Conditions: Solid Tumor
Keywords: non-small cell lung cancer (NSCLC) urothelial cancer durvalumab long-term safety, efficacy overall survival immunotherapy checkpoint inhibitor PD-L1 retreatment Gastric adenocarcinoma
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 163
Healthy volunteers: no

Brief summary:
The aims of the study are to monitor the long-term safety of durvalumab, to provide continued treatment or retreatment with durvalumab to eligible patients, and to collect overall survival (OS) information.

Detailed description:
This is a multicenter, open-label, global study that will enroll patients who are currently receiving durvalumab monotherapy, or have previously received durvalumab as monotherapy or in combination with any other approved or investigational anticancer agents, in an eligible AstraZeneca/MedImmune-sponsored clinical study.

Arms:
arm 1: Durvalumab Monotherapy arm 2: Follow up Only

Interventions: intervention 1: Durvalumab
Intervention descriptions: intervention 1: IV infusion q4w with 1500mg durvalumab until progressive disease

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol – v4.0 
AstraZeneca 
Durvalumab-D910FC00001 
 
CONFIDENTIAL AND PROPRIETARY 
1 
 
 
 
Clinical Study Protocol  
 
Drug Substance 
Durvalumab 
 
Study Code 
D910FC00001 
 
Version 
4.0  
 
Date 
12 April 2022  
 
 
An Open-Label, Multi-Center, Global Study to Evaluate Long Term Safety 
and Efficacy in Patients Who are Receiving or Who Previously Received 
Durvalumab in Other Protocols (WAVE) 
 
Sponsor: AstraZeneca AB, 151 85 Södertälje, Sweden 
 
Regulatory Agency Identifying Number(s): EudraCT 2019-001402-20; IND 143828 
 








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TABLE OF CONTENTS 
VERSION HISTORY ............................................................................................. 2 
TABLE OF CONTENTS ........................................................................................ 5 
1.
PROTOCOL SUMMARY .................................................................................... 11 
1.1 
Schedule of activities............................................................................................. 12 
1.2 
Synopsis................................................................................................................. 22 
1.3 
Schema .................................................................................................................. 26 
2.
INTRODUCTION ................................................................................................. 27 
2.1 
Study rationale ....................................................................................................... 27 
2.2 
Background ........................................................................................................... 27 
2.2.1 
Immunotherapies ................................................................................................... 27 
2.2.2 
Durvalumab ........................................................................................................... 28 
2.3 
Benefit/risk assessment ......................................................................................... 30 
2.3.1 
Overall benefits ..................................................................................................... 30 
2.3.1.1 
Benefits of durvalumab as monotherapy ............................................................... 30 
2.3.2 
Overall risks .......................................................................................................... 30 
2.3.2.1 
Potential risks of durvalumab monotherapy .......................................................... 31 
3.
OBJECTIVES AND ENDPOINTS....................................................................... 32 
4.
STUDY DESIGN .................................................................................................. 32 
4.1 
Overall design........................................................................................................ 32 
4.2 
Scientific rationale for study design ...................................................................... 33 
4.2.1 
Rationale for retreatment option............................................................................ 33 
4.3 
Justification for dose ............................................................................................. 33 
4.3.1 
Durvalumab dose and treatment regimen justification .......................................... 33 
4.3.1.1 
Durvalumab monotherapy dose rationale .............................................................. 33 
4.3.1.2 
Rationale for fixed dosing ..................................................................................... 34 
4.3.1.3 
Rationale for duration of treatment ....................................................................... 35 
4.4 
End of study definition .......................................................................................... 35 
5.
STUDY POPULATION........................................................................................ 35 
5.1 
Inclusion criteria .................................................................................................... 36 
5.2 
Exclusion criteria ................................................................................................... 38 
5.3 
Lifestyle restrictions .............................................................................................. 41 
5.4 
Screen failures ....................................................................................................... 43 
6.
STUDY TREATMENTS ...................................................................................... 43 
6.1 
Treatments administered ....................................................................................... 43 
6.1.1 
Investigational product .......................................................................................... 43 


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6.1.1.1 
Durvalumab (MEDI4736) ..................................................................................... 44 
6.1.2 
Dose and treatment regimen .................................................................................. 45 
6.1.2.1 
Durvalumab (MEDI4736) monotherapy ............................................................... 45 
6.1.3 
Duration of treatment and criteria for treatment through progression and for 
retreatment ............................................................................................................. 46 
6.1.4 
Storage ................................................................................................................... 47 
6.2 
Measures to minimize bias: randomization and blinding ...................................... 47 
6.3 
Treatment compliance ........................................................................................... 48 
6.4 
Concomitant therapy ............................................................................................. 48 
6.4.1 
Other concomitant treatment ................................................................................. 50 
6.4.2 
Durvalumab drug-drug interactions ...................................................................... 50 
6.4.3 
Rescue medication ................................................................................................. 50 
6.5 
Dose modification ................................................................................................. 51 
6.6 
Treatment after the end of the study ...................................................................... 51 
7. 
DISCONTINUATION OF TREATMENT AND PATIENT WITHDRAWAL .. 52 
7.1 
Discontinuation of study treatment ....................................................................... 52 
7.1.1 
Procedures for discontinuation of study treatment ................................................ 52 
7.2 
Lost to follow-up ................................................................................................... 53 
7.3 
Withdrawal from the study .................................................................................... 54 
8. 
STUDY ASSESSMENTS AND PROCEDURES ................................................ 54 
8.1 
Safety assessments ................................................................................................ 55 
8.1.1 
Clinical safety laboratory assessments .................................................................. 56 
8.1.2 
Physical examinations ........................................................................................... 57 
8.1.3 
Vital signs .............................................................................................................. 58 
8.1.4 
Early patient review for safety for retreated patients ............................................ 58 
8.1.5 
WHO/ECOG performance status .......................................................................... 59 
8.1.6 
Other safety assessments ....................................................................................... 59 
8.2 
Efficacy assessments ............................................................................................. 60 
8.2.1 
Parent study assessments ....................................................................................... 60 
8.2.2 
Survival assessments ............................................................................................. 61 
8.2.3 
Clinical endpoint assessments ............................................................................... 61 
8.3 
Collection of adverse events .................................................................................. 62 
8.3.1 
Method of detecting AEs and SAEs ...................................................................... 62 
8.3.2 
Time period and frequency for collecting AE and SAE information .................... 62 
8.3.3 
Follow-up of AEs and SAEs ................................................................................. 63 
8.3.4 
Adverse event data collection ................................................................................ 63 
8.3.5 
Causality collection ............................................................................................... 64 
8.3.6 
Adverse events based on signs and symptoms ...................................................... 64 
8.3.7 
Adverse events based on examinations and tests .................................................. 65 
8.3.8 
Hy’s law ................................................................................................................ 65 
8.3.9 
Disease under study ............................................................................................... 65 


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8.3.10 
Disease progression ............................................................................................... 65 
8.3.11 
New cancers .......................................................................................................... 66 
8.3.12 
Deaths .................................................................................................................... 66 
8.3.13 
Adverse events of special interest ......................................................................... 66 
8.3.14 
Safety data to be collected following the final DCO of the study ......................... 68 
8.4 
Safety reporting and medical management ........................................................... 68 
8.4.1 
Reporting of serious adverse events ...................................................................... 68 
8.4.2 
Pregnancy .............................................................................................................. 69 
8.4.2.1 
Maternal exposure ................................................................................................. 69 
8.4.2.2 
Paternal exposure .................................................................................................. 69 
8.4.3 
Overdose ................................................................................................................ 70 
8.4.3.1 
Durvalumab ........................................................................................................... 70 
8.4.4 
Management of durvalumab-related toxicities ...................................................... 70 
8.4.4.1 
Specific toxicity management and dose modification information – 
Durvalumab ........................................................................................................... 71 
8.5 
Pharmacokinetics ................................................................................................... 72 
8.6 
Pharmacodynamics ................................................................................................ 72 
8.7 
Genetics ................................................................................................................. 72 
8.8 
Biomarkers ............................................................................................................ 72 
9. 
STATISTICAL CONSIDERATIONS .................................................................. 72 
9.1 
Sample size determination..................................................................................... 72 
9.2 
Populations for analyses ........................................................................................ 72 
9.3 
Statistical analyses ................................................................................................. 73 
9.3.1 
Safety analyses ...................................................................................................... 73 
9.3.2 
Efficacy analyses ................................................................................................... 73 
9.3.3 
Endpoint measures for analyses ............................................................................ 73 
9.3.3.1 
Calculation or derivation of safety variables ......................................................... 73 
9.3.3.2 
Investigator RECIST 1.1-based assessments ........................................................ 74 
9.3.3.3 
Objective response rate ......................................................................................... 74 
9.3.3.4 
Duration of response ............................................................................................. 74 
9.3.3.5 
Overall survival ..................................................................................................... 74 
9.4 
Interim analyses ..................................................................................................... 74 
9.4.1 
Data monitoring committee ................................................................................... 75 
10. 
REFERENCES ...................................................................................................... 76 
11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ............................................................................................ 79 
11.1 
Study management ................................................................................................ 79 
11.1.1 
Data entry/electronic data capture ......................................................................... 79 
11.1.2 
Source documents.................................................................................................. 79 
11.1.3 
File retention and archiving ................................................................................... 79 
11.1.4 
Quality assurance and monitoring ......................................................................... 80 


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11.1.5 
Data management .................................................................................................. 80 
11.1.6 
Changes to the protocol ......................................................................................... 80 
11.1.7 
Publication policy .................................................................................................. 81 
12. 
ETHICAL AND REGULATORY CONSIDERATIONS .................................... 81 
12.1 
Guiding principles ................................................................................................. 81 
12.2 
Required documents .............................................................................................. 81 
12.3 
Financial disclosure ............................................................................................... 82 
12.4 
Patient information and informed consent ............................................................ 82 
12.5 
Patient confidentiality ............................................................................................ 82 
12.6 
Independent ethics committee (IEC)/institutional review board (IRB) ................ 83 
 


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LIST OF TABLES 
Table 1 
Schedule of assessments for patients currently receiving treatment with 
durvalumab monotherapy (Cohort 1) .................................................................. 14 
Table 2 
Schedule of assessments for patients who completed treatment with 
durvalumab monotherapy or durvalumab in combination with any other 
approved or investigational anticancer agents, and are eligible for future 
retreatment (Cohort 2) ......................................................................................... 17 
Table 3 
Schedule of assessments for patients who previously received treatment with 
durvalumab monotherapy or durvalumab in combination with any other 
approved or investigational anticancer agents, and are not eligible for any 
future treatment (Cohort 3) .................................................................................. 20 
Table 4  Study objectives ................................................................................................... 32 
Table 5  Highly effective methods of contraception (<1% failure rate) ............................. 42 
Table 6  Study treatment ..................................................................................................... 44 
Table 7  Prohibited concomitant medications .................................................................... 49 
Table 8  Supportive medications ........................................................................................ 50 
Table 9  Clinical chemistry ................................................................................................. 56 
Table 10  Hematology .......................................................................................................... 57 
Table 11 Population for statistical analyses ........................................................................ 72 
Table 12  Summary of imaging modalities for tumor assessment ....................................... 94 
Table 13  Evaluation of target lesions .................................................................................. 98 
Table 14  Evaluation of non-target lesions ........................................................................... 99 
Table 15  Overall visit response ......................................................................................... 100 
 
LIST OF FIGURES 
Figure 1 Study design ......................................................................................................... 26 
Figure 2 Durvalumab monotherapy dosing schedule ......................................................... 46 
  


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LIST OF APPENDICES 
Appendix A Adverse Event Definitions and Additional Safety Information ................... 84 
Appendix B Actions Required in Cases of Increases in Liver Biochemistry and 
Evaluation of Hy’s Law ....................................................................................... 88 
Appendix C Guidelines for Evaluation of Objective Tumor Response Using RECIST 
1.1 Criteria (Response Evaluation Criteria in Solid Tumors) .............................. 93 
Appendix D Abbreviations .............................................................................................. 104 
 
 


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1.
PROTOCOL SUMMARY
This is a multicenter, open-label study that will enroll patients who are currently receiving 
durvalumab or have previously received durvalumab as monotherapy or in combination with 
other agents in an eligible AstraZeneca/MedImmune-sponsored clinical study (herein referred to 
as a parent clinical study). The aims of the study are to monitor the long-term safety of 
durvalumab, to provide continued treatment or retreatment with durvalumab to eligible patients, 
and to collect overall survival (OS) information. 
Patients in this study will be enrolled into one of 3 Cohorts: 
Cohort 1 includes patients who received durvalumab monotherapy or durvalumab combination 
therapy under the parent clinical study (including those undergoing retreatment per the parent 
study) who have not clinically progressed and who are eligible to continue durvalumab treatment 
after completing dosing of all other anticancer agents, including other investigational agents, 
which are a formal component of the parent study. If a patient was already retreated with 
durvalumab in the parent clinical study and has not progressed while on treatment, then they 
would be potentially eligible to enter Cohort 1; a combination treatment course initiated in the 
parent clinical study must be completed prior to study entry. All treatment cycle assessments will 
occur every 4 weeks (±3 days) until confirmed progressive disease (PD), unless unacceptable 
toxicity, withdrawal of consent, or another discontinuation criterion is met. Treatment beyond 
disease progression is allowed at the Investigator’s discretion, if it is in the patient’s best interest. 
The baseline imaging results from start of the parent clinical study will be used for baseline 
tumor assessments for Cohort 1. Follow-up tumor assessments will be performed according to 
the Investigator’s standard practice using Response Evaluation Criteria in Solid Tumors version 
1.1 (RECIST v1.1; at least every 12 weeks) (Table 1). Upon discontinuation of durvalumab, 
patients may receive any subsequent anticancer therapy at the discretion of the Investigator and 
will follow the schedule of activities (SoA) detailed for Cohort 3 for safety and survival follow-
up (Table 3).  
Cohort 2 includes patients who completed durvalumab monotherapy or in combination with any 
other approved or investigational anticancer agents in a parent study, without confirmed PD 
during the period of treatment, and who are potentially eligible for retreatment with durvalumab. 
The patient should not have received any other approved or investigational anticancer agents 
since completion of durvalumab treatment. Patients who completed the prespecified duration of 
treatment with durvalumab in a parent clinical study, who received clinical benefit and then 
subsequently experienced confirmed PD after completion of planned treatment, will be permitted 
to restart durvalumab treatment provided they meet the eligibility criteria. If a patient was 
already retreated with durvalumab in the parent clinical study and retreatment has ended, they 
are no longer eligible for retreatment in this study. In addition, intervening chemotherapy 
treatment will not be allowed before retreatment with durvalumab. Cohort 2 patients who will be 
eligible for future retreatment with durvalumab must agree to reconsenting to start retreatment 
and meet the eligibility criteria detailed in Sections 5.1 and 5.2. Patients who undergo 
retreatment will follow assessments as per the SoA for Cohort 1 until confirmed PD, unless 
unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met 
(Table 2). Only 1 course of retreatment is allowed (inclusive of any retreatment in the parent 


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clinical study). Treatment beyond disease progression is allowed at the Investigator’s discretion, 
if it is in the patient’s best interest. The baseline imaging results for Cohort 2 must be available 
within 28 days of retreatment. While on retreatment, follow-up tumor assessments will be 
performed according to the Investigator’s standard practice (at least every 12 weeks) using 
RECIST v1.1 (Table 1). Upon discontinuation of durvalumab, patients may receive any 
subsequent anticancer therapy at the discretion of the Investigator and will follow the SoA 
detailed for Cohort 3 for safety and survival follow-up (Table 3).  
Cohort 3 includes survival follow-up only for patients previously treated with durvalumab 
monotherapy or durvalumab in combination with any other approved or investigational 
anticancer agents who are no longer receiving durvalumab and are not eligible to receive 
retreatment. Safety assessments will be collected among the patients who are within 90 days 
since last dose of study drug in the parent study. The patients would undergo OS assessments as 
per the SoA (Table 3) and may receive any subsequent anticancer therapy at the discretion of the 
Investigator.  
For all cohorts, any assessments which are relevant to preservation of patient safety, as scheduled 
in the parent clinical study, will be conducted and followed up as per the SoA for this study. 
1.1 
Schedule of activities 
The SoA are based on Cohort entry type as part of the study design (Table 1 to Table 3).  
Patients in Cohort 1 and those going onto durvalumab retreatment in Cohort 2 will receive 
durvalumab monotherapy by infusion every 4 weeks on Day 1 of each cycle. For all patients 
treated with durvalumab, cycle assessments will be completed every 4 weeks (±3 days) until 
confirmed PD, unless unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met (Table 1 and Table 2). For the purposes of this study, “confirmed” PD is 
determined by the Investigator using RECIST v1.1 at least every 12 weeks while the patient 
remains on treatment according to standard clinical practice. There are no mandated 
confirmatory scans, unless the Investigator plans to treat the patient beyond PD. All assessments 
on treatment days are to be performed prior to durvalumab infusion, unless otherwise indicated. 
Prior to commencing infusion with durvalumab (within 3 days), the results for liver function 
tests, electrolytes, full blood count, and creatinine must be available and reviewed by the treating 
physician or Investigator. Patients will undergo various assessments for vital signs (including 
temperature, respiratory rate, blood pressure, body weight, and pulse), concomitant medication, 
laboratory, safety, adverse event/serious adverse event, and tumor assessments. Safety 
assessments will be performed according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events v5.0. Any assessments which are relevant to preservation of patient 
safety, as scheduled in the parent clinical study, will be conducted and followed up as per the 
SoA for this study. 
Upon discontinuation of durvalumab, for both Cohort 1 and among the patients who undergo 
retreatment in Cohort 2, follow-up will continue as per the SoA for Cohort 3 (Table 3). Only one 
course of retreatment is allowed (inclusive of any retreatment in the parent clinical study). 


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For patients receiving durvalumab monotherapy 
•
Patients may delay dosing under certain circumstances:
−
Dosing may be delayed per the Dosing Modification and Toxicity Management
Guidelines, due to either an immune or a non-immune-related AE (Annex 1).
−
If dosing must be delayed for reasons other than treatment-related toxicity, dosing
will resume as soon as feasible.
−
Subsequent time between 2 consecutive doses cannot be less than 21 days, based
on the half-lives of durvalumab (see current Investigator’s Brochure for
durvalumab).


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Table 1 
Schedule of assessments for patients currently receiving treatment with durvalumab monotherapy 
(Cohort 1) 
C1 
C2 
C3 
C4 
C5 onwardsa 
Week 
Baselineb/ 
Enrollment 
0 
Q4W ±3 days unless dosing needs to be held for toxicity 
reasons 
Day 
1 
Q28days ±3 days unless dosing needs to be held for toxicity 
reasons 
Informed consent 
Informed consentc 
X 
Eligibility criteriad 
X 
Study procedures 
Vital signse 
X 
X 
X 
X 
X 
X 
Physical examinationf 
X 
X 
X 
X 
X 
X 
WHO/ECOG performance status 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
Laboratory safety assessments 
Clinical chemistryg 
X 
X 
X 
X 
X 
X 
Hematologyg 
X 
X 
X 
X 
X 
X 
TSH (reflex free T3 or free T4)h 
X 
X 
X 
X 
X 
X 
Pregnancy testi 
X 
X 
X 
X 
X 
X 
Monitoring 
AE/SAE assessmentj 
X 
X 
X 
X 
X 
X 
Study drug administrationk 
Durvalumab (monotherapy)l 
X 
X 
X 
X 
X 


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C1 
C2 
C3 
C4 
C5 onwardsa 
Week 
Baselineb/ 
Enrollment 
0 
Q4W ±3 days unless dosing needs to be held for toxicity 
reasons 
Day 
1 
Q28days ±3 days unless dosing needs to be held for toxicity 
reasons 
Tumor assessment 
Tumor assessmentm 
Xn 
Assessment performed according to RECIST v1.1 as determined by the Investigator (at 
least every 12 weeks) until withdrawal of consent, progression or death. 
a.
Patients will continue their assigned treatment and all assessments Q4W (±3 days) until confirmed PD, unless unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met. Upon discontinuation of study drug, patients will follow the study assessments detailed in the follow-
up module (Section 7.1.1,Table 3).
b.
Baseline assessments may be performed over more than 1 visit if necessary. If laboratory or imaging procedures were performed for alternate reasons 
prior to signing the consent, these can be used for baseline assessment purposes with consent of the patient. However, all baseline laboratory 
assessments must be obtained within 3 days prior to Day 1 (first treatment visit). Baseline laboratory assessments performed within 3 days prior to Day 1 
do not need to be repeated at Day 1.
c.
Informed consent of study procedures may be obtained prior to enrollment, if necessary. Patients in Cohort 1 will sign the treatment ICF.
d.
Patient eligibility criteria specific to Cohort 1 that may require additional baseline assessments to be documented and/or performed are described in 
Sections 5.1 and 5.2.
e.
Vital signs include temperature, respiratory rate, BP, and pulse. Body weight is measured along with vital signs. Vital signs should be measured, 
collected/recorded in eCRF prior to the start of the infusion. Patients should be carefully monitored, and BP and other vital signs should be measured 
during and post infusion as per institution standard and as clinically indicated.
f.
Physical examination will include assessments of the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. Targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology. A physical examination should be performed 30 days (±3 days) after treatment 
discontinuation (Table 3). Situations in which physical examination results should be reported as AEs are described in Section 8.3.7.
g.
Serum or plasma chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated. Results for urea and 
electrolytes, full blood count, and liver function tests must be available before commencing an infusion.
h.
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
i.
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a 
pregnancy test within 7 days prior to the first dose of study drug and then every 4 weeks. Pregnancy test may occur on Day 1 of each cycle, but results 
must be available and reviewed by the treating physician or Investigator prior to commencing an infusion. A pregnancy test should also be performed 
30 days (±3 days) after treatment discontinuation (Table 3). Further pregnancy testing after 30 days of treatment discontinuation should be conducted as 
clinically indicated.
j.
For AEs and SAEs reported during the study, additional information such as concomitant medications will be needed. Medical history previously 
recorded in the parent clinical study will be made available in the present study and does not need to be collected. AE/SAE assessment will be 
performed according to CTCAE v5.0.


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k.
Patients will receive durvalumab monotherapy until confirmed PD. Section 6.6 details recommendations for patient management after the end of the 
study.
l.
Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the 
treating physician or Investigator prior to dosing.
m.
Disease progression during treatment should be confirmed by the Investigator according to RECIST v1.1 modified for confirmation of progression, as 
described in Appendix C.
n.
The baseline imaging results from the parent clinical study will be used for baseline tumor assessments for Cohort 1.
Note: All assessments on treatment days are to be performed prior to infusion, unless otherwise indicated.
Cohort 1 will move to SoA for Cohort 3 after durvalumab treatment ends.
AE adverse event; BP blood pressure; C Cycle; CTCAE v5.0 Common Terminology Criteria for Adverse Events version 5.0; ECOG Eastern Cooperative 
Oncology Group; eCRF electronic case report form; GI gastrointestinal; HBV hepatitis B virus; HCV hepatitis C virus; HIV human immunodeficiency virus; 
ICF informed consent form; LFT liver function test; PD progressive disease; Q28days every 28 days; Q4W every 4 weeks; RECIST v1.1 Response 
Evaluation Criteria in Solid Tumors version 1.1; SAE serious adverse event; SoA schedule of activities; SoC standard of care; T3 triiodothyronine; T4 
thyroxine; TSH thyroid-stimulating hormone; WHO World Health Organization.


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Table 2 
Schedule of assessments for patients who completed treatment with durvalumab monotherapy or 
durvalumab in combination with any other approved or investigational anticancer agents, and are eligible 
for future retreatment (Cohort 2) 
Follow-up before retreatment
Retreatment 
Time since the last dose of study 
druga
Long-term 
follow-up 
Baselineb/ 
C1 
C2 
C3 
C4 
C5 
onwardsc 
Week 
Baseline/ 
Enrollmenta
Day (±3 
days) 
Day 
(±7 days) 
Every 3 
months (±2 
weeks)
0 
Q4W ±3 days unless dosing needs to 
be held for toxicity reasons 
Day 
30 
60 
90 
1 
Q28days ±3 days unless dosing needs 
to be held for toxicity reasons 
Informed consent 
Informed consent 
Xd 
Xe 
Eligibility criteria 
Xd 
Xe 
Study procedures 
Vital signsf 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examinationg 
X 
X 
X 
X 
X 
X 
WHO/ECOG performance 
status 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
Laboratory safety 
assessments 
Clinical chemistryh 
X 
X 
X 
X 
X 
X 
X 
X 
Hematologyh 
X 
X 
X 
X 
X 
X 
X 
X 
TSH (reflex free T3 or free 
T4)i 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy testj 
X 
X 
X 
X 
X 
X 


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Follow-up before retreatment
Retreatment 
Time since the last dose of study 
druga
Long-term 
follow-up 
Baselineb/ 
C1 
C2 
C3 
C4 
C5 
onwardsc 
Week 
Baseline/ 
Enrollmenta
Day (±3 
days) 
Day 
(±7 days) 
Every 3 
months (±2 
weeks)
0 
Q4W ±3 days unless dosing needs to 
be held for toxicity reasons 
Day 
30 
60 
90 
1 
Q28days ±3 days unless dosing needs 
to be held for toxicity reasons 
Monitoring 
AE/SAE assessmentk 
X 
X 
X 
Throughout 
Survival statusl 
X 
Study drug administration 
Durvalumab (monotherapy)m 
X 
X 
X 
X 
X 
Tumor assessment 
Tumor assessmentn 
Assessment performed according to the Investigator’s 
standard practice until withdrawal of consent, progression or 
death. 
Xo 
Assessment performed according to 
RECIST v1.1 as determined by the 
Investigator (at least every 12 weeks) until 
withdrawal of consent, progression or death. 
a.
Follow-up visits are performed based on the duration since the last dose of study drug in either the parent clinical study or current study (whichever 
most recently administered the study drug). Patients who are more than 90 days beyond the last dose of study drug, will not undergo follow-up for AEs/
SAEs, vital signs, concomitant medications, or laboratory safety assessments; these patients will be followed for survival and undergo tumor 
assessment per Investigator’s standard practice.
b.
Baseline assessments may be performed over more than 1 visit if necessary. If laboratory or imaging procedures were performed for alternate reasons 
prior to signing the consent, these can be used for baseline assessment purposes with consent of the patient. However, all baseline laboratory 
assessments must be obtained within 3 days prior to Day 1 (first retreatment visit), and baseline imaging results must be obtained within 28 days prior 
to Day 1 of retreatment. Baseline laboratory assessments performed within 3 days prior to Day 1 do not need to be repeated at Day 1. Patients with 
documented HIV test results from the parent clinical study do not need to undergo a repeat test, but HBV and HCV must be retested within the 28-day 
period.
c.
Patients will continue their assigned treatment and all C5 assessments Q4W until confirmed PD, unless unacceptable toxicity, withdrawal of consent, or 
another discontinuation criterion is met. Upon discontinuation of study drug, patients will follow the study assessments detailed in the follow-up 
module (Section 7.1.1, Table 3). Section 6.6 details recommendations for patient management after the end of the study.
d.
Informed consent of study procedures may be obtained prior to enrollment, if necessary. Patients in Cohort 2 will sign the follow-up ICF while off 
treatment, and must meet the eligibility criteria detailed in Sections 5.1 and 5.2.
e.
Patients must agree to reconsenting (treatment ICF) to start retreatment and must meet the eligibility criteria detailed in Sections 5.1 and 5.2 prior to 
starting retreatment.


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f.
Vital signs include temperature, respiratory rate, BP, and pulse. Body weight is measured along with vital signs. Vital signs should be measured, 
collected/recorded in eCRF prior to the start of the infusion. Patients should be carefully monitored, and BP and other vital signs should be measured 
during and post infusion as per institution standard and as clinically indicated.
g.
Physical examination will include assessments of the head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, 
musculoskeletal, neurological, dermatological, hematologic/lymphatic, and endocrine systems. Targeted physical examinations are to be utilized by the 
Investigator on the basis of clinical observations and symptomatology. A physical examination should be performed 30 days (±3 days) after last dose of 
study drug and discontinuation of retreatment (Table 3). Situations in which physical examination results should be reported as AEs are described in 
Section 8.3.7.
h.
Serum or plasma chemistry, hematology, and/or LFT monitoring may be performed more frequently if clinically indicated. Results for urea and 
electrolytes, full blood count, and liver function tests must be available before commencing an infusion.
i.
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
j.
For women of childbearing potential only. A urine or serum pregnancy test is acceptable. Women of childbearing potential are required to have a 
pregnancy test within 7 days prior to the first dose of study drug and then every 4 weeks. Pregnancy test may occur on Day 1 of each cycle, but results 
must be available and reviewed by the treating physician or Investigator prior to commencing an infusion. A pregnancy test should also be performed 30 
days (±3 days) after last dose of study drug and discontinuation of retreatment (Table 3). Further pregnancy testing after 30 days of treatment 
discontinuation should be conducted as clinically indicated.
k.
For AEs and SAEs reported during the study, additional information such as concomitant medications will be needed. Medical history previously 
recorded in the parent clinical study will be made available in the study and does not need to be collected. AE/SAE assessment will be performed 
according to CTCAE v5.0.
l.
Upon completing the 90-day follow-up for AEs and SAEs, patients will be followed for survival. Survival follow-up will be performed by telephone call 
(or a prespecified preferred method of contact, as an alternative). Patients will be contacted by telephone in the week following data cut-offs to confirm 
survival status. No additional retreatment with durvalumab will be allowed.
m.
Results for LFTs, electrolytes, full blood count, and creatinine must be available before commencing an infusion (within 3 days) and reviewed by the 
treating physician or Investigator prior to dosing.
n.
Disease progression during treatment should be confirmed by the Investigator according to RECIST 1.1 modified for confirmation of progression, as 
described in Appendix C.
o.
The most recent imaging results from the parent clinical study may be used as the baseline assessment, provided it was obtained within 28 days prior to 
Day 1.
Note: Cohort 2 will move to SoA for Cohort 3 after retreatment with durvalumab ends. 
AE adverse event; BP blood pressure; C Cycle; CTCAE v5.0 Common Terminology Criteria for Adverse Events version 5.0; ECOG Eastern Cooperative 
Oncology Group; eCRF electronic case report form; GI gastrointestinal; HBV hepatitis B virus; HCV hepatitis C virus; HIV human immunodeficiency virus; 
ICF informed consent form; LFT liver function test; PD progressive disease; Q28days every 28 days; Q4W every 4 weeks; RECIST 1.1 Response 
Evaluation Criteria in Solid Tumors version 1.1; SAE serious adverse event; SoA schedule of activities; SoC standard of care; T3 triiodothyronine; T4 
thyroxine; TSH thyroid-stimulating hormone; WHO World Health Organization.  


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Table 3 
Schedule of assessments for patients who previously received treatment with durvalumab monotherapy or 
durvalumab in combination with any other approved or investigational anticancer agents, and are not eligible 
for any future treatment (Cohort 3) 
Time since the last dose of 
study druga 
Long-term follow-up 
Evaluation 
Baseline/ 
Enrollment 
Day (±3 
days) 
Day (±7 days) 
Every 3 months (±2 weeks) 
30 
60 
90 
Informed consent 
Informed consentb 
X 
Eligibility criteriab 
X 
Study procedures 
Vital signsc 
X 
X 
X 
Physical examinationd 
X 
Concomitant medications 
X 
X 
X 
Subsequent anticancer therapye 
X 
X 
X 
X 
X 
Laboratory safety assessments 
Clinical chemistry 
X 
X 
X 
Hematology 
X 
X 
X 
TSH (reflex free T3 or free T4)f 
X 
X 
X 
Pregnancy testg 
X 
Monitoring 
AE/SAE assessmenth 
X 
X 
X 
Survival statusi 
X 
Tumor Assessments 
Tumor assessmentj 
Assessment performed according to the Investigator’s standard practice until withdrawal of consent, 
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a.
Follow-up visits are performed based on the duration since the last dose of study drug in either the parent clinical study or current study (whichever 
most recently administered the study drug). Patients who are more than 90 days beyond the last dose of study drug will not undergo follow-up for AEs/
SAEs, vital signs, concomitant medications or laboratory safety assessments; these patients will be followed for survival.
b.
Informed consent of study procedures may be obtained prior to enrollment, if necessary. Patients in Cohort 3 will sign the follow-up ICF, and must meet 
the eligibility criteria detailed in Sections 5.1 and 5.2.
c.
Vital signs include temperature, respiratory rate, BP, and pulse. Body weight is measured along with vital signs.
d.
Physical examination should be performed 30 days (±3 days) after treatment discontinuation. A physical examination will include assessments of the 
head, eyes, ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological,
hematologic/lymphatic, and endocrine systems. Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology. Situations in which physical examination results should be reported as AEs are described in Section 8.3.7.
e.
Only the first subsequent anticancer therapy regimen used after durvalumab discontinuation will be collected.
f.
Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
g.
Pregnancy test should be performed 30 days (±3 days) after treatment discontinuation. Further pregnancy testing after 30 days of treatment 
discontinuation should be conducted as clinically indicated.
h.
For AEs and SAEs reported during the study, additional information such as concomitant medications will be needed. Medical history previously 
recorded in the parent clinical study will be made available in the study and does not need to be collected. AE/SAE assessment will be performed 
according to CTCAE v5.0.
i.
Upon completing the 90-day follow-up for AEs and SAEs, patients will be followed for survival. Survival follow-up will be performed by telephone call 
(or a prespecified preferred method of contact, as an alternative). Patients will be contacted by telephone in the week following data cut-offs to confirm 
survival status.
j.
Tumor assessment of best overall response to the first subsequent treatment after durvalumab, only (where evaluable). After that, tumor assessments 
will no longer be required for long-term follow-up.
Note: Following discontinuation of study drug, patients who decline to return to the site for evaluations should be contacted by telephone, or their prespecified 
preferred method of contact, as an alternative. 
AE adverse event; BP blood pressure; CTCAE v5.0 Common Terminology Criteria for Adverse Events version 5.0; PD progressive disease; SAE serious adverse 
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•
Cohort 2: includes patients who completed durvalumab monotherapy or in
combination with any other approved or investigational anticancer agents in a parent
study, without confirmed PD during the period of treatment, and who are potentially
eligible for retreatment with durvalumab. The patient should not have received any
other approved or investigational anticancer agents since completion of durvalumab
treatment. Patients who completed the prespecified duration of treatment with
durvalumab in a parent clinical study, who received clinical benefit and then
subsequently experienced confirmed PD after completion of planned treatment, will be
permitted to restart durvalumab treatment provided they meet the eligibility criteria. If
a patient was already retreated with durvalumab in the parent clinical study and
retreatment has ended, they are no longer eligible for retreatment in this study.
•
Cohort 3: includes patients previously treated with durvalumab monotherapy or in
combination with any other approved or investigational anticancer agents who are no
longer receiving durvalumab and are not eligible to receive retreatment.
In addition to providing continued treatment to eligible patients, the study will monitor long-term 
safety of durvalumab and OS (Cohorts 1 to 3).  
Study Period:  
Estimated date of first patient enrolled: Q3 2019 
Estimated date of last patient visit completed is Q4 2022. 
Number of patients: This study will enroll patients who have been previously treated with 
durvalumab and/or durvalumab in combination with any other approved or investigational 
anticancer agents at any global site. The study will enroll up to 600 patients. The number of 
patients is subject to change as new parent studies are included into this long-term safety and 
efficacy study. 
Treatment and treatment duration 
Patients in Cohort 1 and those going onto durvalumab retreatment in Cohort 2 will receive 
durvalumab monotherapy. Patients in Cohort 3 will not receive any study drug.  
Durvalumab monotherapy 
•
Durvalumab 1500 mg via intravenous (IV) infusion every 4 weeks until confirmed PD,
unless unacceptable toxicity, withdrawal of consent, death, or another discontinuation
criterion is met. Please note, if a patient’s weight falls to 30 kg or below (≤30 kg), then
the patient should receive weight-based dosing equivalent to 20 mg/kg of durvalumab
q4w after consultation between Investigator and Study Physician, until the weight
improves to above 30 kg (>30 kg).


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Duration of treatment 
Patients in Cohort 1 will continue to receive treatment with durvalumab until confirmed PD. This 
includes patients who received durvalumab monotherapy or combination therapy under the 
parent clinical study, and who are eligible to continue durvalumab treatment after completing 
dosing of any other approved or investigational anticancer agents, which are a formal component 
of the parent study. 
Continuation with durvalumab monotherapy (Cohort 1) and retreatment with durvalumab 
monotherapy (Cohort 2) will continue until confirmed PD, unless unacceptable toxicity, 
withdrawal of consent, death, or another discontinuation criterion is met. Patients will only be 
eligible for 1 course of retreatment (inclusive of any retreatment in the parent clinical study and 
this study). Patients will not be eligible to receive retreatment with any other approved or 
investigational anticancer agents administered in the parent clinical study. Disease progression 
will be determined by the Investigator following Response Evaluation Criteria in Solid Tumors 
version 1.1 (RECIST v1.1).  
Cohort 3 includes patients who have previously received durvalumab treatment or durvalumab 
combination therapy and are not eligible for future treatment. These patients will be followed for 
OS. 
Progression during treatment 
Patients receiving the study drug who experience disease progression and, in the Investigator’s 
opinion, continue to receive benefits from their assigned treatment; may continue to receive the 
study drug for as long as they meet specific clinical criteria, and are deriving clinical benefit in 
the opinion of the Investigator.  
For all patients who are treated through progression, the Investigator should ensure that patients 
still meet all the inclusion criteria and none of the exclusion criteria for this study, and obtain 
additional informed consent for continuation of treatment. This consent addendum document will 
be part of the treatment informed consent form (ICF); it will specify that treatment beyond initial 
evidence of PD is not the standard of care and that alternative treatment options, either locally 
licensed treatments or other clinical trials, are potentially available for this patient population. 
Patients with rapid tumor progression or with symptomatic progression that require medical 
intervention (eg, central nervous system metastasis, respiratory failure due to tumor compression, 
spinal cord compression) will not be eligible for continuing durvalumab.  
Follow up of patients post discontinuation of study drug 
Treatment is given until progression, unless there is unacceptable toxicity, withdrawal of 
consent, or another discontinuation criterion is met. Patients in Cohort 1 who discontinue 
durvalumab for any reason will not be eligible for further retreatment and will be followed 
subsequently for safety and survival. All patients in the study will be followed for safety for 
90 days after the last dose of durvalumab and for OS and may receive any subsequent anticancer 
therapy at the discretion of the Investigator. The details of first subsequent anticancer therapy 


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and overall best response after discontinuation of durvalumab treatment will be collected from 
the Investigator. 
Survival 
All patients in the study are followed up for survival every 3 months (±2 weeks) beginning 
90 days after the last dose of the study drug. Patients who enter Cohort 3 are in survival 
follow-up from the time of enrollment since no study drug is being administered to that cohort. 
Survival information may be obtained via telephone contact (or a prespecified preferred method 
of contact, as an alternative) with the patient or the patient’s family, or by contact with the 
patient’s current physician.  
Statistical methods and endpoints 
The primary objective is to monitor long-term safety of durvalumab. The safety analysis set will 
be used to summarize safety data according to the treatment received for all patients who 
received at least one dose of durvalumab. This analysis set would include patients continuing 
study treatment or retreatment, and those who enrolled in this study within 90 days of the last 
dose of durvalumab or durvalumab combination on the respective parent clinical study. Adverse 
events (AEs), vital signs and laboratory safety assessments (clinical chemistry, hematology and 
Thyroid-stimulating hormone [reflex free triiodothyronine or free thyroxine]) will be listed 
individually by patient. The number of patients experiencing each AE will be summarized by 
cohort and the National Cancer Institute Common Terminology Criteria for Adverse Events 
grade (v5.0) (Annex 1).  
The analysis set for assessment of efficacy will be based on patients who are retreated with 
durvalumab in Cohort 2. Efficacy analysis will be performed only if there is sufficient sample 
size; if so, data may be summarized by tumor type in each tumor type, otherwise, only listings 
will be provided as descriptive results. 
One secondary objective is to assess the efficacy of durvalumab in terms of ORR and DOR for 
durvalumab retreatment patients. ORR is defined as the number (%) of patients with at a 
confirmed response of complete response (CR) or partial response (PR). DOR is defined as the 
time from first documented of CR or PR until the time of first documented disease progression or 
death in the absence of disease progression since re-initiation of durvalumab treatment. Tumor 
assessments will be performed by computed tomography scans per standard practice (at least 
every 12 weeks). Tumor assessments will be performed by the Investigator according to RECIST 
v1.1; only the response outcomes will be collected in the case report form.  
The OS is defined as the time from date of randomization/enrollment in the parent clinical study 
until the date of death by any cause. A listing of OS data will be provided for all study patients.  
In addition, OS and tumor efficacy data in this study may be combined with the parent study data 
for integrated analysis.  
No statistical methods will be employed to test a specific hypothesis in this study. In addition to 
the 5 planned interim analyses, ad hoc analyses may be performed at various time points in order 


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to support publications, internal decision making by AstraZeneca, and/or regulatory submissions 
as appropriate.  
Sample size estimate
The number of patients enrolled in this study will be determined by the number of patients who 
received durvalumab and/or durvalumab in combination with any other approved or 
investigational anticancer agents in original trials, and who wish to participate, and who meet the 
eligibility criteria. The study will enroll up to 600 patients and the number of patients may 
change as new parent studies are included into this long-term safety and efficacy study.
1.3
Schema
The general study design for this study is summarized in Figure 1.  
Figure 1 
Study design
SD stable disease.


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2.
INTRODUCTION
2.1 
Study rationale
This is a multicenter, open-label, global study that will enroll patients who are currently 
receiving durvalumab monotherapy, or have previously received durvalumab as monotherapy or 
in combination with any other approved or investigational anticancer agents, in an eligible 
AstraZeneca/MedImmune-sponsored clinical study (herein referred to as a parent clinical study). 
The aims of the study are the following: 
•
To collect long-term safety and survival data from patients who received durvalumab
monotherapy and/or durvalumab in combination with any other approved or
investigational anticancer agents.
•
To provide continued access to durvalumab monotherapy until confirmed progressive
disease (PD) to patients currently receiving treatment.
•
To allow for future retreatment with durvalumab monotherapy upon disease
progression in patients who previously benefited from treatment with durvalumab as
monotherapy, and/or durvalumab in combination with any other approved or
investigational anticancer agents and experienced disease progression after completion
of planned treatment.
The primary aim of this study is to monitor the long-term safety of durvalumab. Extensive 
safety-related data are being collected throughout the course of drug development, and 
knowledge about a drug’s safety profile continually evolves as safety data accumulate. This 
study is aligned with the growing interest in larger, simpler trials to obtain outcome data, 
including long-term effects of drugs and comparative effectiveness and safety. 
2.2 
Background 
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab is 
provided in the Investigator’s Brochure (IB). 
2.2.1 
Immunotherapies 
It is increasingly understood that cancers are recognized by the immune system, and under some 
circumstances, the immune system may control or even eliminate tumors (Dunn et al 2004).  
Programmed death ligand 1 (PD-L1) is part of a complex system of receptors and ligands that are 
involved in controlling T cell activation. The programmed cell death protein 1 (PD-1) receptor 
(CD279) is expressed on the surface of activated T cells (Keir et al 2008). It has 2 known 
ligands: PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273) (Okazaki and Honjo 2007). PD-1 
and PD-L1/PD-L2 belong to a family of immune checkpoint proteins that act as co-inhibitory 
factors, which can halt or limit the development of T cell response. When PD-L1 binds to PD-1, 
an inhibitory signal is transmitted into the T cell, which reduces cytokine production and 


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suppresses T cell proliferation. Tumor cells exploit this immune checkpoint pathway as a 
mechanism to evade detection and inhibit immune response. 
PD-L1 is constitutively expressed by B-cells, dendritic cells, and macrophages (Qin et al 2016). 
Importantly, PD-L1 is commonly over-expressed on tumor cells or on non-transformed cells in 
the tumor microenvironment (Pardoll 2012). PD-L1 expressed on the tumor cells binds to PD-1 
receptors on the activated T cells, leading to the inhibition of cytotoxic T cells. These deactivated 
T cells remain inhibited in the tumor microenvironment. The PD-1/PD-L1 pathway represents an 
adaptive immune resistance mechanism that is exerted by tumor cells in response to endogenous 
antitumor activity. 
The inhibitory mechanism described above is co-opted by tumors that express PD-L1 as a way of 
evading immune detection and elimination. The binding of an anti-PD-L1 agent to the PD-L1 
receptor inhibits the interaction of PD-L1 with the PD-1 and CD80 receptors expressed on 
immune cells (IC). This activity overcomes PD-L1-mediated inhibition of antitumor immunity. 
While functional blockade of PD-L1 results in T cell reactivation, this mechanism of action 
(MOA) is different from direct agonism of a stimulatory receptor such as CD28. 
PD-L1 is expressed in a broad range of cancers. Based on these findings, an anti-PD-L1 antibody 
could be used therapeutically to enhance antitumor immune responses in patients with cancer. 
Results of preclinical and clinical studies of monoclonal antibodies (mAbs) targeting the 
PD-L1/PD-1 pathway have shown evidence of clinical activity and a manageable safety profile, 
supporting the hypothesis that an anti-PD-L1 antibody could be used to therapeutically enhance 
antitumor immune response in cancer patients (Brahmer et al 2012, Hirano et al 2005, 
Iwai et al 2002, Okudaira et al 2009, Topalian et al 2012, Zhang et al 2008) with responses that 
tend to be more pronounced in patients with tumors that express PD-L1 (Powles et al 2014,  
Rizvi et al 2015, Segal et al 2015). In addition, high mutational burden (eg, in bladder 
carcinoma; Alexandrov et al 2013) may contribute to the responses seen with immune therapy. 
Preclinical data has now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T cells such as cytotoxic T-lymphocyte-associated antigen-4 
(CTLA-4) and PD-L1 has promising clinical activity. Ipilimumab was first granted United States 
(US) Food and Drug Administration (FDA) approval for the treatment of metastatic melanoma 
and is currently under investigation for several other malignancies. Nivolumab and 
pembrolizumab, 2 anti-PD-1 agents, and atezolizumab, an anti-PD-L1 agent, have been granted 
approvals by agencies for the treatment of a number of malignancies, including metastatic 
melanoma, squamous and non-squamous cell non-small cell lung cancer (NSCLC), squamous 
cell carcinoma of the head and neck, and urothelial carcinoma. In addition, there are data from 
agents in the anti-PD-1/PD-L1 class showing clinical activity in a wide range of tumor types. 
2.2.2 
Durvalumab 
Durvalumab is a human mAb of the immunoglobulin G (IgG) 1 kappa subclass that blocks the 
interaction of PD-L1 (but not programmed cell death ligand-2) with PD-1 on T cells and CD80 
(B7.1) on IC. It is being developed by AstraZeneca/MedImmune, for use in the treatment of 
cancer. (MedImmune is a wholly owned subsidiary of AstraZeneca; AstraZeneca/MedImmune 
will be referred to as AstraZeneca throughout this document.) The propose MOA for durvalumab 




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2.3 
Benefit/risk assessment 
More detailed information about the known and expected benefits and risks, and reasonably 
expected adverse events (AEs) of durvalumab may be found in the IB. 
2.3.1 
Overall benefits 
As is commonly the case for clinical trials with a fixed treatment or study duration, long-term 
safety and efficacy endpoints often lack feasibility within the time frame permitted by design. 
The benefit of this study, which identifies potentially eligible patients from parent clinical 
studies, allows for the continued access of durvalumab and observation of patients treated with 
durvalumab. Durvalumab will be provided to eligible, treatment-experienced patients who have 
been treated for months under parent clinical studies and have demonstrated a response and 
tolerability to treatment. They will be treated as long as they continue to receive benefit for 
treatment with durvalumab. 
Conducting this study serves the important purpose to better understand the long-term patient 
safety and survival outcomes across a diverse group of patient population exposed to 
durvalumab.  
2.3.1.1 
Benefits of durvalumab as monotherapy 
The majority of the safety and efficacy data currently available for durvalumab are based on 
5 monotherapy studies (CD-ON-MEDI47361108, ATLANTIC, HAWK, PACIFIC, and 
D4190C00007) for which efficacy data are available. Data from these studies have demonstrated 
clinical activity of durvalumab therapy in patients with NSCLC. PACIFIC has shown significant 
improvements in median progression-free survival with durvalumab treatment compared with 
placebo for patients with NSCLC (16.8 months [95% confidence interval {CI}: 13.0, 18.1] 
versus 5.6 months [95% CI: 4.6, 7.8]; stratified hazard ratio for disease progression or death, 
0.52; 95% CI: 0.42, 0.65; p<0.001). Similar findings in favor of durvalumab compared with 
placebo were found for duration of response (DOR; 72.8% versus 46.8% of patients had ongoing 
response at 18 months, respectively) and median time to death or distant metastasis (23.2 months 
versus 14.6 months, respectively; p<0.001). 
2.3.2 
Overall risks 
Monoclonal antibodies directed against immune checkpoint proteins, such as PD-L1 as well as 
those directed against PD-1 or CTLA-4, aim to boost endogenous immune responses directed 
against tumor cells. By stimulating the immune system, however, there is the potential for 
adverse effects on normal tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and that may 
require more frequent monitoring and/or unique interventions, such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ system 
and are most commonly seen as gastrointestinal (GI) AEs such as colitis and diarrhea, 


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pneumonitis/interstitial lung disease (ILD), hepatic AEs such as liver enzyme elevations, skin 
events such as rash and dermatitis, and endocrinopathies including hypo- and hyperthyroidism. 
2.3.2.1 
Potential risks of durvalumab monotherapy 
Risks with durvalumab include, but are not limited to, diarrhea/colitis, pneumonitis/ILD, 
endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, hyper- and 
hypothyroidism, and type I diabetes mellitus [DM]), hepatitis/increases in transaminases, 
nephritis/increases in creatinine, pancreatitis/increases in amylase and lipase, rash/dermatitis, 
myocarditis, myositis/polymyositis, other rare or less frequent inflammatory events including 
neuromuscular toxicities, infusion-related reactions, hypersensitivity reactions, and 
infections/serious infections. 
For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB. 
In monotherapy clinical studies, AEs reported an incidence of ≥20%, this included events such as 
fatigue, cough, decreased appetite, dyspnea, and nausea. A total of 5% to 10% of patients 
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 Grade 3 to 5 events reported across the durvalumab program. 
The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated toxicity (see Section 8.4.4). 
A detailed summary of durvalumab monotherapy AE data can be found in the current version of 
the durvalumab IB. 


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3.
OBJECTIVES AND ENDPOINTS
The objectives and endpoints for this study are listed in Table 4. 
Table 4  
Study objectives 
Primary Objective: 
Endpoints/Variables: 
To monitor long-term safety of durvalumab (all 
cohorts) 
•
All SAEs
•
Non-serious AEs that lead to dose modification,
drug discontinuation, or withdrawal from the
study
•
All Grade 3 and Grade 4 AEs
•
Grade 2 AEs that affect vital organs (eg, heart,
liver)
•
Immune-mediated AEs
•
Laboratory findings qualifying as an SAE/AE
(endpoints defined above) up until 90 days after
the last dose of durvalumab in all patients
Secondary Objectives: 
Endpoints/Variables: 
To assess the efficacy of durvalumab in terms 
of ORR and DOR in patients who undergo 
retreatment with durvalumab (Cohort 2 only)a 
• ORR: Number (%) of patients with a confirmed
response of CR or PR.
• DOR: Time from first documented CR or PR to
time of first documented disease progression or
death in the absence of disease progression
To assess the OS of patients (all cohorts) 
• OS: Time from date of
randomization/enrollment in the parent clinical
study until the date of death by any cause
AE adverse event; CR complete response; DOR duration of response; ORR overall response rate; OS overall 
survival; PR partial response; SAE serious adverse event. 
a.
To be performed only if there is sufficient sample size in retreated Cohort 2 patients to evaluate efficacy;
otherwise, only listings will be provided for this objective (Section 6.6)
4.
STUDY DESIGN
4.1 
Overall design
This is a multicenter, open-label, global study that will enroll patients who are currently 
receiving durvalumab monotherapy, or have previously received durvalumab as monotherapy or 
in combination with any other approved or investigational anticancer agents, in an eligible parent 
clinical study. The study aims to enroll up to 600 patients; study size may increase as new parent 
clinical studies are incorporated into this study. Some of these patients will no longer be eligible 
to receive treatment or retreatment with durvalumab, and will be followed for overall survival 


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(OS). For patients who are eligible to continue treatment or restart durvalumab, treatment will be 
administered every 4 weeks (q4w; ±3 days) until PD, unless there is unacceptable toxicity, 
withdrawal of consent, death, or another discontinuation criterion is met. All patients in the study 
will be followed for safety for 90 days after the last dose of durvalumab, and every 3 months (±2 
weeks) beginning 90 days after the last dose of study drug for OS. For an overview of the study 
design, see Section 1.3. For details on treatments given during the study, see Section 6.1. Upon 
discontinuation of durvalumab, patients may receive any subsequent anticancer therapy at the 
discretion of the Investigator (Section 7.1). 
4.2 
Scientific rationale for study design 
4.2.1 
Rationale for retreatment option 
In contrast to patients treated with chemotherapy, who are unlikely to respond to re-challenge 
with the same agent upon progression, responses have been observed upon retreatment with 
immunotherapies. Several potential mechanisms of resistance to immunotherapy exist, including 
loss of T cell “memory” or recurrence of immune escape, which suggests that retreatment for 
patients who initially respond or demonstrate SD is reasonable. Preliminary data in patients 
previously treated with immunotherapies suggest that responses are similar to those observed 
following initial treatment (Forde et al 2014, Hodi et al 2010).  
Durvalumab has been administered IV in multiple clinical studies up to 12 months. After the 
completion of therapy in these ongoing clinical studies, patients are followed with regular tumor 
assessments to continue monitoring the clinical activity of durvalumab. Emerging data from 
these ongoing studies suggest that some patients lose clinical benefit after completing 12 months 
of therapy.  
4.3 
Justification for dose 
4.3.1 
Durvalumab dose and treatment regimen justification 
4.3.1.1 
Durvalumab monotherapy dose rationale 
A durvalumab dose of 20 mg/kg q4w is supported by in vitro data, preclinical activity, clinical 
PK/pharmacodynamics, biomarkers, and activity data from Study CD-ON-MEDI4736-1108 
(hereafter referred to as Study 1108) in patients with advanced solid tumors and from a Phase I 
study performed in Japanese patients with advanced solid tumor (D4190C00002). 
Pharmacokinetic/Pharmacodynamic data 
Based on available PK/pharmacodynamic data from ongoing Study 1108 with dose ranging from 
0.1 to 10 mg/kg every 2 weeks (q2w) or 15 mg/kg every 3 weeks (q3w), durvalumab exhibited 
nonlinear (dose-dependent) PK consistent with target-mediated drug disposition. The PK 
approached linearity at ≥3 mg/kg q2w, suggesting near complete target saturation (membrane-
bound and soluble PD-L1), and further showed that the durvalumab dosing frequency can be 
adapted to a particular regimen given the linearity seen at doses higher than 3 mg/kg. The 
expected half-life with doses ≥3 mg/kg q2w is approximately 21 days. A dose-dependent 


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suppression in peripheral soluble PD-L1 was observed over the dose range studied, consistent 
with engagement of durvalumab with PD-L1. A low level of immunogenicity has been observed. 
No patients have experienced immune-complex disease following exposure to durvalumab. (For 
further information on immunogenicity, please see the current durvalumab IB.)  
A population PK model was developed using the data from Study 1108 (doses=0.1 to 10 mg/kg 
q2w or 15 mg/kg q3w; Fairman et al 2014). Multiple simulations indicate that a similar overall 
exposure is expected following both 10 mg/kg q2w and 20 mg/kg q4w regimens, as represented 
by AUCss (4 weeks). Median Cmax,ss is expected to be higher with 20 mg/kg q4w (~1.5 fold) and 
median Ctrough,ss is expected to be higher with 10 mg/kg q2w (~1.25 fold). Clinical activity with 
the 20 mg/kg q4w dosing regimen is anticipated to be consistent with 10 mg/kg q2w with the 
proposed similar dose of 20 mg/kg q4w expected to (a) achieve complete target saturation in the 
majority of patients; (b) account for anticipated variability in PK, pharmacodynamics, and 
clinical activity in diverse cancer populations; (c) maintain sufficient PK exposure in case of 
antidrug antibodies impact; and (d) achieve PK exposure that yielded maximal antitumor activity 
in animal models. 
Given the similar area under the serum drug concentration-time curve and modest differences in 
median peak and trough levels at steady state, the observation that both regimens maintain 
complete soluble PD-L1 suppression at trough, and the available clinical data, the 20 mg/kg q4w 
and 10 mg/kg q2w regimens are expected to have similar efficacy and safety profiles, supporting 
further development with a dose of 20 mg/kg q4w.  
Clinical data 
Refer to the current durvalumab IB for a complete summary of clinical information including 
safety, efficacy, and PK at the 20 mg/kg q4w regimen. The IB reflects the current regimen that is 
used across the program when durvalumab monotherapy is dosed q4w. 
4.3.1.2 
Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from 
Study 1108 (N=292; doses=0.1 to 10 mg/kg q2w or 15 mg/kg q3w; solid tumors). Population PK 
analysis indicated only a minor impact of body weight (WT) on the PK of durvalumab 
(coefficient of ≤0.5). The impact of body weight (WT)-based (10 mg/kg q2w) and fixed dosing 
(750 mg q2w) of durvalumab was evaluated by comparing predicted steady state PK 
concentrations (5th, median, and 95th percentiles) using the population PK model. A fixed dose of 
750 mg was selected to approximate 10 mg/kg (based on median body WT of ~75 kg). A total of 
1000 patients were simulated using body WT distribution of 40 to 120 kg. Simulation results 
demonstrate that body WT-based and fixed dosing regimens yield similar median steady state 
PK concentrations with slightly less overall between-patient variability with fixed dosing 
regimen.  
Similar findings have been reported by others (Narwal et al 2013, Ng et al 2006, 
Wang et al 2009, Zhang et al 2012). Wang and colleagues investigated 12 mAbs and found that 
fixed and body weight-based dosing perform similarly, with fixed dosing being better for 7 of 12 
antibodies (Wang et al 2009). In addition, they investigated 18 therapeutic proteins and 


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peptides, and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
between-patient variability in PK/pharmacodynamic parameters (Zhang et al 2012).  
A fixed dosing approach is preferred by the prescribing community, due to ease of use and 
reduced dosing errors. Given the expectation of similar PK exposure and variability, 
AstraZeneca 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. 
4.3.1.3 
Rationale for duration of treatment 
In this study, the duration of treatment was selected to allow eligible patients to continue 
treatment with durvalumab monotherapy until confirmed PD. Additionally, patients who 
completed the defined duration of treatment with durvalumab or durvalumab plus any other 
approved or investigational anticancer agents in a parent clinical study and subsequently 
experienced confirmed PD, will be permitted to start retreatment with durvalumab monotherapy, 
if they meet eligibility criteria. 
4.4 
End of study definition 
The end of study is expected to occur in Q4 2022 and is defined as the date of the last scheduled 
visit of the last participant in the study at the time of the final data cut-off (DCO).  
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last scheduled visit shown in the SoA at the end of study. 
Any patients in Cohort 2 or Cohort 3 not receiving treatment will discontinue further follow-up 
at the end of study.  
For patients receiving treatment in Cohort 1 or 2, refer to Section 6.6 & 8.3.14 which details 
recommendations for patient management following study completion. 
5.
STUDY POPULATION
The study population will consist of patients who are currently receiving or have previously 
received durvalumab monotherapy or durvalumab in combination with any other approved or 
investigational anticancer agents, in a parent clinical study. Patients enrolled on a control arm in 
a parent study are not eligible.  
At enrollment, informed consent to participate in the study will be obtained from all patients, and 
eligible patients will be enrolled in Cohorts 1, 2 or 3, according to their treatment status. There 
are 2 consent forms that will be signed by the patient based on whether the patient is on 
treatment or starting retreatment (treatment informed consent form [ICF]) or off treatment 
(follow-up ICF). All patients in Cohort 1 must sign the treatment ICF. The follow-up ICF will be 
used for patients who enroll in Cohort 3. Cohort 2 patients who will be eligible for future 
retreatment with durvalumab must sign the follow-up ICF at enrollment, then must agree to 


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reconsenting under the treatment ICF to start retreatment, and must meet the eligibility 
criteria detailed in Sections 5.1 and 5.2.  
•
Cohort 1: includes patients who received durvalumab monotherapy or durvalumab
combination therapy under the parent clinical study (including those undergoing
retreatment per the parent study) who have not clinically progressed and who are
eligible to continue durvalumab treatment after completing dosing of all other
anticancer agents, including other investigational agents, which are a formal
component of the parent study. If a patient was already retreated with durvalumab in
the parent clinical study and has not progressed while on treatment, then they would be
potentially eligible to enter Cohort 1; a combination treatment course initiated in the
parent clinical study must be completed prior to study entry.
•
Cohort 2: includes patients who completed durvalumab monotherapy or in
combination with any other approved or investigational anticancer agents in a parent
study, without confirmed PD during the period of treatment, and who are potentially
eligible for retreatment with durvalumab. The patient should not have received any
other approved or investigational anticancer agents since completion of durvalumab
treatment. Patients who completed the prespecified duration of treatment with
durvalumab in a parent clinical study, who received clinical benefit and then
subsequently experienced confirmed PD after completion of planned treatment, will be
permitted to restart durvalumab treatment provided they meet the eligibility criteria. If
a patient was already retreated with durvalumab in the parent clinical study and
retreatment has ended, they are no longer eligible for retreatment in this study.
•
Cohort 3: includes patients previously treated with durvalumab monotherapy or in
combination with any other approved or investigational anticancer agents who are no
longer receiving durvalumab and are not eligible to receive retreatment.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this 
study, to be assigned to a study cohort. Under no circumstances can there be exceptions to this 
rule. Patients who do not meet the entry requirements are screen failures, refer to Section 5.4. 
For procedures for withdrawal of incorrectly enrolled patients see Section 7.3. 
5.1 
Inclusion criteria 
Patients are eligible to be included in the study only if all of the following inclusion criteria and 
none of the exclusion criteria apply: 
General inclusion criteria for all patients: 
1.
Patient must be 18 years or older, at the time of signing the ICF. For subjects aged <20
years and enrolled in Japan, a written ICF should be obtained from the subject and his


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or her legally acceptable representative. 
2.
Patient received durvalumab monotherapy and/or durvalumab containing combination
in an AstraZeneca/MedImmune-sponsored parent clinical study that is approved for
enrollment into this study.
3.
Patients who received durvalumab in combination with any other approved or
investigational anticancer agents in the parent clinical study must have completed or
discontinued all other anticancer therapy (beyond durvalumab regimen).
4.
Patient must be willing and able to provide written informed consent and to comply
with scheduled visits and other study procedures.
Additional inclusion criteria for patients entering Cohort 1: 
5.
Currently receiving durvalumab monotherapy (this includes patients enrolled in
durvalumab combinations who have completed or discontinued all other anticancer
therapy combined with durvalumab in the parent clinical study, and are now receiving
durvalumab monotherapy), and is currently benefiting from treatment with
durvalumab therapy, as determined by the Investigator.
Additional inclusion criteria for patients entering Cohort 1 and Cohort 2: 
6.
Adequate organ function as defined below:
(a) Serum bilirubin ≤1.5 × the upper limit of normal (ULN). This will not apply to
patients with confirmed Gilbert’s syndrome, who will be allowed in consultation
with their physician.
(b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤2.5 × ULN; for patients with hepatic metastases, ALT and AST ≤5 × ULN.
(c) Measured creatinine clearance (CL) >40 mL/min or calculated CL >40 mL/min as
determined by Cockcroft-Gault (using actual body WT)
   Males: 
Creatinine CL = Weight (kg) × (140 – Age) 
(mL/min) 
      72 × serum creatinine (mg/dL) 
Females: 
Creatinine CL = Weight (kg) × (140 – Age) 
 × 0.85 
(mL/min) 
      72 × serum creatinine (mg/dL) 
7.
Evidence of postmenopausal status or negative urinary or serum pregnancy test for
female premenopausal patients. Women will be considered postmenopausal if they
have been amenorrheic for 12 months without an alternative medical cause. The
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(a) Women <50 years of age would be considered postmenopausal 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 postmenopausal range for the institution.
(b) Women ≥50 years of age would be considered postmenopausal 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.
(c) Women who are surgically sterile (eg, bilateral salpingectomy, bilateral
oophorectomy, or complete hysterectomy) are eligible.
8.
World Health Organization (WHO)/Eastern Cooperative Oncology Group (ECOG)
performance status (PS) of ≤2 at enrollment
Additional inclusion criteria for retreatment patients in Cohort 2 
9.
Received durvalumab in a parent clinical study that is approved to enroll into this
study.
10.
Completed the defined treatment duration with durvalumab monotherapy or
durvalumab combination therapy in the parent clinical study, as defined below:
(a) Previously benefited from treatment with durvalumab monotherapy or
durvalumab combination therapy, as determined by the Investigator.
(b) Has not previously received retreatment with durvalumab monotherapy.
(c) Maintained SD or better (Response Evaluation Criteria in Solid Tumors
version 1.1 [RECIST v1.1]) throughout the period of defined treatment duration,
and has not received any subsequent anticancer therapy.
11.
At least 1 lesion that can be accurately measured at baseline as ≥10 mm in the longest
diameter (except lymph nodes which must have a short axis ≥15 mm) with computed
tomography (CT) or magnetic resonance imaging (MRI), and that is suitable for
accurate repeated measurements as per RECIST v1.1 guidelines.
5.2 
Exclusion criteria
Patients must not enter the study if any of the following key exclusion criteria are fulfilled: 
1.
Involvement in the planning and/or conduct of the study (applies to both AstraZeneca
staff and/or staff at the study site).
Additional exclusion criteria for Cohort 1 and Cohort 2: 
2.
Currently receiving treatment in another interventional clinical study other than a
parent clinical study, or received treatment during the follow-up period before
retreatment (Cohort 2 only).


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3.
Experienced an immune-mediated or non-immune-mediated (hematologic and
non-hematologic) toxicity that led to permanent discontinuation of durvalumab in the
parent clinical study.
4.
Any unresolved toxicity National Cancer Institute (NCI) Common Terminology
Criteria for Adverse Events (CTCAE) Grade ≥2 from previous anticancer therapy with
the exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
criteria.
5.
Prior treatment with immunotherapy other than durvalumab, or any other approved or
investigational anticancer agents other than MedImmune/AstraZeneca’s
investigational immunotherapy molecules administered in the parent clinical study.
6.
Any concurrent chemotherapy, investigational product (IP), biologic or hormonal
therapy for cancer treatment. Concurrent use of hormonal therapy for
non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
7.
Active or prior documented autoimmune or inflammatory disorders (including
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or
Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, rheumatoid
arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this criterion:
(a) Patients with vitiligo or alopecia.
(b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on
hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Patients without active disease in the last 5 years may be included but only after
consultation with the Study Physician.
(e) Patients with celiac disease controlled by diet alone.
8.
History of allogenic organ transplantation.
9.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active
infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
angina pectoris, uncontrolled cardiac arrhythmia, active ILD, serious chronic GI
conditions associated with diarrhea, or psychiatric illness/social situations that would
limit compliance with study requirement, substantially increase risk of incurring AEs
or compromise the ability of the patient to give written informed consent.
10.
Documented active infection including tuberculosis (clinical evaluation that includes
clinical history, physical examination and radiographic findings, and tuberculosis
testing in line with local practice), hepatitis B virus (HBV) (known positive HBV
surface antigen [HbsAg] result), hepatitis C virus (HCV), or human immunodeficiency
virus (HIV) (positive HIV 1/2 antibodies). Patients with a past or resolved HBV
infection (defined as the presence of hepatitis B core antibody and absence of HbsAg)
are eligible. Patients positive for HCV antibody are eligible only if polymerase chain
reaction is negative for HCV RNA. Prior HIV and HBV/HCV testing from the parent


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clinical study is acceptable documentation and patients will not need to undergo an 
additional testing prior to Cohort 1 enrollment in this study. For Cohort 2 patients, 
prior HIV testing from the parent clinical study is acceptable documentation and 
patients will not need to undergo an additional test prior to retreatment. However, 
patients will require retesting for HbsAg and HCV within the 28-day window prior to 
retreatment. 
11.
Receipt of live attenuated vaccine within 30 days prior to the first dose of study drug
in the present study. Note: Patients, if enrolled, should not receive live vaccine while
receiving study drug and up to 90 days after the last dose of study drug.
12.
Female patients who are pregnant or breastfeeding, or male or female patients of
reproductive potential who are not willing to employ effective birth control from
screening to 90 days after the last dose of durvalumab monotherapy or 180 days after
the last dose of durvalumab + tremelimumab combination.
−
Highly effective methods of contraception are defined as one that results in a low
failure rate (eg, less than 1% per year) when used consistently and correctly. 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).
−
For patients randomized to receive SoC treatment in parent protocols, follow the
local prescribing information relating to contraception, the time limit for such
precautions, and any additional restrictions for agents in the SoC treatment
regimen.
13.
Diagnosis of a new primary malignancy since enrollment into the parent clinical study,
with the exception of adequately treated non-melanomatous skin cancer and carcinoma
in situ with no evidence of disease.
14.
Must not have required the use of additional immunosuppression other than
corticosteroids for the management of an AE >Grade 1, have not experienced
recurrence of an AE if re-challenged, and not currently require maintenance doses of
>10 mg prednisone or equivalent per day.
15.
Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients.


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5.3 
Lifestyle restrictions 
The following restrictions apply while the patient is receiving durvalumab and for the specified 
times before and after: 
1.
Female patient of childbearing potential
−
Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner, must use at least 1 highly 
effective method of contraception (Table 5) from the time of screening throughout 
the total duration of the drug treatment and the drug washout period (180 days 
after the last dose of durvalumab + tremelimumab combination therapy or 90 days 
after the last dose of durvalumab monotherapy). Non-sterilized male partners of a 
female patient of childbearing potential must use a male condom plus spermicide 
throughout this period. Cessation of birth control after this point should be 
discussed with a responsible physician. Periodic abstinence, the rhythm method, 
and the withdrawal method are not acceptable methods of contraception. Female 
patients should refrain from breastfeeding throughout this period.
−
Pregnancy testing will be performed according to the schedule of activities (SoA)
(Table 1, Table 2, and Table 3).
2.
Male patients with a female partner of childbearing potential
−
Non-sterilized male patients who are not abstinent and intend to be sexually active 
with a female partner of childbearing potential, must use a male condom plus 
spermicide from the time of screening throughout the total duration of the drug 
treatment and the drug washout period (180 days after the last dose of durvalumab
+ tremelimumab combination therapy or 90 days after the last dose of durvalumab 
monotherapy). Periodic 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 5).
Please note, females of childbearing potential are defined as those who are not surgically sterile 
(ie, bilateral salpingectomy, bilateral oophorectomy, or complete hysterectomy) or 
postmenopausal.  
Women will be considered postmenopausal 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 postmenopausal 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 postmenopausal range for the institution.


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•
Women ≥50 years of age would be considered postmenopausal 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.
•
Women who are surgically sterile (ie, bilateral salpingectomy, bilateral oophorectomy,
or complete hysterectomy) are eligible.
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 5. 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 5  
Highly effective methods of contraception (<1% failure rate) 
Barrier/intrauterine 
methods 
Hormonal methods 
•
Copper T intrauterine
device
•
Levonorgestrel-releasing
intrauterine system (eg,
Mirena®)a
•
Implants: Etonogestrel-releasing implants (eg, Implanon® or
Norplant®)
•
Intravaginal Devices: Ethinylestradiol/etonogestrel-releasing
intravaginal devices (eg, NuvaRing®)
•
Injection: Medroxyprogesterone injection (eg,
Depo-Provera®)
•
Combined Pill: Normal and low dose combined oral
contraceptive pill
•
Patch: Norelgestromin/ethinylestradiol-releasing transdermal
system (eg, Ortho Evra®)
•
Minipill: Progesterone-based oral contraceptive pill using
desogestrel: Cerazette® is currently the only highly effective
progesterone-based pill
a
This is also considered a hormonal method. 




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Table 6  
Study treatment 
Treatment 
Study treatment 
name: 
Durvalumab (MEDI4736) 
Dosage 
formulation: 
500-mg vial solution for infusion after dilution, 50 mg/mL
Route of 
administration: 
Intravenous (IV) 
Dose: 
1500 mg 
Dosing 
instructions: 
A dose of 1500 mg will be delivered through an IV administration set with a 
0.2 μm or 0.22 μm filter. If a patient’s weight falls to 30 kg or below (≤30 kg), 
then the patient should receive weight-based dosing equivalent to 20 mg/kg of 
durvalumab q4w until weight improves to above 30 kg (>30 kg). 
Packaging and 
labeling: 
Study drug will be provided in vials. Each vial will be labeled in accordance with 
Good Manufacturing Practice Annex 13 and per country regulatory requirement.a 
Frequency: 
Every 4 weeks 
Manufacturer: 
MedImmune 
Provider: 
AstraZeneca 
a
Label text prepared for durvalumab (MEDI4736) will show the product name as “MEDI4736” or “durvalumab 
(MEDI4736)” depending upon the agreed product name used in the approved study master label document. All 
naming conventions are correct during this transitional period.  
6.1.1.1 
Durvalumab (MEDI4736) 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0 and density of 1.054 g/mL. The nominal fill volume is 
10.0 mL. IP vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. Drug product 
should be kept in original packaging until use to prevent prolonged light exposure. 
Preparation of durvalumab (MEDI4736) doses for administration with an IV bag 
The dose of durvalumab (MEDI4736) for administration must be prepared by the Investigator’s 
or site’s designated IP manager using aseptic technique. Total time from needle puncture of the 
durvalumab (MEDI4736) vial to the start of administration should not exceed:  
•
24 hours at 2°C to 8°C (36°F to 46°F)


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•
4 hours at room temperature
A dose of 1500 mg will be administered using an IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, with a final durvalumab (MEDI4736) concentration ranging from 1 to 15 mg/mL 
and delivered through an IV administration set with a 0.2- or 0.22-μm filter. Add 30.0 mL of 
durvalumab (MEDI4736) (ie, 1500 mg of durvalumab [MEDI4736]) to the IV bag. The IV bag 
size should be selected such that the final concentration is within 1 to 15 mg/mL. Mix the bag by 
gently inverting to ensure homogeneity of the dose in the bag.  
If patient weight falls to ≤30 kg, WT-based dosing at 20 mg/kg will be administered using an IV 
bag containing 0.9% (w/v) saline or 5% (w/v) dextrose, with a final durvalumab (MEDI4736) 
concentration ranging from 1 to 15 mg/mL and delivered through an IV administration set with a 
0.2- or 0.22-μm filter.  
Standard infusion time is one hour; however, if there are interruptions during the infusion, the 
total allowed infusion time should not exceed 8 hours at room temperature.  
Do not co-administer other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used, after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered. 
If either preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials. Durvalumab (MEDI4736) does not contain preservatives and any unused portion 
must be discarded.  
6.1.2 
Dose and treatment regimen 
6.1.2.1 
Durvalumab (MEDI4736) monotherapy  
Patients who receive durvalumab monotherapy treatment (Cohort 1) or durvalumab monotherapy 
retreatment (Cohort 2) will receive 1500 mg durvalumab via IV infusion q4w, until PD is 
determined by the Investigator following RECIST v1.1, unless there is unacceptable toxicity, 
withdrawal of consent, or another discontinuation criterion is met. See Figure 2 (Please note, if a 
patient’s weight falls to 30 kg or below, the patient should receive WT-based dosing equivalent 
to 20 mg/kg of durvalumab q4w after consultation between the Investigator and Study Physician, 
until the weight improves to >30 kg). 
The standard infusion time is 1 hour; however, if there are interruptions during infusion, the total 
allowed time should not exceed 8 hours at room temperature. 


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Figure 2 
Durvalumab monotherapy dosing schedule
Q4W every 4 weeks.
6.1.3
Duration of treatment and criteria for treatment through progression and for 
retreatment
All durvalumab treatment will be administered beginning on Day 1 (Cohort 1) or Day 1 
retreatment (Cohort 2), until progression as determined by the Investigator using RECIST v1.1 
(refer to Appendix C), unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.
Patients receiving durvalumab who experience PD and, in the Investigator’s opinion, continue to 
receive benefit from their assigned treatment may continue to receive durvalumab for as long as
they meet specific clinical criteria and are deriving clinical benefit in the opinion of the 
Investigator. For all patients who are treated through PD, the Investigator should ensure patients 
still meet all of the inclusion criteria and none of the exclusion criteria for this study and obtain
additional informed consent for continuation of treatment. The treatment ICF will specify that 
treatment beyond initial evidence of PD is not the standard of care and that alternative treatment 
options, either locally licensed treatments or other clinical trials, are potentially available for this 
patient population. 
Patients with rapid tumor progression or with symptomatic progression, that require urgent 
medical intervention (eg, central nervous system metastasis, respiratory failure due to tumor 
compression, or spinal cord compression) will not be eligible for continuing durvalumab (refer 
to Appendix C). 
For all patients who are continuously treated through progression and for patients who are 
restarting durvalumab monotherapy, the Investigator should ensure that: 
•
The patient does not have any significant, unacceptable, or irreversible toxicities, that
indicate continuing treatment will not further benefit the patient. The patient may not
have experienced a toxicity that required permanent discontinuation of study
treatment.


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•
There is absence of clinical symptoms or signs indicating clinically significant disease 
progression accompanied by a decline in WHO/ECOG PS to >2
•
There is absence of rapid disease progression or threat to vital organs or critical 
anatomical sites (eg, central nervous system metastasis, respiratory failure due to 
tumor compression, or spinal cord compression) requiring urgent alternative medical 
intervention
•
The patient still fulfills the eligibility criteria for this study (see Sections 5.1 and 5.2). 
Patients must also agree to reconsenting to restart durvalumab monotherapy.
•
The patient has not received an intervening systemic anticancer therapy after their 
assigned treatment discontinuation from the parent study
The patient has had a retreatment baseline tumor assessment within a maximum of 28 days prior 
to restarting durvalumab (Cohort 2). In Cohort 1, patients will continue with durvalumab 
monotherapy at 1500 mg q4w until disease progression as confirmed by the Investigator 
following RECIST v1.1.  
During the retreatment period in Cohort 2, eligible patients will resume durvalumab dosing at 
1500 mg q4w until disease progression as determined by the Investigator following 
RECIST v1.1.  
Patients who the Investigator determines may not continue treatment after PD will be followed 
up for OS, and are no longer eligible for retreatment. Patients who have discontinued treatment 
due to toxicity or symptomatic deterioration, or who have commenced subsequent anticancer 
therapy, will be followed for OS until withdrawal of consent or death. Upon discontinuation of 
durvalumab, patients may receive any subsequent anticancer therapy at the discretion of the 
Investigator. 
6.1.4 
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. 
6.2 
Measures to minimize bias: randomization and blinding 
Not applicable. 


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6.3 
Treatment compliance 
Study measures will be taken to ensure to document durvalumab treatment compliance, with 
dates of administration, dosing information, and any safety events related to medication 
administration will be captured in the study database. Collection and reporting of durvalumab 
overdoses are summarized in Section 8.4.3. 
The administration of all IPs should be recorded in the appropriate sections of the electronic case 
report form (eCRF). 
Any change from the dosing schedule, dose delays/interruptions, and dose discontinuations 
should be recorded in eCRF. Dose reductions are not allowed. 
The IP Storage Manager is responsible for managing the IP from receipt by the study site until 
the destruction or return of all unused IP. 
6.4 
Concomitant therapy 
The Investigator must be informed as soon as possible about any medication taken from the time 
of enrollment until the end of the durvalumab treatment, including the 90-day follow-up period 
following the last dose of study drug. This applies only for patients receiving durvalumab 
through 90 days after the last dose, and does not apply to patients from Cohort 2 who are not 
retreated and patients in Cohort 3. No restrictions apply to patients off treatment who are over 
90 days from their last dose of durvalumab.  
Any medication or vaccine including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements that the patient is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
•
Reason for use
•
Dates of administration including start and end dates
•
Dosage information including dose, unit, and frequency
Patients must be instructed not to take any medications, including over-the-counter products, 
without first consulting with the Investigator. 
Restricted, prohibited, and permitted concomitant medications are described in the following 
tables. Refer also to the Dosing Modification and Toxicity Management Guidelines (see 
Annex 1).  


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Table 7  
Prohibited concomitant medications 
Prohibited medications/class of drug: 
Usage: 
Cohort 1 and retreated patients in Cohort 2, only 
Any investigational anticancer therapy 
other than those under investigation in 
this study 
Should not be given concomitantly while the patient is on 
study treatment 
Monoclonal antibodies against CTLA-4, 
PD-1, or PD-L1 other than those under 
investigation in this study 
Should not be given concomitantly while the patient is on 
study treatment 
Any concurrent chemotherapy, 
radiotherapy, immunotherapy, or 
biologic or hormonal therapy for cancer 
treatment other than those under 
investigation in this study 
Should not be given concomitantly while the patient is on 
study treatment. (Concurrent use of hormones for 
non-cancer-related conditions [eg, insulin for diabetes and 
hormone replacement therapy] is acceptable. Local 
treatment of isolated lesions, excluding target lesions, for 
palliative intent is acceptable [eg, by local surgery or 
radiotherapy].) 
Immunosuppressive medications 
including, but not limited to, systemic 
corticosteroids at doses exceeding 
10 mg/day of prednisone or equivalent, 
methotrexate, azathioprine, and tumor 
necrosis factor-α blockers 
Should not be given concomitantly or used for 
premedication prior to the immuno-oncology infusions. The 
following are allowed exceptions: 
•
Use of immunosuppressive medications for the
management of IP-related AEs
•
Use in patients with contrast allergies
•
In addition, use of inhaled, topical, and intranasal
corticosteroids is permitted
A temporary period of steroids will be allowed if clinically 
indicated and considered to be essential for the 
management of non-immunotherapy related events 
experienced by the patient (eg, chronic obstructive 
pulmonary disease, radiation, nausea, etc). 
Herbal and natural remedies which may 
have immune-modulating effects 
Should not be given concomitantly unless agreed by the 
Sponsor. 
Cohorts 1 to 3 
Live attenuated vaccines 
Should not be given within 30 days prior to the first dose of 
IP in the present study and through 90 days after the last 
dose of IP. 
Drugs with laxative properties and 
herbal or natural remedies for 
constipation 
Should be used with caution through 90 days after the last 
dose of tremelimumab during the study, if the patient 
received combination therapy of tremelimumab and 
durvalumab in the parent clinical study. 
Sunitinib 
Should not be given concomitantly or through 90 days after 
the last dose of tremelimumab (acute renal failure has been 
reported with combination therapy of tremelimumab and 
sunitinib) 


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Prohibited medications/class of drug: 
Usage: 
Epidermal growth factor receptor 
(EGFR) tyrosine kinase inhibitors 
(TKIs) 
Should not be given concomitantly. 
Should be used with caution in the 90 days post last dose of 
durvalumab.  
Increased incidences of pneumonitis (with third generation 
EGFR TKIs) and increased incidence of transaminase 
increases (with first generation EGFR TKIs) has been 
reported when durvalumab has been given concomitantly. 
AE adverse event; CTL cytotoxic T-lymphocyte-associated; EGFR epidermal growth factor receptor; IP 
investigational product; TKI tyrosine kinase inhibitor; PD programmed death 
Table 8  
Supportive medications 
Supportive medications/class of drug: 
Usage: 
Concomitant medications or treatments (eg, acetaminophen or 
diphenhydramine) deemed necessary to provide adequate prophylactic or 
supportive care, except for those medications identified as “prohibited,” as 
listed above  
To be administered 
as prescribed by the 
Investigator 
Best supportive care (including antibiotics, nutritional support, correction of 
metabolic disorders, optimal symptom control, and pain management 
[including palliative radiotherapy to non-target lesions, etc]) 
Should be used, 
when necessary, for 
all patients 
Inactivated viruses, such as those in the influenza vaccine 
Permitted 
6.4.1 
Other concomitant treatment 
Medication other than that described above, which is considered necessary for the patient’s 
safety and wellbeing, may be given at the discretion of the Investigator and recorded in the 
appropriate sections of the case report form (CRF). 
6.4.2 
Durvalumab drug-drug interactions 
Currently, there is no information to date on drug-drug interactions with durvalumab either 
preclinically or in patients. As durvalumab is a mAb and therefore a protein, it will be degraded 
to small peptides and amino acids and will be eliminated by renal and reticuloendothelial CL. It 
is therefore not expected that durvalumab will induce or inhibit the major drug metabolizing 
cytochrome P450 pathways. As a result, there are no expected PK drug-drug interactions. The 
MOA of durvalumab involves binding to PD-L1, and therefore significant pharmacodynamic 
drug interactions with the commonly administered concomitant medications are not expected. 
Despite this, appropriate clinical monitoring in all of the planned clinical studies will be 
conducted to evaluate any potential drug-drug interactions. 
6.4.3 
Rescue medication 
As a result of immune-mediated adverse events (imAEs) that could potentially be experienced by 
patients on durvalumab, steroids and other immunosuppressant rescue medication has to be made 


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available to this patient population. The 2 products that fall into the category of 
immunosuppressants are infliximab (eg, for colitis) and mycophenolate (eg, for hepatitis). 
AstraZeneca supply chain will be responsible for sourcing these 2 rescue medications to the sites 
if local regulations prevent the use of infliximab and mycophenolate in this indication, as they 
are considered off-label for management of immunotherapy-related toxicities. These rescue 
medications must be receipted and controlled by the pharmacist and stored according to the 
labeled storage conditions, with temperature excursions reported accordingly by the pharmacist. 
If required for use as a result of an imAE, then the interactive voice response system 
(IVRS)/interactive web response system (IWRS) will provide to the pharmacists the kit 
identification number to be allocated to the patient at the time.  
6.5 
Dose modification 
Dose delays are permitted for immuno-oncology therapy (see Dosing Modification and Toxicity 
Management Guidelines in Annex 1). However, dose reduction is not permitted.  
6.6 
Treatment after the end of the study 
AstraZeneca will continue to supply durvalumab after completion of this study, for as long as the 
patient is receiving clinical benefit in the opinion of the Investigator, or until the participant 
meets a discontinuation criteria as defined in Section 7.1.  
For patients continuing to receive durvalumab treatment following the final DCO and database 
closure, the procedures defined in the SoA will be limited. It is recommended that the 
participants continue the scheduled site visits and Investigators monitor the patient’s safety 
laboratory results periodically during treatment with durvalumab in order to manage AEs in 
accordance with the durvalumab Dosing Modification and Toxicity Management Guidelines 
(see Annex 1), and as described in Section 8.3.14. 
In the event that product development reaches a point where alternative product supply options 
become available, then these alternative product supply options will be discussed by 
AstraZeneca with the Investigator. AstraZeneca will work with the Investigator to transition the 
patient(s) to alternative supply, where possible.  
In the event that a roll-over or safety extension study is available at the time of the final DCO 
and database closure, patient(s) currently receiving treatment with durvalumab may then be 
transitioned to such a study, and the current study would reach its end. The roll-over or extension 
study would ensure treatment continuation with visit assessments per its protocol, as applicable. 
Any patient who would be eligible to move to such a study would be given a new informed 
consent, as applicable.  


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7.
DISCONTINUATION OF TREATMENT AND PATIENT
WITHDRAWAL
7.1 
Discontinuation of study treatment
An individual patient will not receive any further durvalumab monotherapy if any of the 
following occur in the patient in question: 
•
Withdrawal of consent from further treatment with IP. The patient is, at any time, free 
to discontinue treatment, without prejudice to further treatment. A patient who 
discontinues treatment is normally expected to remain in the study for safety and OS 
follow-up unless they specifically withdraw their consent to all further participation in 
any study procedures and assessments (see Section 7.3).
•
An AE that, in the opinion of the Investigator or AstraZeneca, contraindicates further 
dosing.
•
Any AE that meets criteria for discontinuation as defined in the Dosing Modification 
and Toxicity Management Guidelines (see Annex 1) or as defined in the local 
prescribing information for the agent.
•
Pregnancy or intent to become pregnant
•
Non-compliance with the study protocol that, in the opinion of the Investigator or 
AstraZeneca, warrants withdrawal from treatment with IP (eg, refusal to adhere to 
scheduled visits).
•
Initiation of alternative anticancer therapy including another investigational agent
•
Disease progression as determined by the Investigator following RECIST v1.1 (refer 
to Appendix C) and Investigator determination that the patient is no longer benefiting 
from treatment with IP.
Upon discontinuation of durvalumab, patients may receive any subsequent anticancer therapy at 
the discretion of the Investigator and will follow the schedule of activities (SoA) detailed for 
Cohort 3 for safety and survival follow-up (Table 3). 
7.1.1 
Procedures for discontinuation of study treatment 
Discontinuation of study treatment, for any reason, does not impact the patient’s participation in 
the study. A patient who decides to discontinue IP will always be asked about the reason(s) for 
discontinuation and the presence of any AE. The patient should continue attending subsequent 
study visits, and data collection should continue according to the study protocol (Table 3). If the 
patient does not agree to continue in-person study visits, a modified follow-up must be arranged 
to ensure the collection of endpoints and safety information. This follow-up could be a telephone 
contact with the patient (or a prespecified preferred method of contact, as an alternative), a 
contact with a relative or treating physician, or information from medical records. The approach 


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taken should be recorded in the medical records, and the preferred method of contact will be 
recorded in the patient contact module for this study. A patient that agrees to modified follow-up 
is not considered to have withdrawn consent or to have withdrawn from the study. 
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment. Patients who have permanently 
discontinued treatment will enter follow-up (see Section 1.1). 
All patients will be followed for survival with contact approximately every 3 months (±2 weeks) 
beginning 90 days after the last dose of the study drug until the end of the study.  
Patients who decline to return to the site for evaluations should be contacted by telephone (or a 
prespecified preferred method of contact) as indicated in the SoAs as an alternative.  
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IVRS/IWRS. 
7.2 
Lost to follow-up 
Patients will be considered lost to follow-up only if no contact has been established after 
2 consecutive failed contacts. A “contact” is defined as 3 attempts of the preferred method of 
contact recorded in the patient contact module, and then 3 attempts of the preferred alternative 
contact designee ±2 weeks from the targeted date (set by the interval shown in the SoAs). At this 
time, the patient will be flagged as lost to follow-up in the electronic data capture (EDC; 
2 consecutive time points with no patient or alternative contact), whereby the Investigator would 
be requested to review the patient record and update the patient status, if known. Patients who 
refuse to continue participation in the study, including telephone contact (or a prespecified 
preferred method of contact, as an alternative), should be documented as “withdrawal of 
consent” rather than “lost to follow-up.” Investigators should document attempts to re-establish 
contact with missing patients throughout the study period. If contact with a missing patient is 
re-established, the patient should not be considered lost to follow-up and evaluations should 
resume according to the protocol. 
In order to support key endpoints of OS analyses, the survival status of all patients in the full 
analysis and the safety analysis sets should be re-checked, this includes those patients who 
withdrew consent or are classified as “lost to follow-up.” 
•
Lost to follow-up – site personnel should check hospital records, the patients’ current
physician, and a publicly available death registry (if available) to obtain a current
survival status. (The applicable CRF modules will be updated.)
•
In the event that the patient has actively withdrawn consent to the processing of their
personal data, the survival status of the patient can be obtained by site personnel from
publicly available death registries (if available) where it is possible to do so under
applicable local laws to obtain a current survival status. (The applicable CRF modules
will be updated.)


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7.3 
Withdrawal from the study 
Patients are free to withdraw from the study at any time (IP and assessments) without prejudice 
to further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further 
IP or further study observation, with the exception of follow-up for survival, which will continue 
until the end of the study unless the patient has expressly withdrawn their consent to survival 
follow-up. Note that the patient may be offered additional tests or tapering of treatment to 
withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The Investigator will follow up AEs outside of the clinical study.  
If a patient withdraws consent, they will be specifically asked if they are withdrawing consent to: 
•
All further participation in the study including any further follow up (eg, survival
contact telephone calls)
8. 
STUDY ASSESSMENTS AND PROCEDURES
Data collection and frequency are summarized by each of the 3 cohorts below: 
In Cohort 1, all durvalumab treatment cycle assessments will occur every 4 weeks until 
confirmed PD, unless unacceptable toxicity, withdrawal of consent, or another discontinuation 
criterion is met. The most recent imaging results from the parent clinical study may be used for 
baseline tumor assessments, provided it was obtained within 28 days prior to Day 1, Cycle 1. 
Tumor assessments throughout all cycles will be performed according to RECIST v1.1, as 
determined by the Investigator (at least every 12 weeks) until withdrawal of consent, 
progression, or death. The patients will continue their durvalumab treatment and all cycle 
assessments every 4 weeks ±3 days unless dosing needs to be held for toxicity reasons (Table 1). 
Cohort 2 follow-up prior to retreatment with durvalumab monotherapy follows the SoA for 
Cohort 3, while patients who undergo retreatment begin the assessment as per the SoA for 
patients in Cohort 1. During the follow-up of patients before retreatment, they will undergo 
assessments for vital signs, concomitant medications, laboratory safety and AE/SAE at 30 days 
(±3 days), 60 days (±7 days), and 90 days (±7 days) since the last dose of study drug. The 
assessment for concomitant medications will be collected throughout 90 days post durvalumab 
discontinuation. The survival status for these patients will be collected every 3 months 
(±2 weeks) beginning 90 days after the last dose of the study drug and tumor assessments will be 
performed according to the Investigator’s standard practice until withdrawal of consent, 
progression, or death. For those that start retreatment, patients will continue their durvalumab 
monotherapy and all cycle assessments every 4 weeks ±3 days unless dosing needs to be held for 
toxicity reasons. While on retreatment, tumor assessments and disease progression will be 
determined by the Investigator following RECIST v1.1 (Table 2). 


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Cohort 3 includes safety and survival follow-up only for patients previously treated with 
durvalumab monotherapy or durvalumab in combination with any other approved or 
investigational anticancer agents who are no longer receiving durvalumab and are not eligible to 
receive retreatment. The patients would undergo assessments as per the SoA (Table 3). 
The Investigator will obtain informed consent of study procedures at baseline/enrollment from 
eligible study patients. The Investigator will ensure that data are recorded on the eCRFs. The 
EDC system will be used for data collection and query handling. The Investigator will ensure the 
accuracy and completeness of eCRFs, including timeliness of the data recorded and of the 
provision of answers to data queries according to the Clinical Study Agreement. The Investigator 
will sign the completed eCRFs. A copy of the completed eCRFs will be archived at the study 
site. 
Immediate safety concerns should be discussed with the Sponsor immediately upon occurrence 
or awareness to determine if the patient should continue or discontinue study treatment. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria. The Investigator will maintain an enrollment log to record details of 
all patients screened and to confirm eligibility or record reasons for non-enrollment, as 
applicable.  
Procedures conducted as part of the patient’s routine clinical management (eg, blood count and 
imaging assessments) and obtained before signing of the ICF may be utilized for screening or 
baseline purposes provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the SoA. 
The amount of blood collected from each patient over the duration of the study, including any 
extra assessments that may be required, will be dependent on the local laboratory requirements. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with the 
samples. 
8.1 
Safety assessments 
Planned time points for all safety assessments are provided in the SoA (see Section 1.1). Any 
assessments which are relevant to preservation of patient safety, as scheduled in the parent 
clinical study, will be conducted and followed up as per the SoA for this study. 
The safety and tolerability of durvalumab monotherapy up until 90 days after the last dose of 
study in all patients will be assessed as a primary objective, as described in Section 3. After 
90 days of the last dose of durvalumab, Investigators will be instructed to report any AE/SAE 
according to the standard pharmacovigilance process outside of the remit for this study. 
Additional safety collection and reporting guidelines for this study will be provided in a Safety 
Handling Plan. 


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8.1.1 
Clinical safety laboratory assessments 
Blood and urine samples for determination of clinical chemistry, hematology, and pregnancy will 
be taken at the times indicated in the SoA and as clinically indicated (see Section 1.1).  
Clinical laboratory safety tests, including serum pregnancy tests, will be performed in a licensed 
clinical laboratory according to local standard procedures. Sample tubes and sample sizes may 
vary depending on the laboratory method used and routine practice at the site. Pregnancy tests may 
be performed at the site using a licensed test (urine or serum pregnancy test). Abnormal clinically 
significant laboratory results should be repeated as soon as possible (preferably within 24 to 48 
hours). 
Additional safety samples may be collected if clinically indicated at the discretion of the 
Investigator. The date, time of collection, and results (values, units, and reference ranges) will be 
recorded on the appropriate eCRF. 
The laboratory variables to be measured are presented in Table 9 (clinical chemistry) and Table 10 
(hematology).  
The following laboratory variables will be measured: 
Table 9  
Clinical chemistry 
Albumin 
Lipaseb 
Alkaline phosphatase 
Magnesiumc 
ALTa 
Potassium 
Amylaseb 
Sodium 
ASTa 
Total bilirubina 
Bicarbonatec 
Total protein 
Calcium 
TSHe 
Chloridec 
T3 freef (reflex) 
Creatinined 
T4 freef (reflex) 
Gamma glutamyltransferasec 
Urea or blood urea nitrogen, depending on local practice 
Glucose 
Lactate dehydrogenase 
a.
Tests for ALT, AST, alkaline phosphatase, and total bilirubin must be conducted and assessed concurrently. If
total bilirubin is ≥2 × upper limit of normal (and no evidence of Gilbert’s syndrome), then fractionate into
direct and indirect bilirubin.
b.
It is preferable that both amylase and lipase parameters are assessed. For sites where only 1 of these parameters
is routinely measured, either lipase or amylase is acceptable.
c. 
Bicarbonate (where available), chloride, creatinine clearance, gamma glutamyltransferase, magnesium, testing
is to be performed at baseline, on Day 1 (unless all screening laboratory clinical chemistry assessments are
performed within 3 days prior to Day 1), and if clinically indicated.
d. 
Creatinine clearance will be calculated by data management using Cockcroft-Gault (using actual body weight).
e. 
If TSH is measured within 14 days prior to Day 1 (first infusion day), it does not need to be repeated at Day 1. 


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f. 
Free T3 or free T4 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related
to the endocrine system.
ALT alanine aminotransferase; AST aspartate aminotransferase, T3 triiodothyronine; T4 tetraiodothyronine; TSH 
thyroid-stimulating hormone. 
Table 10  
Hematology 
Absolute neutrophil counta 
Absolute lymphocyte counta 
Hemoglobin 
Platelet count 
Total white cell count 
a.
Can be recorded as absolute counts or as percentages. Absolute counts will be calculated by Data Management
if entered as percentage. Total white cell count therefore has to be provided.
Note: For coagulation parameters, activated partial thromboplastin time and international normalized ratio are to be 
assessed at baseline on Day 1 (unless all screening laboratory hematology assessments are performed within 
3 days prior to Day 1), and as clinically indicated. 
If a patient shows an AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN, refer to 
Appendix B for further instructions on cases of increases in liver biochemistry and evaluation of 
Hy’s Law (HL). These cases should be reported as SAEs if, after evaluation, they meet the 
criteria for a HL case or if any of the individual liver test parameters fulfill any of the SAE 
criteria.  
All patients should have further chemistry profiles performed at 30 days (±3 days), 2 months 
(±1 week), and 3 months (±1 week) after permanent discontinuation of durvalumab (see the 
SoAs). 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the eCRF. Situations in which laboratory safety results should be reported as 
AEs are described in Section 8.3.7. 
All patients with Grade 3 or 4 laboratory values at the time of completion or discontinuation 
from durvalumab must have further tests performed until the laboratory values have returned to 
Grade 1 or 2, unless these values are not likely to improve because of the underlying disease. 
8.1.2 
Physical examinations 
Physical examinations will be performed according to the assessment schedules (see the SoAs). 
Full physical examinations will include assessments of the head, eyes, ears, nose, and throat and 
the respiratory, cardiovascular, GI, urogenital, musculoskeletal, neurological, dermatological, 
hematologic/lymphatic, and endocrine systems. Height will be measured at screening only. 
Targeted physical examinations are to be utilized by the Investigator on the basis of clinical 
observations and symptomatology. Situations in which physical examination results should be 
reported as AEs are described in Section 8.3.7.  


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8.1.3 
Vital signs 
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs. 
First infusion of the retreatment 
On the first infusion day, patients receiving durvalumab monotherapy will be monitored and vital 
signs collected/recorded in the eCRF prior to, during, and after infusion of durvalumab as 
presented in the bulleted list below.  
Blood pressure and pulse will be collected from patients receiving durvalumab treatment before, 
during, and after each infusion at the following times (based on a 60-minute infusion): 
•
Prior to the beginning of the infusion (measured once from approximately 30 minutes
before up to 0 minutes [ie, the beginning of the infusion])
•
Approximately 30 minutes during the infusion (halfway through infusion)
•
At the end of the infusion (approximately 60 minutes ±5 minutes)
If the infusion takes longer than 60 minutes, then BP and pulse measurements should follow the 
principles as described above or be taken more frequently if clinically indicated. A 1-hour 
observation period is recommended after the first infusion of durvalumab.  
Subsequent infusions 
Blood pressure, pulse, and other vital signs should be measured, collected/recorded in eCRF 
prior to the start of the infusion. Patients should be carefully monitored, and BP and other vital 
signs should be measured during and post infusion as per institution standard and as clinically 
indicated. Any clinically significant changes in vital signs should be entered onto an unscheduled 
vital signs CRF page.  
Situations in which vital sign results should be reported as AEs are described in Section 8.3.7. 
For any AEs of infusion reactions, the vital signs values should be entered into the CRF. 
8.1.4 
Early patient review for safety for retreated patients 
Among patients starting retreatment in Cohort 2, it is recommended that patients are contacted 
2 weeks after receiving the first 3 cycles of durvalumab monotherapy (Cycle 1 Day 14, Cycle 2 
Day 14, and Cycle 3 Day 14) of study drug to ensure early identification and management of 
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Review of safety data will be conducted in accordance with AstraZeneca’s Pharmacovigilance 
process.  
8.1.5 
WHO/ECOG performance status 
WHO/ECOG PS will be assessed at the times specified in the assessment schedules (see the 
SoAs) based on the following: 
0.
Fully active; able to carry out all usual activities without restrictions
1.
Restricted in strenuous activity, but ambulatory and able to carry out light work or
work of a sedentary nature (eg, light housework or office work)
2.
Ambulatory and capable of self-care, but unable to carry out any work activities; up
and about more than 50% of waking hours
3.
Capable of only limited self-care; confined to bed or chair more than 50% of waking
hours
4.
Completely disabled; unable to carry out any self-care and totally confined to bed or
chair
5.
Dead
Any significant change from baseline or screening must be reported as an AE. 
8.1.6 
Other safety assessments 
If new or worsening pulmonary symptoms (eg, dyspnea) or radiological abnormality suggestive 
of pneumonitis/ILD is observed, toxicity management as described in detail in the Dosing 
Modification and Toxicity Management Guidelines (see Annex 1) will be applied. The results of 
the full diagnostic workup (including high-resolution computed tomography [HRCT], blood and 
sputum culture, hematological parameters, etc) will be captured in the eCRF. It is strongly 
recommended to perform a full diagnostic workup, to exclude alternative causes such as 
lymphangitic carcinomatosis, infection, allergy, cardiogenic edema, or pulmonary hemorrhage. 
In the presence of confirmatory HRCT scans where other causes of respiratory symptoms have 
been excluded, a diagnosis of pneumonitis (ILD) should be considered and the Dosing 
Modification and Toxicity Management Guidelines should be followed.  
Pneumonitis (ILD) investigation 
The following assessments, and additional assessments if required, will be performed to enhance 
the investigation and diagnosis of potential cases of pneumonitis. The results of the assessment 
will be collected. 
•
Physical examination


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Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including
auscultation for lung field will be assessed.
•
Saturation of peripheral oxygen
•
Other items
−
When pneumonitis (ILD) is suspected during study treatment, the following
markers should be measured where possible:
o
ILD markers (KL-6, SP-D) and β-D-glucan
o
Tumor markers: Particular tumor markers which are related to
disease progression.
o
Additional clinical chemistry: C-reactive protein, lactate
dehydrogenase
8.2 
Efficacy assessments 
Efficacy of durvalumab will be assessed in terms of overall response rate (ORR) and DOR in 
patients who undergo retreatment with durvalumab from Cohort 2 if there is a sufficient sample 
size of retreated patients, otherwise, only listings will be provided. Disease progression will be 
determined by the Investigator following RECIST v1.1; only the results of assessments will be 
entered into the eCRF. The RECIST v1.1 guidelines for Investigator’s tumor assessments, 
including protocol-specific requirements, are summarized in Appendix C.  
8.2.1 
Parent study assessments 
To accurately capture endpoints for this study, the following data elements must be transferred 
from the parent studies for analysis purposes. Minimal mandatory data elements will be entered 
into the EDC (eg, patient identification); the remainder will be retained in a separate database. 
This list may be updated or modified depending on the availability and required elements 
determined for the study endpoints and will be fully captured in the statistical analysis plan 
(SAP).  
•
Parent study name, study code, site name, and site number
•
Patient identification or linkage key, including connection to the IVRS of the parent
study and transfer of old enrollment code (E-code)
•
Date of randomization
•
Demographics: including date of birth and sex
•
HIV status


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•
Baseline disease information: date of cancer diagnosis, indication, and stage of disease
•
All tumor assessment information, including: dates of scans (including baseline
comparison scan), results of each assessment (response, SD, progression)
•
Study drug administration, including:
−
Date of first administration of durvalumab and durvalumab combination treatment
−
Date and last dose of durvalumab and durvalumab combination treatment
administration
•
Ongoing safety events at the end of parent study, including SAEs or adverse events of
special interest (AESIs) while on treatment with durvalumab and/or durvalumab
combination therapy.
•
Ongoing concomitant medications at the end of the parent study
•
First subsequent anticancer therapy after durvalumab discontinuation (Cohort 3 only)
•
Last date of patient contact
•
Contact information (patient, caregiver, physician) as allowed by regulation for each
country
8.2.2 
Survival assessments
Assessments for survival must be made every 3 months (±2 weeks) beginning 90 days after the 
last dose of study drug. Survival information may be obtained via telephone contact with the 
patient or the patient’s family (or a prespecified preferred method of contact, as an alternative), 
or by contact with the patient’s current physician. The details of first subsequent anticancer 
therapy and overall best response after discontinuation of durvalumab treatment will be collected 
from the Investigator.  
In addition, patients on treatment or in survival follow-up will be contacted following the data 
cut-off (DCO) for the primary analysis and all subsequent survival analyses to provide complete 
survival data. These contacts should generally occur within 7 days of the DCO. 
8.2.3 
Clinical endpoint assessments 
Data for the following endpoints will be collected and may be evaluated as part of the analysis in 
the parent clinical studies from which the patients originated. Survival data will be collected in 
terms of OS in all patients. Efficacy variables will be collected in terms of ORR and DOR for 
patients in Cohort 2 who start retreatment according to clinical practice (so long as they satisfy 
eligibility criteria in Section 5.1). These endpoints are defined below:  


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•
OS is defined as the time from date of randomization/enrollment in the parent clinical
study until the date of death by any cause (all cohorts).
•
ORR is defined as the number (%) of patients with a confirmed response of complete
response (CR) or partial response (PR) from the re-initiation of treatment with
durvalumab monotherapy (Cohort 2).
•
DOR is defined as the time from first documented CR or PR until the time of first
documented disease progression or death in the absence of disease progression
(Cohort 2).
Tumor assessments, performed by the Investigator according to standard practice, to determine 
ORR and DOR will be collected for patients in Cohorts 1 and 2 at least every 12 weeks while the 
patient is receiving treatment. Assessments should be performed as deemed medically 
appropriate by the Investigator, for the purpose of maintaining the safety and wellbeing of the 
patient. Investigator reported response will be collected and summarized. 
8.3 
Collection of adverse events 
The Principal Investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
The definitions of an AE or SAE can be found in Appendix A. 
AEs will be reported by the patient (or, when appropriate, by a caregiver, surrogate, or the 
patient’s legally authorized representative).  
The Investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE. For information on how to follow/up AEs, 
see Section 8.3.3.  
8.3.1 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the patient is the preferred method to inquire about 
AE occurrences.  
8.3.2 
Time period and frequency for collecting AE and SAE information 
AEs and SAEs will be collected from the time of the patient signing the ICF until the follow-up 
period is completed (90 days after the last dose of durvalumab). If an event that starts post the 
defined safety follow-up period noted above is considered to be due to a late onset toxicity to 
study drug, then it should be reported as an AE or SAE as applicable. Collection and reporting of 
AEs and SAEs after the final DCO is described in Section 8.3.14. 


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All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix A. The Investigator will submit any updated SAE data to the Sponsor within 
24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study patients. However, if 
the Investigator learns of any SAE, including a death, at any time after a patient’s last visit and 
he/she considers the event to be reasonably related to the study treatment or study participation, 
the Investigator should notify the Sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix A. 
8.3.3 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the Investigator is required to proactively follow each patient at 
subsequent visits/contacts. All SAEs/non-serious AEs/AESIs (as defined in Section 8.3.13 and 
Appendix A) will be followed until resolution, stabilization, the event is otherwise explained, or 
the patient is lost to follow-up  
Any AEs that are unresolved at the patient’s last AE assessment or other assessment/visit as 
appropriate in the study are followed up by the Investigator for as long as medically indicated 
(this may be beyond the 90 days after the last dose of durvalumab), but without further recording 
in the CRF. AstraZeneca retains the right to request additional information for any patient with 
ongoing AE(s)/SAE(s) at the end of the study, if judged necessary. 
8.3.4 
Adverse event data collection 
The following variables will be collected for each AE: 
•
AE (verbatim)
•
The date when the AE started and stopped
•
The maximum CTCAE grade reported
•
Changes in CTCAE grade (report only the maximum CTCAE grade for a calendar
day)
•
Whether the AE is serious or not
•
Investigator causality rating against the IPs (yes or no)
•
Action taken with regard to IPs
•
Administration of treatment for the AE
•
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In addition, the following variables will be collected for SAEs: 
•
Date the AE met criteria for SAE
•
Date the Investigator became aware of the SAE
•
Seriousness criteria
•
Date of hospitalization
•
Date of discharge
•
Probable cause of death
•
Date of death
•
Whether an autopsy was performed
•
Causality assessment in relation to study procedure(s)
•
Causality assessment in relation to other medication, as explained in Section 8.3.5
•
Description of the SAE
The grading scales found in the revised NCI CTCAE version 5.0 will be utilized for all events 
with an assigned CTCAE grading. For those events without assigned CTCAE grades, the 
recommendation in the CTCAE criteria that converts mild, moderate, and severe events into 
CTCAE grades should be used. A copy of the CTCAE version 5.0 can be downloaded from the 
Cancer Therapy Evaluation Program website (http://ctep.cancer.gov). 
8.3.5 
Causality collection 
The Investigator will assess causal relationship between IP and each AE, and answer ‘yes’ or 
‘no’ to the question ‘Do you consider that there is a reasonable possibility that the event may 
have been caused by the IP?’ 
For SAEs, the causal relationship will also be assessed for other medication and study 
procedures and/or AZ Medical device. Note that for SAEs that could be associated with any 
study procedure the causal relationship is implied as ‘yes’. 
A guide to the interpretation of the causality question is found in Appendix A. 
8.3.6 
Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or care provider or reported in response to the 
open question from the study site staff: ‘Have you/the child had any health problems since the 
previous visit/you were last asked?’, or revealed by observation will be collected and recorded in 
the CRF. When collecting AEs, the recording of diagnoses is preferred (when possible) to 


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recording a list of signs and symptoms. However, if a diagnosis is known and there are other 
signs or symptoms that are not generally part of the diagnosis, the diagnosis and each sign or 
symptom will be recorded separately. 
8.3.7 
Adverse events based on examinations and tests 
The results from the clinical study protocol mandated laboratory tests and vital signs will be 
summarized in the clinical study report (CSR). Deterioration as compared to baseline in protocol 
mandated laboratory values and/or vital signs should therefore only be reported as AEs if they 
fulfill any of the SAE criteria or are the reason for discontinuation of treatment with the IP or are 
considered to be clinically relevant as judged by the investigator (which may include but not 
limited to consideration as to whether treatment or non-planned visits were required or other 
action was taken with the study treatment, e.g. dose adjustment or drug interruption). Clinically 
relevant deteriorations in non-mandated parameters should also be reported as AE(s). 
If deterioration in a laboratory value/vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result/vital sign will 
be considered as additional information. Wherever possible the reporting Investigator uses the 
clinical, rather than the laboratory term (eg, anemia versus low hemoglobin value).  
Deterioration of a laboratory value, which is unequivocally due to disease progression, should 
not be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical examination as 
compared with the baseline assessment will be reported as an AE unless unequivocally related to 
the disease under study (DUS), see Sections 8.3.9 and 8.3.10. 
8.3.8 
Hy’s law 
Cases where a patient shows elevations in liver biochemistry may require further evaluation and 
occurrences of AST or ALT ≥3 × ULN together with total bilirubin ≥2 × ULN may need to be 
reported as SAEs. Please refer to Appendix B for further instruction on cases of increases in liver 
biochemistry and evaluation of HL or Potential Hy’s law. 
8.3.9 
Disease under study 
Symptoms of DUS are those which might be expected to occur as a direct result of the patient’s 
primary malignancy. Events which are unequivocally due to DUS should not be reported as an 
AE during the study unless they meet SAE criteria or lead to discontinuation of the IP. 
8.3.10 
Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the IP is being studied. It may be an increase in the severity of the DUS and/or 
increases in the symptoms of the disease. The development of new, or progression of existing 
metastasis to the primary cancer under study should be considered as disease progression and not 


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an AE. Events, which are unequivocally due to disease progression, should not be reported as an 
AE during the study. 
8.3.11 
New cancers 
The development of a new cancer should be regarded as an SAE. New primary cancers are those 
that are not the primary reason for the administration of the IP, and have been identified after the 
patient’s inclusion in this study. 
8.3.12 
Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined follow-up 
period after the administration of the last dose of study drug, must be reported as follows: 
•
Death clearly resulting from disease progression should be reported to the Study
Monitor/Physician at the next monitoring visit and should be documented in the eCRF
in the Statement of Death page. It should not be reported as an SAE.
•
Where death is not due (or not clearly due) to progression of the DUS, the AE causing
the death must be reported to the Study Monitor/Physician as an SAE within 24 hours.
It should also be documented in the Statement of Death page in the eCRF. The report
should contain a comment regarding the co involvement of PD, if appropriate, and
should assign main and contributory causes of death.
•
Deaths with an unknown cause should always be reported as an SAE. It should also be
documented in the Statement of Death page in the eCRF. A post mortem may be
helpful in the assessment of the cause of death, and if performed, a copy of the
post-mortem results should be forwarded to AstraZeneca Patient Safety or its
representative within the usual timeframes.
Deaths occurring after the protocol-defined safety follow-up period after the administration of 
the last dose of study drug should be documented in the Statement of Death page. If the death 
occurred as a result of an event that started post the defined safety follow-up period, and the 
event is considered to be due to a late onset toxicity to study drug, then it should also be reported 
as an SAE. 
8.3.13 
Adverse events of special interest 
An AESI is one of scientific and medical interest specific to understanding of the IP and may 
require close monitoring. 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 IP. 
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, immunosuppressants and/or hormone replacement therapy. These 
AESIs are being closely monitored in clinical studies with durvalumab monotherapy and 


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combination therapy. An imAE is defined as an AESI that is associated with drug exposure and 
is consistent with an immune-mediated MOA and where there is no clear alternate etiology. 
Serologic, immunologic, and histologic (biopsy) data, as appropriate, should be used to support 
an imAE diagnosis. Appropriate efforts should be made to rule out neoplastic, infectious, 
metabolic, toxin, or other etiologic causes of the imAE.  
If the Investigator has any questions in regard to an event being an imAE, the Investigator should 
promptly contact the Study Physician. 
AESIs observed with durvalumab include: 
•
Diarrhea/colitis and intestinal perforation
•
Pneumonitis/ILD
•
Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency,
hyper- and hypothyroidism and type I DM)
•
Hepatitis/transaminase increases
•
Nephritis/blood creatinine increases
•
Pancreatitis/serum lipase and amylase increases
•
Rash/dermatitis
•
Myocarditis
•
Myositis/polymyositis
•
Neuropathy/neuromuscular toxicity (eg, Guillain-Barré and myasthenia gravis)
•
Other inflammatory responses that are rare/less frequent with a potential
immune-mediated etiology include, but are not limited to, pericarditis, sarcoidosis,
uveitis, and other events involving the eye, skin, hematological, and rheumatological
events.
In addition, infusion-related reactions and hypersensitivity/anaphylactic reactions with a different 
underlying pharmacological etiology are also considered AESIs. 
Further information on these risks (eg, presenting symptoms) can be found in the current version 
of the durvalumab IB. More specific guidelines for their evaluation and treatment are described 
in detail in the Dosing Modification and Toxicity Management Guidelines (see Annex 1). These 
guidelines have been prepared by the Sponsor to assist the Investigator in the exercise of his/her 
clinical judgment in treating these types of toxicities. These guidelines apply to AEs considered 
causally related to the study drug/study regimen by the reporting Investigator. 


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8. 3. 1 4  
S afet y d at a t o be c ollecte d f oll o wi n g t he fi n al D C O of t he st u d y 
F or patie nts c o nti n ui n g t o recei ve d ur val u ma b treat me nt after fi nal D C O a n d data base cl os ure, 
A Es a n d S A Es will c o nti n ue t o be c ollecte d, b ut o nl y S A Es will be re p orte d. I n a d diti o n, it is 
rec o m me nde d t hat t he patie nts c o nti n ue t he sc he d ule d site visits a n d I n vesti gat ors m o nit or t he 
patie nt’s safet y la b orat or y res ults peri o dicall y d uri n g treat me nt wit h d ur val u ma b i n or der t o 
ma na ge A Es i n acc or da nce wit h t he d ur val u ma b D osi n g M o dificati o n a n d T o xicit y Ma na ge me nt 
G ui deli nes (see A n ne x 1). All data p ost t he fi nal D C O a n d data base cl os ure will be rec or de d i n 
t he patie nt n otes b ut, wit h t he e xce pti o n of S A Es ( w hic h will be re p orte d o n pa per), will n ot 
ot her wise be re p orte d f or t he p ur p oses of t his st u d y. 
All S A Es t hat occ ur i n patie nts still recei vi n g d ur val u m a b treat me nt ( a n d wit hi n t he 9 0 da ys 
f oll o wi n g t he last d ose of d ur val u ma b treat me nt) p ost t he fi nal D C O a n d data base cl os ure m ust 
be re p orte d as detaile d i n Secti o n 8. 4. 1 . 
8. 4  
S afet y re p orti n g a n d me dic al m a n a ge me nt  
8. 4. 1  
Re p orti n g of seri o us a d verse e ve nts  
All S A Es m ust be re p orte d, w het her or n ot c o nsi dere d ca usall y relate d t o t he I P, or t o t he st u d y 
pr oce d ure (s). All S A Es will be rec or de d i n t he C R F. C ollecti o n a n d re p orti n g of S A Es after t he 
fi nal D C O is descri be d i n Secti o n 8. 3. 1 4 . 
If a n y S A E occ urs i n t he c o urse of t he st u d y, t he n I n vesti gat ors or ot her site pers o n nel i nf or m t he 
a p pr o priate Astra Ze neca re prese ntati ves wit hi n 1 da y (ie, i m me diatel y b ut n o l ater t h a n 
2 4 h o urs of w he n he or s he bec o mes a ware of it). 
T he desi g nate d Astra Ze neca re prese ntati ve w or ks wit h t he I n vesti gat or t o e ns ure t hat all t he 
nece ssar y i nf or mati o n is pr o vi de d t o t he Astra Ze neca Patie nt Safet y data e ntr y site wit hi n 1  
c ale n d ar d a y  of i nitial recei pt f or fatal a n d life -t hreate ni n g e ve nts a n d wit hi n 5 c ale n d ar  d a ys 
of i nitial recei pt f or all ot her S A Es.  
F or fatal or life -t hreate ni n g AEs w here i m p orta nt or rele va nt i nf or mati o n is missi n g, acti ve 
f oll o w- u p is u n derta ke n i m me diatel y. I n vesti gat ors or ot her site pers o n nel i nf or m Astra Ze neca 
re prese ntati ves of a n y f oll o w- u p i nf or mati o n o n a pre vi o usl y re p orte d S A E wit hi n 1 cale n dar da y 
(ie, i m me diatel y b ut n o l ater t h a n 2 4 h o urs of w he n he or s he bec o mes a ware of it). 
T he f oll o wi n g e- mail a d dre ss s h o ul d be use d f or all ot her cli nical st u d y case re p orts, a n d f or 
re p orti n g of S A Es after t he fi nal D C O; 
 
As a bac k - u p, i n t he e ve nt of a sec ure e- mail li n k is u na vaila ble e. g. d ue t o net w or k iss ues, t he 
f oll o wi n g fa x n u m bers s h o ul d be use d. 
Fa x n u m bers: 
•
P P D
P P D


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F or f urt her g ui da nce o n t he defi niti o n of a S A E, see  A p pe n di x A  of t he Cli nical St u d y Pr ot oc ol. 
8. 4. 2  
Pre g n a nc y  
All pre g na ncies a n d o utc o mes of pre g na nc y s h o ul d be re p orte d t o Astra Ze neca e xce pt f or: 
•
If t he pre g na nc y is disc o vere d bef ore t he st u d y patie nt has recei ve d a n y st u d y dr u g
If a pre g na nc y is re p orte d, t he In vesti gat or sh o ul d i nf or m the S p o ns or w it hi n 2 4 h o urs of 
lear ni n g of t he pr e g na nc y. 
A b n or mal p re g na nc y o utc o mes (eg, s p o nta ne o us ab orti o n, fetal de at h, still birt h, c o n ge nital 
a n o malies,  ect o pic pre g na nc y)  are c o nsi dere d SA Es.  
8. 4. 2. 1  
M at er n al ex p os ure  
If a pa tie nt b ec o mes p re g na nt d ur i n g t he co urse o f the stu d y, t he IP sh o ul d be di sc o nti n ue d 
i m me diatel y. 
Pre g na nc y itself is n ot re gar de d as a n A E u nl ess there is a sus pici o n t hat t he IP u n de r st u d y ma y 
ha ve i nterfere d  wit h the  effecti ve ness of a co ntrace pti ve m e dicati o n. C o n ge nital 
a b n or malities/ birt h defects an d s p o nta ne o us m iscarria ges sh o ul d be re p orte d a n d ha n dle d as 
S A Es. Electi ve ab orti o ns w it h o ut co m plicati o ns s h o ul d n ot b e ha n dle d as A Es. T he o ut c o me o f 
all pre g na ncies (s p o nta ne o us miscarria ge, electi ve ter mi nati o n, ect o pic pr e g na nc y, n or mal bi rt h 
or co n ge nital ab n or malit y) sh o ul d be foll o we d u p an d d oc u me nte d e ve n if t he pa tie nt was 
disc o nti n ue d fr o m t he st u d y. 
If an y pre g na nc y occ urs i n t he co urse of the st u d y, t he n t he I n vesti gat or or other site  pers o n nel 
i nf or ms t he a p pr o priate  Astra Ze neca  represe ntati ves  wit hi n 1 day  (ie, i m me diatel y but n o l ater 
t h a n 2 4 h o urs of  whe n  he or s he bec o mes a ware of  it). 
T he desi g nate d  Astra Ze neca re prese ntati ve w or ks wit h the  I n vesti gat or t o e nsure t hat all rele va nt 
i nf or mati o n is pr o vi de d to  t he Astra Ze neca Patie nt Safet y  data entr y  site wit hi n 1 or 5 cale n dar 
da ys f or  SA Es (see Secti o n  8. 4. 1 ) a n d wit hi n 3 0 da ys f or all ot her pre g na ncies. 
T he sa m e ti meli nes a p pl y whe n  o utc o me i nf or mati o n  is a vaila ble. 
8. 4. 2. 2  
P ater n al  e xp os ure  
Male pa tie nts sh o ul d refrai n fr o m fat heri n g a c hil d or d o na ti n g s per m d u ri n g t he st u d y an d f or 
1 8 0 da ys after  the  last dose of  d ur val u ma b  + tre meli m u ma b c o m bi nati o n t hera p y or 9 0 da ys after  
t he last d os e of d ur val u ma b m o n ot hera p y, w hic he ver is t he l o n ger ti me peri o d.  
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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 180 days after the last dose 
of durvalumab + tremelimumab combination therapy or 90 days after the last dose of 
durvalumab monotherapy, whichever is the longer time period 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. 
Patients who are permanently discontinued from further receipt of IP, regardless of the reason, 
will be identified as having permanently discontinued treatment and will enter follow-up (see the 
SoAs). 
8.4.3 
Overdose 
8.4.3.1 
Durvalumab 
Use of durvalumab in doses in excess of that specified in the protocol is considered to be an 
overdose. There is currently no specific treatment in the event of an overdose of durvalumab, and 
possible symptoms of overdose are not established.  
•
An overdose with associated AEs is recorded as the AE diagnosis/symptoms on the
relevant AE modules in the CRF and on the Overdose CRF module.
•
An overdose without associated symptoms is only reported on the Overdose CRF
module.
If an overdose on an AstraZeneca study drug occurs in the course of the study, then the 
Investigator or other site personnel inform appropriate AstraZeneca representatives immediately, 
or no later than 24 hours of when he or she becomes aware of it. 
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is provided to the AstraZeneca Patient Safety data entry site. 
For overdoses associated with an SAE, the standard reporting timelines apply, see Section 8.3.2. 
For other overdoses, reporting must occur within 30 days. 
8.4.4 
Management of durvalumab-related toxicities  
The following general guidance should be followed for the management of toxicities. 
•
Treat each of the toxicities with maximum supportive care (including holding the
agent suspected of causing the toxicity if required).


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•
If the symptoms promptly resolve with supportive care, consideration should be given
to continue the same dose of the assigned IP along with appropriate continuing
supportive care. If medically appropriate, dose modifications are permitted.
•
All dose modifications should be documented with clear reasoning and documentation
of the approach taken.
All toxicities will be graded according to NCI CTCAE, version 5.0 (see Annex 1).  
8.4.4.1 
Specific toxicity management and dose modification information – Durvalumab 
Comprehensive toxicity management guidelines (TMGs) have been developed to assist 
investigators with the recognition and management of toxicities associated with use of the 
immune checkpoint inhibitors. Given the similar underlying mechanism of toxicities observed 
with these 2 compounds, these TMGs are applicable to the management of patients receiving 
either drug as monotherapy or both drugs in combination. Additionally, these guidelines are 
applicable when either drug is used alone or both drugs are used in combination and, also other 
anticancer drugs (ie, antineoplastic chemotherapy, targeted agents) are administered concurrently 
or sequentially as part of a protocol-specific treatment regimen. The TMGs provide information 
for the management of immune-mediated reactions, infusion-related reactions, and non-immune-
mediated reactions that may be observed with checkpoint inhibitor monotherapy or combination 
checkpoint inhibitor regimens, with specific instructions for checkpoint inhibitor-specific dose 
modifications (including discontinuation) and treatment interventions. Investigators are advised 
however to use local practice guidelines and consult local references for the management of 
toxicities observed with other anticancer treatment. 
The most current version of the TMGs is provided to the investigative site as an Annex to 
Protocol document entitled, “Dosing Modification and Toxicity Management Guidelines for 
Immune-Mediated, Infusion-Related, and Non-Immune–Mediated Reactions (MEDI4736 
Monotherapy or Combination Therapy with Tremelimumab or Tremelimumab Monotherapy),” 
and is maintained within the Site Master File. In addition, a current version of TMGs is available 
through the following link: https://tmg.azirae.com. Please contact the clinical study associate for 
information on how to gain access to this website. 
Patients should be thoroughly evaluated, and appropriate efforts should be made to rule out 
neoplastic, infectious, metabolic, toxin, or other etiologic causes of the imAE. Serologic, 
immunologic, and histologic (biopsy) data, as appropriate, should be used to support an imAE 
diagnosis. In the absence of a clear alternative etiology, events should be considered potentially 
immune-related. In addition, there are certain circumstances in which durvalumab should be 
permanently discontinued (see Section 7.1 of this protocol and the TMGs). Following the first 
dose of IP, subsequent administration of durvalumab can be modified based on toxicities 
observed as described in the Dosing Modification and Toxicity Management Guidelines (see 
Annex 1). These guidelines have been prepared by the Sponsor to assist the Investigator in the 
exercise of his/her clinical judgment in treating these types of toxicities. These guidelines apply 
to AEs considered causally related to durvalumab monotherapy and the durvalumab combination 
regimen by the reporting Investigator. 


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8.5 
Pharmacokinetics 
Not applicable. 
8.6 
Pharmacodynamics 
Not applicable. 
8.7 
Genetics 
Not applicable. 
8.8 
Biomarkers 
Not applicable. 
9.
STATISTICAL CONSIDERATIONS
9.1 
Sample size determination
The number of patients enrolled in this study will be determined by the number of patients who 
received durvalumab and/or durvalumab in combination with any other approved or 
investigational anticancer agents in original trials, and who wish to participate and who meet the 
eligibility criteria. The study will enroll up to 600 patients and the number of patients may 
increase as new parent studies are included into this long-term safety and efficacy study. 
9.2 
Populations for analyses 
The study population used for statistical analyses in this study is described in Table 11. Full 
details will be provided in the SAP. 
Table 11 
Population for statistical analyses 
Analysis sets 
Description 
Full analysis set 
Patients enrolled in the study. 
Safety analysis set 
Patients who received at least 1 dose of durvalumab on this study or 
enrolled on this study within 90 days of the last dose of durvalumab or 
durvalumab combination on the respective parent clinical study. 
Response evaluable 
analysis seta 
Patients who are retreated with durvalumab in Cohort 2. 
a.
To be performed if there is a sufficient sample size of retreated patients; otherwise, only listings will be
provided.


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9.3 
Statistical analyses 
There are no statistical methods that will be employed to test a specific hypothesis. A 
comprehensive SAP will describe the patient populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a summary of 
the planned statistical analyses of the primary and secondary endpoints. Any deviations from this 
plan will be reported in the CSR. 
9.3.1 
Safety analyses 
Safety data will be summarized according to the treatment received for the safety analysis set (all 
patients who received at least 1 dose of durvalumab either as continuation of study treatment or 
retreatment in this study, and inclusive of patients who received the last dose of durvalumab or 
durvalumab combination from the parent clinical study within 90 days of enrollment [all 
cohorts]). AEs, vital signs, and laboratory safety assessments (clinical chemistry, hematology 
and thyroid-stimulating hormone [reflex free triiodothyronine or free thyroxine]) will be listed 
individually by patient. The number of patients experiencing each AE will be summarized by 
study cohort and CTCAE grade (v5.0) (see Annex 1). 
9.3.2 
Efficacy analyses 
One secondary objective is to assess the efficacy of durvalumab in terms of ORR and DOR for 
retreated patients. The analysis set for ORR and DOR will be based on the patients who undergo 
retreatment with durvalumab in Cohort 2. Data will be summarized by tumor type if there is 
sufficient sample size in each tumor type. ORR will be estimated with a 95% CI using the exact 
probability method. The median DOR and its 95% CI will be estimated using the Kaplan-Meier 
method. ORR and DOR will be assessed in the response evaluable analysis set. If there are not 
sufficient counts of retreated patients to conduct the efficacy analysis, then only listings will be 
provided. Further detail will be provided in the SAP. 
A listing of OS data will be provided for full analysis set. 
In addition, survival and tumor efficacy data in this study may be combined with the parent study 
data for integrated analysis. In the integrated analysis, OS will be described using the 
Kaplan-Meier method. 
Efficacy of durvalumab will be assessed in terms of ORR, DOR, and OS as defined in 
Section 9.3.3. 
9.3.3 
Endpoint measures for analyses 
9.3.3.1 
Calculation or derivation of safety variables 
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, and exposure (ie, durvalumab monotherapy or combination therapy). These will 
be collected for all patients. “On treatment” will be defined as assessments between date of start 
dose and 90 days following discontinuation of IP (ie, the last dose of durvalumab in combination 


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with any other approved or investigational anticancer agents or durvalumab monotherapy). For 
AEs, on treatment (or treatment-emergent AEs) will be defined as any AEs that started after 
dosing or prior to dosing and which worsens following exposure to the treatment. For the change 
from baseline summaries for vital signs, laboratory data, and physical examinations, the baseline 
value will be the latest result obtained prior to the start of study treatment, or the date of 
enrollment if the patient is not to receive study treatment (Cohort 3). The denominator in vital 
signs data should include only those patients with recorded data. 
AEs observed up until 90 days following discontinuation of durvalumab will be used for the 
reporting of the AE summary tables. Any AEs in this period that occur after a patient has 
received subsequent anticancer therapy will be flagged. Reporting and collection of late onset 
toxicity after the 90-day period is described in Section 8.3.2. 
More details will be provided in the SAP. 
9.3.3.2 
Investigator RECIST 1.1-based assessments 
Tumor assessments will be conducted by the Investigator using RECIST v1.1 (Appendix C).  
9.3.3.3 
Objective response rate 
ORR is defined as the number (%) of patients with a confirmed response of CR or PR. Data 
obtained up until progression, or the last evaluable assessment in the absence of progression, will 
be included in the assessment of ORR. Patients who go off treatment without progression, 
receive a subsequent therapy, and then respond will not be included as responders in the ORR.  
9.3.3.4 
Duration of response 
DOR is defined as the time from the date of first documented response (which is subsequently 
confirmed) until the first date of progression or death in the absence of disease progression. DOR 
will not be defined for patients who do not have documented response. 
9.3.3.5 
Overall survival 
OS is defined as the time from date of randomization/enrollment in the parent clinical study until 
the date of death by any cause.  
9.4 
Interim analyses 
There are 5 interim analyses planned for this study, anticipated to occur annually starting 1 year 
after the first patient is enrolled. No formal statistical adjustments will be made for these interim 
looks and additional analyses may be performed for the purpose of better characterizing the 
safety of these patients with long-term follow-up. The SAP will describe the planned interim 
analyses in greater detail.  


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9.4.1 
Data monitoring committee 
Review of safety data will be conducted in accordance with AstraZeneca’s Pharmacovigilance 
process (Section 8.1).  


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10.
REFERENCES
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Alexandrov et al 2013 
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Blankin AV, et al. 
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Brahmer et al 2012 
Brahmer JR, Tykodi SS, Chow LQM, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
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Dunn et al 2004 
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
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Fairman et al 2014 
Fairman D, Narwal R, Liang M, Robbins PB, Schneider A, Chavez C, et al. Pharmacokinetics of 
durvalumab, a fully human anti-PDL1 monoclonal antibody, in patients with advanced solid 
tumors. J Clin Oncol, 2014 ASCO Annual Meeting Abstracts;32(5s): (suppl; abstr 2602).  
Forde et al 2014 
Forde PM, Kelly RJ, Brahmer JR. New strategies in lung cancer: translating immunotherapy 
into clinical practice. Clin Cancer Res 2014;20(5):1067-73. 
Hirano et al 2005 
Hirano F, Kaneko K, Tamura H, Dong H, Wang S, Ichikawa M, et al. Blockade of B7-H1 and 
PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. Cancer Res 
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Hodi et al 2010 
Hodi FS, O’Day SJ, McDermott DF, Weber RW, Sosman JA, Haanan JB, et al. Improved 
survival with ipilimumab in patients with metastatic melanoma [published erratum appears in 
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Iwai et al 2002 
Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. Involvement of PD-L1 on tumor 
cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. 
Proc Natl Acad Sci USA 2002;99:12293-7. 
Keir et al 2008 
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
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Narwal et al 2013 
Narwal R, Roskos LK, Robbie GJ. Population pharmacokinetics of sifalimumab, an 
investigational anti-interferon alpha monoclonal antibody, in systemic lupus erythematosus. Clin 
Pharmacokinet 2013;52:1017-27. 
Ng et al 2006 
Ng CM, Lum BL, Gimenez V, Kelsey S, Allison D. Rationale for fixed dosing of pertuzumab in 
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Okazaki and Honjo 2007 
PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 2007;19(7) :813-24. 
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Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-H1 
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Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
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Powles et al 2014 
Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) 
treatment leads to clinical activity in metastatic bladder cancer. Nature 2014;515(7528):558-62. 
Qin et al 2016 
Mechanisms of immune evasion and current status of checkpoint inhibitors in non-small cell 
lung cancer. Cancer Med 2016;9:2169–70. 
Rizvi et al 2015 
Rizvi N, Brahmer J, Ou S-H, Segal NH, Khleif SN, Hwu WJ. Safety and clinical activity of 
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Santini 2018 
Fernando C. Santini. Safety and Efficacy of Re-treating with Immunotherapy after Immune-
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Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
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Stewart et al 2015 
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification and 
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Zhang et al 2008 
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Antitumor immunotherapy by blockade of the 
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11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS
11.1 
Study management 
This study will be performed by AstraZeneca’s representative with the guidance, input, review 
and approval of AstraZeneca, including development of materials, recruitment, training and 
management of sites, EDC and data management and analysis.  
11.1.1 
Data entry/electronic data capture 
All data will be collected and entered directly into the EDC system. All participating sites will 
have access to the data entered regarding the individual site its own enrolled patients. All sites 
will be fully trained on using the on-line data capture system, including eCRF completion 
guidelines and help files. Sites will be responsible for entering extracted patient data into a 
secure internet-based EDC registry database via the eCRF. Investigators and site personnel will 
be able to access their account with a username and password. All eCRFs should be completed 
by designated, trained personnel or the study coordinator, as appropriate. In most cases, the 
eCRF should be reviewed, electronically signed, and dated by the Principal Investigator. All 
changes or corrections to eCRFs are documented in an audit trail and an adequate explanation is 
required. 
11.1.2 
Source documents 
In most cases, the source documents are contained in the patient’s medical record and data 
collected on the CRFs must match the data in the medical records. In some cases, the CRF, or 
part of the CRF, may also serve as source documents. In these cases, a document should be 
available at the Investigator’s site and clearly identifying those data that will be recorded in the 
CRF, and for which the CRF will stand as the source document. All original source 
documentation is expected to be stored at the site for the longest possible time required by local 
applicable regulations.  
11.1.3 
File retention and archiving 
To enable evaluations and/or audits from regulatory authorities or AstraZeneca, the Investigator 
agrees to keep records, including the identity of all participating patients, all original signed 
ICFs, copies of all CRFs, SAE forms, source documents and adequate documentation of relevant 
correspondence (eg, letters, meeting minutes, telephone calls reports). The records should be 
retained by the Investigator according to local regulations, or as specified in the study contract, 
whichever is longer. 
Each site will receive a study site file at study initiation which contains all documents necessary 
for the conduct of the registry and is updated throughout the study. This file must be available for 
review in the event the site is selected for monitoring, audits, or inspections and must be safely 
archived for at least 5 years after the completing participation in the study. Documents to be 
archived include the patient enrollment log and the signed ICF. In the event that archiving of the 
file is no longer possible at the site, the site will be instructed to notify AstraZeneca. 


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11.1.4 
Quality assurance and monitoring 
A study monitoring plan, including for-cause monitoring, that is appropriate for the study design 
will be developed and implemented.  
During the site initiation visit (performed remotely with the exception of sites in Japan), the 
monitor will provide training on the conduct of the study to the Investigator, co-Investigator(s), 
and all site staff involved in the study. In order to ensure the integrity of the data, sites will be 
monitored. Remote site monitoring will be performed by AstraZeneca’s representative to 
examine compliance with the protocol and adherence to the data collection procedures, to assess 
the accuracy and completeness of submitted clinical data, and to verify that records and 
documents are being properly maintained for the duration of the study. The monitor will perform 
source data verification by review of original patient records. 
The monitor will close out each site (performed remotely with the exception of sites in Japan) 
after the last patient’s final follow-up assessment is completed, all data have been entered and all 
outstanding monitoring issues have been resolved or addressed. All monitoring procedures and 
frequency of monitoring visits will be described in a monitoring plan. Monitor contact details for 
each participating site will be maintained in the Investigator Site File. 
Representatives of AstraZeneca’s quality assurance unit/monitoring team and competent 
regulatory authorities must be permitted to inspect all study-related documents and other 
materials at the site, including the Investigator Site File, the completed eCRFs and the patients’ 
original medical records. Audits may be conducted at any time during or after the study to ensure 
the validity and integrity of the study data. 
11.1.5 
Data management 
A data management plan will be created before data collection begins and will describe all 
functions, processes, and specifications for data collection, cleaning and validation. The eCRFs 
will include programmable edits to obtain immediate feedback if data are missing, out of range, 
illogical or potentially erroneous. Concurrent manual data review will be performed based on 
parameters dictated by the plan. Ad hoc queries will be generated within the EDC system and 
followed up for resolution.  
High data quality standards will be maintained, and processes and procedures utilized to 
repeatedly ensure that the data are as clean and accurate as possible when presented for analysis. 
Data quality will be enhanced through a series of programmed data quality checks that 
automatically detect out of range or anomalous data.  
11.1.6 
Changes to the protocol 
Changes to the protocol will be documented in written protocol amendments. Major (ie, 
substantial, significant) amendments will usually require submission to the relevant IRB/IECs for 
approval or favorable opinion. In such cases, the amendment will be implemented only after 
approval or favorable opinion has been obtained. 


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Minor (non-substantial) protocol amendments, including administrative changes, will be filed by 
at each participating site and will be submitted to the relevant IRB/IEC or regulatory authorities 
where required by pertinent regulations. Any amendment that could have an impact on the 
patient’s agreement to participate in the study requires the patient’s informed consent prior to 
continued participation in the study. 
11.1.7 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before submission. 
This allows the Sponsor to protect proprietary information and to provide comments. 
The Sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the Sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating Investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
12.
ETHICAL AND REGULATORY CONSIDERATIONS
12.1 
Guiding principles
To ensure the quality and integrity of research, this study will be conducted under the guidelines 
good pharmacoepidemiology practices issued by the International Society for 
Pharmacoepidemiology, the Declaration of Helsinki and its amendments, and any applicable 
national guidelines. 
The study will be conducted in compliance with the US FDA Title 21 Code of Federal 
Regulations Part 50 – Protection of Human Patients and/or Part 56 –IRB; the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) E6(R2) guidelines 
(15 December 2016) as they apply to non-interventional studies; the Declaration of Helsinki and 
its amendments; and the Health Insurance Portability and Accountability Act of 1996. 
12.2 
Required documents 
Prior to the enrollment of any patients in the study, the following documents must be provided 
by the site to the Sponsor (or their designee): 
•
Copy of the IRB/IEC approval letter for the protocol and informed consent (all written
information provided to the patient must be approved by the IRB/IEC)
•
Copy of the IRB/IEC-approved informed consent document to be used
•
Copy of the protocol sign-off page signed by the Investigator


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•
Fully executed site agreement
12.3 
Financial disclosure 
Investigators and sub-investigators will provide the Sponsor with sufficient, accurate financial 
information as requested to allow the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
12.4 
Patient information and informed consent 
An ICF must be signed by the patient (or the patient’s legally authorized representative) before 
his or her participation in the study. The medical file for each patient should document the 
informed consent process and that written informed consent was obtained prior to participation 
in the study. A copy of each signed ICF must be provided to the patient or the patient’s legally 
authorized representative. If applicable, it will be provided in a certified translation of the local 
language. All signed and dated ICFs must remain in each patient’s study file and must be 
available for verification by study monitors at any time. 
The ICF should be revised whenever there are changes to procedures outlined in the informed 
consent or when new information becomes available that may affect the willingness of the 
patient to participate. For any updated or revised ICFs, the medical file for each patient should 
document the informed consent process and that written informed consent was obtained for the 
updated/revised ICF for continued participation in the study. 
12.5 
Patient confidentiality 
In order to maintain patient confidentiality, each patient will be assigned a unique patient 
identifier upon study enrollment. This patient identifier will be used in place of patient name for 
the purpose of data analysis and reporting. Medical record number or other local reference 
identifiers are not collected as part of the database. All parties will ensure protection of patient 
personal data and will not include patient names on any study forms, reports, publications, or in 
any other disclosures, except where required by law. In accordance with local regulations in each 
of the registry countries, patients will be informed about data handling procedures and asked for 
their consent. Data protection and privacy regulations will be observed in capturing, forwarding, 
processing, and storing patient data. Every effort will be made to protect participant 
confidentiality according to the Regulation (EU) 2016/679 (of the European Parliament and of 
the Council of 27 April 2016 on the protection of natural persons with regard to the processing of 
personal data and on the free movement of such data, and repealing Directive 95/46/EC (General 
Data Protection Regulation)), and refer to the European Commission “Standard Contractual 
Clauses” with respect to data transfers to Non-EU countries where appropriate. 
The database will be housed at the AstraZeneca’s representative in a physically and logically 
secure computer system maintained by AstraZeneca’s representative in accordance with a 
written security policy. The system meets approved established standards for the security of 


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health information and is validated. The system also meets the standards of the ICH GCP E6 
guideline (revision 2) regarding electronic study data handling and is available for audit upon 
request. Patient confidentiality will be strictly maintained.  
12.6 
Independent ethics committee (IEC)/institutional review board (IRB) 
Consistent with local regulations and prior to enrollment of patients at a given site, the study 
protocol will be submitted together with its associated documents (eg, ICF) to the responsible 
IRB/IEC for its review. Patient enrollment will not start at any site before the Client has obtained 
written confirmation of a favorable opinion/approval from the relevant central or local IRB/IEC. 
The IRB/IEC will be asked to provide documentation of the date of the meeting at which the 
favorable opinion/approval was given that clearly identifies the study, the protocol version, and 
the ICF version reviewed. 
Before implementation of any substantial changes to the protocol, protocol amendments will also 
be submitted to the relevant IRB/IEC in a manner consistent with local regulations. Pertinent 
safety information will be submitted to the relevant IECs during the course of the study in 
accordance with local regulations and requirements. It is the responsibility of the Investigator to 
have prospective approval of the study protocol, protocol amendments, and ICF, and other 
relevant documents, if applicable, from their local IRB/IEC and provide documentation of 
approval to AstraZeneca’s representative. All correspondence with the IRB/IEC should be 
retained in the Investigator file.  
Should the study be terminated early for any unanticipated reason, the Investigator will be 
responsible for informing the IRB/IEC of the early termination. 

SAP_001.pdf: 
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Statistical Analysis Plan
Study Code
D910FC00001
Edition Number
2.0
Date
23/11/2022
An Open-Label, Multi-Center, Global Study to Evaluate Long 
Term Safety and Efficacy in Patients Who are Receiving or Who 
Previously Received Durvalumab in Other Protocols (WAVE)


Statistical A nal ysis Pla n 
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C O N FI D E N TI A L A N D P R O P RI E T A R Y
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A n  Op e n -L a bel, M u lti-Ce nter, Gl o b al St u d y t o E v al u ate L o n g Ter m S afet y 
a n d Effic ac y i n P atie nts W h o 
are Recei vi n g or W h o 
Pre vi o usl y Recei ve d 
D u r v al u m a b i n Ot her Pr ot oc ols ( W A V E)
St u d y St atistici a n (I Q VI A)
Date
St u d y St atistici a n ( A Z)
Date
Gl o b al Pr o d uct St atistici a n ( A Z)
Date
P P D
P P D
P P D


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TABLE OF CONTENTS
SIGNATURE OF STUDY STATISTICIAN......................................................................... 2
1
STUDY DETAILS ............................................................................................. 6
1.1
Study objectives.................................................................................................. 6
1.2
Study design ....................................................................................................... 7
1.3
Number of subjects............................................................................................. 8
2
ANALYSIS SETS .............................................................................................. 8
2.1
Definition of analysis sets ................................................................................... 8
2.1.1
Full Analysis Set (FAS)...................................................................................... 8
2.1.2
Response evaluable analysis set .......................................................................... 8
2.1.3
Safety Analysis Set (SAS) .................................................................................. 8
2.2
Violations and deviations.................................................................................... 9
3
PRIMARY AND SECONDARY VARIABLES ............................................... 12
3.1
Efficacy variables ............................................................................................. 12
3.1.1
Objective response rate (ORR).......................................................................... 12
3.1.2
Duration of response (DOR) ............................................................................. 13
3.1.2.1
Time to response (TTR).................................................................................... 13
3.1.3
Overall survival (OS)........................................................................................ 14
3.2
Safety variables ................................................................................................ 16
3.2.1
Adverse events.................................................................................................. 16
3.2.2
Physical examinations....................................................................................... 18
3.2.3
Vital signs......................................................................................................... 19
3.2.4
Laboratory safety assessments .......................................................................... 19
3.2.5
Durvalumab exposure....................................................................................... 20
3.2.6
Relative Dose Intensity (RDI)........................................................................... 21
4
OTHER ASSESSMENTS................................................................................. 21
5
ANALYSIS METHODS................................................................................... 24
5.1
General principles............................................................................................. 24
5.2
Analysis methods.............................................................................................. 25
5.2.1
Overall survival (OS)........................................................................................ 25
5.2.2
Objective response rate (ORR).......................................................................... 25
5.2.3
Duration of response (DOR) ............................................................................. 25
5.2.4
Time to response (TTR).................................................................................... 26
5.2.5
Safety ............................................................................................................... 26
5.2.6
Demographics and baseline characteristics........................................................ 27
5.2.7
Concomitant and other treatments, and concomitant procedures........................ 28
5.2.8
Exposure........................................................................................................... 28
5.2.9
Subsequent therapy........................................................................................... 28
6
INTERIM ANALYSES.................................................................................... 28
7
CHANGES OF ANALYSIS FROM PROTOCOL............................................ 28


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8
REFERENCES................................................................................................. 29
9
APPENDIX ...................................................................................................... 29
9.1
List of AESI ..................................................................................................... 29
LIST OF TABLES
TABLE 1. STUDY OBJECTIVES AND ENDPOINTS..........................................................6
TABLE 2. PARENT STUDY ASSESSMENTS....................................................................21
LIST OF FIGURES
FIGURE 1: STUDY DESIGN.................................................................................................8
LIST OF ABBREVIATIONS
Abbreviation or special 
term
Explanation
AE
Adverse Event
AESI
AE of Special Interest
ATC
Anatomical Therapeutic Chemical
CI
Confidence Interval
CR
Complete Response
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTMS
Clinical Trial Management System
DCO
data cut-off
DOR
Duration of response
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
FAS
Full Analysis Set
GI
Gastro-Intestinal
HbsAg
Hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus


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Abbreviation or special 
term
Explanation
IP
Investigational Product
IxRS
Interactive Voice/Web Response System
KM
Kaplan Meier
MedDRA
Medical Dictionary for Regulatory Activities
NED
No Evidence of Disease
ORR
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PE
Physical Examination 
PR
Partial Response
RDI
Relative Dose Intensity
SAE
Serious Adverse Events
SAP
Statistical Analysis Plan
SAS
Safety Analysis Set
SD
Stable Disease
Sd
Standard Deviation
SDTM
Study Data Tabulation Model
SoAs
Schedule of Activities
TTR
Time To Response
AMENDMENT HISTORY
Date
Brief description of change
04 Nov 2022

The characteristics at the baseline have been clarified.

Durvalumab exposure actual treatment duration was updated to better clarify 
how the variable is derived, adding an additional step. 

In the “Violations and deviations” section, a text was added to clarify that 
despite starting date comes from parent studies, the analyzed data only come 
from WAVE study. Additionally, the protocol deviations process was 
updated according to the new standards used to capture subject and site 
important protocol deviations using the Clinical Trial Management System 
(CTMS) data. Protocol deviations (2 and 3) wording was improved.

Adverse events definition was updated, clarifying the period time. 

In the “Overall Survival” (OS) section, for the single-arm parent studies the 
calculation wording of OS was improved.


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1
STUDY DETAILS
1.1
Study objectives
The study objectives will be assessed among 3 cohorts defined according to treatment status, 
these cohorts are described in Section 1.2.
The objectives of this study as well as corresponding endpoints are as follows: 
Table 1. Study objectives and endpoints
Primary objective
Endpoints/Variables:
To monitor long term safety of durvalumab (all
cohorts)

All SAEs

Non-serious AEs that lead to dose 
modification, drug discontinuation, or 
withdrawal from the study

All Grade 3 and Grade 4 AEs

Grade 2 AEs that affect vital organs (eg, 
heart, liver)

Immune-mediated AEs

Laboratory findings qualifying as an 
SAE/AE (endpoints defined above) up until 
90 days after the last dose of durvalumab in 
all patients
Secondary Objectives:
Endpoints/Variables:
To assess the efficacy of durvalumab in terms
of ORR and DOR in patients who undergo
retreatment with durvalumab (Cohort 2 only)
ORR: Number (%) of patients with a confirmed
response of CR or PR.
DOR: Time from first documented CR or PR to 
time of first documented disease progression or 
death in the absence of disease progression
To assess the OS of patients (all cohorts)
OS: Time from date of
randomization/date of first dose a in the parent 
clinical study until the date of death by any 
cause
AE adverse event; CR complete response; DOR duration of response; ORR Objective response rate; OS overall 
survival; PR partial response; SAE serious adverse event.
a For randomized parent studies, the randomization date will be used in the calculation of OS. For single-arm 
parent studies, the date of first dose will be used in the calculation of OS.


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1.2
Study design
This is a multi-center, open-label study that will enroll patients who are currently receiving 
durvalumab or have previously received durvalumab as monotherapy or in combination with 
other agents in an eligible AstraZeneca/MedImmune-sponsored clinical study (herein referred 
to as “a parent clinical study”).
The general study design for this study is summarized in Figure 1. Patients may enroll under 
one of three cohorts described as follows:

Cohort 1: includes patients who received durvalumab monotherapy or durvalumab 
combination therapy under the parent clinical study (including those undergoing
retreatment per the parent study) who have not clinically progressed and who are 
eligible to continue durvalumab treatment after completing dosing of all other 
anticancer agents, including other investigational agents, which are a formal 
component of the parent study. If a patient was already retreated with durvalumab in 
the parent clinical study and has not progressed while on treatment, then they would be 
potentially eligible to enter Cohort 1; a combination treatment course initiated in the 
parent clinical study must be completed prior to study entry.

Cohort 2: includes patients who completed durvalumab monotherapy or in 
combination with any other approved or investigational anticancer agents in a parent 
study, without confirmed progressive disease (PD) during the period of treatment, and 
who are potentially eligible for retreatment with durvalumab. The patient should not 
have received any other approved or investigational anticancer agents since 
completion of durvalumab treatment. Patients who completed the prespecified duration 
of treatment with durvalumab in a parent clinical study, who received clinical benefit 
and then subsequently experienced confirmed PD after completion of planned 
treatment, will be permitted to restart durvalumab treatment provided they meet the 
eligibility criteria. If a patient was already retreated with durvalumab in the parent 
clinical study and retreatment has ended, they are no longer eligible for retreatment in 
this study.

Cohort 3: includes patients previously treated with durvalumab monotherapy or in 
combination with any other approved or investigational anticancer agents who are no 
longer receiving durvalumab and are not eligible to receive retreatment.


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Figure 1: Study design
1.3
Number of subjects
This study will enroll patients who have been previously treated with durvalumab and/or 
durvalumab in combination with any other approved or investigational anticancer agents in 
any parent clinical study at any global site. The study will initially enroll approximately 600 
patients.
2
ANALYSIS SETS
2.1
Definition of analysis sets
2.1.1
Full Analysis Set (FAS) 
The FAS will include all patients enrolled in the study, regardless of the treatment received.
OS analysis will be performed on the FAS. In addition, demographic and patient 
characteristics will be summarized amongst the FAS population.
2.1.2
Response evaluable analysis set
The response evaluable analysis set will consist of patients who are retreated with durvalumab 
in Cohort 2. This will be the analysis set for ORR and DOR.
2.1.3
Safety Analysis Set (SAS) 
The SAS will consist of patients who received at least 1 dose of durvalumab on this study or 
enrolled on this study within 90 days of the last dose of durvalumab or durvalumab 
combination on the respective parent clinical study. The primary objective analysis will be 
assessed in the SAS.


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2.2
Violations and deviations
The following general categories will be considered important protocol deviations; such 
protocol deviations will be reviewed and categorized by the medical team, and the 
Epidemiology team based on data from the Clinical Trial Management System (CTMS) data, 
and finally confirmed with the site management team. Subject and site level protocol 
deviations are collected from the CTMS. Subject-level protocol deviations   will be listed and 
discussed in the clinical study report (CSR) as appropriate:

Deviation 1: Patients who deviate from key entry criteria per the Clinical Study 
Protocol (CSP). Key entry criteria are the following (please refer to the CSP for more 
details):
o
Patient received durvalumab monotherapy and/or durvalumab containing 
combination in an AstraZeneca/MedImmune-sponsored parent clinical study that is 
approved for enrollment into this study.
o
Patients who received durvalumab in combination with any other approved or 
investigational anticancer agents in the parent clinical study must have completed 
or discontinued all other anticancer therapy (beyond durvalumab regimen).
[Additional inclusion criteria for patients entering Cohort 1]
o
Currently receiving durvalumab monotherapy (this includes patients enrolled in 
durvalumab combinations who have completed or discontinued all other anticancer 
therapy combined with durvalumab in the parent clinical study, and are now 
receiving durvalumab monotherapy), and is currently benefiting from treatment 
with durvalumab therapy, as determined by the Investigator.
[Additional inclusion criteria for patients entering Cohort 1 and Cohort 2]
o
Adequate organ function (see detailed definition in the CSP)
o
Evidence of postmenopausal status or negative urinary or serum pregnancy test for 
female premenopausal patients.
o
World Health Organization / Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of ≤2 at enrolment
[Additional inclusion criteria for retreatment patients in Cohort 2]
o
Received durvalumab in a parent clinical study that is approved to enroll into this 
study
o
Completed the defined treatment duration with durvalumab monotherapy or 
durvalumab combination therapy in the parent clinical study (see more details in 
the CSP)
o
At least 1 lesion that can be accurately measured at baseline as ≥10 mm in the 
longest diameter (except lymph nodes which must have a short axis ≥15 mm) with 
computed tomography or magnetic resonance imaging), and that is suitable for 
accurate repeated measurements as per RECIST v1.1 guidelines.


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In addition, patients are considered as with deviation if any of the exclusion criteria 
are met:
o
Involvement in the planning and/or conduct of the study (applies to both 
AstraZeneca staff and/or staff at the study site).
[Additional exclusion criteria for Cohort 1 and Cohort 2]
o
Currently receiving treatment in another interventional clinical study other than a 
parent clinical study, or received treatment during the follow-up period before 
retreatment (Cohort 2 only).
o
Experienced an immune-mediated or non-immune-mediated (hematologic and 
non-hematologic) toxicity that led to permanent discontinuation of durvalumab in 
the parent clinical study.
o
With any unresolved toxicity National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) Grade ≥2 from previous 
anticancer therapy with the exception of alopecia, vitiligo, and the laboratory 
values defined in the inclusion criteria
o
Prior treatment with immunotherapy other than durvalumab, or any other approved 
or investigational anticancer agents other than MedImmune/AstraZeneca’s 
investigational immunotherapy molecules administered in the parent clinical study
o
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, 
or Wegener syndrome [granulomatosis with polyangiitis, Graves’ disease, 
rheumatoid arthritis, hypophysitis, uveitis, etc]). The following are exceptions to 
this criterion:
(a) Patients with vitiligo or alopecia.
(b) Patients with hypothyroidism (eg, following Hashimoto syndrome) stable 
on hormone replacement.
(c) Any chronic skin condition that does not require systemic therapy.
(d) Patients without active disease in the last 5 years may be included but only   
after consultation with the Study Physician.
(e) Patients with celiac disease controlled by diet alone.
o
History of allogenic organ transplantation
o
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, uncontrolled hypertension, 
unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung 
disease, serious chronic Gastro Intestinal (GI) conditions associated with diarrhea, 
or psychiatric illness/social situations that would limit compliance with study 
requirement, substantially increase risk of incurring AEs or compromise the ability 
of the patient to give written informed consent.


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o
Documented active infection including tuberculosis (clinical evaluation that 
includes clinical history, physical examination(PE) and radiographic findings, and 
tuberculosis testing in line with local practice), hepatitis B virus (HBV) (known 
positive HBV surface antigen [HbsAg] result), hepatitis C virus (HCV), or human 
immunodeficiency virus (HIV) (positive HIV 1/2 antibodies). Patients with a past 
or resolved HBV infection (defined as the presence of hepatitis B core antibody 
and absence of HbsAg) are eligible. Patients positive for HCV antibody are eligible 
only if polymerase chain reaction is negative for HCV RNA. Prior HIV and 
HBV/HCV testing from the parent clinical study is acceptable documentation and 
patients will not need to undergo an additional testing prior to Cohort 1 enrollment 
in this study. For Cohort 2 patients, prior HIV testing from the parent clinical study 
is acceptable documentation and patients will not need to undergo an additional 
test prior to retreatment. However, patients will require retesting for HbsAg and 
HCV within the 28-day window prior to retreatment
o
Receipt of live attenuated vaccine within 30 days prior to the first dose of study 
drug in the present study. Note: Patients, if enrolled, should not receive live 
vaccine while receiving study drug and up to 90 days after the last dose of study 
drug
o
Female patients who are pregnant or breastfeeding, or male or female patients of 
reproductive potential who are not willing to employ effective birth control from 
screening to 90 days after the last dose of durvalumab monotherapy or 180 days 
after the last dose of durvalumab + tremelimumab combination.
o
Diagnosis of a new primary malignancy since enrollment into the parent clinical 
study, with the exception of adequately treated non-melanomatous skin cancer and 
carcinoma in situ with No Evidence of Disease (NED).
o
Must not have required the use of additional immunosuppression other than 
corticosteroids for the management of an AE >Grade 1, have not experienced 
recurrence of an AE if re-challenged, and not currently require maintenance doses 
of >10 mg prednisone or equivalent per day
o
Known allergy or hypersensitivity to any of the study drugs or any of the study 
drug excipients

Deviation 2: Baseline RECIST scan date is greater than 28 days before the date of 
starting Cycle 1 of retreatment for Cohort 2, during the WAVE study period.

Deviation 3: No baseline RECIST 1.1 assessment on or before the date of starting 
Cycle 1 of retreatment (Cohort 2), during the WAVE study period.

Deviation 4: Received prohibited concomitant medications (including other anticancer
agents). Please refer to the CSP Section 6.4 for those medications that are detailed as 
being ‘excluded’ from permitted use during the study. This will be used as a guiding 
principle for the medical data reviewer of all medications prior to database lock. 
All the violations and deviations considered only come from WAVE without taking into 
account data from parent studies. The important subject-level protocol deviations will be listed
and summarized by treatment group (study cohort) in the main part of the CSR. All 


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participants with important protocol deviations will be listed by center, as an appendix. Site 
level protocol deviations are collected from the CTMS. The important site level protocol 
deviations will be listed, as an appendix of the CSR. 
3
PRIMARY AND SECONDARY VARIABLES
3.1
Efficacy variables 
3.1.1
Objective response rate (ORR)
ORR is defined as the percentage of patients with a confirmed investigator-assessed response 
of complete response (CR) or partial response (PR) from the date of re-initiation of treatment 
with durvalumab monotherapy. ORR will be assessed in the response evaluable analysis set 
(patients who are retreated with durvalumab in Cohort 2).
A confirmed response of CR/PR means that a response of CR/PR is recorded at one visit and 
confirmed by repeat imaging not less than 4 weeks after the visit when the response was first 
observed with no evidence of progression between the initial and CR/PR confirmation visit. 
Data obtained up until progression, or last evaluable assessment in the absence of progression, 
will be included in the assessment of ORR. Patients who discontinue treatment without 
progression, receive a subsequent anticancer therapy (note that for this analysis radiotherapy is 
not considered a subsequent anticancer therapy) and then respond will not be included as 
responders in the ORR (i.e., both visits contributing to a response must be prior to subsequent 
therapy for the patient to be considered as a responder).
In the case where a patient has two non-consecutive visit responses of PR, then, as long as the 
time between the 2 visits of PR is greater than 4 weeks and there is no PD between the PR 
visits, the patient will be defined as a responder. Similarly, if a patient has visit responses of 
CR- Not evaluable (NE), CR, then, as long as the time between the 2 visits of CR is greater 
than 4 weeks, then a best response of CR will be assigned.
CR and PR can be assessed using the following Electronic Case Report Form (eCRF)
modules:

Overall Exam Assessment (OVERALL):
Overall Assessment of Target and Non-Target Lesions
o
Assess Target Lesions as a Whole (CR; PR; PD; Stable Disease [SD]/ Not 
Evaluable)
o
Assess Non-Target Lesions as a Whole (CR/PD/ Non-CR/Non-PD; Not Evaluable)
o
Overall Tumor Response Assessment (CR; PR; PD; SD; NED); Not Evaluable
o
Latest Scan Date for the Timepoint
o
Progression Scan Date


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
Tumor Evaluation: New Lesions and Investigator Assessment of Response 
(RECIST2)
Overall visit response
o
RECIST response (CR; PR; PD; SD(Non-CR/Non-PD); Not evaluable)
o
Investigator's opinion agrees with RECIST response (yes/no)
o
Investigator’s opinion of patient status (Responding; Stable; Progressing)
3.1.2
Duration of response (DOR)
DOR will be assessed in the response evaluable analysis set (patients who are retreated with 
durvalumab in Cohort 2). To be consistent with RECIST 1.1 guidelines, the starting point for 
DOR is the first time at which the visit response is PR or CR.
DOR will be defined as the time from the date of first documented (which is subsequently 
confirmed) CR or PR until date of documented progression or death in the absence of disease 
progression (i.e. date of documented disease progression or death in the absence of disease 
progression, or censoring – date of first response + 1). DOR will be expressed in months.
The time of the initial response will be defined as the latest of the dates contributing towards 
the first visit that was CR or PR that was subsequently confirmed.
If a patient does not progress or die following a response, then their DOR analysis will be 
censored at the time of the latest date of assessment from their last evaluable RECIST 
assessment. However, if the patient progresses or dies immediately after two or more 
consecutive missed visits, the patient will be censored at the time of the latest evaluable 
RECIST 1.1 assessment prior to the two missed visits. The minimum elapsed time from the 
previous RECIST 1.1 assessment defined as two missed visits is calculated as 2 * (the 
protocolled time between scans + the protocol allowed visit window): 2 * 12 = 24 weeks.
Note: NE visit is not considered as missed visit.
Same eCRF modules described in Section 3.1.1 will be used to retrieve the date of first 
documented CR or PR, the date of the latest evaluable RECIST 1.1 assessment, as well as the 
date of progression (if any). The date of death will be retrieved from “DEATH” module of the 
e-CRF.
3.1.2.1
Time to response (TTR)
TTR will be used in support to the DOR endpoint and will be assessed in the response 
evaluable analysis set (patients who are retreated with durvalumab in Cohort 2).
TTR is defined as the time from the date of first retreatment dose until the date of first 
documented response (CR or PR), which is subsequently confirmed. 


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TTR will be calculated as follows: date of documented response (CR or PR) – date of first 
retreatment dose +1. The date of first documented response will coincide with that used for 
the DOR endpoint. TTR will be expressed in months.
TTR will not be defined for those patients who do not have a documented response (CR/PR) 
that is subsequently confirmed.
3.1.3
Overall survival (OS)
OS will be assessed in the FAS. 
OS is defined as the time from the date of randomization/date of first dose in the parent 
clinical study until death due to any cause. For randomized parent studies, the randomization 
date will be used in the calculation of OS. For single-arm parent studies (durvalumab 
monotherapy) and combination parent studies, the date of first dose (durvalumab or 
combination treatment) will be used in the calculation of OS.
Any patient not known to have died at the time of analysis will be censored based on the last 
recorded date on which the patient was known to be alive (Date subject confirmed to be alive 
(SUR_DAT), recorded within the SURVIVE module of the eCRF). 
Patient contact calls to determine survival will be made within 7 days following the date of 
DCO for the OS analysis, and if patients are confirmed to be alive or if the death date is after 
the DCO date these patients will be censored at the date of DCO. The status of ongoing, 
withdrawn (from the study) and “lost to follow-up” patients at the time of the final OS 
analysis should be obtained by the site personnel by checking the patient’s notes, hospital 
records, contacting the patient’s general practitioner and checking publicly available death 
registries. In the event that the patient has actively withdrawn consent to the processing of 
their personal data, the vital status of the patient can be obtained by site personnel from 
publicly available resources where it is possible to do so under applicable local laws.
Note that when a survival sweep is performed the SURVIVE module should be completed for 
every patient.
Note, for any OS analysis performed prior to the final OS analysis, in the absence of survival 
calls being made, it may be necessary to use all relevant case report forms (CRF) fields to 
determine the last recorded date on which the patient was known to be alive for those patients 
still on treatment (since the SURVIVE module is only completed for patients off treatment if a 
survival sweep is not performed). The last date for each individual patient is defined as the 
latest among the following dates recorded on the CRFs:

AE start and stop dates

Admission and discharge dates of hospitalization




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3.2
Safety variables
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, and exposure (i.e., durvalumab monotherapy or combination therapy). These 
will be collected for all patients. The following safety variables will be assessed:

All SAEs

Non-serious AEs that lead to dose modification, drug discontinuation, or withdrawal 
from the study

All Grade 3 and Grade 4 AEs

Grade 2 AEs that affect vital organs (e.g., heart, liver, kidney, lungs, central nervous 
system)

Immune-mediated AEs

Laboratory findings qualifying as an SAE/AE (endpoints defined above) up until 90 
days after the last dose of durvalumab in all patients
3.2.1
Adverse events
“On treatment” will be defined as assessments between date of start dose and 90 days 
following discontinuation of Investigational Product (IP) (i.e., the last dose of durvalumab in 
combination with any other approved or investigational anticancer agents or durvalumab 
monotherapy). For AEs, on treatment (or treatment-emergent AEs) will be defined as any AEs 
that started after dosing or prior to dosing and which worsens following exposure to the 
treatment. The Medical Dictionary for Regulatory Activities (MedDRA) (using the latest or 
current MedDRA version) will be used to code the AEs. AEs will be graded according to the 
National Cancer Institute Common Terminology Criteria for AEs (using the CTCAE version
5).
AEs will be assessed using the following eCRF modules:
Adverse Events (AE)

Adverse Event (y/n)

AE medical code

Date AE started

Date AE stopped

Serious AE (y/n)

Action taken with durvalumab (Dose not changed; Drug Interrupted; Drug 
permanently discontinued; Not applicable)

AE outcome (Recovered/resolved; Recovering/resolving; Recovered/resolved with; 
sequelae, Not recovered/not resolved; Fatal)

Reasonable Possibility AE Caused by durvalumab (y/n)


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
CTCAE Grade (Mild AE; Moderate AE; Severe AE; Life-threatening or disabling AE; 
Death related to AE)

Dose Limiting Toxicity (y/n)

Immune-mediated AE (y/n)

Infusion Reaction AE (y/n)
Serious Adverse Event Report (SERAE)

AE medical code

Date AE met criteria for serious AE

Date investigator aware of serious AE

AE is serious due to (medical code)

Death (y/n)

Inpatient hospitalization or prolongation of existing inpatient hospitalization (y/n)

Congenital anomaly or birth defect (y/n)

Life-threatening (y/n)

Persistent or significant disability/incapacity (y/n)

Important medical event (y/n)

Date of hospitalization 

Date of discharge

SAE caused by other medication (y/n)

SAE caused by study procedure(s) (y/n)

Description of AE
AE of Special Interest (AESI)

AE medical code

AE SI (full list of AESI is reported in the Appendix section)

Current Bowel Movements CTCAE Grade (Mild AE, Moderate AE, Severe AE, Life-
threatening or Disabling AE, Death Related to AE)

Body Surface Area Covered (<10%, 10-30%, >30%)

Anatomical Site [up to 6 sites] (Lower Leg, Other, Abdominal Cavity, Inguinal 
Region, Back, Neck, Face, Chest, Arm, Foot, Hand, Buttock, Scalp)

Signs and Symptoms (Abdominal Pain, Paresthesia, Loss of Deep Tendon Reflexes, 
Rapid Progressive Weakness, Respiratory Insufficiency, etc.)


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
Specialist Consulted or Additional Inv (y/n)

Services and Result Description

Any Additional Laboratory Investigations (y/n)

Any Significant Medic or Surgical History (y/n)

Event Triggered by Disease Progression (y/n)

Event Attributed to Disease/Metastasis (y/n)

Anatomic Location

Potential Alternate Etiology (y/n)
In addition to the above modules, AEs can be detected based on examinations and tests
(physical examinations, vital signs and laboratory tests; these are described in Sections 3.2.2, 
3.2.3, and 3.2.4 respectively). Situations in which examinations and tests results should be 
reported as AEs are described in Section 8.3.7 of the CSP.
AE imputation rules
For missing AE start dates, the following imputation rules will be applied 

If the day is missing, the 1st day of the month will be used unless month is the same as 
month of the first dose of study drug then the first dose date will be used.

If the day and month are missing, 1st January will be used unless year is the same as 
first dose date then the first dose date will be used.

Completely missing-impute first dose date unless the end date suggests it could have 
started prior to this in which case impute the 1st January of the same year as the end 
date.
For missing AE end dates, the following imputation rules will be applied:

If the day is missing, the last day of the month will be used unless month is the same 
as month of study discontinuation, then impute as study discontinuation date.

If the day and month is missing, the 31st December will be used unless year is the 
same as year of study discontinuation then impute study discontinuation date.
3.2.2
Physical examinations
Physical examinations (PE) will be performed according to the assessment schedules (see the
Schedule of Activities (SoAs) in CSP). Full PE will include assessments of the head, eyes, 
ears, nose, and throat and the respiratory, cardiovascular, GI, urogenital, musculoskeletal, 
neurological, dermatological, hematologic/lymphatic, and endocrine systems. Height will be 


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measured at screening only. Targeted PE are to be utilized by the Investigator on the basis of 
clinical observations and symptomatology. 
As reported in the CSP, any new or aggravated clinically relevant abnormal medical finding at 
a PE as compared with the baseline assessment will be reported as an AE unless 
unequivocally related to the disease under study, see Sections 8.3.9 and 8.3.10 of CSP.
Height will be retrieved from parent clinical studies. PE are assessed under “Physical 
Examination (PE)” eCRF module, the following information are reported:

Was the PE performed? (y/n)

What was the PE date?
3.2.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs. Body weight is also recorded at each visit along with vital signs.
Situations in which vital sign results should be reported as AEs are described in Section 8.3.7
for the CSP. 
Vital signs are assessed under “Vital Signs Pre-Infusion (VS)”, “Vital Signs During Infusion 
(VS1)”, and “Vital Signs Post Infusion (VS2)” eCRF modules. The following information are 
reported in these modules:

Date of assessment

Test name (Temperature, Weight, Systolic blood pressure, Diastolic blood pressure, 
Pulse Rate, Respiratory rate)

Assessment result and unit
3.2.4
Laboratory safety assessments
Laboratory safety assessments consist of blood and urine samples for determination of clinical 
chemistry, hematology, TSH, and pregnancy. Situations in which laboratory safety results 
should be reported as AEs are described in Section 8.3.7 of the CSP.
Laboratory safety assessments are assessed under the following eCRF modules:

Non-central Laboratory Test Results (LB) - Clinical Chemistry:
o
lab specimen collection date
o
name of the laboratory used
o
test results (including but not limited to: Blood Urea Nitrogen, Bicarbonate, 
Amylase, Chloride, Lipase, etc.)

Non-central Laboratory Test Results (LB2) – Hematology


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o
lab specimen collection date
o
name of the laboratory used
o
test results (including but not limited to: Hemoglobin, Platelets, Neutrophils 
Absolute Count, Lymphocytes %/Ratio, Neutrophils %/Ratio, Lymphocytes, 
Absolute Count, White Blood Cells, etc.)

Non-central Laboratory Test Results (LB3) - Thyroid Function Tests
o
lab specimen collection date
o
name of the laboratory used
o
test results (T3, Free; T4, Free; Thyroid Stimulating Hormone; Time field for Lab 
CFs)

Pregnancy Test (PREG)
o
Sampling date
o
Pregnancy test results (positive/negative)

Pregnancy Report (PREGREP)
o
Last menstrual period
o
Expected delivery date
o
Subject using hormonal contraception (oral or implant) or an IUD at time of 
conception (y/n)
o
Previous pregnancies details:

Overall number

Number of normal deliveries

Number of spontaneous miscarriages

Number of other previous pregnancies
o
Relevant pregnancy risk factor (smoking, alcohol, etc)
o
Relevant family history
3.2.5
Durvalumab exposure 
Exposure (i.e. duration of treatment) will be defined as follows:
Total exposure of study treatment: 
Total (or intended) exposure= min (last dose date where dose > 0 [units] + 27 (where 27 is the 
number of days between dosing – 1), date of death, date of DCO) – first dose date +1. 
Total (or intended) exposure will be expressed in months.
Actual exposure of study treatment


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Actual exposure = intended exposure – total duration of dose interruptions, where intended 
exposure will be calculated as above and a dose interruption is defined as any length of time 
where the patient has not taken any of the planned daily dose; hence, the total duration of dose 
interruptions in days is calculated as the cumulated lengths between the interruption dose date 
and the resuming dose day + 1.
Actual exposure and total duration of dose interruptions will be expressed in months. The 
actual exposure calculation will make no adjustment for any dose reductions that may have 
occurred.
3.2.6
Relative Dose Intensity (RDI)
Relative dose intensity (RDI) is the percentage of the actual dose delivered relative to the 
intended dose through to treatment discontinuation. RDI will be defined as follows:
RDI = 100% * d/D, where:

d is the actual cumulative dose delivered up to the actual last day of dosing. Actual 
dose (in mg) is reported in “Exposure - durvalumab (EX)” eCRF form as “Study drug 
dose per administration” Actual cumulative dose will be calculated by summing all 
doses for each day, across all treatment cycles.

D is the intended cumulative dose up to and including the actual last day of dosing. D 
is the total dose that would be delivered, if there were no modification to dose or 
schedule. Intended dose (in mg) is reported in “Exposure - durvalumab (EX)” eCRF 
form as “Planned study drug dose per administration”. 
The total number of planned doses will be calculated as the following: round ((last 
dosed date – first dosed date +28)/28)
When accounting for the calculation of intended cumulative dose 3 days will be added 
to the date of last dose to reflect the protocol allowed window for dosing.
4
OTHER ASSESSMENTS
In addition to primary and secondary variables that will be collected under this study, other 
key information will be collected using either directly into Electronic Data Capture (EDC)
system or transferred from clinical parent studies (Table 2).
Table 2. Parent study assessments
Study variables 
Data source 

Parent study protocol number, study e-CODE

Vital signs (weight, temperature, blood pressure, pulse 
rate, respiratory rate)

Date and last dose of durvalumab and durvalumab 
combination treatment administration

Ongoing safety events at the end of parent study
EDC entry


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Study variables 
Data source 

Ongoing concomitant medications at the end of the 
parent study

Subsequent anticancer therapy

Patient identification or linkage key, including 
connection to the Interactive Voice/Web Response 
System (IxRS) and EDC and transfer of old enrolment 
code (E-code)

Demographics: date of birth 
New IxRS system

Date of randomization from parent study (for 
randomized parent studies)

Date of first administration of durvalumab and 
durvalumab combination treatment (for non-
randomized parent studies).

Height
Transfer of data from clinical
parent study (SDTM data)

Contact information: (patient, caregiver, physician) as 
allowed by regulation for each country
Patient contact module
In addition to parent study assessments, the following data will be collected and described:

Disposition of Subjects, assessed at study termination, under “disposition (DS)” eCRF 
module. The following information will be collected:
o
Discontinuation date 
o
Subject’s status at discontinuation: Death, Lost to follow-up, Screen failure, 
Withdrawal by subject, Withdrawal by parent/guardian, Development of study-
specific withdrawal criteria (to be specified), Other (to be specified), Adverse 
Event, and Pregnancy

Patient demographic and Other Baseline Characteristics assessed at baseline visit:
o
Age 
o
Sex
o
Race 
o
Ethnicity 
o
Country 

[Only for Cohort 1 and Cohort 2] Exposure to durvalumab assessed under 
“Exposure - durvalumab (EX)” eCRF module. The following information will be 
collected:
o
Start date and time
o
End date and times
o
Dose per administration


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o
Dose units
o
Action taken (dose not changed, drug interrupted, Drug permanently discontinued)
o
Main reason for action taken (AE, other (to be specified)
o
Treatment cycle delayed (y/n)
o
Reason for treatment cycle delayed (Delayed hematological recovery, Adverse 
event, Disease symptoms, Logistic, Subject decision, Lab abnormality not reported 
as an AE, Other (to be specified))

Concomitant and other treatments assessed under “Prior and Concomitant Medications 
(CM)” eCRF module. The following information will be collected:
o
Medication verbatim name
o
AE number for which medication taken
o
Medical history condition(s) number for which medication taken
o
Medication route of administration
o
Total daily dose
o
Dose unit
o
Medication dosing frequency
o
Treatment start date
o
Treatment stop date
o
Ongoing treatment (y/n)
o
Indication 

Concomitant Procedures assessed under “Concomitant Procedures (CONPRO)” eCRF 
module:
o
Procedure text
o
Procedure start date
o
Procedure reason

Current and Concurrent cancer therapy assessed under “Current Cancer Therapy 
(CAPRX1)” and “Cancer Therapy - Post withdrawal of IP (CAPRX2)” eCRF modules 
respectively. The following information will be collected:
o
Cancer therapy agent name
o
Route of administration
o
Number of cycles
o
Therapy class (Immunotherapy, Hormonal Therapy, Cytotoxic chemotherapy, 
Systemic Therapy, Targeted Therapy, Antiangiogenic Therapy, Taxane 
chemotherapy, Radiopharmaceuticals, Platinum Chemotherapy, PARP Inhibitor, 
Biologic therapy, Experimental therapy, Other)


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o
Start and stop dates 
o
Best response (CR, PR, SD, Progression, Non-evaluable, Not applicable)
o
Treatment status (line of therapy, adjuvant/non-adjuvant, palliative, maintenance, 
Definitive, Not applicable)

Radiotherapy:
o
Timing against withdrawal of IP: previous, current, post
o
Radiotherapy site or region
o
Radiotherapy start and stop dates
o
Dose per fraction (Gy)
o
Number of fraction doses (total)
o
Treatment status (Adjuvant, Neo-adjuvant, Palliative, Definitive, Not applicable)
5
ANALYSIS METHODS
5.1
General principles
The below mentioned general principles will be followed throughout the study:

Descriptive statistics will be used for all variables, as appropriate. Continuous 
variables will be summarized by the number of observations, mean, standard 
deviation(Sd), median, upper and lower quartiles minimum, and maximum. 
Categorical variables will be summarized by frequency counts and percentages for 
each category.

Unless otherwise stated, percentages will be calculated out of the population total for 
the corresponding analysis set. 

For continuous data, the mean and median will be rounded to 1 additional decimal 
place compared to the original data. The Sd will be rounded to 2 additional decimal 
places compared to the original data. Minimum and maximum will be displayed with 
the same accuracy as the original data.

For categorical data, percentages will be rounded to 1 decimal place.

There are no statistical methods that will be employed to test a specific hypothesis.

SAS® version 9.4 or later will be used for all analyses.
For efficacy endpoints (only considered for Cohort 2), the last observed measurement prior to 
retreatment will be considered the baseline measurement. 
For safety endpoints (where all cohorts are considered) the last observation before the first 
dose of study treatment will be considered the baseline measurement. For assessments on the 
day of first dose/randomization date where time is not captured, a nominal pre-dose indicator 
will serve as sufficient evidence that the assessment occurred prior to first dose. Assessments 


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on the day of the first dose where neither time nor a nominal pre-dose indicator are captured 
will be considered prior to the first dose if such procedures are required by the protocol to be 
conducted before the first dose.
In all summaries change from baseline variables will be calculated as the post-treatment value 
minus the value at baseline. The percentage change from baseline will be calculated as (post-
baseline value - baseline value) / baseline value x 100. 
5.2
Analysis methods
5.2.1
Overall survival (OS)
A listing of the OS data will be provided in the FAS, for each cohort. This listing will contain 
the following information: patient identifier, cohort, date of randomization, date of first dose, 
survival status (death or no death), date of death or date last known to be alive; days from 
randomization to death with a flag indicating if the value is censored, cause of death, autopsy
performed (yes/no), and death related to disease under investigation (yes/no).
Note: In addition to listings, survival and tumor efficacy data may be combined with the 
parent study data for an integrated analysis on a “as needed” basis. The Kaplan Meier (KM)
approach, Log-Rank test, Cox Proportional Hazards model, etc., will be used if OS analyses 
are requested for a parent study.
5.2.2
Objective response rate (ORR)
ORR will be assessed in the response evaluable analysis set (patients who undergo retreatment 
with durvalumab in Cohort 2). The ORR will be based on the site investigator RECIST 1.1 
data and using all tumor assessments, regardless of whether they were scheduled or not. 
Descriptive statistics will be performed on the ORR and the following data will be presented: 
the number of observations, 95% (Confidence Interval) CIs estimated using the exact 
probability method. Data will be summarized by tumor type if there is sufficient sample size 
in each tumor type.
In case there is no sufficient sample size in retreated Cohort 2, the corresponding tables will 
be purely informative and only listings will be used for the assessment of this objective.
5.2.3
Duration of response (DOR)
DOR will be assessed in the response evaluable analysis set (patients who undergo retreatment 
with durvalumab in Cohort 2). KM plots of DOR based on the investigator assessment of 
RECIST will be presented. Median DOR (with associated 95% CI) will be calculated from the 
KM curve and summarized. Only patients who have a confirmed response will be included in 
this summary table. In addition, swimmer plots that show the profile of each patient who 
responds will also be produced.


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Results will be summarized by tumor type if there is sufficient sample size in each tumor type.
In case there is no sufficient sample size in retreated Cohort 2, the corresponding tables and 
graphs will be purely informative and only listings will be used for the assessment of this 
objective.
5.2.4
Time to response (TTR)
Descriptive data will be provided for TTR in responding patients. In addition, KM plots of 
TTR will be produced where patients without a response will be censored at their last RECIST 
assessment. Median TTR (with associated 95% CI) will be calculated from the KM curve and 
summarized. Results will be summarized by tumor type if there is sufficient sample size in 
each tumor type.
In case there is no sufficient sample size in retreated Cohort 2, the corresponding tables and 
graphs will be purely informative and only listings will be used for the assessment of this 
objective.
5.2.5
Safety
Safety data will be summarized according to the treatment received for the SAS (all patients 
who received at least 1 dose of durvalumab either as continuation of study treatment or 
retreatment in this study, and inclusive of patients who received the last dose of durvalumab 
or durvalumab combination from the parent clinical study within 90 days of enrollment [all 
cohorts]). AEs, vital signs, dose at time of AE, and laboratory safety assessments (clinical 
chemistry, hematology and thyroid stimulating hormone [reflex free triiodothyronine or free 
thyroxine]) will be listed individually by patient. 
The number of patients experiencing each AE will be summarized by study cohort and 
CTCAE grade (v5.0). Each patient will be represented with the maximum reported CTCAE 
grade for each system organ class / preferred term. Number (%) of patients with AEs, will be 
sorted by international System Organ Classes (SOC) order and alphabetical PT and then 
maximum grade. Event rate per 100 patient-years will also be calculated for each AE.
Individual laboratory measurements and vital signs data will be presented in listing format.
For laboratory measurements, the following data will be listed:

Subject identifier and cohort

Age/sex/race

Analysis visit

Category of lab test

Lab test examination name


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
Result/finding 

Units 

Reference range indicator 
For vital signs, the following data will be listed:

Subject identifier and cohort

Vital signs test name 

Analysis visit 

Result 

Unit

Result clinically significant (yes/no)

Reference ranges (upper and lower limits).
For vital signs, the following reference ranges and units will be used:

For Diastolic blood pressure: Range = 40-110, Unit = mmHg

For Heart rate/Pulse: Range = 50-120, Unit = beats/min

For Respiratory rate: Range = 12-35, Unit = breaths/min

For Systolic blood pressure: Range = 60-160, Unit = mmHg

For Temperature: Range = 35-39, Unit = °C / Range = 95-102.3, Unit = °F

For Weight: Range = 30-140, Unit = Kg / Range = 66-308, Unit = LB

Oxygen saturation: 95-100%, unit-free. 
Note: Based on an “as needed” request from parent clinical studies, safety data from WAVE 
may be combined with parent study data in order to update safety summaries.
5.2.6
Demographics and baseline characteristics
The following will be summarized for all patients in the FAS by treatment group (cohort 1, 
cohort 2, cohort 3). Continuous variables will be summarized by the number of observations, 
mean, Sd, median, upper and lower quartiles minimum, and maximum. Categorical variables 
will be summarized by frequency counts and percentages for each category:

Patient disposition (including screening failures) and inclusion in analysis sets

Demographics (age, age group [<50, ≥ 50 - < 65, ≥ 65 - < 75 and ≥ 75 years], sex, 
race, ethnicity, and country)

Subject recruitment by clinical parent study (for each parent study; the study design, 
code, total number of patients in parent study and in WAVE study)

Patient recruitment by country and by center


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
Patient characteristics at baseline (height, weight, BMI)

Disease characteristics at baseline (ECOG performance status, primary tumor location)

Extent of disease at baseline: locally advanced/metastatic, site of disease
5.2.7
Concomitant and other treatments, and concomitant procedures
All concomitant and other treatment, and concomitant procedures data will be listed in the 
FAS, using Anatomical Therapeutic Chemical (ATC) classification and ATC coding. Missing 
coding terms will be listed and summarized as "Uncoded".
5.2.8
Exposure
Exposure to durvalumab treatment will be summarized for the SAS, only in Cohort 1 and 
Cohort 2 (retreatment). Mean, Sd, median and ranges will be produced for the following 
summaries:

Summary of duration of exposure of study treatment (total treatment duration 
(months), actual treatment duration (months)), 

Summary of delays in study treatment cycles as well as reasons of delays,

Summary of dose intensity: 
o
RDI defined as the percentage of the actual dose delivered relative to the intended 
dose through treatment discontinuation 
o
Percent intended dose defined as the percentage of the actual dose delivered 
relative to the intended dose through progression.

Cumulative exposure over time.
5.2.9
Subsequent therapy
Cancer therapy post-discontinuation of durvalumab will be summarized in the FAS. For each 
cohort, the number (%) of patients will be summarized by tumor location and anticancer 
regimen.
6
INTERIM ANALYSES
No interim analysis has been planned for this study. 
7
CHANGES OF ANALYSIS FROM PROTOCOL
There are no changes to the analyses specified in the version of protocol that this SAP is based 
on.


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8
REFERENCES
There are no references listed in this document.
9
APPENDIX
9.1
List of AESI 
The following AESI are listed in the current version of eCRF:

Potential Endocrinopathies

Potential Hepatic Events

Potential Nephritis or Renal Dysfunction

Potential Neuropathy/Neuro-muscular Toxicity

Potential Pancreatitis

Potential Rash or Dermatitis

Potential GI Toxicity

Potential Myositis/Polymyositis

Potential Myocarditis

Other (to be specified in EDC)


SI G N A T U R E P A G E
T his is a re prese nt ati o n of a n electr o nic rec or d t h at w as si g ne d
electr o nic ally a n d t his p a ge is t he m a nifest ati o n of t he electr o nic si g n at ure
D oc u me nt N a me: D 9 1 0 F C 0 0 0 0 1-sa p- v 2-e d
D oc u me nt Title:
Statistical A nal ysis Pla n - Versi o n 2 - E diti o n
D oc u me nt I D:
Versi o n L a bel:
3. 0 C U R R E N T L A T E S T A P P R O V E D
Ser ver D ate
( d d- M M M- y y y y H H: m m ‘ U T C’ Z)
Si g ne d b y
Me a ni n g of Si g n at ure
0 2- Dec- 2 0 2 2 1 3: 3 5 U T C
 ( C ytel I nc)
C o nte nt A p pr o val
0 2- Dec- 2 0 2 2 1 3: 4 2 U T C
C o nte nt A p pr o val
.
P P D
P P D
C CI
C CI