumab 
3 mg/kg. The most frequent treatment-related grade 3 and 4 adverse events were 
diarrhoea (11%), colitis (9%), and increased lipase (8%). Evidence of clinical activity was 
noted both in patients with PD-L1-positive tumours and in those with PD-L1-negative 
tumours. Investigator-reported confirmed objective responses were achieved by six (23%, 
95% CI 9-44) of 26 patients in the combined tremelimumab 1 mg/kg cohort, comprising 
two (22%, 95% CI 3-60) of nine patients with PD-L1-positive tumours and four (29%, 95% 
CI 8-58) of 14 patients with PD-L1-negative tumours, including those with no PD-L1 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  25 
 
staining (four [40%, 95% CI 12-74] of ten patients).16  
 
For bladder cancer patients, durvalumab 10 mg/kg every 2 weeks was administered 
intravenously for up to 12 months. The most common treatment-related adverse events 
(AEs) of any grade were fatigue (13.1%), diarrhea (9.8%), and decreased appetite (8.2%). 
Grade 3 treatment-related AEs occurred in three patients (4.9%); there were no treatment-
related grade 4 or 5 AEs. The objective response rate was 31.0% (95% CI, 17.6 to 47.1) in 
42 response-evaluable patients, 46.4% (95% CI, 27.5 to 66.1) in the PD-L1-positive 
subgroup, and 0% (95% CI, 0.0 to 23.2) in the PD-L1-negative subgroup. Durvalumab 
demonstrated a manageable safety profile and evidence of meaningful clinical activity in 
PD-L1-positive patients with bladder cancer, many of whom were heavily pretreated.17  
 
At present, studies of durvalumab with or without other agents for various tumor types 
are still ongoing.18-22 Risks with durvalumab include, but are not limited to, diarrhoea/colitis, 
pneumonitis/interstitial 
lung 
disease 
(ILD), 
endocrinopathies 
(ie, 
events 
of 
hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and hypothyroidism, type I 
diabetes mellitus (which may present with diabetic ketoacidosis),  and diabetes insipidus), 
hepatitis/increases in transaminases, nephritis/increases in creatinine, rash/dermatitis 
(including pemphigoid), myocarditis, myositis/polymyositis, immune thrombocytopenia, 
infusion related reactions, hypersensitivity reactions, pancreatitis, encephalitis, serious 
infections, subcutaneous injection site reaction, and other rare or less frequent 
inflammatory events including neuromuscular toxicities (eg, Guillain-Barré syndrome, 
myasthenia gravis).  
For information on all identified and potential risks with durvalumab please always refer 
to the current version of the durvalumab IB. 
In monotherapy clinical studies, AEs at an incidence of ≥ 20% include events such as 
fatigue and decreased appetite. Approximately 10% of participants discontinued the drug 
due to an AE.  
Please see the current version of the IB for a detailed summary of the monotherapy data 
including AEs, serious adverse events (SAEs), and Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 to 5 events reported across the durvalumab program.  
 
 
3.3. FIXED DOSING 
 
A population PK model was developed for durvalumab using monotherapy data from a 
Phase 1 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 PK 
of durvalumab (coefficient of ≤ 0.5). The impact of body WT-based (10 mg/kg Q2W) and 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  26 
 
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-
subject variability with fixed dosing regimen.   
 
Similar findings have been reported by others.24-27 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.25 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-subject 
variability 
in 
pharmacokinetic/pharmacodynamics parameters.26  
 
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. Fixed dosing of durvalumab is recommended only 
for subjects with > 30kg body weight due to endotoxin exposure.  Patients with a body 
weight less than or equal to 30 kg should be dosed using a weight-based dosing schedule 
(Appendix B).  
 
 
3.4. RATIONALE OF THE STUDY 
 
PD-1 blockade (pembrolizumab) demonstrated promising efficacy outcomes in patients 
with MMR deficient or MSI-H mCRC.10 Another immune check point blockade, targeting 
PD-L1 in these patients also demonstrated promising activity (nivolumab for MSI-H mCRC, 
CHECKMATE-142, NCT02060188); the confirmed response rate was 27% (9/33) without any 
significant adverse event.28  
 
Immunotherapy for this population is worthy of further investigation and in unmet needs 
both in terms of finding adequate agents and selecting adequate population. On the bases 
of these results, we planned this study of durvalumab monotherapy, another PD-L1 
blockade, for MMR deficient or MSI-H or POLE mutated mCRC patients to evaluate the 
efficacy and safety. 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  27 
 
4. STUDY OBJECTIVES 
 
The objective of this study is to investigate the efficacy and safety of durvalumab in patients 
with mismatch repair deficient or microsatellite instable or POLE mutated metastatic colorectal 
cancer refractory to irinotecan, oxaliplatin and fluoropyrimidines. 
 
4.1. PRIMARY OBJECTIVE 
 
- 
Objective response rates (RECIST 1.1) 
 
 
4.2. SECONDARY OBJECTIVES 
 
- 
Response rates by irRECIST 
- 
Disease control rates 
- 
Progression-free survival 
- 
Overall survival 
- 
Safety and toxicity assessments 
- 
Exploratory biomarker analysis 
- 
Opal Multiplex Tissue Staining with OpalTM including PD-1 and PD-L1 
 
 
5. STUDY DESIGN 
 
5.1. DESIGN OVERVIEW 
 
This is a prospective, open-label, multicenter phase II study to investigate the efficacy and 
safety of durvalumab monotherapy.  
 
A total of 33 patients who meet the eligible criteria will be accrued (17 for mismatch repair 
deficient or microsatellite instable colorectal cancer and 16 for POLE mutated colorectal 
cancer).  
 
Study treatment will be continued until at least one of the following occurs; 
- 
Progressive disease as defined by Response Evaluation Criteria In Solid Tumors (RECIST) 
version 1.1. or clinical progression by the decision of investigators; Treatment through 
progression is at the investigator’s discretion, and the investigator should ensure that 
patients do not have any significant, unacceptable, or irreversible toxicities that 
indicate that continuing treatment will not further benefit the patient. The Investigator 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  28 
 
should ensure that patients still meet all of the inclusion criteria and none of the 
exclusion criteria for this study. 
- 
Death. 
- 
Unacceptable adverse events. 
- 
Withdrawal of consent or lost to follow-up. 
- 
Adverse events that, in the opinion of the investigator or the sponsor, contraindicates 
further dosing. 
- 
Subject is determined to have met one or more of the exclusion criteria for study 
participation at study entry and continuing investigational therapy might constitute a 
safety risk. 
- 
Treating physician determines discontinuation of treatment is in the subject’s best 
interest. 
- 
Non-compliance to the study protocol. 
- 
Pregnancy or intent to become pregnant. 
 
5.2. JUSTIFICATION OF THE DESIGN 
 
As described previously, limited drugs are available in patients with metastatic colorectal 
cancer who have failed after standard therapies. Later-line treatments of currents showed 
limited antitumor activity in this setting. Mismatch repair deficiency (microsatellite 
instability) and POLE mutation is proved to be a reasonable target for immunotherapy for 
colorectal cancer patients; therefore, durvalumab monotherapy in this setting could be a 
valid option. 
 
 
6. STUDY POPULATION 
 
6.1. ELIGIBILITY 
 
6.1.1. INCLUSION CRITERIA 
 
1. 
Histologically or cytologically confirmed adenocarcinoma of the colon or the rectum. 
2. 
Mismatch repair deficient or microsatellite instable (defined below), or POLE mutated 
tumors 
A. Mismatch repair deficient: loss of expression by immunohistochemical stains ≥ 1 
out of 4 markers (MLH1, MSH2, MSH6, PMS2) 
B. Microsatellite instable: loss of stability ≥2 out of 5 gene panels (BAT-25, BAT-26, 
D2S123, D5S346, D17S250) 
C.  POLE gene: P286R mutation or other mutation 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  29 
 
3. 
Refractory to prior fluoropyrimidines, irinotecan and oxaliplatin (progressed during or 
within 6 months of those agents). 
4. 
≥ 1 measurable lesion(s) by RECIST 1.1. 
5. 
Unresectable advanced or metastatic disease. 
6. 
Age over 20 years old. 
7. 
ECOG performance status of 0-1 or lower. 
8. 
Adequate organ functions. 
A. Bone marrow function: Hemoglobin ≥ 9.0 g/dL, ANC ≥ 1,500/mm3, platelet ≥
 
100,000/mm3 
B. Hepatic functions: bilirubin ≤ 1.5 X ULN, AST/ALT ≤ 2.5 X ULN (≤ 5 X ULN in cases 
of liver metastasis) 
C. Renal functions: serum Cr ≤ 1.5 X ULN or calculated CCr (Cockroft) > 40 ml/min 
9. 
Be willing and able to comply with the protocol for the duration of the study. 
10. Give written informed consent prior to study-specific screening procedures, with the 
understanding that the patient has the right to withdraw the study at any time, without 
prejudice. 
11. Female subjects must either be of non-reproductive potential (  60 years old and no 
menses for  1 year without an alternative medical cause, or history of hysterectomy, 
or history of bilateral tubal ligation, or history of bilateral oophorectomy) or must have 
a negative serum pregnancy test upon study entry. 
12. Women of childbearing potential and men must agree to use adequate contraception 
since signing of the IC form until at least 90days after the last study drug 
administration. 
 
 
6.1.2. EXCLUSION CRITERIA 
 
All of the following exclusion criteria should be checked at the time of screening procedure. 
 
1. Any prior treatment with PD-1 or PD-L1 inhibitor, including durvalumab. 
2. Involvement in the planning and/or conduct of the study. 
3. Receipt of the last dose of chemotherapy ≤ 28 days prior to the first dose of study 
drugs. 
4. Mean QT interval corrected for heart rate (QTc)  470 msec calculated from 3 
electrocardiograms (ECGs) using Frediricia’s Correction. 
5. 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  
6. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after 
consultation with the Study Physician. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  30 
 
7. Patients with irreversible toxicity not reasonably expected to be exacerbated by 
treatment with durvalumab may be included only after consultation with the Study 
Physician. 
8. Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment. 
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone 
replacement therapy) is acceptable. 
9. Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or 
systemic corticosteroids at physiologic doses, which are not to exceed 10 mg/day of 
prednisolone, or an equivalent corticosteroid. 
10. 
Concurrent or previous history of another primary cancer within 3 years prior to 
randomisation except for curatively treated cervical cancer in situ, non-melanomatous 
skin cancer, superficial bladder cancer (pTis and pT1) and curatively treated thyroid 
cancer of any stage. Concurrent, histologically confirmed, unresected thyroid cancer 
without distant metastasis could be allowed with the agreement of the chief principal 
investigator. 
11. 
Uncontrolled CNS metastases; permitted if asymptomatic or neurologically stable. 
12. 
Prior radiation therapy would be permitted, but non-radiated evaluable lesions 
should be present at study entry. 
13. 
Radiation therapy during study treatment is not permitted, but if the local 
investigator decides that radiation therapy should be given during study treatments, he 
should be convinced that there is no evidence of disease progression with agreement 
of the chief principal investigator.  
14. 
Congestive heart failure ≥ New York Heart Association (NYHA) class 2. 
15. 
Unstable angina, new-onset angina within 3 months, or history of myocardial 
infarction within 6 months before the study entry. 
16. 
Active or prior documented autoimmune disease within the past 2 years; subjects 
with vitiligo, Grave’s disease, or psoriasis not requiring systemic treatment (within the 
past 2 years) are not excluded. 
17. 
Active or prior documented inflammatory bowel disease. 
18. 
History of prior immunodeficiency. 
19. 
History of allogeneic organ transplantation. 
20. 
History of hypersensitivity to durvalumab or any excipient. 
21. 
Clinical diagnosis of active tuberculosis. 
22. 
Receipt of live attenuated vaccination within 30 days prior to study entry. 
23. 
Known history of testing positive for HIV 
24. 
 Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive 
HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive)  
Except, resolved HBV infection (as evidenced by detectable HBV surface antibody, 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  31 
 
detectable HBV core antibody, undetectable HBV DNA, and undetectable HBV surface 
antigen) or Chronic HBV infection (as evidenced by detectable HBV surface antigen 
or HBV DNA). Subjects with chronic HBV infection must have HBV DNA < 100 IU/mL 
and must be on antiviral therapy. 
25. 
Major surgery or significant traumatic injury within 28 days prior to study 
treatment. 
26. 
Non-healing wound, ulcer, or bone fracture. 
27. 
Current evidence of significant gastrointestinal bleeding or (impending) 
obstruction. 
28. 
Concomitant participation in another interventional clinical trial. 
29. 
Pregnant of breast-feeding subjects. Women of child-bearing potential must have 
pregnancy test within 7 days and a negative result must be documented before start 
of study treatment. 
30. 
Substance abuse, medical, psychological or social conditions that may interfere 
with the subject’s participation in the study or evaluation of the study results. 
 
6.2. WITHDRAWAL OF SUBJECTS 
 
Subjects should be withdrawn from the study treatment for the any of the following 
reasons; 
 
- 
At their own or legally acceptable representative request. 
- 
At any time of subject’s decision not to participate further. 
- 
In case of investigator’s decision that the continuation of study treatment would be 
harmful to the subject. 
- 
Use of other substances or herbal medicines that may affect the treatment and the results 
of this study. 
- 
Development of more beneficial treatment, by investigator’s judgment, for the subject in 
the treatment continuum. 
- 
Disease progression or unacceptable adverse events. 
- 
Development of a secondary malignancy. 
- 
Lost to follow-up. 
- 
Interruption of study drug due to drug related adverse events is longer than 4 consecutive 
weeks. 
 
6.3. REPLACEMENT 
 
A subject withdrawn from the study treatment will not be replaced. 
7. STUDY TREATMENT 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  32 
 
7.1. DURVALUMAB 
 
Durvalumab will be supplied by AstraZeneca as a 500-mg vial solution for infusion after 
dilution. The solution contains 50 mg/mL of 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. The nominal fill volume is 10.0 mL.  Investigational product vials 
are stored at 2°C to 8°C (36°F to 46 °F) and must not be frozen.  
 
The dose of durvalumab for administration must be prepared by aseptic technique.  Total 
in-use storage time from needle puncture of durvalumab vial to the start of administration 
should not exceed: 
 
4 hours at room temperature 
 
24 hours at 2°C to 8°C (36°F to 46°F).  
 
Infusion solution must be allowed to equilibrate to room temperature prior to 
commencement of administration.   
 
Preparation of durvalumab doses for administration with an IV bag 
 
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 20 mg/mL, and delivered through an IV administration set with a 0.2- 
or 0.22μm in-line filter. Add 30.0 mL (1500 mg) of durvalumab to the IV bag. The IV bag 
size should be selected such that the final concentration is between 1 and 20 mg/ml. Mix 
the bag by gentle inversion to ensure homogeneity of the dose in the bag. 
 
Weight-based dosing (for patients ≤ 30 kg) will be a 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 20 mg/mL, and delivered through an IV administration set with a 0.2- 
or 0.22-μm in-line filter.  Appendix B includes an example of a weight-based dose 
calculation. 
 
Standard infusion time is 60 minutes (± 5 minutes).  Less than 55 minutes is considered 
a deviation.  In the event that there are interruptions during infusion, the total allowed 
time should not exceed 8 hours at room temperature.   
 
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 complete the 
infusion according to institutional policy to ensure the full dose is administered and 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  33 
 
document if the line was not flushed. 
 
In the event that 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.  
No incompatibilities between durvalumab and polyvinylchloride or polyolefin IV bags have 
been observed. 
 
Monitoring of dose administration 
 
Patients will be monitored during and after the infusion with assessment of vital signs at 
the times specified in the Study Protocol. 
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 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. For management of patients who experience an infusion reaction, 
please refer to the toxicity and management guidelines in Appendix A. 
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. 
 
7.2. DOSE AND TREATMENT REGIMEN 
 
Patients (> 30 kg in weight) will receive 1500 mg of durvalumab via intravenous infusion 
every 4 weeks. Patients (≤ 30 kg in weight) will receive weight based dosing of 20 mg/kg 
durvalumab via intravenous infusion every 4 weeks.   
 
Durvalumab treatment can be continued up to the 36-cycle dosing. After 36 cycles of 
treatment, durvalumab should be discontinued.  
 
7.3. DOSE MODIFICATION AND DELAYS 
 
7.3.1. GENERAL RULES FOR DOSE MODIFICATION AND DELAYS 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  34 
 
- 
Dose modification (reduction or escalation) is not allowed. 
- 
Dose delays in case of clinically meaningful events are permitted; however, study treatment 
should be discontinued in case of 4 weeks delays. 
- 
All the response evaluation procedures including CT scans should be performed as planned 
in patients with treatment delay without regard to the cycles of study treatment. Dose 
delays, reasons for treatment delay, actions to be taken and outcome will be recorded in 
patient chart and CRF. 
- 
Regarding the adverse events, dose delays could be made under investigators’ discretion.  
- 
When the study treatment is restarted, the investigator should ensure that AE is recovered 
≤ grade 1 or there is no safety risk for the patients. 
- 
Prophylactic use of G-CSF (or GM-CSF) or erythropoietin is not allowed. 
 
7.4. LABELING 
 
Labels will be prepared in accordance with Good Manufacturing Practice (GMP) and local 
regulatory guidelines. The labels will fulfil GMP Annex 13 requirements for labeling. Label 
text will be translated into local language. 
Labels will be provided as either a single panel label or as multi-language booklet labels. 
 
7.5. STORAGE 
 
The Investigator, or an approved representative (eg, pharmacist), will ensure that all IP is 
stored in a secured area, in refrigerated temperatures (2°C to 8°C) and in accordance with 
applicable regulatory requirements. A temperature log will be used to record the 
temperature of the storage area. Temperature excursions outside the permissible range 
listed in the clinical supply packaging are to be reported to the monitor upon detection. 
A calibrated temperature monitoring device will be used to record the temperature 
conditions in the drug storage facility. Storage conditions stated in the IB may be 
superseded by the label storage. 
 
7.6. COMPLIANCE 
 
The administration of all study drugs (including IP) should be recorded in the appropriate 
sections of the eCRF. Treatment compliance will be assured by site reconciliation of 
medication dispensed and returned. 
 
7.7. CONCOMITANT THERAPY 
 
7.7.1. PROHIBITED CONCOMITANT MEDICATIONS 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
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- 
Any investigational anticancer therapy other than those under investigation in this study. 
- 
Any concurrent chemotherapy, immunotherapy or biologic or hormonal therapy for 
cancer treatment. 
- 
Any concurrent radiotherapy is not permitted; however, if the local investigator decides 
that radiation therapy should be given during study treatments, he should be convinced 
that there is no evidence of disease progression and there is no target lesion(s) included 
in the field of radiotherapy with agreement of the chief principal investigator.  
- 
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. 
- 
Live attenuated vaccines are not permitted; inactivated vaccines (i.e. influenza vaccines) 
are permitted. 
- 
Drugs with laxative properties and herbal or natural remedies for constipation. 
- 
Prophylactic administration of G-CSF (or GM-CSF) or erythropoietin. 
- 
All traditional medicines with an intention to control the tumor without regard to their 
truth  
 
7.7.2. PERMITTED CONCOMITANT MEDICATIONS 
 
- 
Standard therapies for treatment of concurrent medical conditions and complications 
or symptomatic therapy of adverse events are permitted. 
- 
Blood transfusion. 
- 
G-CSF (or GM-CSF) for febrile neutropenia or infection with neutropenia; however, the 
prophylactic use of these agents are not permitted even for 2nd occurrence without 
evidence of fever or infection. 
- 
Antiemetics: as for acute nausea/vomiting, intravenous administration of 5-HT3 
antagonist can be considered, but not recommended routinely. Metoclopramide, 
lorazepam or corticosteroid might be used. 
- 
Antidiarrheals: in general, loperamide is recommended as the standard treatment. 
Because any agents having purgative activity might aggravate diarrhea, its use should 
be avoided. Make patients contact with investigators about the use of a purgative. 
- 
Antibiotics, analgesics, analgesic antipyretics, steroidal agents, opioids including 
morphine, fentanyl patches, etc. 
 
7.8.  RESTRICTIONS 
The following restrictions apply while the patient is receiving study treatment and for the 
specified times before and after: 
 
7.8.1. FEMALE PATIENT OF CHILD-BEARING POTENTIAL  


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  36 
 
- 
Females of childbearing potential who are sexually active with a non-sterilized male 
partner must use at least 1 highly effective method of contraception (Table 1) from the 
time of screening and must agree to continue using such precautions for 90 days after 
the last dose of durvalumab monotherapy. Non-sterilized male partners of a female 
patient must use male condom plus spermicide throughout this period. Cessation of 
birth control after this point should be discussed with a responsible physician. Not 
engaging in sexual activity for the total duration of the drug treatment and the drug 
washout period is an acceptable practice; however, periodic abstinence, the rhythm 
method, and the withdrawal method are not acceptable methods of birth control. 
Female patients should also refrain from breastfeeding throughout this period. 
 
7.8.2. MALE PATIENT WITH A FEMALE PARTNER OF CHILDBEARING POTENTIAL 
 
- 
Non-sterilized males who are sexually active with a female partner of childbearing 
potential must use a male condom plus spermicide from screening through 90 days 
after receipt of the final dose of durvalumab monotherapy. Not engaging in sexual 
activity is an acceptable practice; however, occasional abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of contraception. Male patients 
should refrain from sperm donation throughout this period. 
Female partners (of childbearing potential) of male patients must also use a highly 
effective method of contraception throughout this period (Table 1). N.B Females of 
childbearing potential are defined as those who are not surgically sterile (ie, bilateral 
tubal ligation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal.  
Women will be considered post-menopausal if they have been amenorrheic for 12 
months without an alternative medical cause. The following age-specific requirements 
apply:  
 
• 
Women <50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of exogenous hormonal 
treatments and if they have luteinizing hormone and follicle-stimulating hormone 
levels in the post-menopausal range for the institution or underwent surgical 
sterilization (bilateral oophorectomy or hysterectomy).  
 
• 
Women ≥50 years of age would be considered post-menopausal if they have been 
amenorrheic for 12 months or more following cessation of all exogenous 
hormonal treatments, had radiation-induced menopause with last menses >1 year 
ago, had chemotherapy-induced menopause with last menses >1 year ago, or 
underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy 
or hysterectomy). 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  37 
 
 
Highly effective methods of contraception, defined as one that results in a low failure rate 
(ie, less than 1% per year) when used consistently and correctly are described in Table 1. 
Note that some contraception methods are not considered highly effective (eg. male or 
female condom with or without spermicide; female cap, diaphragm, or sponge with or 
without spermicide; non-copper containing intrauterine device; progestogen-only oral 
hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action 
[excluding Cerazette/desogestrel which is considered highly effective]; and triphasic 
combined oral contraceptive pills). 
 
Table 1. Highly effective methods of contraception (<1% failure rate) 
Nonhormonal methods 
Hormonal Methods 
 
Total sexual abstinence (evaluate in relation to 
the duration of the clinical study and the 
preferred and usual lifestyle choice of 
participant) 
 
Vasectomised sexual partner (with participant 
assurance that partner received post-
vasectomy confirmation of azoospermia)  
 
Tubal occlusion: Intrauterine device (provided 
coils are copper-banded)  
 
 
Implants: Etonogestrel-releasing implants 
(e.g. Implanon® or Norplant®) 
 
Intravaginal device: Ethinylestradiol/ 
etonogestrel-releasing intravaginal devices 
(e.g. NuvaRing®) 
 
Injection: Medroxyprogesterone injection 
(e.g. Depo-Provera® )  
 
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
 
Patch: Norelgestromin/ethinylestradiol-
releasing transdermal system (e.g. 
OrthoEvra®) 
 
Mini pill: Progestrone based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly 
effective progesterone- based based 
 
Levonorgestrel-releasing intrauterine 
system (e.g. Mirena® ) 
 
7.8.3. BLOOD DONATION 
Subjects should not donate blood while participating in this study, or for at least 90 days 
following the last infusion of durvalumab 
 
7.9.  POST-STUDY TREATMENT 
 
All subjects will enter the follow-up period upon discontinuation of either randomized 


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study treatment. Regardless of the reason for discontinuation, all subjects will be followed 
for survival until death is documented, except for those who specifically withdraw consent 
to follow-up. Subjects who withdraw consent from study drug treatment may enter the 
Follow-up Period. Assessment of survival status will be performed approximately every 3 
months. In addition, for subjects who discontinue study treatment and have not 
experienced PD, available tumor assessments will be recorded in the CRF until PD is 
documented. Additionally, the administration of any anti-cancer drugs must be recorded 
in the CRF. 
 
8. STUDY PROCEDURE AND SCHEDULE 
 
8.1. TABULATED OVERVIEW 
 
Study Period 
Screening 
Study Treatment 
(-/+ 1 week) 
Post 
Treatment 
(-/+ 2 weeks) 
Study Procedures: Study Day: 
D-14  
to -1 
Every 
cycle 
Every 
8 weeks 
End of 
Treatment 
Every 
3 months 
Informed consent 
O 
 
 
 
 
Inclusion/Exclusion criteria review 
O 
 
 
 
 
Demographics; medical history 
O 
 
 
 
 
Complete physical examination 
O 
O 
 
O 
 
Vital Signs 
O 
O 
 
O 
 
ECOG performance status 
O 
O 
 
O 
 
Electrocardiography 1) 
O 
 
 
O 
 
Concomitant medication 
O 
O 
 
O 
 
Chest X-ray 
O 
 
O 
O 
 
Tumor Assessment (CT or MRI) 
O 
 
O 
O 
 
Other imaging procedure if needed 
O 
 
O 
O 
 
Assessment of response 
 
 
O 
O 
 
Toxicity assessment (CTCAE version 
4.0) 
 
O 
 
O 
 
Survival 
 
 
 
 
O 
Subsequent treatment 
 
 
 
 
O 
CBC 
O 
O 
 
O 
 
Chemistry 2), Amylase/Lipase 
O 
O 
 
O 
 
CEA 
O 
 
O 
O 
 
Thyroid function test (TSH, T3, free 
O 
 
O 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  39 
 
T4) 
Routine urinalysis 
O 
 
 
 
 
Urine β-hCG pregnancy test 3) 
O 
 
 
 
 
Height (screening only)/Weight 
O 
O 
 
O 
 
Biomarker assessment 4) 
O 
 
 
 
 
1) In patients without prior history of cardiovascular disease and showed normal 
electrocardiography, further examinations such as MUGA scan and echocardiography are not 
mandatory; however, patients with prior history of cardiac disease or those showed abnormal 
electrocardiography results, they would be checked with further examinations either with MUGA 
scan or echocardiography by the investigator’s decision. 
2) Chemistry labs include calcium, phosphorus, glucose, BUN, creatinine, total protein, albumin, 
AST/ALT, alkaline phosphatase, total bilirubin, uric acid and electrolytes( Na, K, Cl, Mg). 
3) Urine β-hCG should be performed in women with child-bearing potential. 
4) Perform tests for pertinent tumor markers if informative in the investigator’s opinion and 
document at screening or as clinically indicated. 
 
8.2. EVALUATION BEFORE STUDY TREATMENT (WITHIN 2 WEEKS) 
 
- 
Complete medical history. 
- 
Physical examination including ECOG performance status. 
- 
Radiologic assessments using RECIST 1.1. (permitted to be assessed within 28 days from 
the study treatment) 
- 
CBC with differentials. 
- 
Serum chemistry: calcium, phosphorus, glucose, BUN, creatinine, total protein, albumin, 
AST/ALT, alkaline phosphatase, total bilirubin, uric acid and electrolytes. 
- 
Routine urinalysis 
- 
Serum CEA 
- 
Serum TSH, T3 and free T4 
- 
Serum amylase/lipase 
- 
EKG (3 consecutive EKG for eligibility check) 
- 
Chest X-rays 
- 
Urine β-hCG will be performed in women with child-bearing potential. 
- 
Other tests (i.e. bone scans) if clinically indicated 
- 
Exploratory biomarker assessments:  
- 
Opal Multiplex Tissue Staining with OpalTM including PD-1 and PD-L1 
- 
Biological samples will be obtained for biomarker evaluation from all eligible patients at 
the screening visit. 
 
8.3. EVALUATION DURING STUDY TREATMENT (EVERY CYCLES OF STUDY TREATMENT) 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  40 
 
 
- 
Physical examination including ECOG performance status and drug-related side effects. 
- 
CBC with differentials. 
- 
Serum chemistry: calcium, phosphorus, glucose, BUN, creatinine, total protein, albumin, 
AST/ALT, alkaline phosphatase, total bilirubin, uric acid and electrolytes. 
- 
Serum amylase/lipase 
- 
Toxicity assessments (NCI-CTCAE version 4.0) 
 
8.4. RESPONSE EVALUATION (EVERY 8 WEEKS ± 1 WEEK WINDOW PERIOD) 
 
- 
Serum CEA, TSH, T3 and free T4 
- 
CT (or MRI) scans of evaluable/measurable lesions by RECIST 1.1. 
- 
Other test (i.e. bone scans) if clinically indicated 
- 
Response evaluation will be performed every 8 weeks without regard to the schedules 
of study treatment. 
 
8.5. POST-TREATMENT FOLLOW-UP (EVERY 3 MONTHS) 
 
- 
Subsequent treatments (chemotherapy, immunotherapy or radiotherapy) and their 
responses 
- 
Survival information on subject 
- 
Status of disease and date of progression (in patients who stopped study treatment 
without documentation of disease progression) 
- 
Date and cause of death 
 
Telephone follow-up is acceptable. Site staff must use caution when contacting the 
subject’s family for this information, especially if they are no longer under the care of the 
investigator, so as to not inadvertently cause any distress to the family of a subject who is 
no longer alive. Additional phone contacts will be required for formal survival sweeps at 
the time of primary analysis. 
 
 
9. ADVERSE EVENTS 
 
9.1. DEFINITIONS 
 
9.1.1. ADVERSE EVENT 
 
The term adverse event covers any unfavorable and unintended sign, symptom, syndrome, 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
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or illness that develops or worsens during the period of observation in the clinical study. 
Clinically relevant abnormal results of diagnostic procedures including abnormal laboratory 
findings (e.g., requiring unscheduled diagnostic procedures or treatment measures, or 
resulting in withdrawal from the study) are considered to be adverse events. 
 
Worsening of a sign or symptom of the condition under treatment will normally be 
measured by safety parameters. However, if the outcome fulfills the definition of «serious 
adverse event», it must be recorded as such. 
The adverse event may be: 
- 
A new illness 
- 
Worsening of a concomitant illness 
- 
An effect of the study medication, including comparator 
- 
A combination of two or more of these factors 
- 
No causal relationship with the study medication or with the clinical study itself is implied 
by the use of the term «adverse event». 
- 
Adverse events fall into the categories «non serious» and «serious». 
 
Surgical procedures themselves are not adverse events; they are therapeutic measures for 
conditions that require surgery. The condition for which the surgery is required is an 
adverse event, if it occurs or is detected during the study period. Planned surgical measures 
permitted by the clinical study protocol and the condition(s) leading to these measures 
are not adverse events, if the condition(s) was (were) known before the start of study 
treatment. In the latter case the condition should be reported as medical history. 
 
9.1.2. SERIOUR ADVERSE EVENTS 
 
 
A serious adverse event is one that at any dose (including overdose): 
- 
Results in death 
- 
Is life-threatening 1 
- 
Requires in-patient hospitalization or prolongation of existing hospitalization 
- 
Results in persistent or significant disability or incapacity 2 
- 
Is a congenital anomaly or birth defect 
- 
Is an important medical event 3 
 
1 «Life-threatening» means that the subject was at immediate risk of death at the time of 
the serious adverse event; it does not refer to a serious adverse event that hypothetically 
might have caused death if it were more severe. 
 
2 «Persistent or significant disability or incapacity» means that there is a substantial 


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DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  42 
 
disruption of a person’s ability to carry out normal life functions. 
 
3 Medical and scientific judgment should be exercised in deciding whether expedited 
reporting is appropriate in situations where none of the outcomes listed above occurred. 
Important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
one of the other outcomes listed in the definition above should also usually be considered 
serious. Examples of such events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in in-patient hospitalization, or the development of drug dependency or drug abuse. 
A diagnosis of cancer during the course of a treatment should be considered as medically 
important. The List of Critical Terms (1998 adaptation of WHO Adverse Reaction Terminology 
Critical Terms List, provided in the «Instructions for completing the ‘Serious Adverse 
Event/Expedited Report from a Clinical Trial’ form») should be used as guidance for adverse 
events that may be considered serious because they are medically important. 
 
Clarification of the difference in meaning between «severe» and «serious»: 
The term «severe» is often used to describe the intensity (severity) of a specific event (as in 
mild, moderate, or severe myocardial infarction); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
«serious», which is based on the outcome or action criteria usually associated with events 
that pose a threat to life or functioning. Seriousness (not severity) serves as a guide for 
defining regulatory reporting obligations. 
 
9.1.3. 
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 and rapid communication by the investigator to the sponsor. An AESI may be 
serious or non-serious. The rapid reporting of AESIs allows ongoing surveillance of these 
events in order to characterize and understand them in association with the use of this 
investigational product. AESIs for durvalumab include but are not limited to events with a 
potential inflammatory or immune-mediated mechanism and which may require more 
frequent monitoring and/or interventions such as steroids, immunosuppressant and/or 
hormone replacement therapy. These AESIs are being closely monitored in clinical studies 
with durvalumab monotherapy and combination therapy. An immune-related adverse 
event (irAE) is defined as an adverse event that is associated with drug exposure and is 
consistent with an immune-mediated mechanism of action and where there is no clear 
alternate aetiology. Serologic, immunologic, and histologic (biopsy) data, as appropriate, 


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should be used to support an irAE diagnosis. Appropriate efforts should be made to rule 
out neoplastic, infectious, metabolic, toxin, or other etiologic causes of the irAE. If the 
Investigator has any questions in regards to an adverse event (AE) being an irAE, the 
Investigator should promptly contact the Study Physician. AESIs observed with 
durvalumab include: 
• 
Diarrhea/ Colitis and intestinal perforation 
• 
Pneumonitis/ILD 
• 
hepatitis / transaminase increase 
• 
Neuropathy / neuromuscular toxicity (e.g. Guillain-Barré, and myasthenia gravis) 
• 
Endocrinopathy (i.e. events of hypophysitis/hypopituitarism, adrenal insufficiency, 
and hyper- and hypothyroidism and type I diabetes mellitus) 
• 
Rash/Dermatitis 
• 
Nephritis/Blood creatinine increases 
• 
Pancreatitis  (or labs suggestive of pancreatitis - increased serum lipase , 
increased serum amylase)   
• 
Myocarditis 
• 
Myositis / Polymyositis 
• 
Other inflammatory responses that are rare / less frequent with a potential im
mune-mediated aetiology include, but are not limited to, pericarditis, sarcoido
sis, uveitis and other events involving the eye, skin, haematological and rheu
matological 
events, 
vasculitis, 
non-infectious 
meningitis 
and 
non-
infectious encephalitis 
 
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 Brochure. 
 
9.1.4. RECORDING OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
Adverse events will be recorded CRF using a recognized medical term or diagnosis that 
accurately reflects the event. Adverse events will be assessed by the investigator for severity, 
relationship to the investigational product, possible etiologies, and whether the event meets 
criteria of an SAE and therefore requires immediate notification to AstraZeneca/MedImmune 
Patient Safety.  
 
The following variables will be collected for each AE: 
• 
AE (verbatim) 


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• 
The date <<and time>> when the AE started and stopped 
• 
Changes in NCI CTCAE grade and the maximum CTC grade attained 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against durvalumab (yes or no)  
• 
Action taken with regard to durvalumab /comparator/combination agent 
• 
Outcome 
 
In addition, the following variables will be collected for SAEs as applicable: 
• 
Date AE met criteria for serious AE 
• 
Date Investigator became aware of serious AE 
• 
AE is serious due to <<criteria>> 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Autopsy performed 
• 
Description of AE 
• 
Causality assessment in relation to Study procedure(s) 
 
9.2. DOCUMENTATION AND REPORTING OF ADVERSE EVENTS BY INVESTIGATOR 
 
All adverse events that occur during the observation period set in this protocol must be 
documented on the pages provided in the case report form in accordance with the 
instructions for the completion of adverse event reports in clinical studies. These instructions 
are provided in the case report form itself. 
 
The following approach will be taken for documentation: 
 
1) All adverse events (whether serious or non-serious) must be documented on the 
«Adverse Event» page of the case report form. 
2) If the adverse event is suspected, serious, and unexpected, the investigator must complete, 
in addition to the «Adverse Event» page in the case report form, a «Serious Adverse 
Event/Expedited Report from a Clinical Trial» form at the time the serious adverse event 
is detected. When this form is completed, designated staff member of the Korean Cancer 
Study Group should be notified by e-mail within 1 working day and it also should be 
reported to IRBs according to their procedures. 
3) When a «significant overdose» of the investigational product occurs without an adverse 
event, the investigator should only complete a «Serious Adverse Event/Expedited Report 
from a Clinical Trial» form. Instructions on where to send this form will be provided by 


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the the Korean Cancer Study Group. In this case, there is no need to complete the 
«Adverse Event» page in the case report form. 
4) Every attempt should be made to describe the adverse event in terms of a diagnosis. If a 
clear diagnosis has been made, individual signs and symptoms will not be recorded unless 
they represent atypical or extreme manifestations of the diagnosis, in which case they 
should be reported as separate events. If a clear diagnosis cannot be established, each 
sign or symptom should be recorded individually. 
 
All subjects who have adverse events, whether considered associated with the use of the 
investigational products or not, must be monitored to determine the outcome. The clinical 
course of the adverse event will be followed up according to accepted standards of medical 
practice, even after the end of the period of observation, until a satisfactory explanation is 
found or the investigator considers it medically justifiable to terminate follow-up. Should the 
adverse event result in death, a full pathologist’s report should be supplied, if possible. 
 
All questions on the completion and supply of adverse event report forms and any further 
forms issued to the investigator at a later date to clarify unresolved issues should be 
addressed by the end of study.  
 
REPORTING OF SAEs 
 
All SAEs will be reported, whether or not considered causally related to the investigational 
product, or to the study procedure(s). The reporting period for SAEs is the period immediately 
following the time that written informed consent is obtained through 90 days after the last 
dose of durvalumab or until the initiation of alternative anticancer therapy. The investigator 
and/or Sponsor are responsible for informing the Ethics Committee and/or the Regulatory 
Authority of the SAE as per local requirements. 
 
All SAEs should be reported to the Sponsor(PI): Send SAE report and accompanying cover 
page by way of email to AstraZeneca’s designated mailbox:  
AEMailboxClinicalTrialTCS@astrazeneca.com 
 
9.3. IMMEDIATE REPORTING BY INVESTIGATOR TO IRB AND MONITORING COMMITTEE 
 
Serious, suspected, and unexpected adverse events and adverse events that fulfill a reason 
for expedited reporting to Pharmacovigilance must be documented on a «Serious Adverse 
Event/Expedited Report from a Clinical Trial» form in accordance with the «Instructions for 
completing the ‘Serious Adverse Event/Expedited Report from a Clinical Trial» form. This form 
must be completed and supplied to the sponsor within 1 working day. The «Serious Adverse 


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Event/Expedited Report from a Clinical Trial» form and the instructions are provided in the 
investigator’s study file. 
 
The initial report must be as complete as possible, including details of the current illness and 
(serious) adverse event, and an assessment of the causal relationship between the event and 
the investigational product(s). 
Information not available at the time of the initial report (e.g., an end date for the adverse 
event or laboratory values received after the report) must be documented on a follow-up 
«Serious Adverse Event/Expedited Report from a Clinical Trial» form. 
 
The «Instructions for completing the ‘Serious Adverse Event/Expedited Report from a Clinical 
Trial» form give more detailed guidance on the reporting of serious adverse events, adverse 
events that comply with alert terms, and adverse events initially reported as non-serious that 
become serious. In the latter situation, when a non-serious event becomes serious, details 
must be forwarded immediately to the Chief Principal Investigator on a «Serious Adverse 
Event/Expedited Report from a Clinical Trial» form. 
 
9.4. OTHER EVENTS REQUIRING REPORTING 
 
9.4.1. Timeline 
  If an event of medication error, drug abuse, or drug misuse occurs during the study, then 
the investigator or other site personnel informs the appropriate AstraZeneca/MedImmune 
representatives within 1 day, ie, immediately but no later than 24 hours of when they 
become aware of it. The designated AstraZeneca/MedImmune representative works with 
the investigator to ensure that all relevant information is completed within 1 (Initial 
Fatal/Life-threatening or follow-up Fatal/Life-threatening) or 5 (other serious initial and 
follow-up) calendar days if there is an SAE associated with the event of medication error, 
drug abuse, or drug misuse and within 30 days for all other events.  
 
9.4.2. 
Medication Error  
For the purposes of this clinical study a medication error is an unintended failure or mistake 
in the treatment process for study participants that either causes harm to the participant or 
has the potential to cause harm to the participant.  
 
9.4.3. 
Drug Abuse 
 Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of 
study intervention or AstraZeneca NIMP for a perceived reward or desired non-therapeutic 
effect.  
 


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9.4.4. 
Drug Misuse 
Drug misuse is the intentional and inappropriate use (by a study participant) of study 
intervention for medicinal purposes outside of the authorised product information, or for 
unauthorised study intervention, outside the intended use as specified in the protocol and 
includes deliberate administration of the product by the wrong route. 
 
9.4.5. HEPATIC FUNCTION ABNOMALITY 
Hepatic function abnormality that fulfills the biochemical criteria of a potential Hy’s Law case 
in a study subject, with or without associated clinical manifestations, is required to be 
reported as “hepatic function abnormal” within 24 hours of knowledge of the event to the 
sponsor and AstraZeneca/MedImmune Patient Safety using the designated Safety e-mailbox 
(see Section 9.2 for contact information, unless a definitive underlying diagnosis for the 
abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to investigational 
product has been confirmed.  
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 subject 
will be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study subject must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
 
9.4.6. PREGNANCY 
 
- 
Maternal exposure 
 
If a patient becomes pregnant during the course of the study, the IPs should be discontinued 
immediately.   
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study 
may have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities or birth defects and spontaneous miscarriages should be reported and handled 
as SAEs.  Elective abortions without complications should not be handled as AEs.  The 
outcome of all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, 
normal birth, or congenital abnormality) should be followed up and documented even if the 


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patient was discontinued from the study.   
If any pregnancy occurs in the course of the study, then the Investigator or other site 
personnel should inform the appropriate AstraZeneca representatives within 1 day, ie, 
immediately, but no later than 24 hours of when he or she becomes aware of it.   
The designated AstraZeneca representative will work with the Investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 
5 calendar days for SAEs and within 30 days for all other pregnancies.   
The same timelines apply when outcome information is available.   
 
- 
Paternal exposure 
 
Male patients should refrain from fathering a child or donating sperm during the study and 
for 90 days after the last dose of durvalumab monotherapy.   
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal 
birth, or congenital abnormality) occurring from the date of the first dose until 90 days after 
the last dose should, if possible, be followed up and documented.   
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 local procedures and submit it to 
the relevant Ethics Committees (ECs)/Institutional Review Boards (IRBs) prior to use.   
 
10. STATISTICAL CONSIDERATION 
 
10.1. ANALYSIS SET 
 
10.1.1. EFFICACY ANALYSIS SET 
 
- 
Intent-to-Treat Population 
All patients who were screened and were eligible will be included in the intent-to-treat 
population. 
 
- 
Per-Protocol Population 
The per-protocol population excludes patients who did not receive at least one dose 
study treatment, or who had a major violation of protocol inclusion or exclusion criteria. 
 
10.1.2. SAFETY ANALYSIS SET 
 


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Safety analysis set comprises subjects who have been registered and took the study 
treatment at least once. 
 
10.2. SAMPLE SIZE AND RATIONALE 
 
The primary endpoint is objective response rate of durvalumab in mismatch repair deficient 
(microsatellite instable) or POLE mutated metastatic colorectal cancer patients who have 
progressed after standard therapies. 
Assuming the target of response rate was set to 30% and a rate of 10% or below was 
considered futile. A 2-stage optimal design, as proposed by Simon, was used to allow early 
termination of any ineffective treatment early in the study. With a 1-sided, type I error of 
5% and power of 0.8, the planned study was to proceed in 2 steps. In the first step, 10 
patients were required, and if complete or partial response was observed in 2 or more 
patients, the study was to proceed to the second step with 19 additional patients (29 
patients as a total). If this condition was not met, the study would be stopped for futility. 
In the second step, if complete or partial response was observed in 6 or more patients, 
the treatment will be considered effective. Assuming a dropout rate of 10%, 33 patients 
were required. 
 
10.3. STATISTICAL PARAMETERS AND STATISTICAL ANALYSIS PLAN 
 
Safety analysis will be conducted in the safety analysis set. Safety evaluation will include 
all patients who receive at least one dose of study drug. The safety analysis is based on 
the abnormality of laboratory test and clinical adverse events. Considering the 
percentage of laboratory abnormalities or clinical adverse events, descriptive statistics (or 
Fisher’s exact test, Chi-square test for comparison between parameters) will be used. The 
primary endpoint, the objective response rates, will be described with percentage (%) 
and 95% confidence intervals. The survival outcomes, secondary endpoints, will be 
calculated using Kaplan-Meier method, compared using long-rank test and described 
with 95% confidence intervals. The disease-control rates will be described with 
percentage (%) and 95% confidence intervals, and compared using odds ratio and Chi-
square tests. The Kaplan-Meier method will be used to estimate progression-free and 
overall survival curves, and the Cox proportional hazards regression model will be used 
for multivariate analysis of prognostic factors for survival outcomes. 
 
10.4. FINAL ANALYSIS 
 
Final analysis will be conducted in all patients for all endpoints at completion of follow-
up. 


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11. ETHICAL AND LEGAL ASPECTS 
 
11.1. GOOD CLINICAL PRACTICE (GCP) 
 
This study is to be conducted according to globally accepted standards of good clinical 
practice (as defined in the Korean GCP), in agreement with the Declaration of Helsinki 
and in keeping with local regulations. 
 
11.2. DELEGATION OF INVESTIGATOR DUTIES 
 
The investigator should ensure that all persons assisting with the study are adequately 
qualified, informed about the protocol, any amendments to the protocol, the study 
treatments, and their study-related duties and functions. The investigator should maintain 
a list of sub-investigators and other appropriately qualified persons to whom he or she 
has delegated significant trial-related duties. 
 
11.3. SUBJECT INFORMATION AND INFORMED CONSENT 
 
Before being enrolled in the clinical study, subjects must consent to participate after the 
nature, scope, and possible consequences of the clinical study have been explained in a 
form understandable to them. An informed consent document that includes both 
information about the study and the consent form will be prepared and given to the 
subject. This document will contain all the elements required by the KGCP and any 
additional elements required by local regulations. The document must be in a language 
understandable to the subject and must specify who informed the subject. Where 
required by local law, the person who informs the subject must be a physician. After 
reading the informed consent document, the subject must give consent in writing. The 
subject’s consent must be confirmed at the time of consent by the personally dated 
signature of the subject and by the personally dated signature of the person conducting 
the informed consent discussions. If the subject is unable to read, oral presentation and 
explanation of the written informed consent form and information to be supplied to 
subjects must take place in the presence of an impartial witness. Consent must be 
confirmed at the time of consent orally and by the personally dated signature of the 
subject or by a local legally recognized alternative (e.g., the subject’s thumbprint or mark). 
The witness and the person conducting the informed consent discussions must also sign 
and personally date. A copy of the signed consent document must be given to the 
subject. The original signed consent document will be retained by the investigator. The 
investigator will not undertake any measures specifically required only for the clinical 
study until valid consent has been obtained. The investigator should inform the subject’s 


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primary physician about the subject’s participation in the study if the subject has a 
primary physician and if the subject agrees to the primary physician being informed. 
 
11.4. CONFIDENTIALITY 
 
All the information related to this study will be used only for research and all personal 
data will be handled in strictest confidence. Only the subject number and subject initials 
will be recorded in the case report form, and all personal information and/data will be 
handled as independent data to enable records to be identified with securing 
confidentiality. Study findings stored on a computer will be stored in accordance with 
local data protection laws. The subjects will be informed that representatives of the 
sponsor, institutional review board (IRB), or regulatory authorities may inspect their 
medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance 
with the Korean Medical Service Act. 
 
11.5. PROTOCOL AMENDMENTS 
 
Without investigators agreement this clinical study protocol will not be modified. Once 
the study has started, amendments should be made only in exceptional cases. The 
changes then become part of the clinical study protocol. When contents of the analysis 
protocol are modified, the contents of all modifications will be described in the analysis 
protocol and final report of the study. Background for modification of the analysis 
protocol will be recorded. 
 
11.6. APPROVAL OF THE CLINICAL STUDY PROTOCOLS AND AMMENDMENTS 
 
Before the start of the study, the clinical study protocol, informed consent document, 
and any other appropriate documents will be submitted to the IRB with a cover letter or 
a form listing the documents submitted, their dates of issue, and the site (or region or 
area of jurisdiction, as applicable) for which approval is sought. If applicable, the 
documents will also be submitted to the authorities, in accordance with local legal 
requirements. Before the first subject is enrolled in the study, all ethical and legal 
requirements must be met. The IRB and, if applicable, the authorities must be informed 
of all subsequent protocol amendments and administrative changes, in accordance with 
local legal requirements. Amendments must be evaluated to determine whether formal 
approval must be sought and whether the informed consent document should also be 
revised. The investigator must keep a record of all communication with the IRB and, if 
applicable, between a coordinating investigator and the IRB. This also applies to any 


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communication between the investigator (or coordinating investigator, if applicable) and 
the authorities. 
 
11.7. CLOSURE OF THE STUDY 
 
The study must be closed at the site on completion. Furthermore, the sponsor or the 
investigator has the right to close this study site at any time. As far as possible, premature 
closure should occur after mutual consultation. Depending on local legislation, it may be 
necessary to inform IRB and the regulatory authorities when the study site is closed. 
11.8. FINANCIAL DISCLOSURE 
 
Not applicable to this study 
 
 
12. Exploratory biomarker studies  
 
Additional genetic tests will be performed in tumor tissues of patients participating in the 
study, and tests are performed to find predictive factors for treatment in patients with and 
without response. At least 10 slides from the paraffin block of the tumor tissue (primary or 
metastatic) will be prepared, therefore, in some patients with both primary and metastatic 
tumor tissues, a total of 20 (10) primary and metastatic sites can be prepared. The screening 
number and date of collection will be described and delivered to the Asan Medical Center, 
Seoul, Korea. The details of sample delivery, slide production, processing and delivery shall 
be as provided to each joint research institution. Providing slides for biomarker studies is 
not mandatory for participation in this study. However, because of the use of the stored 
tumor tissue, the patient is not burdened with any additional expense or procedure, and 
encourages active provision of the patient if there is no additional personal information or 
the risk of exposure of genetic information. 
 
Biomarkers to be examined are as follows. 
- Opal Multiplex Tissue Staining with OpalTM including PD-1 and PD-L1 
 
 
 


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11.Michael J. Overman, Sara Lonardi, Francesco Leone, et al. Nivolumab in patients with DNA 
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12. Howitt BE, Shukla SA, Sholl LM, et al. Association of Polymerase e-Mutated and 
Microsatellite-Instable Endometrial Cancers With Neoantigen Load, Number of Tumor-
Infiltrating Lymphocytes, and Expression of PD-1 and PD-L1. JAMA Oncol 2015; 1(9): 1319-


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  54 
 
23. 
13. Kane DP, Shcherbakova PV. A common cancer-associated DNA polymerase epsilon mutation 
causes an exceptionally strong mutator phenotype, indicating fidelity defects distinct from 
loss of proofreading. Cancer Res 2014; 74(7): 1895-901. 
14. van Gool IC, Eggink FA, Freeman-Mills L, et al. POLE Proofreading Mutations Elicit an 
Antitumor Immune Response in Endometrial Cancer. Clin Cancer Res 2015; 21(14): 3347-55. 
15. Ahn SM, Ansari AA, Kim J, et al. The somatic POLE P286R mutation defines a unique 
subclass of colorectal cancer featuring hypermutation, representing a potential genomic 
biomarker for immunotherapy. Oncotarget 2016. 
16. Antonia S, Goldberg SB, Balmanoukian A, et al. Safety and antitumour activity of 
durvalumab plus tremelimumab in non-small cell lung cancer: a multicentre, phase 1b study. 
Lancet Oncol 2016; 17(3): 299-308. 
17. Massard C, Gordon MS, Sharma S, et al. Safety and Efficacy of Durvalumab (MEDI4736), an 
Anti-Programmed Cell Death Ligand-1 Immune Checkpoint Inhibitor, in Patients With 
Advanced Urothelial Bladder Cancer. J Clin Oncol 2016; 34(26): 3119-25. 
18. Planchard D, Yokoi T, McCleod MJ, et al. A Phase III Study of Durvalumab (MEDI4736) With 
or Without Tremelimumab for Previously Treated Patients With Advanced NSCLC: Rationale 
and Protocol Design of the ARCTIC Study. Clin Lung Cancer 2016; 17(3): 232-6 e1. 
19. Gibbons DL, Chow LQ, Kim DW, et al. 57O Efficacy, safety and tolerability of MEDI4736 
(durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, 
combined with gefitinib (G): A phase I expansion in TKI-naive patients (pts) with EGFR mutant 
NSCLC. J Thorac Oncol 2016; 11(4 Suppl): S79. 
20. Mok T, Schmid P, Aren O, et al. 192TiP: NEPTUNE: A global, phase 3 study of durvalumab 
(MEDI4736) plus tremelimumab combination therapy versus standard of care (SoC) platinum-
based chemotherapy in the first-line treatment of patients (pts) with advanced or metastatic 
NSCLC. J Thorac Oncol 2016; 11(4 Suppl): S140-1. 
21. Peters S, Antonia S, Goldberg SB, et al. 191TiP: MYSTIC: a global, phase 3 study of 
durvalumab (MEDI4736) plus tremelimumab combination therapy or durvalumab 
monotherapy versus platinum-based chemotherapy (CT) in the first-line treatment of 
patients (pts) with advanced stage IV NSCLC. J Thorac Oncol 2016; 11(4 Suppl): S139-40. 
22. Rothschild SI, Zippelius A, Prince SS, et al. 129TiP: SAKK 16/14 - anti-PD-L1 antibody 
durvalumab (MEDI4736) in addition to neoadjuvant chemotherapy in patients with stage IIIA 
(N2) non-small cell lung cancer (NSCLC). A multicenter single-arm phase II trial. J Thorac 
Oncol 2016; 11(4 Suppl): S112. 
23. Wang E, Kang D, et al. Population pharmacokinetic and pharmacodynamics analysis of 
tremelimumab in patients with metastatic melanoma. J Clin Pharmacol. 2014 Oct; 
54(10):1108-16.  
24. Ng CM, Lum BL, Gimenez V, et al. Rationale for fixed dosing of pertuzumab in cancer 
patients based on population pharmacokinetic analysis. Pharm Res. 2006;23(6):1275–84. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  55 
 
25. Wang DD, Zhang S, Zhao H, et al. Fixed dosing versus body size based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol. 2009;49(9):1012–24. 
26. Zhang S, Shi R, Li C, et al. Fixed dosing versus body size-based dosing of therapeutic 
peptides and proteins in adults. J Clin Pharmacol. 2012;52(1):18–28. 
27.Narwal R, Roskos LK, Robbie GJ (2013) Population Pharmacokinetics of Sifalimumab, an 
Investigational Anti-Interferonalpha Monoclonal Antibody, in Systemic Lupus Erythematosus. 
Clin Pharmacokinet 52:1017–1027 
28.Overman MJ, Kopetz S, McDermott RS, et al. Nivolumab {+/-} ipilimumab in treatment (tx) 
of patients (pts) with metastatic colorectal cancer (mCRC) with and without high 
microsatellite instability (MSI-H): CheckMate-142 interim results. ASCO Meeting Abstracts 
2016; 34(15_suppl): 3501. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  56 
 
Appendix A. 
Dosing Modification and Toxicity Management Guidelines (TMGs) for Durvalumab Monotherapy, Durval
umab in Combination with other Products, or Tremelimumab Monotherapy –October 2022  
General Considerations Regarding Immune-Mediated Reactions 
These guidelines are provided as a recommendation to support investigators in the management of potential immune-mediated adverse events (imAEs).  
 
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible immune-mediated reactions. Inves
tigators are advised to take into consideration the appropriate practice guidelines and other society guidelines (e.g., National Comprehensive Cancer Network (N
CCN), European Society of Medical Oncology (ESMO)) in the management of these events.  Refer to the section of the table titled “Other -Immune-Mediated
 Reactions” for general guidance on imAEs not noted in the “Specific Immune-Mediated Reactions” section. 
Early identification and management of imAEs is essential to ensure safe use of the study drug.  Monitor patients closely for symptoms and signs that may b
e clinical manifestations of underlying imAEs. Patients with suspected imAEs  should be thoroughly evaluated to rule out any alternative etiologies (e.g., disea
se progression, concomitant medications, infections). In the absence of a clear alternative etiology, all such events should be managed as if they were immune-
mediated.  Institute medical management promptly, including specialty consultation as appropriate. In general, withhold study drug/study regimen  for severe (G
rade 3) imAEs. Permanently discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require systemic
 immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day within 12 weeks of initiating
 corticosteroids.  
Based on the severity of the imAE, durvalumab and/or tremelimumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, c
orticosteroid should be tapered over ≥ 28 days.  More potent immunosuppressive agents should be considered for events not responding to systemic steroids. 
Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of the investigator based on clinical practice and relevant
 guidelines. With long-term steroid and other immunosuppressive use, consider the need for  glucose monitoring. 
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI CTCAE version in the applicable 
study protocol. 
 
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor Immunotherapy 
 
Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation  
 
Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when the patient is taking steroid therapy 
 
Osteoporosis: Consider measures for prevention and mitigation of osteoporosis .  
 
Relevant Society Guidelines for Management of imAEs 
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please note, these were the current versio
ns of these guidelines at the time of updating TMGs. Please refer to the most up to date version of these guidelines. 
 
1. 
Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-related adverse events. J Immunother 
Cancer 2021;9:e002435 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  57 
 
2. 
Brahmer JR, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical 
Oncology Clinical Practice Guideline. J Clin Oncol 2018;36(17):1714-1768. 
3. 
Haanen JBAG, et al. Management of toxicities for immunotherapy: European Society for Medical Oncology (ESMO) clinical practice guidelines for diagnosis, 
treatment, and follow-up. Annals Oncol 2017;28(Suppl4):i119-i1142. 
4. 
Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J Hepatol 2020;72(2):320-341. 
5. 
Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related toxicities version 1.2022. Published February 
28, 2022. 
Pediatric Considerations Regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study drug/study regimen based
 on CTCAE grade/severity is the same for pediatric patients as it is for adu
lt patients, as well as to permanently discontinue study drug/study regimen i
f unable to reduce corticosteroid ≤ a dose equivalent to that required for cor
ticosteroid replacement therapy within 12 weeks of initiating corticosteroids.  
− 
All recommendations for specialist consultation should occur with a pediatric 
specialist in the specialty recommended. 
− 
The recommendations for steroid dosing (i.e., mg/kg/day) provided for adult 
patients should also be used for pediatric patients. 
− 
The recommendations for intravenous immunoglobulin (IVIG) and 
plasmapheresis use provided for adult patients may be considered for pediatric 
patients. 
− 
The infliximab 5 mg/kg IV one time dose recommended for adults is the same 
as recommended for pediatric patients ≥ 6 years old. For subsequent dosing 
and dosing in children < 6 years old, consult a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult a pediatric specialist. 
− 
With long-term steroid and other immunosuppressive use, consider need for 
PJP prophylaxis, gastrointestinal protection, and glucose monitoring. 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  58 
 
Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade of 
the Event  
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial Lung Disea
se (ILD) 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology with similar clinical 
presentation (e.g. infection, progressive disease). 
− 
Monitor patients for signs (e.g. tachypnoea) and 
symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough). Evaluate 
patients with imaging and pulmonary function tests, 
including other diagnostic procedures as described 
below.  
− 
Suspected pneumonitis should be confirmed with 
radiographic imaging and other infectious and 
disease-related etiologies excluded, and managed as 
described below. 
− 
Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), laboratory work-up (including  
clinically relevant culture specimens to rule out 
infection), 
 
and high- resolution computed 
tomography (CT) scan. 
− 
Consider Pulmonary and Infectious Diseases 
consults. 
Grade 1 
 
No dose modifications required. Howev
er, consider holding study drug/study r
egimen dose as clinically appropriate a
nd during diagnostic work-up for other 
etiologies. 
For Grade 1  
− 
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. 
Grade 2 
 
Hold study drug/study regimen dose un
til Grade 2 resolution to Grade ≤1. 
 
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 
For Grade 2 
− 
Monitor 
symptoms 
daily 
and 
consider 
hospitalization, as clinically indicated. 
− 
Consider Pulmonary and Infectious Diseases 
Consults;  
− 
Promptly start systemic steroids (e.g., prednisone 1 
to 2 mg/kg/day PO or IV equivalent). 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  59 
 
steroid taper (<10 mg prednisone or 
equivalent). 
− 
Consider HRCT or chest CT with contrast, Repeat  
imaging study as clinically indicated  
− 
If no improvement within 2 to 3 days, additional 
workup should be considered and prompt treatment 
with IV methylprednisolone 2 to 4 mg/kg/day 
started. 
− 
If no improvement within 2 to 3 days despite IV 
methylprednisolone at 2 to 4 mg/kg/day, promptly 
start immunosuppressive therapy. such as tumor 
necrosis factor (TNF) inhibitors (e.g., infliximab at 
5 mg/kg IV once, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider or relevant practice guidelines). Caution: It 
is important to rule out sepsis and refer to infliximab 
label for general guidance before using infliximab. 
− 
Consider, discussing with Clinical Study Lead. 
Grade 3 or 4 
 
 
Permanently discontinue study drug/stud
y regimen. 
For Grade 3 or 4 
− 
Hospitalize the patient  
− 
Promptly initiate empiric IV methylprednisolone 1 to 
4 mg/kg/day or equivalent.  
− 
Obtain Pulmonary and Infectious Diseases Consults; 
consider discussing with Clinical Study Lead, as 
needed. 
− 
Consider starting anti-infective therapy if infection is 
still a consideration on the basis of other diagnostic 
testing despite negative culture results 
− 
Supportive care (e.g., oxygen). 
− 
If no improvement within 2 days, additional workup 
should be considered and prompt treatment with 
additional immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider or relevant practice 
guidelines). Caution: rule out sepsis and refer to 
infliximab label for general guidance before using 
infliximab. 
Diarrhea/Colitis 
 
Any Grade 
(Refer to NCI CTCA
E applicable version 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  60 
 
 
 
in study protocol for 
defining the CTCAE 
grade/severity) 
other medications, or infections), including testing 
for Clostridium difficile toxin, etc. 
− 
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). 
− 
Consider further evaluation with imaging study with 
contrast.  
− 
Consult a gastrointestinal (GI) specialist for 
consideration of further workup. 
− 
WHEN 
SYMPTOMS 
OR 
EVALUATION 
INDICATE AN INTESTINAL PERFORATION 
IS SUSPECTED, CONSULT A SURGEON 
EXPERIENCED IN ABDOMINAL SURGERY 
IMMEDIATELY WITHOUT ANY DELAY.  
− 
PERMANENTLY 
DISCONTINUE 
STUDY 
DRUG FOR ANY GRADE OF INTESTINAL 
PERFORATION.  
− 
Steroids should be considered in the absence of clear 
alternative etiology, even for low-grade events, in 
order to prevent potential progression to higher grade 
events, including intestinal perforation.  
− 
Use analgesics carefully; they can mask symptoms of 
perforation and peritonitis. 
Grade 1 
 
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), 
loperamide, and other supportive care measures.  
− 
If symptoms persist, consider checking lactoferrin; 
if positive, treat as Grade 2 below. If negative and 
no infection, continue Grade 1 management. 
Grade 2 
 
Hold study drug/study regimen until re
solution to Grade ≤1 
 
If toxicity improves to Grade ≤1, 
then study drug/study regimen can be 
For Grade 2 
− 
Consider 
symptomatic 
treatment, 
including 
hydration, electrolyte replacement, dietary changes 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  61 
 
resumed after completion of steroid 
taper 
(<10 
mg 
prednisone, 
or 
equivalent). 
(e.g., American Dietetic Association colitis diet), and 
loperamide and/or budesonide. 
− 
Consider further evaluation with imaging study with 
contrast.  
− 
Consider consult of a gastrointestinal (GI) specialist 
for consideration of further workup. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If no improvement  within  3 days despite therapy 
with 1 to 2 mg/kg IV methylprednisolone, reconsult 
GI specialist and, if indicated, promptly start 
additional 
immunosuppressant 
agent 
such 
as 
infliximab at 5 mg/kg IV, may be repeated at 2 and 6 
weeks after initial dose at the discretion of the 
treating provider or relevant practice guidelines. 
Caution: it is important 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. 
− 
Consider, as necessary, discussing with Clinical 
Study Lead if no resolution to Grade ≤1 in 3 to 
4 days. 
Grade 3 or 4 
 
 
Grade 3 
 
For patients treated with durvalumab 
monotherapy, hold study drug/study 
regimen until resolution to Grade ≤
1; study drug/study regimen can be 
resumed after completion of steroid 
taper (<10 mg prednisone per day, or 
equivalent).   
 
For patients treated with durvalumab 
in combination with other products 
(not tremelimumab), decision to be 
made at the discretion of the study 
For Grade 3 or 4 
− 
Urgent GI consult and imaging and/or colonoscopy 
as appropriate. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
Monitor stool frequency and volume and maintain 
hydration. 
− 
If still no improvement within 2 days, continue 
steroids 
and 
promptly 
add 
further 
immunosuppressants. (e.g., infliximab at 5 mg/kg IV, 
may be repeated at 2 and 6 weeks after initial dose at 
the discretion of the treating provider or relevant 
practice guidelines). Caution: Ensure GI consult to 
rule out bowel perforation and refer to infliximab 
label for general guidance before using infliximab.  


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  62 
 
investigator, in discussion with 
AstraZeneca Clinical Study Lead. 
For patients treated with durvalu
mab in combination with tremeli
mumab or tremelimumab monoth
erapy,  
Permanently discontinue both du
rvalumab and tremelimumab for 
1) Grade 3 diarrhea/colitis or 2) 
Any grade of intestinal perforatio
n  
      Grade 4  
Permanently discontinue  
study drug/study regimen. 
− 
If perforation is suspected, consult a surgeon 
experienced in abdominal surgery immediately 
without any delay. 
Hepatitis  
Infliximab should not be used for man
agement of immune-related hepatitis. 
 
 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., viral hepatitis, disease 
progression, concomitant medications). 
− 
Monitor and evaluate transaminases  (aspartate 
aminotransferase [AST], alanine aminotransferase 
[ALT], alkaline phosphatase [ALP]) and total 
bilirubin . 
ALT or AST ≤  3 
x ULN or total bilir
ubin ≤ 1.5  x ULN
  
 
No dose modifications. 
 
If it worsens, then consider holding 
therapy. 
− 
Continue transaminase and total bilirubin monitoring 
per protocol. 
ALT or AST > 3 ≤
 5 x ULN or total b
ilirubin > 1.5 ≤ 3 x
 ULN  
 
− 
Hold study drug/study regimen dose 
until  ALT or AST ≤  3 x ULN or 
total bilirubin ≤ 1.5  x ULN. 
Resume study drug/study regimen 
after completion of steroid taper (<10 
mg prednisone or equivalent). 
− 
Permanently 
discontinue 
study 
drug/study regimen for any case 
meeting Hy’s law laboratory criteria 
(AST or ALT >3 × ULN  AND 
bilirubin >2 × ULN without initial 
− 
Regular and frequent checking of transaminases and 
total bilirubin (e.g., every 1 to 2 days) until 
transaminases and total bilirubin elevations improve 
or resolve. 
− 
If no resolution to  ALT or AST ≤  3 x ULN or 
total bilirubin ≤ 1.5  x ULN  in 1 to 2 days, 
consider discussing with Clinical Study Lead, as 
needed. 
− 
If event is persistent (>2 to 3 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
PLEASE SEE shaded area 
immediately below this 
section to find guidance 
for 
management 
of 
“Hepatitis 
(elevated 
LFTS)” in hepatocellular 
carcinoma (HCC) patients 
(or 
secondary  
tumour 
involvement 
of 
the 
liver with 
abnormal 
baseline values [BLV]) 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  63 
 
findings of cholestasis (i.e., elevated 
ALP) and in the absence of any 
alternative cause. 
ALT or AST > 5-
≤ 10 x ULN 
 
− 
Hold 
study 
drug/study 
regimen. 
Resume study drug/study regimen if 
elevations downgrade to  ALT or 
AST ≤  3 x ULN or total bilirubin 
≤ 1.5  x ULN after completion of 
steroid taper (<10 mg prednisone, or 
equivalent).  
− 
If in combination with 
tremelimumab, do not restart 
tremelimumab. 
 
− 
Promptly initiate empiric IV methylprednisolone at 1 
to 2 mg/kg/day or equivalent. 
− 
Perform Hepatology Consult, abdominal workup, 
and imaging as appropriate. 
− 
If still no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with an additional 
immunosuppressant.(e.g., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead if 
mycophenolate is not available. Infliximab should 
NOT be used. 
 
Concurrent ALT or 
AST > 3 x ULN and 
total bilirubin > 2 x U
LN 
 
ALT or AST > 1
0 x ULN OR total bil
irubin > 3 x ULN 
Permanently discontinue study drug
/study regimen. 
− 
Promptly initiate empiric IV methylprednisolone at 1 
to 2 mg/kg/day or equivalent. 
− 
If still no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day methylprednisolone IV or equivalent, 
promptly start treatment with an additional 
immunosuppressant.(e.g., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult or relevant practice 
guidelines). Discuss with Clinical Study Lead if 
mycophenolate is not available. Infliximab should 
NOT be used. 
− 
Perform Hepatology Consult, abdominal workup, 
and imaging as appropriate. 
Hepatitis  
(elevated transaminases and total bilir
ubin) 
Infliximab should not be used for man
agement of immune-related hepatitis.  
 
Any Elevations of A
ST, ALT, or T. Bili
 as Described Below 
 
General Guidance 
 
For Any Elevations Described 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., viral hepatitis, disease 
progression, concomitant medications, worsening of 
liver cirrhosis [e.g., portal vein thrombosis]). 
− 
Monitor and evaluate AST, ALT, ALP, and T. Bili. 
− 
For hepatitis B (HBV) + patients: evaluate 
quantitative HBV viral load, quantitative Hepatitis B 
surface antigen (HBsAg), or Hepatitis B envelope 
antigen (HBeAg). 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  64 
 
 
 
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 
− 
For hepatitis C (HCV) + patients: evaluate 
quantitative HCV viral load. 
− 
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or starting 
antiviral HBV medications if HBV viral load is 
>2000 IU/ml. 
− 
Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or starting 
antiviral HCV medications if HCV viral load has 
increased by ≥2-fold. 
− 
For HCV+ with Hepatitis B core antibody 
(HBcAb)+: Evaluate for both HBV and HCV as 
above. 
 
 Isolated AST or AL
T >ULN and ≤2.5×
BLV,  
− 
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 
 
 
  ALT or AST > 2.
5-≤ 5X BLV and 
≤ 20xULN 
 
 
 
 
Hold study drug/study regimen dose 
until  resolution to AST or ALT ≤
2.5×BLV . 
 
If toxicity worsens, then treat as  
described for elevations in the rows 
below. If toxicity improves to  AST 
− 
Regular and frequent checking of Transaminases and 
total bilirubin (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 Clinical 
Study Lead. 
THIS shaded area is guidance 
only 
for 
management 
of 
“Hepatitis (elevated LFTs)” in 
HCC 
patients 
(or 
secondary  
tumour 
involvement of the liver with 
abnormal 
baseline 
values 
[BLV]) 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  65 
 
or ALT ≤2.5×BLV , resume study 
drug/study regimen after completion 
of steroid taper (<10 mg prednisone, 
or equivalent). 
 
− 
If event is persistent (>2 to 3 days) or worsens, and 
investigator suspects toxicity to be an imAE, start 
prednisone 1 to 2 mg/kg/day PO or IV equivalent. 
− 
If still no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day of prednisone PO or IV equivalent, 
consider additional workup. If still no improvement 
within 2 to 3 days despite 2mg/kg/day of IV 
methylprednisolone, consider additional abdominal 
workup (including liver biopsy) and imaging (i.e., 
liver ultrasound), and consider starting additional 
immunosuppressants. (e.g., mycophenolate mofetil 
0.5 – 1 g every 12 hours then taper in consultation 
with hepatology consult or relevant practice 
guidelines). Discuss Clinical Study Lead if 
mycophenolate mofetil is not available.  
Infliximab should NOT be used. 
 
ALT or AST >5-7X 
BLV and ≤ 20X UL
N OR concurrent 2.5
-5X BLV and ≤ 20
XULN AND total bil
irubin > 1.5 - < 2 x 
ULN  
 
− 
Withhold durvalumab and 
permanently discontinue 
tremelimumab 
− 
Resume study drug/study regimen if 
elevations downgrade to  AST or 
ALT 
≤2.5×BLV 
 
and 
after 
completion of steroid taper (<10 mg 
prednisone, or equivalent). 
− 
Permanently 
discontinue 
study 
drug/study regimen if the elevations 
do not downgrade to  AST or ALT 
≤2.5×BLV within 14 days 
 
− 
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 discussing with Clinical Study Lead, as 
needed. 
− 
If investigator suspects toxicity to be immune-
mediated, 
promptly 
initiate 
empiric 
IV 
methylprednisolone 
at 
1 
to 
2 mg/kg/day 
or 
equivalent. 
− 
If no improvement within 2 to 3 days despite 1 to 
2 mg/kg/day methylprednisolone IV or equivalent, 
obtain liver biopsy (if it has not been done already) 
and promptly start treatment with an additional 
immunosuppressant. 
 
(e.g.,., 
mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with a hepatologist or relevant practice 
guidelines). Discuss with Study Clinical Lead if 
mycophenolate is not available.  
Infliximab should NOT be used. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  66 
 
ALT or AST > 7 X 
BLV OR > 20 ULN 
whichever occurs firs
t OR bilirubin > 3UL
N 
Permanently discontinue study drug/stud
y regimen. 
Same as above  
(except recommend obtaining liver biopsy early) 
 
Nephritis and/or renal dysfunction 
 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
infections, recent IV contrast, medications, fluid 
status). 
− 
Consider Consulting a nephrologist.  
− 
Consider imaging studies to rule out any alternative 
etiology 
− 
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, 
decreased urine output, or proteinuria). Follow urine 
protein/creatinine ratio every 3-7 days 
Grade 1 
 
No dose modifications. 
For Grade 1 
− 
Monitor 
serum 
creatinine 
weekly 
and 
any 
accompanying symptoms. 
 
If creatinine returns to baseline, resume regular 
monitoring per study protocol. 
 
If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 
− 
Consider hydration, electrolyte replacement, and 
diuretics, as clinically indicated. 
− 
Consider nephrologist consult if not resolved within 
14 days, or earlier as clinically indicated 
Grade 2 
 
Hold study drug/study regimen until re
solution to Grade ≤1 or baseline.  
 
If toxicity improves to Grade ≤1 or 
baseline, then resume study 
drug/study regimen after completion 
of steroid taper (<10 mg prednisone, 
or equivalent). 
For Grade 2 
− 
Consider 
including 
hydration, 
electrolyte 
replacement, and diuretics as clinically indicated 
− 
Follow urine protein/creatinine ratio every 3-7 days 
− 
Carefully monitor serum creatinine as clinically 
warranted. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  67 
 
                                            
 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
Start prednisone 0.5 – 1 mg/kg/day if other causes are 
ruled out 
− 
If event is persistent beyond 5 days or worsens, 
increase to prednisone up to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 5 days or worsens 
despite prednisone at 1 to 2 mg/kg/day PO or IV 
equivalent, consider additional workup. When event 
returns to baseline, resume study drug/study regimen 
and routine serum creatinine monitoring per study 
protocol. 
Grade 3 or 4 
 
 
Permanently discontinue study drug/stud
y regimen. 
For Grade 3 or 4 
− 
Carefully monitor serum creatinine daily. 
− 
Follow urine protein/creatinine ratio every 3-7 days 
− 
Consult nephrologist and consider renal biopsy if 
clinically indicated. 
− 
Promptly start prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
− 
If event is not responsive within 3 to 5 days of 
steroids or worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, consider additional 
workup 
and 
prompt 
treatment 
with 
an 
immunosuppressant  
Rash or Dermatitis 
(Including Pemphigoid) 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
definition of severity/
grade depending on t
ype of skin rash) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology. 
− 
Monitor for signs and symptoms of dermatitis (rash 
and pruritus). 
HOLD STUDY DRUG IF GRADE 3 PEMPH
IGOID OR SEVERE CUTANEOUS ADVERS
E REACTION (SCAR)1  IS SUSPECTED.  
− 
PERMANENTLY DISCONTINUE STUDY 
DRUG IF SCAR OR GRADE 3 PEMPIGOID IS 
CONFIRMED. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  68 
 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) 
and topical therapy (e.g., emollient, lotion, or 
institutional standard). 
Grade 2 
For persistent (>1 week) Grade 2 event
s, hold scheduled study drug/study regi
men until resolution to Grade ≤1 or b
aseline. 
 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper (<10 mg prednisone, or 
equivalent). 
For Grade 2 
− 
Consider dermatology consult and skin biopsy, as 
indicated. 
− 
Consider symptomatic treatment, including oral 
antipruritics (e.g., diphenhydramine or hydroxyzine) 
and topical therapy  
− 
Consider moderate-strength topical steroid. 
− 
If no improvement of rash/skin lesions occurs within 
1 week or is worsening despite symptomatic 
treatment and/or use of moderate strength topical 
steroid, consider discussing with Clinical Study 
Lead, as needed, and promptly start systemic steroids 
such as prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
Grade 3 
For Grade 3 
− 
Hold study drug/study regimen until 
resolution to Grade ≤1 or baseline. 
− 
If toxicity improves to Grade ≤1 or 
baseline, then resume drug/study 
regimen after completion of steroid 
taper 
(<10 
mg 
prednisone, 
or 
equivalent). 
For Grade  
− 
Reconsult a dermatologist. Consider skin biopsy 
(preferably more than 1) as clinically feasible. 
− 
Promptly initiate empiric IV methylprednisolone 1 to 
2 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor the extent of rash [Rule of Nines]. 
− 
Consider, as necessary, discussing with Clinical 
Study Lead. 
 
Grade 4 
For Grade 4 
Permanently discontinue study drug/stud
y regimen. 
For Grade 4 
− 
Reconsult a dermatologist. Consider skin biopsy 
(preferably more than 1) as clinically feasible. 
− 
Promptly initiate empiric IV methylprednisolone 1 
to 2 mg/kg/day or equivalent. 
− 
Consider hospitalization. 
− 
Monitor the extent of rash [Rule of Nines]. 
Consider, as necessary, discussing with Clinical Stud


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  69 
 
y Lead. 
Endocrinopathy 
(e.g., hyperthyroidism, thyroiditis, hypoth
yroidism,  type 1 diabetes mellitus, hyp
ophysitis, hypopituitarism, and adrenal in
sufficiency) 
 
Any Grade 
(Depending on the ty
pe of endocrinopathy,
 refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression 
including brain metastases, or infections). 
− 
Consider consulting an endocrinologist for endocrine 
events. 
− 
Consider discussing with Clinical Study Lead, as 
needed. 
− 
Monitor patients for signs and symptoms of 
endocrinopathies. (Non-specific symptoms include 
headache, fatigue, behaviour changes, mental status 
changes, photophobia, visual field cuts, vertigo, 
abdominal pain, unusual bowel habits, polydipsia, 
polyuria, hypotension, and weakness.) 
− 
Depending on the suspected endocrinopathy, 
monitor and evaluate thyroid function tests: thyroid 
stimulating hormone (TSH), free T3 and free T4 and 
other relevant endocrine and related labs (e.g., blood 
glucose and ketone levels, hemoglobin A1c 
(HgA1c)). If a patient experiences an AE that is 
thought to be possibly of autoimmune nature (e.g., 
thyroiditis, pancreatitis, hypophysitis, or diabetes 
insipidus), the investigator should send a blood 
sample for appropriate autoimmune antibody testing. 
− 
Investigators should ask subjects with 
endocrinopathies who may require prolonged or 
continued hormonal replacement, to consult their 
primary care physicians or endocrinologists about 
further monitoring and treatment after completion of 
the study. 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Monitor patient with appropriate endocrine function 
tests. 
− 
For 
suspected 
hypophysitis/hypopituitarism, 
consider consulting an endocrinologist to guide 
assessment of early morning adrenocorticotropin 
hormone (ACTH), cortisol, TSH and free T4; also 
consider gonadotropins, sex hormones, and prolactin 
levels, as well as cosyntropin stimulation test (though 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  70 
 
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, 3, or 4 
− 
For Grade 2-4  endocrinopathies 
other than hypothyroidism and type 1 
diabetes mellitus (T1DM), consider 
holding study drug/study regimen 
dose until acute symptoms resolve. 
− 
Study drug/study regimen can be 
resumed once patient stabilizes and 
after completion of steroid taper (<10 
mg prednisone, or equivalent). 
− 
Patients with endocrinopathies who 
may require prolonged or continued 
steroid replacement (e.g., adrenal 
insufficiency) can be retreated with 
study drug/study regimen if the 
patient is clinically stable as per 
investigator or treating physician’s 
clinical judgement. 
 
For Grade 2, 3, or 4  
− 
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 T1DM, 
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. 
− 
Isolated hypothyroidism may be treated with 
replacement therapy, without study drug/study 
regimen 
interruption, 
and 
without 
corticosteroids. 
− 
Isolated T1DM may be treated with appropriate 
diabetic therapy, and without corticosteroids. 
Only hold study drug/study regimen in setting of 
hyperglycemia when 
diagnostic workup is 
positive for diabetic ketoacidosis.  
− 
For patients with normal endocrine workup 
(laboratory assessment or magnetic resonance 
imaging 
(MRI) 
scans), 
repeat 
laboratory 
assessments/MRI as clinically indicated. 
Amylase/Lipase increased 
 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g. disease progression, 
viral infection, concomitant medications, substance 
abuse). 
− 
For modest asymptomatic elevations in serum 
amylase and lipase, corticosteroid treatment is not 
 
Grade 1 
No dose modifications. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  71 
 
 
Grade 2, 3, or 4 
For Grade 2, 3, or 4 
In consultation with relevant gastroente
rology specialist  consider continuing s
tudy drug/study regimen if no clinical/r
adiologic evidence of pancreatitis ± im
provement in amylase/lipase. 
indicated as long as there are no other signs or 
symptoms of pancreatic inflammation.  
− 
Assess for signs/symptoms of pancreatitis  
− 
Consider appropriate diagnostic testing (e.g., 
abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic evidence 
on CT) 
− 
If isolated elevation of enzymes without evidence of 
pancreatitis, continue immunotherapy.  Consider 
other causes of elevated amylase/lipase 
− 
If evidence of pancreatitis, manage according to 
pancreatitis recommendations  
Acute Pancreatitis 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology. 
− 
Consider Gastroenterology referral  
 
Grade 2 
Consider holding study drug/regimen 
Grade 2 
− 
Consider IV hydration 
− 
Consider Gastroenterology referral 
 
Grade  3, or 4 
For Grade 3 
Hold study drug/study regimen until re
solution of elevated enzymes and no ra
diologic findings 
If no elevation in enzymes or return to
 baseline values, then resume study dr
ug/study regimen after completion of st
eroid taper (<10 mg prednisone, or equ
ivalent). 
For Grade 4 
Permanently discontinue study drug/stud
y regimen. 
For Grade  3, or 4 
− 
Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
− 
IV hydration 
Nervous System Disorders 
Aseptic Meningitis 
Any Grade 
(Refer to NCI CTCA
General Guidance 
For Any Grade 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  72 
 
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
− 
Symptoms may include headache, 
photophobia, and neck stiffness, 
nausea/ vomiting which may resemble 
an infectious meningitis.  
− 
Patients may be febrile.  
− 
Mental status should be normal
 
 
− 
Consider neurology consult 
− 
Consider MRI brain with and without contrast with 
pituitary protocol and a lumbar puncture for 
diagnosis. 
− 
Exclude bacterial and viral infections. (ie HSV) 
− 
Consider IV acyclovir until polymerase chain 
reactions are available 
 
Any Grade  
Permanently discontinue study drug/stud
y regimen   
For Any Grade 
− 
Consider neurology consult 
− 
Consider MRI brain with and without contrast with 
pituitary protocol and a lumbar puncture for 
diagnosis. 
− 
Exclude bacterial and viral infections. (ie HSV) 
− 
Consider IV acyclovir until polymerase chain 
reactions are available 
− 
Consider, as necessary, discussing with Clinical 
Study Lead.( Last bullet) 
− 
Consider hospitalization. 
− 
Once infection has been ruled out promptly initiate 
empiric IV methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
Encephalitis 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
− 
Symptoms may include Confusion, 
altered 
behaviour, 
headaches, 
seizures, short-term memory loss, 
depressed level of consciousness, 
focal 
weakness, 
and 
speech 
abnormality.  
− 
 
For Any Grade 
− 
Consider neurology consult 
− 
Consider testing including MRI of the brain with 
and without contrast, lumbar puncture, 
electroencephalogram (EEG) to evaluate for 
subclinical seizures, ESR, CRP, antineutrophil 
cytoplasmic antibody (ANCA) (if vasculitic process 
suspected), thyroid panel including TPO and 
thyroglobulin and additional autoantibodies to rule 
out paraneoplastic disorders. 
− 
Exclude bacterial and viral infections. (i.e. 
HSV)Consider IV acyclovir until polymerase chain 
reactions are available. 
 
Grade 2 
For Grade 2 
Permanently discontinue study drug/stud
For Grade 2 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  73 
 
y regimen. 
− 
Consider, as necessary, discussing with the Clinical 
Study Lead. 
− 
Once 
infection 
has 
been 
ruled 
out 
methylprednisolone 1–2 mg/kg/day 
− 
For progressive symptoms or if oligoclonal bands are 
present consider methylprednisolone 1 g IV daily for 
3–5 days plus IVIG or plasmapheresis 
 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/stud
y regimen. 
For Grade 3 or 4 
− 
Consider, as necessary, discussing with Clinical 
Study Lead. 
− 
Consider hospitalization. 
− 
Once infection is ruled out, start methylprednisolone 
1 g IV daily for 3–5 days for progressive symptoms 
consider adding IVIG or plasmapheresis 
Transverse Myelitis 
Any Grade 
General Guidance 
− 
Permanently discontinue 
immunotherapy 
− 
Consider MRI of the spine and brain 
− 
Once imaging is complete, consider 
lumbar puncture 
Consider testing to rule out 
additional aetiologies: B12, 
HIV, rapid plasma reagin (R
PR), ANA, anti-Ro/La antibo
dies, aquaporin-4 IgG, myeli
n oligodendrocyte glycoprotei
n (MOG) IgG, paraneoplastic
 panel for anti-Hu and anti-
CRMP5/CV2 
For Any Grade 
− 
Consider neurology consult 
− 
Inpatient care 
− 
Consider prompt initiation of high 
methylprednisolone pulse dosing  
− 
Strongly consider IVIG or plasmapheresis 
 
Peripheral neuropathy 
 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be evaluated to rule out any 
alternative etiology for neuropathy (e.g., disease 
progression, infections, metabolic syndromes or 
medications). It should be noted that the diagnosis of 
immune-mediated peripheral neuromotor syndromes 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  74 
 
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 neurological consult. 
− 
Neurophysiologic 
diagnostic 
testing 
(e.g., electromyogram 
and 
nerve 
conduction 
investigations are routinely indicated upon suspicion 
of such conditions and may be best facilitated by 
means of a neurology consultation. 
 
Grade 1 
No dose modifications. 
For Grade 1 
− 
Consider discussing with the Clinical Study Lead, as 
needed. 
− 
Monitor symptoms for interference with ADLS, gait 
difficulties, imbalance, or autonomic dysfunction 
 
Grade 2 
Hold study drug/study regimen dose un
til resolution to Grade ≤1. 
 
For Grade 2 
− 
Consult a neurologist. 
− 
Consider EMG/NCS 
− 
Consider discussing with the Clinical Study Lead, as 
needed. 
− 
Observation for additional symptoms or consider 
initiating  prednisone 0.5–1 mg/kg orally 
− 
If progression, initiate methylprednisolone 2–4 
mg/kg/day and treat as GBS 
− 
Sensory neuropathy/neuropathic pain may be 
managed 
by 
appropriate 
medications 
(e.g., 
gabapentin or duloxetine). 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/stud
y regimen. 
For Grade 3 or 4  
− 
Consider discussing with Clinical Study Lead, as 
needed. 
− 
Recommend hospitalization. 
− 
Monitor symptoms and consult a neurologist. 
− 
Treat per  Guillain-Barré Syndrome 
recommendations 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  75 
 
 
Guillain-Barré Syndrome (GBS) 
 
General Guidance 
− 
Recommend hospitalization 
− 
Obtain neurology consult 
− 
Obtain MRI of spine to rule out compression lesion 
− 
Obtain lumbar puncture 
− 
Antibody tests for GBS variants 
− 
Pulmonary function tests 
− 
Obtain electromyography (EMG) and nerve 
conduction studies 
− 
Frequently monitor pulmonary function tests and 
neurologic evaluations 
− 
Monitor for concurrent autonomic dysfunction 
− 
Initiate medication as needed for neuropathic pain  
 
Grade 2-4 
Grade 2-4 
Permanently discontinue 
Start IVIG or plasmapheresis in additio
n to methylprednisolone 1 gram daily fo
r 5 days, then taper over 4 weeks.  
Myasthenia gravis  
 
 
General Guidance 
− 
Obtain neurology consult 
− 
Recommend hospitalization 
− 
Obtain pulmonary function tests 
− 
Obtain labs: ESR, CRP, creatine phosphokinase 
(CPK), aldolase and anti-striational antibodies 
− 
Consider 
 
cardiac 
exam, 
ECG, 
troponin, 
transthoracic 
echocardiogram 
for 
possible 
concomitant myocarditis 
− 
Obtain 
electromyography 
(EMG) 
and 
nerve 
conduction studies 
− 
Consider MRI of brain/spine to rule out CNS 
involvement by disease 
− 
Avoid medications that might exacerbate MG (e.g. 
beta blockers, some antibiotics, IV magnesium)  
 
Grade 2 
Permanently discontinue 
− 
Consider pyridostigmine 30mg three times daily and 
gradually increase based on symptoms (max dose 
120mg four times daily) 
− 
Consider starting low dose prednisone 20mg daily 
and increase every 3-5 days. (Target dose 
1mg/kg/day. Max dose 100mg daily) 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  76 
 
 
Grade 3-4 
Permanently discontinue 
− 
Start methylprednisolone 1-2mg/kg/day. Taper 
steroids based on symptom improvement 
− 
Start plasmapheresis or IVIG 
− 
Consider rituximab if refractory to plasmapheresis 
or IVIG 
− 
Frequent PFT assessments 
− 
Daily neurologic evaluations 
Myocarditis 
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
Discontinue drug permanently if biopsy
-proven immune-mediated myocarditis. 
For Any Grade 
− 
Initial work-up should include clinical evaluation, B-
type natriuretic peptide (BNP), cardiac enzymes, 
electrocardiogram (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) 
− 
The 
prompt 
diagnosis 
of 
immune-mediated 
myocarditis is important, particularly in patients with 
baseline cardiopulmonary disease and reduced 
cardiac function.  
− 
Consider discussing with the Clinical Study Lead, as 
needed. 
− 
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). Consult a cardiologist early, to 
promptly assess whether and when to complete a 
cardiac biopsy, including any other diagnostic 
procedures. 
− 
as indicated. Spiral CT or cardiac MRI can 
complement 
ECHO 
to 
assess 
wall 
motion 
abnormalities when needed. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  77 
 
 
 
Grade 2, 3 or 4 
 
 
 
 
If Grade 2-4, permanently discontinue 
study drug/study regimen. 
For Grade 2-4 
− 
Monitor symptoms daily, hospitalize. 
− 
Consider cardiology consultation and a prompt start 
of high-dose/pulse corticosteroid therapy 
− 
Supportive care (e.g., oxygen). 
− 
If 
no 
improvement 
consider 
additional  
immunosuppressive therapy such as TNF inhibitors 
(e.g., infliximab), IVIG or plasmapheresis or other 
therapies depending on the clinical condition of the 
patient, based on the discretion of the treating 
specialist consultant r or relevant practice guidelines. 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before 
using 
infliximab. 
 
Infliximab 
is 
contraindicated for patients who have heart 
failure. 
 Myositis/ Polymyositis  
Any Grade 
(Refer to NCI CTCA
E applicable version 
in study protocol for 
defining the CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
− 
Patients should be thoroughly evaluated to rule out 
any alternative etiology (e.g., disease progression, 
other medications, or infections). 
− 
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, and; 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. 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  78 
 
− 
Consider, as necessary, discussing with the Clinical 
Study Lead. 
− 
Initial work-up should include clinical evaluation, 
creatine kinase, aldolase, lactate dehydrogenase 
(LDH), blood urea nitrogen (BUN)/creatinine, 
erythrocyte sedimentation rate or C-reactive protein 
(CRP) 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. 
 
Grade 1 
 
 
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 Clinical 
Study Lead. 
 
Grade 2 
 
 
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. 
− 
Consider Rheumatology or Neurology consult, and 
initiate evaluation. 
− 
Consider, as necessary, discussing with the Clinical 
Study Lead. 
− 
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 2 to 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  79 
 
3 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 days, consider additional 
− 
 immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab), IVIG or 
plasmapheresis, or other therapies based on the 
discretion of the treating specialist consultant  or 
relevant practice guideline Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab. 
 
Grade 3 
 
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 3 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Consider Rheumatology and/or Neurology consult 
− 
Consider discussing with the Clinical Study Lead, 
as needed. 
− 
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 2 to 3 
days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (e.g., infliximab at 
5 mg/kg  IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider  or relevant practice guidelines). 
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. 
 
Grade 4 
For Grade 4 
Permanently discontinue study drug/stud
y regimen. 
Grade 4 
− 
Monitor symptoms closely; recommend 
hospitalization. 
− 
Consider Rheumatology and/or Neurology consult 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  80 
 
 
1 SCAR terms include Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), Erythema Multiforme, Acute Generalized 
Exanthematous Pustulosis, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) and Drug-induced hypersensitivity syndrome.  
− 
Consider discussing with the Clinical Study Lead, 
as needed. 
− 
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 2 to 3 
days, consider starting another immunosuppressive 
therapy such as a TNF inhibitor (e.g., infliximab at 
5 mg/kg  IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider  or relevant practice guidelines). 
Caution: It is important to rule out sepsis and 
refer to infliximab label for general guidance 
before using infliximab. 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  81 
 
Other–Immune-Mediated Reactions 
Severity Grade of the Event (R
efer to NCI CTCAE applicable 
version in study protocol for de
fining the CTCAE grade/severit
y) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: It is possible that events with an inflammatory 
or immune mediated mechanism could occur in nearly 
all organs, some of them are not noted specifically in 
these guidelines (e.g. immune thrombocytopenia, haem
olytic anaemia, uveitis, vasculitis). 
− 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other medications, 
or infections).  
− 
The Clinical Study Lead may be contacted for immune-mediated 
reactions not listed in the “specific immune-mediated reactions” 
section 
− 
Consultation with relevant specialist 
− 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Monitor as clinically indicated 
Grade 2 
− 
Hold study drug/study regimen until resolution to ≤
Grade 1 or baseline. 
− 
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. 
− 
Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they do 
not rapidly improve to Grade <1 upon treatment with 
systemic steroids and following full taper 
For Grade 2, 3, or 4 
Treat accordingly, as per institutional standard, appropri
ate clinical practice guidelines, and society guidelines. 
(See page 4). 
Grade 3 
Hold study drug/study regimen  
Grade 4 
 
Permanently discontinue study drug/study regimen  
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 Clinical Study Lead.” 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  82 
 
Infusion-Related Reactions 
Severity Grade of the Even
t (Refer to NCI CTCAE ap
plicable version in study pr
otocol for defining the CTC
AE grade/severity) 
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 b
e 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 or study protocol 
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 standard, 
appropriate clinical practice guidelines, and society guidelines.  
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  83 
 
Non-Immune-Mediated Reactions 
Severity Grade of the Event 
(Refer to NCI CTCAE appli
cable version in study proto
col for defining the CTCAE 
grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not dee
med to be related to study treatment (i.e., events due to und
erlying disease) or for laboratory abnormalities not deemed t
o be clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1 
No dose modifications. 
Treat accordingly, as per institutional standard. 
Grade 2-3 
Hold study drug/study regimen until resolution to ≤Grade 1
 or baseline. 
Treat accordingly, as per institutional standard. 
Grade 4 
 
Discontinue study drug/study regimen (Note: For Grade 4 la
bs, decision to discontinue should be based on accompanyin
g clinical signs/symptoms, the Investigator’s clinical judgmen
t, 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 Clinical Study Lead.” 
 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  84 
 
APPENDIX B. 
 
Durvalumab weight based dose calculation 
 
For durvalumab dosing done depending on subject weight. Weight-based dosing should be utilized 
for patients ≤ 30 kg: 
1. Cohort dose: X mg/kg 
2. Subject weight: Y kg 
3. Dose for subject: XY mg = X (mg/kg) × Y (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = XY mg / 50 (mg/mL)  
where 50 mg/mL is durvalumab nominal concentration. 
The corresponding volume of durvalumab should be rounded to the nearest tenth mL (0.1 mL). 
Dose adjustments for each cycle are only needed for greater than 10% change in weight. 
5. The number of vials required for dose preparation is the next greatest whole number of vials 
from the following formula: 
 
Number of vials = Dose (mL) / 10.0 (mL/vial) 
 
Example:  
1. Cohort dose: 20 mg/kg 
2. Subject weight: 30 kg 
3. Dose for subject: 600 mg = 20 (mg/kg) × 30 (kg) 
4. Dose to be added into infusion bag:  
Dose (mL) = 600 mg / 50 (mg/mL) = 12.0 mL 
5. The number of vials required for dose preparation:  
Number of vials = 12.0 (mL) / 10.0 (mL/vial) = 2 vials 
 


A phase II study of durvalumab in patients with mismatch repair deficient or POLE mutated metastatic colorectal cancer (ver. 1.7) 
 
DNA 복구 유전자 결핍 또는 POLE 유전자 돌연변이가 있는 전이성 대장암에서 durvalumab의 효능을 평가하는 2상 연구 (ver. 1.7)  85 
 
APPENDIX C. 
 
POLE 
After peer review (by a pathologist) of matched H&E slides for each of the FFPE tissues under the 
microscope, two to five 6 μm sections will be used for extraction of genomic DNA per FFPE tissue 
specimen, depending on tumor size and cellularity. After treatment with xylene and ethanol for de-
paraffinization, genomic DNA will be isolated using the NEXprep FFPE Tissue Kit (#NexK-9000; 
Geneslabs, Gyeonggi, Korea) in accordance with the manufacturer's recommendations. The tissue 
pellet will be completely lysed overnight at 56°C by incubation with proteinase K in lysis buffer, 
followed by an additional incubation for 3 min with magnetic beads and solution A at room 
temperature. After incubation for 5 min on the magnetic stand, the supernatant is removed, and 
then washed with ethanol three times. After the beads are dried for 5 min, DNA is eluted in 50 μL 
DNase-/RNase-free water, followed by quantification using the Quant-iT™ PicoGreen dsDNA Assay 
kit (Invitrogen Life Technologies). Exon 9 will be amplified with the following primers: 5′-
CTCCCTGTTGGTGATGAGGT-3′ (forward) and 5′-GGGTCCTTCTCCCAGCTCTA-3′ (reverse). The Sanger 
sequencing of all PCR products will be subsequently conducted on an ABI Prism 3730xl Genetic 
Analyzer (Life Technologies, Carlsbad, CA) for detecting POLE mutations. The representative hotspots 
for mutated POLE include P286R and V411L.