Phase I/II, Open-Label Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Durvalumab Monotherapy or in Combination With Tremelimumab in Pediatric Patients With Advanced Solid Tumors and Hematological Malignancies.
Phase: PHASE1
Conditions: Pediatric Cancer, Solid Tumor Pediatric, Hematological Malignancies
Sponsor: AstraZeneca

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Cli nic al St u d y Pr ot oc ol 
Dr u g S u bsta nce
D ur val u ma b a n d 
tr e meli m u ma b
St u d y C o de
D 4 1 9 E C 0 0 0 0 1
Versi o n
6. 0
Date
1 2 Dece m ber 2 0 2 2
P h ase I/II, O pe n -L a bel, M ultice nter St u d y t o E v al u ate t he S afet y, T oler a bilit y, 
a n d Preli mi n ar y Effic ac y of D ur v al u m a b M o n ot her a p y or D ur v al u m a b i n 
C o m bi n ati o n wit h Tre meli m u m a b i n Pe di atric P atie nts wit h A d v a nce d S oli d 
T u m ors a n d He m at ol o gic al M ali g n a ncies
S p o ns or: Astr a Ze nec a A B, 1 5 1 8 5 S ö dert älje, S we de n 
Re g ul at or y A ge nc y I de ntif yi n g N u m ber(s):
E u dra C T n u m ber: 2 0 1 8- 0 0 3 1 1 8- 4 2
I N D: C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y

F o ot n otes descri bi n g sa m pli n g f or s ol u ble pr o gra m me d cell deat h li ga n d 1, i n 
r elat i on t o d ur val u ma b or tre meli m u ma b i nf usi o n, u p date d t o clarif y  timi n gs

Ra di ol o gi c al i ma gi n g sc he d ule m o difie d t o all o w a re d uce d fre q ue nc y of t u m or 
assess me nts, as cli nicall y in dicate d, f or patie nts ac hie vi n g a n o bje ct i ve res p o nse or 
sta ble disease still e vi de nt at 1 2 m o nt hs (a n i nter val o f 1 6 wee ks vers us 8 wee ks)

Fre q ue nc y of Ta n ner sta gi n g a n d t u m or mar ker assess me nts clarifie d t o ali g n wit h 
t he mo difie d ra di ol o gi cal i ma gi n g sc he d ule
Secti o n 1. 1 T a ble 2 Sc he d ule of acti vities f or d ur v al u m a b ± tre meli m u m a b 
d ose -e x p a nsi o n p h ase:

P har mac o ki net ic sa m pli n g u p date d t o re m o ve c ollecti o n of t he C ycle 6 a n d 
C ycle 1 0 sa m pl es f or d ur val u ma b

I mm u n o ge nicit y assess me nt at C ycle 6 re m o ve d a n d re place d wit h assess me nt at 
C ycle 4 f o r d ur valu ma b

Testi c ular e xa m for m ale pat ient s i n ac ute l y m p h o blastic le u ke mia c o h ort re m o ve d

 assess me nts f or t he H o d g ki n’s l y m p h oma c o h ort re m o ve d (t o 
clarif y re mo v al of t his c o h ort fr o m t he d ose-e x pa nsi o n p hase)

Ra di ol o gi c al i ma gi n g sc he d ule m o difie d t o all o w a re d uce d fre q ue nc y of t u m or 
assess me nts, as cli nicall y in dicate d, f or patie nts ac hie vi n g a n o bject i ve res p o nse or 
sta ble disease still e vi de nt at 1 2 m o nt hs (a n i nter val o f 1 6 wee ks vers us 8 wee ks)

Fre q ue nc y of Ta n ner sta gi n g a n d t u m or mar ker assess me nts clarifie d t o ali g n wit h 
t he mo difie d ra di ol o gi cal i ma gi n g sc he d ule

F o ot n otes descri bi n g sa m pli n g f or s ol u ble pr o gra m me d cell deat h li ga n d 1, i n 
r elat i on t o d ur val u ma b or tre meli m u ma b i nf usi o n, u p date d t o clarif y  timi n gs

Ta ble a n d f o ot n o tes u p date d t o clarif y re m o val of t he H o d g ki n’s l y m p h o ma, 
ne ur o blast o ma ( a n d ass ociate d t u m or mar ker assess me nts [ uri ne catec h o lami nes ]), 
a n d ot her he mat ol o gical mali g na ncies c o h orts fr o m t he d ose -e x pa nsi o n p hase
Secti o n 1. 1 T a ble 3 Sc he d ule of acti vities f or p atie nts w h o h a ve disc o nti n ue d all st u d y 
tre at me nts ( d ur v al u m a b m o n ot her a p y or d ur v al u m a b a n d tre meli m u m a b c o m bi n ati o n 
t her a p y) i n t he d ose-fi n di n g or t he d ose-e x p a nsi o n p h ases:

Ta ble a n d f o ot n otes u p date d t o reflect m o difie d fre q ue nc y o f r a diol o gical  efficac y 
assess me nts (a n i nter val of 1 6 wee ks vers us 8 wee ks) f or patie nts ac hie vi n g a n 
o bj ect i ve res p o nse or sta ble disease w hic h is still e vi de nt at 1 2 m o nt hs
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Clinical Study Protocol - 6.0
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CONFIDENTIAL AND PROPRIETARY
Section 1.2 Objectives and Endpoints:

Primary objective “To determine the preliminary antitumor activity of patients from 
the HL dose-expansion cohort treated with durvalumab monotherapy with a q4w 
dosing schedule, using cohort-specific response criteria (eg, Cheson criteria, Wayne 
criteria, RECIST 1.1, and INRC)” and corresponding endpoints removed

Safety objective “To determine the safety profile and tolerability of patients from 
the HL dose-expansion cohort treated with durvalumab monotherapy with a q4w 
dosing schedule” and corresponding endpoints removed

Primary, secondary, and safety objectives (and corresponding endpoints) for the 
dose-expansion phase updated to reflect removal of Hodgkin’s lymphoma and other 
hematological malignancies cohorts
Section 1.2 Overall design:

Text updated to clarify changes to the design for the dose-expansion phase (see 
changes listed under ‘All Sections’)

Sample size described for newly combined SARCOMA cohort; 11 patients to be 
enrolled in initial stage (with requirement that ≥40% of the patients enrolled must 
have soft-tissue sarcomas), followed by an additional 15 patients in the expansion 
stage, for a total of 26 patients
Section 1.2 Number of patients:

Sample size for dose-expansion phase revised to clarify changes to cohorts; 
expected range for evaluable patients revised to 38 to 66 patients, and total number 
of patients (assuming 20% are non-evaluable) revised to 46 to 80 patients
Section 1.3 Schema:

Figure 1 updated to clarify changes to the overall study design (specifically, updates 
to the cohorts included in the dose-expansion phase)
Section 2.3.2.1 Durvalumab:

Risks with durvalumab treatment updated to include pemphigoid, immune 
thrombocytopenia, and neuromuscular toxicities (Guillain-Barré syndrome, 
myasthenia gravis) to reflect the latest clinical information available 
Section 3 Objectives and endpoints:

Table 4 updated to remove following primary objective and corresponding 
endpoints for dose-expansion phase: “To determine the preliminary antitumor 
activity of patients from the HL dose-expansion cohort treated with durvalumab 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
monotherapy with a q4w dosing schedule, using cohort-specific response criteria 
(eg, Cheson criteria, Wayne criteria, RECIST 1.1, and INRC)”

Table 4 updated to remove following safety objective and corresponding endpoints 
for dose-expansion phase: “To determine the safety profile and tolerability of 
patients from the HL dose-expansion cohort treated with durvalumab monotherapy 
with a q4w dosing schedule”

Table 4 updated to clarify changes to primary, secondary, and safety objectives (and 
corresponding endpoints) for dose-expansion phase (due to removal of Hodgkin’s 
lymphoma and other hematological malignancies cohorts)
Section 4 Study design:

Table 5 Disease cohorts separated into two tables (by study phase) and 
corresponding text updated to clarify changes to the design of the dose-expansion 
phase (see changes listed under ‘All Sections’)

Sample size described for newly combined SARCOMA cohort; 11 patients to be 
enrolled in initial stage (with requirement that ≥40% of the patients enrolled must 
have soft-tissue sarcomas), followed by an additional 15 patients in the expansion 
stage, for a total of 26 patients

New section titled “Study Conduct Mitigation During Study Disruptions Due to 
Cases of Civil Crisis, Natural Disaster, or Public Health Crisis” added (as 
Section 4.1.5), to describe changes to study conduct in light of disruptions, 
including disruption due to pandemics
Section 4.1.2 Definition of dose-limiting toxicities and stopping criteria:

Term ‘irAE’ replaced with ‘imAE’ throughout section, for consistency with 
language used elsewhere in protocol
Section 5.1.2 Inclusion criteria (Malignant neoplasms of hematopoietic and lymphoid 
tissue and myelodysplastic syndrome):

Section title revised to “Non-Hodgkin’s lymphoma”, and introductory paragraph 
and inclusion criterion 3 updated to reflect that only NHL (including, primary 
mediastinal B-cell lymphoma and anaplastic large-cell lymphoma) will be evaluated 
for malignant neoplasms of hematopoietic and lymphoid tissue 
Section 5.2 Exclusion criteria (all patients):

Exclusion criterion 1 revised to remove criteria for Hodgkin’s lymphoma, acute 
myeloid leukemia, and acute lymphoblastic leukemia

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Secti o n 8 St u d y assess me nts a n d pr oce d ures

Ta ble 1 7 V ol u me of bl o o d t o be c ollecte d ( b y  wei g ht a n d i ncl u di n g W orl d Health 
Or ga nisat i on li mits) u p date d t o reflect re d uce d n u m ber of bl o o d sa m ples re q uire d 
f or researc h la b orat or y ( p har mac o ki netic a n d a nt i-dr u g a nti b o d y ) assess me nts i n t he 
d ose -e x pa nsi o n p hase ( v o l ume fr om C ycle 3 u nt il pr o gressi o n re vise d fr o m “ u p t o 
5. 5 m L ” t o “ u p t o 6 m L ”)
Secti o n 8. 1 Effic ac y Assess me nts:

Ra di ol o gi c al i ma gi n g sc he d ule m o difie d t o all o w a re d uce d fre q ue nc y of t u m or 
assess me nts, as cli nicall y in dicate d, f or patie nts ac hie vi n g a n o bject i ve res p o nse or 
sta ble disease still e vi de nt at 1 2 m o nt hs (a n i nter val o f 1 6 wee ks vers us 8 wee ks)
Secti o n 8. 2. 4 T a n ner st a gi n g:

Fre q ue nc y of Ta n ner sta gi n g clarifie d t o ali g n wit h t he m o difie d ra di o l ogi cal 
i ma gi n g sc he d ule
Secti o n 8. 3. 1 3 A d verse e ve nts of s peci al i nterest:

List of a d verse e ve nts of s pecial i nterest o bser ve d wit h d ur val u ma b ± 
tr e meli m u ma b u p date d t o i ncl u de ne ur o m usc ular t o xicit ies (G uillai n -Barré 
s y n dr ome, m yast he nia gra vis ) t o reflect t he latest cli nical i nf or mati o n a vaila ble 
Secti o n 8. 4. 5. 1 S pecific t o xic it y m a n a ge me nt a n d d ose m o dific ati o n i nf or m ati o n –
D ur v al u m a b a n d d ur v al u m a b + tre meli m u m a b:

Cr oss -refere nce t o T M G d oc u me nt re m o ve d
Secti o n 8. 8. 3 E x pl or at or y Bi o m ar kers:

Re q ui re me nt f or c ollecti on of 
 i n patie nts 
wi t h ne ur o blast o ma is reflecte d o nl y f or patie nts e nr olle d d uri n g d ose -fi n di n g p hase
Secti o n 9. 2 S a m ple size deter mi n ati o n ( D ose -e x p a nsi o n p h ase):

S a m ple size a d de d f or ne wl y c o m bi ne d S A R C O M A c o h ort; 1 1 patie nts t o be 
e nr o lle d i n i nitial sta ge (wi t h re q uire me nt t hat ≥4 0 % of t he patie nts e nr o lle d m ust 
ha ve s oft-tiss ue sarc o mas), f oll owe d b y  a n a d ditio n al 1 5 patie nts i n t he e x pa nsi o n 
sta ge, f or a t otal of 2 6 patie nts

S a m ple size f or d ose - e x pa nsi o n p hase re vise d t o clarif y c ha n ges t o c o h orts; 
e x pecte d ra n ge f or e va l ua ble patie nts re vise d t o 3 8 t o 6 6 patie nts, a n d t otal n u m ber 
of  p atie nts (ass u mi n g 2 0 % are n o n-e val ua ble) re vise d t o 4 6 t o 8 0 patie nts
Secti o n 9. 6 I nteri m a n al yses:
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Clinical Study Protocol - 6.0
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY

Number of patients for evaluation of ORR updated to reflect revised sample sizes 
for dose-expansion cohorts (11 patients for the SARCOMA cohort and 9 patients 
for the NHL cohort)
Section 11 Supporting Documentation:

Appendix titled “Actions required in cases of increases in liver biochemistry and 
evaluation of Hy's law” updated to include revised guidance for identifying and 
following-up potential Hy’s law cases.

Appendices titled “Response Criteria in Acute Myeloid Leukemia” and “Response 
Criteria in Acute Lymphoblastic Leukemia” deleted from Section 11

Appendix titled “Changes Related to Mitigation of Study Disruptions Due to Cases 
of Civil Crisis, Natural Disaster, or Public Health Crisis, including COVID-19 
Outbreak” added to Section 11
All sections:

Modifications to the study design have been made throughout the protocol to reflect 
the following changes to the disease cohorts in the dose-expansion phase, as 
approved by the Pediatric Committee (PDCO) of the European Medicines Agency 
in January 2021:
Consolidation of the previous two sarcoma cohorts (SARC-1 [bone sarcomas] 
and SARC-2 [soft-tissue sarcomas]) in a single sarcoma cohort with a 
requirement that at least 40% of the enrollment must reflect soft-tissue sarcomas
Suspension of the neuroblastoma cohort due to a) lack of activity during the 
dose-finding phase and b) checkpoint inhibitor therapy not reflected as a target 
within the recent Neuroblastoma Drug Development Strategy summary issued 
by the Innovative Therapies for Children with Cancer and the International 
Society of Pediatric Oncology Europe Neuroblastoma
Non-Hodgkin’s lymphoma cohort modified to limit enrollment to only 
2 subtypes: primary mediastinal B-cell lymphoma and anaplastic large cell 
lymphoma
Suspension of the Hodgkin’s lymphoma cohort due to feasibility challenges
Suspension of the other hematological malignancies cohort (acute leukemias, 
myelodysplastic syndrome) due to a) feasibility challenges with prioritization of 
other therapies for acute lymphoblastic leukemia and b) emergence of a regimen 
combining a checkpoint inhibitor with a hypomethylating agent as a more
appropriate regimen for acute myeloid leukemia/myelodysplastic syndrome

Abbreviations were updated, and minor typographical errors and inconsistencies 
were corrected throughout

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y

F o ot n ote b u p date d t o refer t o “i ma gi n g /st a gi n g e x a mi n ati o n ” res ults f or 
clarificatio n ( b ot h ta bl es)

F o ot n otes j  a n d l u p date d t o stip ulate t hat pre -d ose sa m ple s h o ul d be wit hi n 
6 0 mi n utes of start of i nf usi o n ( b ot h ta bles)

Testi c ular e xa m for m ale ac ute ly m p h o blast ic le u ke mia pat ient s a d de d t o p h ysical 
e xa mi nat i on ( Ta ble 2)

Cl arifie d details of re q uire me nts (li mite d sa m pli n g) f or 
 in f oot n ote r 
( Ta ble 2)
Secti o n 1. 1 T a ble 3 Sc he d ule of acti vities f or p atie nts w h o h a ve disc o nti n ue d all st u d y 
tre at me nts:

Ta ble u p date d t o ali g n t he t otal i nter val f or A E/ S A E assess me nts wit h t he pr ot oc ol 
te xt (ie, t otal int er val of 9 0 da ys, t o be perf or me d at 3 0, 6 0, a n d 9 0 da y s)
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Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Section 1.2 Synopsis

Updated for consistency with changes within main body of protocol
Section 1.3 Schema

Figure 1 updated to clarify the overall study design (primarily to provide clarity for 
the dose-expansion representation)
Section 2.2.2 Durvalumab:

Information on the ongoing investigator-initiated study (durvalumab monotherapy) 
updated to reflect current status (also updated in Sections 2.3.2, 2.3.2.1, and 4.3.1.2)
Section 2.3.2.1 Durvalumab:

Text revised to include the data cut-off date for monotherapy clinical studies and 
refer to the IB for updated information
Section 2.3.2.3 Durvalumab + tremelimumab:

Reference to the current version of the IB added for detailed information
Section 2.3.3 Overall benefit/risk:

Text revised to refer to the DRC rather than a committee composed by the Sponsor 
or designee and selected key trial Investigators
Section 3 Objectives and Endpoints:

Study objectives updated to reflect safety and efficacy of the durvalumab and 
tremelimumab combination followed by durvalumab monotherapy; for HL cohort, 
safety and efficacy reflect durvalumab monotherapy
Section 4.1 Overall design

Text revised to specify that pembrolizumab has also been approved for use in HL

Dates for when the study is planned to be conducted were updated to reflect the 
current status
Section 4.1.1 Dose-finding phase:

Text revised to provide description of the modified 3 + 3 design

Figure 3 updated to clarify reduction in dose from DL 1 to DL-1

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y

Te xt re vi se d t o pr o vide details o n w he n a de q uate pe diatric e x p os ure will be 
decl are d
Secti o n 4. 1. 2 Defi niti o n of d ose -li miti n g t o xicities:

Secti o n title re vise d t o “ Defi nit i on of d ose -li miti n g t o xicities a n d st o p pi n g criteria”

List of e xce pt i ons f or a d ose-li miti n g t o xicity re vise d t o i ncl u de Gra de 3 
h y p ot h y r oidis m  a de q uatel y treate d wit h h or mo ne re pl ace me nt t hera p y (r e placi n g 
refere nce t o Gra de 4 h yp ot h y r oidis m )

Te xt re vi se d t o descri be h ol d a n d st o p pi n g criteria f or d ose-fi n di n g a n d 
d ose -e x pa nsi o n p hases, i n t he c o nte xt of n u m ber of pat ient s e x perie nci n g 
d ose -li miti n g t o xicities
Secti o n 4. 1. 3 Deter mi ni n g a rec o m me n de d P h ase II d ose:

Te xt a n d Ta ble 6 re vise d t o descri be w hat will be c o nsi dere d f or d ose escalati on 
decisi o ns a n d deter mi nat i on of R P 2 D
Secti o n 4. 1. 4 D ose -e x p a nsi o n p h ase:

Te xt re vi se d t o pr o vide a d di tio n al  descript i on of t he Si m o n 2 -sta ge desig n
Secti o n 4. 4 E n d of st u d y defi niti o n:

Te xt re vise d t o i n dicate t hat st u d y will (i nstea d of m ay ) be st o p pe d f or c ha n ge i n 
ris k d ue t o cli nicall y sig nifica nt fi n di n gs 
Secti o n 5. 1. 1 S oli d m ali g n a nt t u m ors (e xce pt pri m ar y ce ntr al ner v o us s yste m m ali g n a nt 
t u m ors a n d Secti o n 5. 1. 2 M ali g n a nt ne o pl as ms of he m at o p oietic a n d l y m p h oi d tiss ue 
a n d m yel o d ys pl astic s y n dr o me:

I ncl usi on cri t erio n 3 re vise d t o reflect t hat all pat ient s must be refract or y  t o sta n dar d 
t hera p y a n d for w h o m , n o sta n dar d of care treat me nts e xist

I ncl usi on cri t erio n 4 re vise d t o 
 

I ncl usi on cri t erio n 7 re vise d t o f urt her defi ne i m m u ne t hera pies re prese nt i n g pri or 
treat me nts t hat will e xcl u de a patie nt fr o m t he st u d y, t o i ncl u de n o pri or e x p os ure t o
i m m u ne c hec k p oi nt i n hi bit ors or ge neticall y e n gi neere d cell ular t hera pies

I ncl usi on cri t erio n 8 re vise d as f o ll ows:

U p date d he mat ol o gic para meters f or s oli d t u m or patie nts wit h b o ne marr o w 
i n v ol ve me nt
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Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Updated upper-limit allowed for serum bilirubin, for patients with Gilbert’s 
syndrome
Updated text to define acceptable renal function based on age-appropriate 
creatinine or, if abnormal, use of Schwartz formula to calculate or use of 
24-hour urine collection or radioisotope study, to determine creatinine clearance
Section 5.2 Exclusion criteria (all patients):

Exclusion criterion 1 revised to clarify that patients who have previously received 
an autologous bone marrow transplant are eligible

Exclusion criterion 2 revised to include autoimmune myocarditis and autoimmune 
pneumonitis (ie, conditions with an autoimmune etiology)

Exclusion criterion 7 revised to exclude patients with chloroma

Exclusion criterion 12 revised to permit use of intrathecal chemotherapy as 
prophylaxis/management for patients with high-risk leukemia or NHL disease

Exclusion criterion 20 revised to specify a highly effective birth control method 
should be used
Section 5.4 Screen failures

Text revised to describe additional procedures for handling screen failures
Section 6.1.1.1 Dose-finding phase

Text added to describe restarting treatment with the combination of durvalumab and 
tremelimumab for patients with initial clinical benefit, who have progressed on 
durvalumab monotherapy
Section 6.1.1.2 Dose-expansion phase

Text revised to reflect combination treatment starting at Cycle 1 (total of 4 cycles, 
Cycles 1 to 4) 

Text added to describe restarting treatment with the combination of durvalumab and 
tremelimumab for patients with initial clinical benefit, who have progressed on 
durvalumab monotherapy

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Section 6.1.2 Study Drug Administration

Text revised to specify a low-protein binding in-line filter is to be used for study 
drug administration, for both durvalumab and tremelimumab infusions
Section 6.1.3 Study Drug Preparation

Text revised to reflect that either an IV bag or syringe preparation can be used for 
administration of both durvalumab and tremelimumab for patients ≥20 kg
Section 6.1.3.1 Durvalumab (MEDI4736)

Text revised to reflect the use of the 500-mg vial size 
Section 6.4 Concomitant therapy
Table 14 (prohibited medications) revised as follow:

Intrathecal chemotherapy as prophylaxis/management for patients with high-risk 
leukemia or NHL disease is permitted

Reference to EGFR TKIs changed to Tyrosine-kinase inhibitors
Section 8 Study assessments and procedures:

Text revised to reflect scheduling of treatment visits for the dose-finding phase (to 
align with the SoA tables)

Section amended to include instructions for collecting blood samples for patients 
with a body weight of <6 kg.  Current Table 16 replaced with new table with blood 
volumes collected by body weight and including World Health Organisation limits. 
Sampling prioritization details added for dose-finding and dose-expansion phases, 
specifically for young children
Section 8.2.1 Clinical safety laboratory assessments:

Table 17 (footnote) revised to reflect the corrected creatinine clearance equation 
(Schwartz equation) and acceptable methods for creatinine clearance determinations

Coagulation added as additional laboratory assessment in Table 18 (hematology) 
Section 8.2.2 Physical examinations:

Text revised to clarify that urogenital assessment can include testicular exam for 
male acute lymphoblastic leukemia patients

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Section 9.3.3 Safety analysis set:

Text revised for definition of safety analysis set
Section 9.4.1.6 Best objective response:

Corrected reference for NHL response criteria (Cheson 2007)
Section 9.4.1.7 Disease control rate:

Text revised to provide additional details about definition of disease control rate
Section 9.5.1 Efficacy analyses:
Table 21 revised as follows:
Remove reference to irRECIST
Correct description of analysis required for proportion alive and 
progression-free at 12 and 18 months, and proportion alive at 12 and 24 months
Section 9.6.1 Data Review Committee:

Text revised to reflect requirement of DRC to perform a benefit/risk assessment at 
the completion of safety data analysis prior to expansion into cohort of children 
<1 year old; notification of health authority of decision, if necessary per local 
requirements
Section 11 Supporting documentation and operational considerations, Appendix A 1 
Regulatory and ethical considerations and related text in synopsis:

Text revised to include the requirement of regulatory authority (in addition to 
IRB/IEC) approval of protocol amendments before their implementation 
Section 11 Supporting documentation and operational considerations, Appendix A 10 
Standard therapies:

List updated to include chimeric antigen receptor T-cell therapies (CAR-T) as an 
approved standard therapy for acute lymphoblastic leukemia
Section 11 Supporting documentation and operational considerations, Appendix D 
Actions required in cases of increases in liver biochemistry and evaluation of Hy’s law:

Text revised to include new version of Hy’s Law appendix

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY

Footnote p revised to align with infusion times in Section 6.1.2 Study Drug 
Administration.

Lumbar puncture assessment included.
Table 2 Schedule of activities for durvalumab ± tremelimumab dose-expansion phase:

Table revised to include oxygen saturation as part of vital sign assessments.

Footnote p revised to align with infusion times in Section 6.1.2 Study Drug 
Administration.

Lumbar puncture assessment included.
Table 3 Schedule of activities for patients who have discontinued all study treatments 
(durvalumab monotherapy or durvalumab and tremelimumab combination therapy) in 
the dose-finding or the dose-expansion phases:

Table revised to include oxygen saturation as part of vital sign assessments.
Section 5.1.1 Solid Malignant Tumors Inclusion Criteria:

Inclusion criteria 3 reworded to clarify the patient type and disease characteristics 
for patients with solid malignant tumors (“Patients must have a histopathologic 
confirmation of malignancy.  Patients must have progressed or are refractory 
to standard therapies, and for whom no standard of care treatments exist”).
Section 4.1.2 Definition of Dose-Limiting Toxicities:

Text revised to provide clarify the definition of a dose-limiting toxicity (“Any of the 
AE’s listed below encountered between Cycle 1 Day 1 and Cycle 2 Day 28 (ie, 56 
day DLT monitoring period for combination therapy) and in the opinion of the 
Investigator is thought to be attributable to durvalumab or/and tremelimumab, given 
a reasonable possibility based on temporal exposure to IP and for which an 
alternate etiology does not exist or cannot be identified, will be classified as 
DLTs.”).

The parameters for hematologic and non-hematologic dose-limiting toxicities were 
revised after discussion with the Food and Drug Administration.
Section 4.1.3 Determining a recommended Phase II dose:

Text revised to clarify the basis for decisions about the recommended Phase II dose 
(“A DRC will be established prior to the initiation of the study to review all the 
data, with a primary emphasis on safety and PK, to establish RP2D to be further 
explored in the dose‑expansion phase of the study.  Decisions about RP2D doses 
for the start of expansion cohorts will be based on safety assessments from at 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
TABLE OF CONTENTS
TITLE PAGE.......................................................................................................1
VERSION HISTORY ..........................................................................................2
TABLE OF CONTENTS ...................................................................................21
1.
PROTOCOL SUMMARY .................................................................................28
1.1
Schedule of Activities (SoA)..............................................................................28
1.2
Synopsis.............................................................................................................43
1.3
Schema ..............................................................................................................54
2.
INTRODUCTION .............................................................................................56
2.1
Study rationale ...................................................................................................56
2.2
Background........................................................................................................57
2.2.1
Immunotherapies................................................................................................57
2.2.2
Durvalumab .......................................................................................................59
2.2.3
Tremelimumab...................................................................................................60
2.2.4
Durvalumab in combination with tremelimumab................................................60
2.3
Benefit/risk assessment ......................................................................................61
2.3.1
Potential benefits................................................................................................61
2.3.1.1
Durvalumab .......................................................................................................61
2.3.1.2
Durvalumab + tremelimumab.............................................................................62
2.3.2
Overall risks.......................................................................................................62
2.3.2.1
Durvalumab .......................................................................................................63
2.3.2.2
Tremelimumab...................................................................................................64
2.3.2.3
Durvalumab + tremelimumab.............................................................................64
2.3.3
Overall benefit/risk.............................................................................................65
3.
OBJECTIVES AND ENDPOINTS ....................................................................66
4.
STUDY DESIGN...............................................................................................69
4.1
Overall design....................................................................................................69
4.1.1
Dose-finding phase.............................................................................................71
4.1.2
Definition of dose-limiting toxicities and stopping criteria .................................75
4.1.3
Determining a recommended Phase II dose ........................................................77
4.1.4
Dose-expansion phase ........................................................................................78
4.1.5
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil 
Crisis, Natural Disaster, or Public Health Crisis .................................................78
4.2
Scientific rationale for study design....................................................................79
4.3
Justification for dose ..........................................................................................79
4.3.1
Durvalumab and tremelimumab dose and treatment regimen justification...........79
4.3.1.1
Durvalumab + tremelimumab combination therapy dose rationale......................79
4.3.1.2
Durvalumab monotherapy dose rationale............................................................80

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
4.3.1.3
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy ......................................................................................................81
4.4
End of study definition.......................................................................................81
5.
STUDY POPULATION.....................................................................................81
5.1
Inclusion criteria ................................................................................................82
5.1.1
Solid malignant tumors (except primary central nervous system malignant 
tumors)...............................................................................................................82
5.2
Exclusion criteria (All Patients)..........................................................................84
5.3
Lifestyle restrictions...........................................................................................87
5.4
Screen failures....................................................................................................88
6.
STUDY TREATMENTS ...................................................................................89
6.1
Treatments administered ....................................................................................89
6.1.1
Dose and treatment regimens..............................................................................89
6.1.1.1
Dose-finding phase.............................................................................................89
6.1.1.2
Dose-expansion phase ........................................................................................91
6.1.2
Study Drug Administration ................................................................................92
6.1.3
Study Drug Preparation......................................................................................92
6.1.3.1
Durvalumab (MEDI4736) ..................................................................................94
6.1.3.2
Tremelimumab...................................................................................................96
6.1.4
Duration of treatment and criteria for restarting treatment with durvalumab in 
combination with tremelimumab ........................................................................98
6.1.5
Storage...............................................................................................................99
6.2
Measures to minimize bias: randomization and blinding.....................................99
6.2.1
Patient enrollment and randomization.................................................................99
6.2.2
Procedures for handling incorrectly enrolled patients........................................100
6.2.3
Methods for ensuring blinding..........................................................................100
6.3
Treatment compliance ......................................................................................100
6.4
Concomitant therapy........................................................................................100
6.4.1
Background medication....................................................................................102
6.4.2
Other concomitant treatment ............................................................................102
6.4.3
Durvalumab drug-drug interactions..................................................................103
6.4.4
Tremelimumab drug-drug interactions..............................................................103
6.4.5
Rescue medication ...........................................................................................103
6.5
Dose modification............................................................................................103
6.6
Continued Access to Study Intervention After the Final DCO: Patient 
Management ....................................................................................................103
7.
DISCONTINUATION OF TREATMENT AND SUBJECT WITHDRAWAL.104
7.1
Discontinuation of study treatment...................................................................104
7.1.1
Procedures for discontinuation of study treatment ............................................105
7.2
Lost to follow-up..............................................................................................106

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
7.3
Withdrawal from the study...............................................................................106
8.
STUDY ASSESSMENTS AND PROCEDURES.............................................107
8.1
Efficacy assessments........................................................................................110
8.1.1
Central reading of scans ...................................................................................111
8.1.2
Survival assessments........................................................................................112
8.2
Safety assessments ...........................................................................................112
8.2.1
Physical examinations ......................................................................................112
8.2.2
Clinical safety laboratory assessments..............................................................112
8.2.3
Vital signs........................................................................................................115
8.2.4
Tanner staging..................................................................................................116
8.2.5
Electrocardiograms ..........................................................................................116
8.2.6
Early patient review for safety..........................................................................117
8.2.7
Performance status ...........................................................................................117
8.2.8
Other safety assessments ..................................................................................117
8.2.8.1
Other assessments ............................................................................................117
8.3
Collection of adverse events.............................................................................118
8.3.1
Method of detecting AEs and SAEs..................................................................118
8.3.2
Time period and frequency for collecting AE and SAE information .................118
8.3.3
Follow-up of AEs and SAEs.............................................................................118
8.3.4
Adverse event data collection...........................................................................119
8.3.5
Causality collection..........................................................................................120
8.3.6
Adverse events based on signs and symptoms ..................................................120
8.3.7
Adverse events based on examinations and tests...............................................120
8.3.8
Hy’s law...........................................................................................................121
8.3.9
Disease under study..........................................................................................121
8.3.10
Disease progression..........................................................................................121
8.3.11
New cancers.....................................................................................................121
8.3.12
Deaths..............................................................................................................121
8.3.13
Adverse events of special interest.....................................................................122
8.3.14
Safety data to be collected following the final DCO of the study......................123
8.4
Safety reporting and medical management .......................................................123
8.4.1
Reporting of serious adverse events..................................................................123
8.4.2
Pregnancy ........................................................................................................124
8.4.2.1
Maternal exposure............................................................................................125
8.4.2.2
Paternal exposure .............................................................................................125
8.4.3
Overdose..........................................................................................................126
8.4.3.1
Durvalumab or tremelimumab..........................................................................126
8.4.4
Medication error, Drug Abuse, and Drug Misuse..............................................126
8.4.4.1
Medication error...............................................................................................126
8.4.4.2
Drug Abuse......................................................................................................127
8.4.4.3
Drug Misuse.....................................................................................................127
8.4.5
Management of IP-related toxicities .................................................................127
8.4.5.1
Specific toxicity management and dose modification information –
Durvalumab and durvalumab + tremelimumab.................................................127

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
8. 5
P har mac o ki net ics a n d a nti-dr u g a nti b o dies .......................................................1 2 8
8. 5. 1
C ollect i on of p har mac o ki net ic sa m ples a n d deter mi nati on of dr u g 
c o nce ntrati o n ....................................................................................................1 2 8
8. 5. 2
C ollect i on of sa m ples t o meas ure f or t he prese nce of A D As a n d A D A-
ne utralizi n g a nt i b o dies .....................................................................................1 2 9
8. 5. 3
St ora ge a n d destr ucti o n of p har mac o ki net ic/a nti-dr u g a nti b o d y  s a mples ...........1 2 9
8. 6
P har mac o d y na mics ..........................................................................................1 2 9
8. 7
Ge net ics ...........................................................................................................1 3 0
8. 8
Bi o m ar kers .......................................................................................................1 3 0
8. 8. 1
C ollect i on of pat ient  sa mpl es f or 
.........................................1 3 0
8. 8. 2
............................................................................1 3 1
8. 8. 3
E x pl or at or y  bio m ar kers ....................................................................................1 3 2
8. 8. 4
St ora ge, re -use a n d destr ucti o n of bi o mar ker sa m ples .......................................1 3 3
8. 8. 5
La beli n g a n d s hi p me nt of bi o lo gical  sa m ples ...................................................1 3 3
8. 8. 6
C hai n o f c ust o d y of biol o gical sa m ples ............................................................1 3 4
8. 8. 7
Wit h dra wal o f i nf or me d c o nse nt f or d o nate d bi ol ogi cal sa m ples ......................1 3 4
8. 9
Effect of i m m u ne c hec k p o i nt i n hi biti on i n res p o nse t o r o uti ne i m m u nizati ons ..1 3 4
9.
S T A TI S TI C A L C O N SI D E R A TI O N S ..............................................................1 3 5
9. 1
Stati stical h y p ot heses .......................................................................................1 3 5
9. 2
S a m ple size deter mi nat i on ................................................................................1 3 5
9. 3
P o p ul at i ons f or a nal yses...................................................................................1 3 6
9. 3. 1
F ull a nal ysis set ................................................................................................1 3 7
9. 3. 2
E val ua ble f or res p o nse a nal ysis set ...................................................................1 3 7
9. 3. 3
S af et y a nal ysis set ............................................................................................1 3 7
9. 3. 4
D ose -li miti n g t o xicity e val ua ble a nal ysis set ....................................................1 3 8
9. 3. 5
P har mac o ki net ic a nal ysis set ............................................................................1 3 8
9. 3. 6
Ot her a nal ysis sets ............................................................................................1 3 8
9. 4
O utc o m e meas ures f or a nal yses ........................................................................1 3 8
9. 4. 1
Calc ulati o n or deri vat i on of efficac y varia bles ..................................................1 3 8
9. 4. 1. 1
R E CI S T 1. 1 a n d I N R C -base d e n d p oi nts ...........................................................1 3 8
9. 4. 1. 2
Pri mar y e n d p o i nt: O bject i ve res p o nse rate........................................................1 3 9
9. 4. 1. 3
Pr o gressi o n -free s ur vi val..................................................................................1 3 9
9. 4. 1. 4
O verall s ur vi val ................................................................................................1 3 9
9. 4. 1. 5
D urati o n of  res p o nse ........................................................................................1 4 0
9. 4. 1. 6
Best o bjecti ve res p o nse ....................................................................................1 4 0
9. 4. 1. 7
Di sease c o ntr ol r at e..........................................................................................1 4 0
9. 4. 1. 8
Pr o p orti o n ali ve a n d pr o gressi o n free at 1 2 a n d 1 8 m o nt hs ...............................1 4 1
9. 4. 1. 9
O verall s ur vi val at 1 2 a n d 2 4 m o nt hs ................................................................1 4 1
9. 4. 2
Calc ulati o n or deri vat i on of safet y varia bles .....................................................1 4 1
9. 4. 2. 1
A d verse e ve nts .................................................................................................1 4 1
9 . 4. 2. 2
S af et y assess me nts ...........................................................................................1 4 1
9. 4. 3
Calc ulati o n or deri vat i on of p har mac o ki netic varia bles ....................................1 4 2
9. 4. 3. 1
P o p ul at i on p har mac o ki net ics a n d e x p os ure-res p o nse/safety a nal ysis ................1 4 2
C CI
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
9.4.3.2
Pharmacokinetic non-compartmental analysis ..................................................142
9.4.3.3
Immunogenicity analysis..................................................................................142
9.4.4
Calculation or derivation of biomarker variables ..............................................143
9.4.5
Calculation or derivation of pharmacogenetic variables....................................143
9.5
Statistical analyses ...........................................................................................143
9.5.1
Efficacy analyses..............................................................................................143
9.5.1.1
Primary endpoint: objective response rate ........................................................144
9.5.1.2
Duration of response ........................................................................................145
9.5.1.3
Disease control rate..........................................................................................145
9.5.1.4
Best objective response ....................................................................................145
9.5.1.5
Progression-free survival..................................................................................145
9.5.1.6
Overall survival................................................................................................145
9.5.1.7
Proportion alive and progression-free at 12 and 18 months...............................145
9.5.1.8
Overall survival at 12 and 24 months................................................................146
9.5.2
Safety analyses.................................................................................................146
9.5.3
Pharmacokinetic data .......................................................................................146
9.5.4
Immunogenicity data........................................................................................146
9.5.5
Pharmacokinetic/pharmacodynamic relationships.............................................146
9.5.6
Biomarker data.................................................................................................147
9.5.7
Methods for multiplicity control.......................................................................147
9.6
Interim analyses ...............................................................................................147
9.6.1
Data Review Committee...................................................................................147
10.
REFERENCES ................................................................................................149
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL
CONSIDERATIONS .......................................................................................155
LIST OF TABLES
Table 1
Schedule of activities for durvalumab ± tremelimumab dose-finding phase ...... 29
Table 2
Schedule of activities for durvalumab ± tremelimumab dose-expansion phase.. 34
Table 3
Schedule of activities for patients who have discontinued all study treatments 
(durvalumab monotherapy or durvalumab and tremelimumab combination 
therapy) in the dose-finding or the dose-expansion phases ............................... 39
Table 4
Schedule of activities for patients receiving ongoing treatment beyond final 
data cutoff (DCO)............................................................................................ 41
Table 5
Study objectives............................................................................................... 66
Table 6
Disease cohorts for dose-finding phase............................................................. 70
Table 7
Disease cohorts for dose-expansion phase ........................................................ 70
Table 8
Key considerations for dose escalation decisions.............................................. 77

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 9
Highly effective methods of contraception (<1% failure rate)........................... 88
Table 10 Planned dose level 1......................................................................................... 90
Table 11 Planned dose level 2......................................................................................... 90
Table 12 Planned dose level 3......................................................................................... 90
Table 13 Planned dose level -1........................................................................................ 90
Table 14 Study treatments............................................................................................... 93
Table 15 Syringe administration volumes for patients ≤20 kg ......................................... 93
Table 16 Prohibited concomitant medications............................................................... 101
Table 17 Supportive medications .................................................................................. 102
Table 18 Volume of blood to be collected (by weight and including World Health 
Organisation limits) ....................................................................................... 110
Table 19 Clinical chemistry .......................................................................................... 113
Table 20 Hematology.................................................................................................... 114
Table 21 Urinalysis....................................................................................................... 114
Table 22 Summary of outcome variables and analysis populations................................ 137
Table 23 Pre-planned statistical analyses to be conducted ............................................. 144
Table 24 Summary of imaging modalities for tumor assessment ................................... 175
Table 25 Evaluation of target lesions ............................................................................ 179
Table 26 Evaluation of non-target lesions ..................................................................... 180
Table 27 Overall visit response..................................................................................... 181
Table 28 Key terms for International Neuroblastoma Response Criteria........................ 186
Table 29 Primary (soft tissue) tumor response............................................................... 186
Table 30 Tumor response at metastatic soft tissue and bone sites .................................. 187
Table 31 Bone marrow metastasis responsea ................................................................. 189
Table 32 Determination of overall response .................................................................. 190
Table 33 Immune-related Response Criteria (Baseline)................................................. 191
Table 34 Immune-related Response Criteria (Follow-up).............................................. 192
Table 35 Immune-related Response Criteria (Overall Tumor Assessments) .................. 192

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
LIST OF FIGURES
Figure 1 Study design..................................................................................................... 55
Figure 2 Dose-finding: escalation schema ...................................................................... 73
Figure 3 Dose-finding: de-escalation schema ................................................................. 74
LIST OF APPENDICES
Appendix A
Regulatory, ethical and study oversight considerations............................ 156
Appendix B
Adverse event definitions and additional safety information.................... 162
Appendix C
Handling of human biological samples.................................................... 167
Appendix D
Actions required in cases of increases in liver biochemistry and 
evaluation of Hy’s law................................................................................... 169
Appendix E
Guidelines for evaluation of objective tumor response using RECIST 1.1 
Criteria (Response Evaluation Criteria in Solid Tumors)................................ 174
Appendix F
International Neuroblastoma Response Criteria (INRC) .......................... 185
Appendix G
Immune-related Response Criteria: irRECIST ........................................ 191
Appendix H
Tanner Staging ....................................................................................... 194
Appendix I
Karnofsky Performance Status ................................................................. 195
Appendix J
Lansky Play Performance Scale............................................................... 196
Appendix K
Changes Related to Mitigation of Study Disruptions Due to Cases of 
Civil Crisis, Natural Disaster, or Public Health Crisis, including COVID-19 
Outbreak........................................................................................................ 197
Appendix L
Abbreviations.......................................................................................... 201

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
1.
PROTOCOL SUMMARY
1.1
Schedule of Activities (SoA)
The procedures for the screening and treatment periods in this study are presented in 

Table 1 for the dose-finding phase 

Table 2 for the dose-expansion phase  

Table 3 for the procedures for the follow-up period (for patients off study treatment).  

Table 4 for the procedures (management, reporting) for patients receiving ongoing 
treatment beyond database cutoff
The timing of the vital signs assessments should be such that it allows the blood draw eg, 
pharmacokinetic (PK) blood sample, to occur at the timepoints indicated in the schedule of 
activities (SoAs).  Whenever electrocardiograms (ECGs), vital signs, and blood draws are 
scheduled for the same nominal time, the assessments should occur in the following order: ECG, 
vital signs, and then blood draws.  The timing of the first 2 assessments should be such that it 
allows the blood draw (eg, PK blood sample) to occur at the timepoints indicated in the SoAs.  
Vital signs should always be assessed before blood draws.  
For both durvalumab monotherapy or durvalumab in combination with tremelimumab

Patients may delay dosing under certain circumstances:

Dosing may be delayed per the Dosing Modification and Toxicity 
Management Guidelines, due to either immune or non-immune-related 
adverse events (AEs).

If dosing must be delayed for reasons other than treatment-related toxicity, 
dosing will resume as soon as feasible.

A treatment delay of up to 14 days is permitted in the event that any AEs 
prevent the patient from starting the following cycle as planned. 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 1
Schedule of activities for durvalumab ± tremelimumab dose-finding phase
Screening
Cycle 1 (28 days)
Cycle 2 (28 days)
Cycle 3 to progression 
(each cycle is 28 days)
End of 
Treatment 
visit
For details, see 
Section
Day of cycle
-28 to -1
1
8
15
1
8
15
1
Visit windowa
±3 
days
±3 days
±4 days
±3 days
±3 
days
±4 days
Informed consent
Informed consent/ 
assent: study 
proceduresb 
X
5.1
Study procedures
Physical exam (full)
X
8.2.1
Targeted physical 
exam
X
X
X
X
X
X
X
X
8.2.1
Vital signs (including 
peripheral oxygen 
saturation)
X
X
X
X
X
X
X
X
X
8.2.3
Weight
X
X
X
8.2.1
Height  
X
X
X
8.2.1
Tanner staging
X
To be measured at visits where tumor efficacy assessments are made (see 
Section 8.1) until progression
8.2.4
ECGc (single)
X
As clinically indicated
8.2.5
Concomitant 
medications 
(including vaccines)
X
X
X
X
X
X
X
X
X
6.4
Demography, 
including baseline 
characteristics and 
tobacco used
X
Eligibility criteria
X
5.1, 5.2

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Screening
Cycle 1 (28 days)
Cycle 2 (28 days)
Cycle 3 to progression 
(each cycle is 28 days)
End of 
Treatment 
visit
For details, see 
Section
Day of cycle
-28 to -1
1
8
15
1
8
15
1
Visit windowa
±3 
days
±3 days
±4 days
±3 days
±3 
days
±4 days
Laboratory assessments
Clinical chemistrye
X
Xf
X
X
X
X
X 
Table 19
Hematologye
X
Xf
X
X
X
X
X
Table 20
Coagulation
Xf
Table 20
TSHg, (if abnormal 
free T4h ±free T3)
X
X
X
X
X
Table 19
Urinalysis
X
X
X
X
X
X
X
Table 21
Hepatitis B and C 
and HIV
X
8.2.1
Pregnancy testi
X
X
X
X
X
8.2.1
Durvalumab PK 
sample (serum)
Xj,k
Pre- and 
post-infusion 
of Durva
X
X
Xj,k
Pre-l and 
post-infusion 
of Durva
Xj,k
Pre- and post-infusion of 
Durval in C4, C6, C8, 
C10, and C12
8.5
Tremelimumab PK 
sample (serum)
Xj,k
Pre- and 
post-infusion 
of Treme 
X
X
X
Pre- and post-infusion of 
Treme in C3, C4, and 
C5j,k
Random sample in C8m
Xt
8.5
Durvalumab 
immunogenicity 
assessment ADA 
(serum)
Xj
Pre-infusion 
of Durva 
only
C6j
Pre-infusion of Durva 
only
8.5
Tremelimumab 
immunogenicity 
assessment ADA 
(serum)
Xj
Pre-infusion 
of Treme 
only
C5j and C8m
Pre-infusion of Treme 
only
8.5

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Scree ni n g
C ycle 1 ( 2 8 d a ys)
C ycle 2 ( 2 8 d a ys)
C ycle 3 t o pr o gressi o n 
(e ac h c ycle is 2 8 d a ys)
E n d of 
Tre at me nt 
visit
F or det ails, see 
Secti o n
D a y of c ycle
-2 8 t o - 1 
1 
8 
1 5 
1
8 
1 5
1
Visit wi n d o w a
± 3 
d a ys
± 3 d a ys
± 4 d a ys 
± 3 d a ys
± 3 
d a ys
± 4 d a ys
M o nit ori n g
Perf or ma nce Sc ore 
( La ns k y or 
Kar n ofs k y) n
X
X  
X  
X  
X  
X  
X
X
X
8. 2. 7
A E/ S A E assess me nt o
X
X  
X  
X  
X  
X  
X
X
X
8. 3
I P a d mi nistr ati o n
D ur val u ma b 
i nf usi o nf, p
X
X
X
6. 1. 1
6. 1. 2
Tre meli m u ma b 
i nf usi o nf, p
X
C 3, C 4 a n d C 5 o nl y
6. 1. 1
6. 1. 2
Ot her assess me nts a n d ass a ys
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Scree ni n g
C ycle 1 ( 2 8 d a ys)
C ycle 2 ( 2 8 d a ys)
C ycle 3 t o pr o gressi o n 
(e ac h c ycle is 2 8 d a ys)
E n d of 
Tre at me nt 
visit
F or det ails, see 
Secti o n
D a y of c ycle
-2 8 t o - 1 
1 
8 
1 5 
1
8 
1 5
1
Visit wi n d o w a
± 3 
d a ys
± 3 d a ys
± 4 d a ys 
± 3 d a ys
± 3 
d a ys
± 4 d a ys
Effic ac y e v al u ati o n
Ra di ol o gical efficac y 
assess me nts s
Da ys -2 1 t o 
- 1
O n -st u d y t u m or assess me nts occ ur e ver y 8 wee ks ± 1 wee k (al wa ys relati ve t o t he date of first d ose), 
u ntil ra di ol o gical pr o gressi o n pl us a n a d diti o nal re g ularl y sc he d ule d f oll o w - u p sca n.  F or patie nts 
w h o ac hie ve a n o bjecti ve re s p o nse ( C R, P R) or sta ble disease, a n d f or w h o m t he res p o nse is still 
e vi de nt at 1 2 m o nt hs, s u bse q ue nt t u m or assess me nts are t o occ ur e ver y 1 6 wee ks.  U nsc he d ule d 
assess me nts ca n be perf or me d at a n y ti me d uri n g t he st u d y, as cli nicall y i n dicate d, base d o n si g ns a n d 
s y m pt o ms
8. 1
N ote: All assess me nts o n treat me nt da ys are t o be perf or me d pri or t o i nf usi o n, u nless ot her wise i n dicate d.
N ote: Patie nts w h o restart c o m bi nati o n t hera p y ( ha vi n g s u bse q ue ntl y pr o gresse d o n d ur val u ma b m o n ot hera p y f oll o wi n g t he c o m pleti o n of 4 m o nt h s of c o m bi nati o n t hera p y) 
s h o ul d c o m plete t he sa me assess me nts starti n g fr o m t he C ycle 2 Da y 1 of t he d ose -fi n di n g p hase, wit h t he e xce pti o n of t he P K, A D A, bl o o d f or
 a nal ysis, a n d 
t u m or bi o psies. 
a 
Visit wi n d o ws are relati ve t o t he first da y of eac h c ycle.
b
Writte n i nf or me d c o nse nt/asse nt a n d a n y l ocall y re q uire d pri vac y act d oc u me nt a ut h orizati o n m ust be o btai ne d p ri or t o perf or mi n g a n y pr ot oc ol-s pecific pr oce d ures, 
i ncl u di n g scree ni n g/ baseli ne e val uati o ns.  If la b orat or y or i ma gi n g pr oce d ures were perf or me d f or alter nate reas o ns pri or t o si g ni n g c o nse nt, t hese ca n be use d f or scree ni n g 
p ur p oses wit h c o nse nt of t he patie nt’s pare nt(s)/le gall y a ut h orize d re prese ntati ve(s).  H o we ver, all scree ni n g la b orat or y assess me nts m ust ha ve bee n o btai ne d wit hi n 2 8 da ys 
of C ycle 1 Da y 1 a n d i ma gi n g/sta gi n g e xa mi nati o n res ults m ust ha ve bee n o btai ne d wit hi n 2 1 da ys of C ycle 1 Da y 1 .  T he u ni q ue e nr oll me nt c o de will be o btai ne d after I C F 
si g nat ure.  D ose-fi n di n g p hase will be ma n uall y s u p plie d.
c
A n y cli nicall y si g nifica nt a b n or malities detecte d re q uire a c o nfir mat or y E C G res ult. 
d
T o bacc o use will be c ollecte d at t he I n vesti gat or’s discreti o n.
e
Ser u m or plas ma cli nical c he mistr y (i ncl u di n g L F T m o nit ori n g) a n d he mat ol o g y ma y be perf or me d m ore fre q ue ntl y if cli nicall y i n dicate d.
f
Res ults f or L F Ts, electr ol ytes, f ull bl o o d c o u nt, urea, a n d creati ni ne m ust be a vaila ble bef ore c o m me nci n g a n i nf usi o n ( wit hi n 3 da ys) a n d re vie we d b y t he treati n g p h ysicia n 
or I n vesti gat or pri or t o d osi n g.  If scree ni n g cli nical c he mistr y a n d he mat ol o g y a ssess me nts are perf or me d wit hi n 3 da ys pri or t o Da y 1 (first i nf usi o n da y), t he y d o n ot nee d 
t o be re peate d at Da y 1.  F or c oa g ulati o n para meters, acti vate d partial t hr o m b o plasti n ti me a n d i nter nati o nal n or malize d ratio are t o be assesse d at baseli ne o n Da y 1 ( u nless 
perf or me d wit hi n 3 da ys pri or t o Da y 1).  
g
If T S H is meas ure d wit hi n 1 4 da ys pri or t o Da y 1 (first i nf usi o n da y), it d oes n ot nee d t o be re peate d at Da y 1.  T S H t o be meas ure d e ver y 4 wee ks fr o m baseli ne.
h
Free T 4 ± free T 3 will o nl y be measure d if T S H is a b n or mal or if t here is cli nical s us pici o n of a n A E relate d t o t he e n d ocri ne s yste m.
i
F or fe males of c hil d beari n g p ote ntial o nl y.  A uri ne or ser u m pre g na nc y test is acce pta ble.  Fe males of c hil d beari n g p ote ntia l are re q uire d t o ha ve a pre gna nc y  test wit hi n 
7 da ys pri or t o t he first d ose of I P a n d t he n e ver y 4 wee ks.  Pre g na nc y test ma y occ ur o n Da y 1, b ut res ults m ust be a vaila ble a n d re vie we d b y t he treati n g p h ysicia n or 
I nvesti gat or pri or t o c o m me nci n g a n i nf usi o n. 
j
Pre d ose wit hi n 6 0 mi n utes of start of t he 1 st i nf usi o n.
k
Wit hi n 1 0 mi n utes of t he e n d of t he 2
n d i nf usi o n.
l 
D uri n g t he c o m bi nati o n treat me nt peri o d, pre d ose sa m ples f or d ur val u ma b P K sa m ples s h o ul d i deall y be ta ke n i n t he wi n d o w afte r tre meli m u ma b has bee n i nf use d a n d 
bef ore d ur val u ma b is i nf use d, wit hi n 6 0 mi n utes of start of i nf usi o n.  H o we ver, sa m pli n g pri or t o tre meli m u ma b i nf usi o n is al s o acce pta ble, if c o nsi dere d necessar y f or 
l o gistical/ o perati o nal reas o ns.
m
T he C 8 f oll o w -u p tre meli m u ma b P K a n d A D A sa m ple will b e ta ke n 3 m o nt hs ( ± 1 wee k) after t he last d ose of t his I P ( meets re q uire me nt i n Ta ble 3 ).
n 
Kar n ofs k y scale t o be use d f or patie nts ≥1 6 years of a ge; La ns k y scale t o be use d f or patie nts ≥1 a n d < 1 6 years of a ge.
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 2
Schedule of activities for durvalumab ± tremelimumab dose-expansion phase
Screening
Cycle 1 (28 days)
Cycle 2 (28 days)
Cycle 3 to progression 
(each cycle is 28 days)
End of 
Treatment visit 
For 
details, see 
Section
Day of cycle
-28 to -1
1
8
15
1
15
1
Visit windowa
±3 
days
±3 
days
±4 days
±3 
days
±4 days
Informed consent
Informed consent/assent: study 
proceduresb
X
5.1
Study procedures
Physical exam (full)
X
8.2.1
Targeted physical exam 
X
X
X
X
X
X
X
8.2.1
Vital signs (including 
peripheral oxygen saturation)
X
X
X
X
X
X
X
X
8.2.3
Weight
X
X
X
8.2.1
Height  
X
X
X
8.2.1
Tanner staging
X
To be measured at visits where tumor efficacy assessments are made (see 
Section 8.1), until progression
8.2.4
ECGc (single)
X
As clinically indicated
8.2.5
Concomitant medications 
(including vaccines)
X
X
X
X
X
X
X
X
6.4
Demography, including 
baseline characteristics and 
tobacco used
X
5.1
Eligibility criteria
X
5.1, 5.2
Laboratory assessments
Clinical chemistrye
X
Xf
X
X
X
X
X
Table 19
Hematologye
X
Xf
X
X
X
X
X
Table 20
Coagulation
Xf
Table 20

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Screening
Cycle 1 (28 days)
Cycle 2 (28 days)
Cycle 3 to progression 
(each cycle is 28 days)
End of 
Treatment visit 
For 
details, see 
Section
Day of cycle
-28 to -1
1
8
15
1
15
1
Visit windowa
±3 
days
±3 
days
±4 days
±3 
days
±4 days
TSHg, (if abnormal free T4h ± 
free T3)
X
X
X
X
X
Table 19
Urinalysis
X
X
X
X
X
X
X
Table 21
Hepatitis B and C and HIV
X
8.2.1
Pregnancy testi
X
X
X
X
X
8.2.1
Durvalumab PK sample 
(serum)
Xj,k
Pre- and 
post-infusion 
of Durva
X
X
Xj,k
Prel- and 
post-infusion 
of Durva 
Xj,k
Pre- and post-infusion 
of Durva in C4l, C8, 
C12
8.5
Tremelimumab PK sample 
(serum)
Xj,k
Pre- and 
post-infusion 
of Treme
X
X
Xj,k
Pre- and 
post-infusion 
of Treme
X
C4 Pre- and 
post-infusion of Treme
j,k
Random sample in C7m
8.5
Durvalumab immunogenicity 
assessment ADA (serum)
Xj
Pre-infusion 
of Durva onlyl
C4j
Pre-infusion of Durva 
only
8.5
Tremelimumab 
immunogenicity assessment 
ADA (serum)
Xj
Pre-infusion 
of Treme only
C4j
Pre-infusion of Treme 
only
Random sample in C7m
8.5
Monitoring
Performance Score (Lansky or 
Karnofsky)n
X
X
X
X
X
X
X
X
8.2.7
AE/SAE assessmento
X
X
X
X
X
X
X
X
8.3

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Scree ni n g  
C ycle 1 ( 2 8 d a ys)
C ycle 2 ( 2 8 d a ys)
C ycle 3 t o pr o gressi o n 
(e ac h c ycle is 2 8 d a ys)
E n d of 
Tre at me nt visit 
F or 
det ails, see 
Secti o n
D a y of c ycle
-2 8 t o - 1 
1
8 
1 5 
1 
1 5
1
Visit wi n d o w a
± 3 
d a ys
± 3 
d a ys
± 4 d a ys
± 3 
d a ys
± 4 d a ys
I P a d mi nistr ati o n
D ur val u ma b i nf usi o n f, p
X
X
X
6. 1. 1
6. 1. 2
Tre meli m u ma b i nf usi o n f, p
X
X
C 3 a n d C 4 o nl y
6. 1. 1
6. 1. 2
Ot her assess me nts a n d ass a ys
 
Bl o o d sa m ple f or vacci ne 
a nti b o d y titer meas ure me nts 
( bl o o d)q
X
At least 4 wee ks after vacci nati o n
X
8. 9
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Scree ni n g  
C ycle 1 ( 2 8 d a ys)
C ycle 2 ( 2 8 d a ys)
C ycle 3 t o pr o gressi o n 
(e ac h c ycle is 2 8 d a ys)
E n d of 
Tre at me nt visit 
F or 
det ails, see 
Secti o n
D a y of c ycle
-2 8 t o - 1 
1
8 
1 5 
1 
1 5
1
Visit wi n d o w a
± 3 
d a ys
± 3 
d a ys
± 4 d a ys
± 3 
d a ys
± 4 d a ys
Effic ac y e v al u ati o ns
Ra di ol o gical efficac y 
assess me nts u
X
O n -st u d y efficac y assess me nts occ ur e ver y 8 wee ks ± 1 wee k (al wa ys relati ve t o t he date of 
first d ose), u ntil ra di ol o gical pr o gressi o n pl us a n a d diti o nal re g ularl y sc he d ule d f oll o w- u p 
sca n.  T his sc he d ule M U S T be f oll o we d re gar dless of a n y dela ys i n d osi n g.  F or patie nts 
w h o ac hie ve a n o bjecti ve res p o nse ( C R, P R) or sta ble disease, a n d f or w h o m t he res p o nse is 
still e vi de nt at 1 2 m o nt hs, s u bse q ue nt t u m or assess me nts are t o occ ur e ver y 1 6 wee ks.  
U nsc he d ule d assess me nts ca n be perf or me d at a n y ti me d uri n g t he st u d y, as cli nicall y 
i n dicate d, base d o n si g ns a n d s y m pt o ms
8. 1
N ote: All assess me nts o n treat me nt da ys are t o be perf or me d pri or t o i nf usi o n, u nless ot her wise i n dicate d.
N ote: Patie nts w h o restart c o m bi nati o n t hera p y ( ha v i n g s u bse q ue ntl y pr o gresse d o n d ur val u ma b m o n ot hera p y f oll o wi n g t he c o m pleti o n of 4 m o nt hs of c o m bi nati o n t hera p y) 
s h o ul d c o m plete t he sa me assess me nts starti n g fr o m C ycle 1 Da y 1 of t he d ose -e x pa nsi o n p hase, wit h t he e xce pti o n of P K, A D A, t u m or bi o psies, bl o o d f or 
 
a nal ysis, bl o o d f or  
 se q ue nci n g, a n d 
.
a 
Visit wi n d o ws are relati ve t o t he first da y of eac h c ycle.
b
Writte n i nf or me d c o nse nt/asse nt a n d a n y l ocall y re q uire d pri vac y act d oc u me nt a ut h orizati o n m ust be o btai ne d pri or t o perf or mi n g a n y pr ot oc ol -s pecific pr oce d ures, 
i ncl u di n g scree ni n g/ baseli ne e val uati o ns.  If la b orat or y or i ma gi n g pr oce d ures were perf or me d f or alter nate reas o ns pri or t o si g ni n g c o nse nt, t hese ca n be use d f or scree ni n g 
p ur p oses wit h c o nse nt of t he patie nt’s pare nt(s)/le gall y a ut h orize d re prese ntati ve(s).  H o we ver, all scree ni n g la b orat or y assess me nts m ust ha ve bee n o btai ne d wit hi n 2 8 da ys 
of C ycle 1 Da y 1 a n d i ma gi n g/sta gi n g e xa mi nati o n res ults m ust ha ve bee n o btai ne d wit hi n 2 1 da ys of C ycle 1 Da y 1.  T he u ni q ue e nr oll me nt c o de will be o btai ne d after I C F 
si g nat ure, t hr o u g h t he I R T/ R T S M.
c
A n y cli nicall y si g nifica nt a b n or malities detecte d re q uire a c o nfir mat or y E C G res ult. 
d
T o bacc o use will be c ollecte d at t he I n vesti gat or’s discreti o n.
e
Ser u m or plas ma cli nical c he mistr y (i ncl u di n g L F T m o nit ori n g) a n d he mat ol o g y ma y be perf or me d m ore fre q ue ntl y if cli nicall y i n dicate d.
f
Res ults f or L F Ts, electr ol ytes, f ull bl o o d c o u nt, urea, a n d creati ni ne m ust be a vaila ble bef ore c o m me nci n g a n i nf usi o n ( wit hi n 3 da ys) a n d re vie we d b y t he treati n g p h ysicia n 
or I n vesti gat or pri or t o d osi n g.  If scree ni n g cli nical c he mistr y a n d he mat ol o g y assess me nts are perf or me d wit hi n 3 da ys pri o r t o Da y 1 (first i nf usi o n da y), t he y d o n ot nee d 
t o be re peate d at Da y 1.  F or c oa g ulati o n para meters, acti vate d partial t hr o m b o plasti n ti me a n d i nter nati o nal n or malize d rati o are t o be assesse d at baseli ne o n Da y 1 ( u nless 
perf or me d wit hi n 3 da ys pri or t o Da y 1).  
g
If T S H is meas ure d wit hi n 1 4 da ys pri or t o Da y 1 (first i nf usi o n da y), it d oes n ot nee d t o be re peate d at Da y 1.  T S H t o be meas ure d e ver y 4 wee ks fr o m baseli ne.
h
Free T 4 ± free T 3 will o nl y be meas ure d if T S H is a b n or mal or if t here is cli nical s us pici o n of a n A E relate d t o t he e n d ocri n e s yste m.
i
F or fe males of c hil d beari n g p ote ntial o nl y.  A uri ne or ser u m pre g na nc y test is acce pta ble.  Fe males of c hil d beari n g p ote ntial are re q uire d t o ha ve a p re g na nc y test wit hi n 
7 da ys pri or t o t he first d ose of I P a n d t he n e ver y 4 wee ks.  Pre g na nc y test ma y occ ur o n Da y 1, b ut res ults must be a vaila ble a n d re vie we d b y t he treati n g p h ysicia n or 
I nvesti gat or pri or t o c o m me nci n g a n i nf usi o n. 
j
Pre d ose wit hi n 6 0 mi n utes of start of t he 1 st i nf usi o n. 
k
Wit hi n 1 0 mi n utes of t he e n d of t he 2
n d i nf usi o n.
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
l 
D uri n g t he c o m bi nati o n treat me nt per i o d, pre d ose sa m ples f or d ur val u ma b P K sa m ples s h o ul d i deall y be ta ke n i n t he wi n d o w after tre meli m u ma b has bee n i nf use d a n d 
bef ore d ur val u ma b is i nf use d, wit hi n 6 0 mi n utes of start of i nf usi o n.  H o we ver, sa m pli n g pri or t o tre meli m u ma b i nf usi o n is al s o acce pta ble, if c o nsi dere d necessar y f or 
l o gistical/ o perati o nal reas o ns.
m
T he C 7 f oll o w -u p tre meli m u ma b P K a n d A D A sa m ple will be ta ke n 3 m o nt hs ( ± 1 wee k) after t he last d ose of t his I P (Ta ble 3 ). 
n 
Kar n ofs k y scale t o be use d f or patie nts ≥1 6 years of a ge; La ns k y scale t o be use d f or patie nts ≥1 a n d < 1 6 years of a ge.
o
F or A Es/ S A Es re p orte d d uri n g scree ni n g, a d diti o nal i nf or mati o n s uc h as me dical hist or y a n d c o nc o mita nt me dicati o ns ma y be nee de d.
p
D uri n g t he c o m bi nati o n p orti o n of treat me nt, tre meli m u ma b will be a d mi nistere d first; t he d ur val u ma b i nf usi o n will start a p pr o xi matel y 1 h o ur after t he e n d of t he 
tre meli m u ma b i nf usi o n.  See Secti o n 6. 1. 2 ( St u d y Dr u g A d mi nistrati o n).
q
Bl o o d sa m ple f or a nti b o d y titer meas ure me nt will be ta ke n fr o m all patie nts at C 1 D 1 a n d fr o m at least 1 4 patie nts o n d ur val u ma b pl us tre meli m u ma b c o m bi nati o n t hera p y.  
At C y cle 1 Da y 1, sa m ples will be c ollecte d bef ore tre meli m u ma b i nf usi o n.  After war ds, a ne w sa m ple s h o ul d be c ollecte d at least 4 wee ks after a vacci ne has bee n gi ve n 
a n d e n d of treat me nt visit .  U p o n c o nfir mati o n t hat a s ufficie nt n u m ber of sa m ples has bee n s uccessf ull y a nal yze d, sites will be i nf or me d s o t hat f urt her c ollecti o n of sa m ples 
ca n be disc o nti n ue d.   
r
Bl o o d sa m ples f or 
 will be c ollecte d f or at least 1 0 patie nts recei vi n g d ur val u ma b pl us tre meli m u ma b c o m bi nati o n t hera p y.
s 
See Secti o n  8. 8. 1 f or details ar o u n d c ollecti o n, re q uire me nt, a n d e xe m pti o n f or 
.
t
T he f oll o wi n g t u m or mar kers will be assesse d i n t his st u d y: al p ha -fet o pr otei n f or patie nts wit h he pat o blast o ma a n d 
 
f or patie nts wit h ger m cell t u m ors.
u
See Secti o n 6. 1. 4 a n d Secti o n 8. 1 f or a d diti o nal details.  I ma gi n g m o dalities a p pr o priate f or t he t u m or t y pe u n der c o nsi derati o n s h o ul d be perf or me d a n d t he c orres p o n di n g 
o bjecti ve criteria use d t o m o nit or efficac y: s oli d t u m ors ( R E CI S T 1. 1 [A p pe n di x E ]).  C o nfir mat or y sca ns will be re q uire d.
A D A
A nti -dr u g a nti b o d y; A E A d verse e ve nt; C C ycle; C R
C o m plete res p o nse; C S F Cere br os pi nal fl ui d; D
da y; D ur va D ur val u ma b; E C G
Electr ocar di o gra m; 
F F P E F or mali n -fi xe d paraffi n-e m be d de d;  HI V
H u ma n i m m u n o deficie nc y vir us; I C F
I nf or me d c o nse nt f or m; I M I ntra m usc ular; I P I nvesti gati o nal pr o d uct; I nteracti ve 
Res p o nse Tec h n ol o g y (I R T); Ra n d o mizati o n a n d Trial S u p pl y Ma na ge me nt ( R T S M); L F T
Li ver f u nc ti o n test; L P L u m bar p u nct ure; 
; 
N A
N ot a p plica ble; 
; P K P har mac o ki netics; 
P R Partial res p o nse; q X w E ver y X wee ks; R E CI S T
Res p o nse E val uati o n Criteria I n S oli d T u m ors; S A E Seri o us a d verse e ve nt; 
 
; Tre me tre meli m u ma b; T 3 Trii o d ot h yr o ni ne; T 4 T h yr o xi ne; 
; T S H T h yr oi d -sti m ulati n g h or m o ne; W Wee k.
C CI
C CI
C CI
C CI
C CI
C CI
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 3
Schedule of activities for patients who have discontinued all study treatments (durvalumab monotherapy or 
durvalumab and tremelimumab combination therapy) in the dose-finding or the dose-expansion phases
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
For details, see 
Section
30
2
3 
4 months and every 
2 months thereafter 
(±2 weeks)  
Physical examination (full)
X
8.2.1
Vital signs (temperature, respiratory rate, blood 
pressure, pulse, and peripheral oxygen saturation)
X
X
X
8.2.3
Weight
X
X
X
8.2.1
Pregnancy testa
X
X
X
8.2.1
AE/SAE assessment
X
X
X
8.3
Concomitant medications
X
X
X
6.4
Performance Score (Lansky or Karnofsky) 
performance statusb
X
8.2.7
Subsequent anticancer therapyc
X 
X
X
X
8.1.2
Survival statusd
X
X
X
X
8.1.2
Hematology
X
X
X
Table 20
Clinical chemistry
X
X
X
Table 19
TSHe (if abnormal free T4 ± free T3)
X
X
X
Table 19
Durvalumab PK sample (serum)f
X
8.5
Tremelimumab PK sample (serum)f
X
8.5
Durvalumab immunogenicity assessment ADA 
(serum)f
X
8.5

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Time since last dose of IP
Evaluation
Day (±3)
Months (±1 week)
For details, see 
Section
30
2
3 
4 months and every 
2 months thereafter 
(±2 weeks)  
Tremelimumab immunogenicity assessment ADA 
(serum)f
X
8.5
Radiological efficacy assessmentsg 
Efficacy assessments occur every 8 weeks (or every 16 weeks for patients who achieve an 
objective response [CR, PR] or stable disease disease and for whom the response is still evident 
at 12 months) ± 1 week relative to the date of first dose, until radiological progression plus an 
additional regularly scheduled follow-up scan or death (whichever comes first). Additional 
scans to be completed per standard practice post-progression
7.1
Note: Patients who permanently discontinue drug for reasons other than objective PD should continue to have objective response assessments performed every 8 weeks ± 1 week 
(when clinically indicated) thereafter until PD plus an additional follow-up assessment or death (whichever comes first).  For patients who achieve an objective response 
(CR, PR) or stable disease and for whom the response is still evident at 12 months, subsequent tumor assessments are to occur every 16 weeks.  If a patient is discontinued 
for PD, then the patient should have 1 additional follow-up assessment performed preferably at the next (and no later than the next) scheduled imaging visit, and no less than 
4 weeks after the prior assessment of PD.
a
For females of childbearing potential only.  A urine or serum pregnancy test is acceptable. 
b
Karnofsky scale to be used for patients ≥16 years of age; Lansky scale to be used for patients ≥1 and <16 years of age.  
c
Details of any treatment for the malignancy under study (including surgery) post the last dose of IP must be recorded in the CRF.  At minimum, collect the start date and 
description of the subsequent anticancer therapy. 
d
Patients/parents/legally authorized representatives may be contacted in the week following data cut offs to confirm survival status.  Details of any treatment for the 
malignancy under study (including surgery) post the last dose of IP must be recorded in the CRF.
e
Free T4 ± free T3 will only be measured if TSH is abnormal or if there is clinical suspicion of an AE related to the endocrine system.
f
PK and immunogenicity samples for durvalumab and tremelimumab are collected 90 days (3 months) (±7 days) after the last dose of that IP (eg, if the last dose of 
tremelimumab is at C4D1 [12 weeks], then the follow-up samples for tremelimumab PK/ADA will be taken 90 days ± 7 days after that date, so equivalent to C7D1 
[24 weeks] of durvalumab monotherapy; if the last dose of durvalumab is, for example, at C8D1, then the follow-up samples for durvalumab PK/ADA will be taken
90 days ± 7 days after that date.
g
See Section 7.1 for additional details.  Imaging modalities appropriate for the tumor type under consideration should be performed and the corresponding objective criteria 
used to monitor efficacy.
ADA Anti-drug antibody; AE Adverse event; CR Complete response; CRF Case report form; IP Investigational product; NA Not applicable; PD progression of disease; 
PK Pharmacokinetics; PR Partial response; SAE serious adverse event; T3 Triiodothyronine; T4 Thyroxine; TSH Thyroid-stimulating hormone.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 4
Schedule of activities for patients receiving ongoing treatment beyond final data cutoff (DCO)
IP Administration
Durvalumab administration
Every 28 days until disease progression (or meeting criteria for treatment discontinuation) 
Laboratory assessments
Clinical chemistry
Standard of care, per local clinical practice
Hematology
Standard of care, per local clinical practice
TSH 
Standard of care, per local clinical practice
Required Monitoring and Reporting
SAE reporting
Any time during study treatment and up until 90 days after the last durvalumab infusion. If 
an event occurs after the 90-day period and is considered to be due to a late onset toxicity to 
study treatment, it should be reported as a SAE.
AESI reporting
Any time during study treatment and up until 90 days after the last durvalumab infusion.. If 
an event occurs after the 90-day period and is considered to be due to a late immune-related 
toxicity to study treatment, it should be reported as an AESI.
Pregnancy testing
For females of childbearing potential:
Monthly while on study treatment and then monthly x 3 following the completion of study 
treatment.
Pregnancy reporting
Any time during study treatment
Overdose reporting
Any time during study treatment
Efficacy evaluation

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Radiological efficacy assessments
Imaging schedule as standard of care, per local clinical practice 

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
O bjecti ves a n d E n d p oi nts
T o deter mi ne t he safet y pr ofile of d ur val u ma b i n 
c o m bi nati o n wit h tre meli m u ma b a n d 
d ur val u ma b as m o n ot hera p y f oll o wi n g 
c o m bi nati o n t hera p y
I de ntif y t he safet y a n d t olera bilit y of d ur val u ma b i n 
c o m bi nati o n wit h tre meli m u ma b a n d d ur val u ma b 
as mo n ot hera p y f oll o wi n g c o m bi nati o n t hera p y at 
t he a d ult e q ui vale nt e x p os ure/ M T D a m o n g c hil dre n 
a n d y o u n g a d ults fr o m birt h t o < 1 8 years of a ge 
wit h a d va nce d s oli d t u m ors usi n g a q 4 w d osi n g 
sc he d ule.  E n d p oi nts i ncl u de A Es, vital si g ns, 
p h ysical e xa mi nati o ns, E C Gs, a n d la b orat or y 
e val uati o ns.
Pri m ar y O bjecti ve ( D ose -e x p a nsi o n p h ase):
E n d p oi nt/ V ari a ble:
T o deter mi ne t he preli mi nar y a ntit u m or acti vit y 
of d ur val u ma b i n c o m bi nati o n wit h 
tre meli m u ma b a n d d ur val u ma b as m o n ot hera p y 
f oll o wi n g c o m bi nati o n t hera p y, at t he 
r ec o m me n de d d ose, usi n g c o h ort -s pecific 
r es p o nse criteria (e g, R E CI S T 1. 1).
O bjecti ve res p o nse rate as dete r mi ne d b y t he 
I n vesti gat or assesse d R E CI S T 1. 1 or alter nati ve 
pr e -s pecifie d t u m or-s pecific res p o nse rates f or 
differ e nt sc ori n g s yste ms.
Assess me nt of a ntit u m or acti vit y will be s pecific t o 
t u m or c o h ort, e g, I n vesti gat or assesse d R E CI S T 
1. 1. 
A d diti o nal ef ficac y e n d p oi nts t hat will be c ollecte d 
i ncl u de D o R, B o R, D C R, P F S, A P F 1 2, a n d A P F 1 8 
base d o n R E CI S T 1. 1 assesse d b y t he I n vesti gat or, 
a n d O S, O S 1 2, a n d O S 2 4 as a p pr o priate t o eac h 
i n di vi d ual c o h ort.
Sec o n d ar y O bjecti ve ( D ose -fi n di n g a n d 
D ose -e x p a nsi o n p hases):
E n d p oi nt/ V ari a ble:
T o descri be t he P K of d ur val u ma b a n d 
tre meli m u ma b i n c o m bi nati o n a n d d ur val u ma b 
as mo n ot hera p y f oll o wi n g c o m bi nati o n t hera p y , 
i n c hil dre n a n d y o u n g a d ults wit h s oli d t u m ors, 
or he mat ol o gical mali g na ncies.
I n di vi d ual d ur val u ma b a n d tre meli m u ma b 
c o nce ntrati o ns i n ser u m, a n d P K para meters 
i ncl u di n g Cma x , Cmi n , A U C, a n d ot her para meters 
w her e a p pr o priate.
T o deter mi ne t he i m m u n o ge nicit y of 
d ur val u ma b a n d tre meli m u ma b i n c o m bi nati o n 
a n d d ur val u ma b as m o n ot hera p y f oll o wi n g 
c o m bi nati o n t hera p y, i n c hil dre n a n d y o u n g 
a d ults wit h s oli d t u m ors.
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
O bjecti ves a n d E n d p oi nts
T o deter mi ne t he i m m u n o ge nicit y of 
d ur val u ma b i n c o m bi nati o n wit h tre meli m u ma b 
a n d d ur val u ma b as m o n ot hera p y f oll o wi n g 
c o m b i nati o n t hera p y, i n c hil dre n a n d y o u n g 
a d ults wit h he mat ol o gical mali g na ncies.
T o meas ure effects o n i m m u ne c hec k p oi nt 
i n hi biti o n i n res p o nse t o r o uti ne i m m u nizati o ns 
( d ose-e x pa nsi o n p hase o nl y).
I n di vi d ual a nti b o d y titer meas ure me nts 
 
 
 
T o e val uate i m m u ne acti vati o n a n d c o u nts of 
N K -, B- a n d T -cells.
S afet y o bjecti ve:
E n d p oi nt/ v ari a ble:
T o deter mi ne t he safet y pr ofile a n d t olera bilit y 
of patie nts fr o m d ose -e x pa nsi o n c o h ort(s) 
treate d wit h d ur val u ma b i n c o m bi nati o n wit h 
tre meli m u ma b wit h a q 4 w d osi n g sc he d ule.
A d verse e ve nts, vital si g ns, p h ysical e xa mi nati o ns, 
E C Gs, a n d la b orat or y e val uati o ns.
E x pl or at or y o bjecti ve:
E n d p oi nt/ v ari a ble:
T o c ollect bi o mar ker a n d i m m u ne res p o nse data 
i n patie nts treate d wit h d ur val u ma b i n 
c o m bi nati o n wit h tre meli m u ma b a n d 
d ur val u ma b as m o n ot hera p y f oll o wi n g 
c o m bi nati o n t hera p y.  
T he e n d p oi nts relate d t o ca n di date pre dicti ve a n d/ or 
pr o g n ostic bi o mar kers will f oc us o n  
 
, ac k n o wle d gi n g 
t hat pe diatric patie nts wit h a d va nce d ca ncer ha ve 
li mitati o ns o n 
 t hat ca n be 
har veste d f or c orrelati ve st u dies.  If tec h nicall y 
f easi ble t he c urre nt tra nslati o nal pla n will i ncl u de 
assess me nt of:
C CI
C CI
C CI
C CI
C CI
C CI

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
O bjecti ves a n d E n d p oi nts
I n a d diti o n, a n e x pl orat or y assess me nt relate d t o 
bi o mar kers will be perf or me d base d o n t he 
a vaila bil it y of 
 
t o e xa mi ne t he relati o ns hi p bet wee n a patie nt’s 
healt h 
 pri or t o treat me nt as well 
as a n y m o d ulati o ns w hic h ma y occ ur d uri n g a n d/ or 
f oll o wi n g treat me nt relati ve t o cli nical o utc o me, as 
a p plica ble.  If sa mples are a vaila ble, assa ys ma y 
i ncl u de: 
 
T o c o m pare R E CI S T 1. 1 wit h ir R E CI S T as 
assess me nt met h o d ol o gies f or cli nical be nefit of 
d ur val u ma b a n d d ur val u ma b i n c o m bi nati o n 
wit h tre meli m u ma b.
Pr o gressi o n -free s ur vi val (a n d O R R) acc or di n g t o 
R E CI S T 1. 1 a n d ir R E CI S T (ir R E CI S T will o nl y be 
use d as a n e x pl orat or y e n d p oi nt).
A D A
A n ti-dr u g a nti b o d y; A E A d verse e ve nt; A P F 1 2 / A P F 1 8 Pr o p orti o n of patie n ts ali ve a n d pr o gressi o n-free at 
1 2 / 1 8 m o nt hs fr o m first d ose of I P; A U C
Ar ea u n der t he plas ma dr u g c o nce ntrati o n -ti me c ur ve; B o R Best 
o bjecti ve res p o nse; C D
Cl uster of differe ntiati o n; C ma x
Ma xi m u m ser u m c o nce ntrati o n; C
mi n
Mi ni m u m ser u m 
c o nce ntrat i o n; D C R Disease c o ntr ol rate; D o R
D urati o n of res p o nse; E C G
Electr ocar di o gra m; 
 
; I F N I nterfer o n; ir R E CI S T i m m u ne-relate d Res p o nse E val uati o n Criteria i n S oli d T u m ors; 
M T D
Ma xi m u m t olerate d d ose; N K
Nat ural killer; O R R
O bjecti ve res p o nse rate; O S O verall s ur vi val; 
 P K P h ar mac o ki netics; q 4 w E ver y 4 wee ks; R E CI S T
Res p o nse 
E val uati o n Criteria i n S oli d T u m ors; R P 2 D Rec o m me n de d P hase II d ose; 
.
O ver all desi g n:
O pe n -la bel, n o n- ra n d o mize d, i nter nati o nal, m ultice nter st u d y in vest i gati n g d ur val u ma b i n 
c o m bi nat i on wi t h tre meli m u ma b ( q 4 w f or 4 c ycles o nl y) f o ll owe d b y  d ur val u ma b mo n ot hera p y  
( q 4 w) i n pe diatric patient s fr om birt h t o < 1 8 y ears of a ge wit h r ela pse d or refract or y mali g na nt 
s oli d t u m ors. D ur val u ma b i n c o m bi nat i on wi t h tre meli m u ma b will be e xa mi ne d i n all s oli d 
mali g na nt t u m ors (e xce pt pri mar y  c e ntral ner v o us s yste m t u m ors).
T he st u d y  will be c o n d ucte d i n 2 se q ue ntial p hases: a d ose -fi n di n g p hase, f oll owe d b y a 
d ose -e x pa nsio n  p hase.
Eac h treat me nt c y cle is 2 8 da ys.
P hase I: D ose -fi n di n g p hase
C CI
C CI
C CI
C CI
C CI
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
The dose-finding phase of the study will be conducted using a modified 3 + 3 design to 
determine whether durvalumab and tremelimumab can be administered safely in pediatric 
patients and if adult exposures can be achieved.  Pediatric patients with relapsed or refractory 
malignant solid tumors (osteosarcoma and Ewing sarcoma [SARC-1], rhabdomyosarcoma, 
non-rhabdomyosarcoma, and other sarcomas [SARC-2], neuroblastoma [NB]), other solid 
tumors (STO), will be enrolled in 2 arms:

Arm A: patients weighing ≥35 kg

Arm B: patients weighing <35 kg.
Patients will be treated in Cycle 1 with durvalumab monotherapy, Cycles 2 to 5 with durvalumab 
combined with tremelimumab, and from Cycle 6 with durvalumab alone until progression of 
disease (PD). 
Based on the available clinical and PK data and simulations, the administration of an adult 
weight-adjusted dose in children with a body weight of ≥35 kg is anticipated to result in PK and 
target engagement profiles similar to adults.  However, patients with a body weight less than 
35 kg, may have exposures lower than those in adults, and thus may require higher doses to 
achieve exposures similar to adults.  Consequently dose-finding will be conducted in 2 body 
weight-based arms (ie patients, ≥35 kg and <35 kg) in parallel.  Based on emerging data during 
the conduct of the study, cohorts may also be backfilled to provide further assessment of safety 
and PK in specific age groups and to ensure a broad representation of ages/weights at a given 
dose level (DL).
Three DLs may be explored in each of the arms as outlined in the figure below.  Dose level 1 
will be 100% of the recommended adult dose of both durvalumab and tremelimumab 
administered as weight-adjusted doses.  The doses and schedules are as follows:
1.
Cycle 1 (durvalumab monotherapy): durvalumab 20 mg/kg
2.
Cycles 2 to 5 (durvalumab in combination with tremelimumab): durvalumab 20 mg/kg 
and tremelimumab 1 mg/kg (4 cycles administered every 28 days)
3.
From Cycle 6 onwards, treatment will continue until a discontinuation criterion is met, 
with durvalumab monotherapy administered at 20 mg/kg every 28 days.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
This figure shows the maximum doses for durvalumab at DLs 2 and 3 (40 mg/kg) and tremelimumab at DL 3 (2 mg/kg).  Lower 
doses may be tested, depending on the obtained PK modeling data. 
DL Dose level; NB Neuroblastoma; SARC-1 Osteosarcoma and Ewing sarcoma; SARC-2 Rhabdomyosarcoma, non-
rhabdomyosarcoma, and other sarcomas; STO Solid tumor other.
A Data Review Committee (DRC) will be established prior to the initiation of the study to 
review all the data, including with a primary emphasis on safety and PK, to make decisions on 
dose escalations and determination of a recommended Phase II dose (RP2D) to be further 
explored in the dose-expansion phase. 
Dose escalation decisions will aim to identify the RP2D for durvalumab and tremelimumab in 
combination. Dose escalation decisions and determination of RP2D will mainly consider safety 
assessments from at least 3 patients followed up for 4 cycles, to include a single cycle of 
durvalumab and 3 cycles of the combination of durvalumab and tremelimumab (for a total of 
120 days).  This includes assessment of pre-defined dose-limiting toxicities (DLTs) in the first 
2 cycles.
A de-escalation step may occur for durvalumab or tremelimumab, with reduced doses 
of 15 mg/kg and 0.75 mg/kg, respectively, if DL 1 is considered not tolerated.  Furthermore, if 
exposure of durvalumab or/and tremelimumab proves inadequate, intermediate DLs may also be 
tested. 
In addition, 3 patients older than 2 years of age must be treated with durvalumab in combination 
with tremelimumab and clear the DLT period before children less than 2 years old may be 
enrolled in the dose-finding phase.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Phase II: Dose-expansion phase
The dose-expansion phase will be conducted using a Simon 2-stage optimal design with an 
additional provision to include 1 mixed disease cohort (other malignant solid tumors).
Once the RP2D has been established, patients will be recruited to each of the following cohorts:
1.
SARCOMA (bone sarcomas: osteosarcoma, Ewing sarcoma; soft-tissue sarcomas 
[≥40% of enrollment]: rhabdomyosarcoma, non-rhabdomyosarcoma, and other 
sarcomas)
2.
STO (other solid tumors).
For the SARCOMA cohort, the initial stage will allow 11 evaluable patients, to be dosed in this 
disease-specific cohort. If 2 or more responses in either of these cohorts are observed, additional 
patients will be accrued, as part of the second stage, into the corresponding expansion cohort; 
15 patients will be accrued into the SARCOMA expansion cohort for a total of 26 evaluable 
patients. If there has been ≤1 objective response in the SARCOMA cohort (11 patients), at the 
time that evaluable patients dosed in the initial stage have been followed/assessed for at least 3 
cycles, the cohort will be discontinued for lack of benefit.
For the STO cohort, 10 evaluable patients will be enrolled into this mixed-disease cohort; Simon 
rules are not applicable for this cohort.
Study period:
Date of first patient enrolled: Q1 2019.
Estimated date of last patient completed: Q1 2023.
Number of patients:
Dose-finding phase: The final sample size in the dose-finding phase will depend on the number 
of DLTs and on the number of DLs to be explored.  In addition, any patients not evaluable will 
be replaced in order to have the required number of patients evaluable at each DL.  A minimum 
of 12 patients is anticipated to be dosed, to enable exploration of one DL in both patients 
weighing 35 kg and greater, and patients weighing under 35 kg.  If all 3 DLs are used at both 
weight-based arms, then 36 evaluable patients would be necessary to complete the dose-finding 
phase. If approximately 20% of patients need to be replaced due to non-evaluability, then a 
maximum of 45 patients will be enrolled on the dose-finding cohorts.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Dose-expansion phase:

Following a Simon 2-stage optimal design, a total of 26 evaluable patients 
(11 evaluable patients in the initial stage and an additional 15 patients in the second 
stage), are expected to be enrolled in the SARCOMA cohort.

The STO cohort is planned to recruit 10 evaluable patients.
With the above considerations, the sample size for evaluable patients in the dose-expansion 
phase is expected to range from 38 to 66.  Assuming that about 20% of patients may not be 
evaluable for objective response rate (ORR), the total number of patients dosed in the 
dose-expansion phase may range from approximately 46 to 80. 
Screen failures are patients who do not fulfill the eligibility criteria for the study, and therefore 
must not be dosed.  Patients may be rescreened a single time.
Treatments and treatment duration:
Durvalumab + tremelimumab combination therapy (dose-finding phase):

Durvalumab monotherapy, administered as a single cycle, will be given via 
intravenous (IV) infusion at Cycle 1.  Patients will receive durvalumab in combination 
with tremelimumab via IV infusion q4w, starting on Cycle 2, for up to a maximum of 
4 doses/cycles.  Four weeks after the last infusion of the combination, treatment 
continues with durvalumab monotherapy q4w until clinical or confirmed PD, or other 
discontinuation criteria is met, whichever comes first.
Durvalumab + tremelimumab combination therapy (dose-expansion phase):

Durvalumab in combination with tremelimumab via IV infusion q4w will be given for 
up to a maximum of 4 doses/cycles.  Four weeks after the last infusion of the 
combination, treatment continues with durvalumab monotherapy q4w until clinical or 
confirmed PD, or other discontinuation criteria is met, whichever comes first.
Duration of treatment
Unless specific treatment discontinuation criteria are met, patients will continue therapy until 
clinical progression/deterioration or confirmed radiological progression, and scanning/tumor 
assessments continue throughout treatment until radiological progression plus an additional 
follow-up scan (if clinically feasible).
Progression during treatment
All patients will receive 4 cycles of durvalumab in combination with tremelimumab (Cycles 2 to 
5 in the dose-finding phase and Cycles 1 to 4 in the dose-expansion phase).  Treatment with 
durvalumab alone will be continued q4w until clinical progression or confirmed radiological 
progression, unless there is unacceptable toxicity, withdrawal of consent, or another 
discontinuation criterion is met.  

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
If a patient progresses while receiving durvalumab monotherapy after receiving an initial 
4 cycles of the combination of durvalumab and tremelimumab, such patients may restart 
treatment with the combination treatment for 4 additional cycles.
Follow-up of patients post discontinuation of study drug
Patients who have discontinued treatment due to toxicity or symptomatic deterioration, clinical 
progression, or who have commenced subsequent anticancer therapy will be followed for PK and 
survival.  Efficacy assessments are to be done according to Table 3 (ie, until radiological 
progression plus an additional regularly scheduled follow-up scan or death; whichever comes 
first).  
Survival
All patients in the study will be followed up for survival.
Data Review Committee:
A DRC will be established prior to the initiation of the study and will review the safety and PK 
data.  The DRC membership will comprise of participating Investigators and representatives 
from both AstraZeneca (Pharmacovigilance Scientists for durvalumab and tremelimumab, PK 
Scientist, Study Physician and Biostatistician) and IQVIA (Study Physician, Safety Physician 
and Biostatistician).  On a case-by-case basis, the DRC may also seek advice from pediatric 
oncologists with the required site specialization expertise. 
Recommendations and decisions will be made through consensus of opinion amongst the DRC 
members with all decisions being documented and distributed to DRC members.  
The key tasks of the DRC members will be to review the data recorded in the clinical database in 
conjunction with the PK data to:
1.
Determine whether DLTs have occurred
2.
Decide whether additional patients should be added to a cohort
3.
Recommend de-escalating a dose that was poorly tolerated or escalating a dose if PK 
exposures inferior to those observed in adults, were achieved
4.
Declare that dose finding is complete
5.
Recommend a Phase II dose to be explored in the dose-expansion phase of the study
6.
Perform a benefit/risk assessment at the completion of safety data analysis for children
<1 year old prior to enrolling a patient less than 1 year old; notify local health 
authority of decision, if applicable, as per local requirements
7.
Put enrollment on hold
8.
End the study.

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During the dose-expansion phase, the DRC will review safety, tolerability, PK, and efficacy data 
to make consensual decisions on cohort expansion or closure, and end the study, among others.
Statistical methods
There is no formal statistical testing for the dose-finding phase of the study. 
The dose-expansion phase of the study will formally test the following hypothesis: 

H0: ORR  ≤10%

H1: ORR >10%.
The test will be performed for the SARCOMA cohort and it will be done at the 1-sided 5% level.  
No formal statistical testing will be performed for the STO cohort.
Five analysis sets will be used for data analysis:

The full analysis set (FAS) will include all patients who were assigned to treatment 
and received at least 1 dose of study treatment.  The FAS (or subset of the FAS 
specified below) will be used for all efficacy analyses.  Patients will be summarized 
and analyzed according to their assigned study treatment, regardless of the treatment 
actually received. 

Evaluable for response analysis set is a subset of patients in the FAS who had 
measurable disease at baseline.

The safety analysis set (SAS) will consist of all patients who received any amount of 
study treatment.  Safety data will be summarized using the SAS according to the 
treatment received. 

The DLT evaluable analysis set is a subset of the SAS for the dose-finding phase of 
the study.  It includes all patients enrolled in the dose-finding phase of the study who 
receive the protocol-assigned treatment with durvalumab + tremelimumab and 
complete the safety follow-up through the DLT evaluation period (Cycle 1 + Cycle 2) 
or experience a DLT during the DLT evaluation period. 

The PK analysis set will consist of all patients who receive at least 1 dose of IP per the 
protocol for whom any postdose data are available and who do not violate or deviate 
from the protocol in ways that would significantly affect the PK analyses.  
The population will be defined by the Study Physician, Pharmacokineticist, and 
Statistician prior to any analyses being performed.
The analysis of the primary endpoint, ORR, and the analyses of the secondary endpoints, 
progression-free survival (PFS), duration of response (DoR), and disease control rate (DCR), 
will be based on the site Investigator assessments using Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 for solid tumors. Immune-related Response Evaluation Criteria will also 

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be assessed for ORR and PFS. In addition, OS, another secondary endpoint, will also be 
evaluated. 
The 2 phases of the study will be summarized and analyzed separately.  For the dose-finding 
phase, summaries will be presented by DL.  For the dose-expansion phase, summaries and 
analyses will be presented by cohort.
Methods for statistical analysis:
The following table presents the analyses planned for the efficacy endpoints.  All tumor-related 
endpoints will be analyzed using Investigator RECIST 1.1 assessments.
Pre-planned statistical analyses to be conducted
Endpoints analyzed
Notes
Objective response rate
Exact 90% 2-sided CI (Mid-P) 
Duration of response 
Median estimated from KM curve
Disease control rate 
Exact 90% 2-sided CI (Mid-P)
Best objective response 
n (%) of patients in each response category
Progression-free survival 
Median estimated from KM curve 
Overall survival
Median estimated from KM curve
Proportion alive and 
progression-free at 12 months
90% 2-sided CI estimated from KM curve
Proportion alive and 
progression-free at 18 months
90% 2-sided CI estimated from KM curve
Proportion alive at 12 months
90% 2-sided CI estimated from KM curve
Proportion alive at 24 months 
90% 2-sided CI estimated from KM curve
CI Confidence interval; KM Kaplan-Meier.
No multiplicity adjustment will be applied.
Safety and tolerability data will be presented by DL in dose-finding phase and by cohort in 
dose-expansion phase, using the SAS. Data from all cycles of treatment will be combined in the 
presentation of safety data. 
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, physical examinations and exposure to durvalumab + tremelimumab 
combination therapy, and durvalumab monotherapy.  Time on study, 
durvalumab + tremelimumab combination therapy, and durvalumab monotherapy dose delays 
will also be summarized.  
Pharmacokinetic data will be summarized and analyzed based on the PK analysis set.

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P har mac o ki net ic c o nce ntrati o n data will be liste d f or eac h patie nt a n d eac h d osi n g da y a n d a 
s u m mar y will be pr o vi de d f or all e val ua ble pat ient s.
I mm u n o ge nicit y res ults will be liste d b y patient , a n d a s u m mar y will be pr o vi de d b y t he n u m ber 
a n d perce nta ge of patie nts w h o de vel o p detecta ble a nt i-d ur val u ma b a n d a nt i-tr e meli m u ma b 
a nt i b o dies.  T he i m m u n o ge nicity titer a n d ne utralizi n g A D A data will be liste d f or sa m ples 
c o nfir me d p osit i ve f or t he prese nce of a nti-d ur val u ma b or a nti -tr e meli m u ma b a nti b o die s. 
Vacci ne i n di vi d ual a nti b o d y  titer data a n d 
 data will be liste d f or eac h patie nt a n d 
a s u m mar y will be pr o vide d.
T he rel at i ons hi p of 
 t o cli nical 
o utc o m es (i ncl u di n g b ut n ot restricte d t o) of O R R, D C R, P F S a n d O S will be prese nte d.
1. 3
Sc he m a
T he ge neral st u d y  desi g n is s u m marize d i n Fi g ure 1 .
C CI
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Figure 1
Study design
This figure shows the maximum doses at dose-finding for durvalumab at DLs 2 and 3 (40 mg/kg) and tremelimumab at DL 3 (2 mg/kg).  Lower doses may be tested, depending on
the obtained PK modeling data 
DL Dose level,  NB Neuroblastoma; SARC-1 Osteosarcoma and Ewing sarcoma; SARC-2 Rhabdomyosarcoma, non-rhabdomyosarcoma, and other sarcomas; 
SARCOMA Osteosarcoma and Ewing sarcoma, and Rhabdomyosarcoma, non-rhabdomyosarcoma, and other sarcomas; STO Solid tumor other.

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2.
INTRODUCTION
According to the RARECARE dataset (website: http://www.rarecare.eu), the most common 
extracranial solid tumors in children (aged 0 to 14 years) include neuroblastoma (NB), Wilms 
tumor, and sarcomas, including rhabdomyosarcoma, osteosarcoma, and Ewing sarcoma.  
Survival rates are highly variable with the type of solid tumor, although high overall survival 
(OS) rates are reported at 1 year (92%) and 5 years (76%) overall.
Pediatric hematopoietic and lymphoid malignancies are typically of an aggressive type, with 
acute lymphoblastic leukemia being the most common childhood cancer.  According to 
RARECARE, other prevalent cancers of this type in ages 0 to 14 years include non-Hodgkin’s 
lymphoma (NHL), Hodgkin’s lymphoma (HL), and acute myeloid leukemia.  Data from 
RARECARE also show high survival rates in children with HL (99% at 1 year) and remains high 
5 years after diagnosis.  For other lymphoid tumors, survival is also relatively high (>70%).  
Standard therapy for solid and hematological pediatric tumors includes various combinations of 
surgery, cytotoxic chemotherapy, and radiation.  These treatments can have detrimental 
consequences to a developing child, and many survivors carry a substantial burden of long-term 
morbidities.  With improved survival rates, children with cancer are likely to live longer, with the 
risk of long-term toxicity being an important crucial factor.  In addition, there is an overall unmet 
medical need for more effective therapies for pediatric patients who have relapsed/refractory 
disease.  Attractive alternatives would include biological agents that do not include toxic 
chemotherapy and target alternative carcinogenesis pathways that may have acquired resistance 
from the previous therapies.  Immune checkpoint inhibitors may be such candidates, with 
promising and positive outcomes in adults with melanoma, lung cancer, bladder cancer, gastric 
cancer, microsatellite instability in colorectal cancer, and other malignancies 
(SIOPE briefing, 2015).  
2.1
Study rationale
Therapeutic options are lacking for the treatment of relapsed/refractory solid tumors and 
hematological malignancies in the pediatric population.  Additionally, conventional pediatric 
therapies often produce long-term side effects.  Therapies with less frequent and non-overlapping 
long-term side effect profiles would likely improve the quality of life of these patients.  
Based on results of immune checkpoint inhibitor therapies in adults with relapsed/refractory 
solid tumors and lymphomas (see Section 2.2.1), durvalumab monotherapy or durvalumab plus 
tremelimumab combination therapy may represent an effective treatment for the pediatric 
population.  The proposed study will evaluate durvalumab in combination with tremelimumab in 
pediatric patients with refractory/relapsed solid tumors and lymphoid malignancies.
This study has been discussed and agreed with the European Medicines Agency (EMA) 
Paediatric Committee (PDCO) and forms a key commitment as part of the Pediatric Investigation 
Plan.

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2.2
Background
A detailed description of the chemistry, pharmacology, efficacy, and safety of durvalumab and 
tremelimumab is provided in the respective Investigator’s Brochures (IBs).
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 cell 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 1 (PD-1) receptor 
(cluster of differentiation [CD]279) is expressed on the surface of activated T-cells 
(Keir et al 2008).  It has 2 known ligands: PD-L1 (B7-H1; CD274) and programmed cell death 
ligand 2 (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 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 (ICs).  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 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 pre-clinical 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.

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In contrast, anti-cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is constitutively 
expressed by regulatory T-cells and upregulated on activated T-cells.  CTLA-4 delivers a 
negative regulatory signal to T-cells upon binding of CD80 (B7.1) or CD86 (B7.2) ligands on 
antigen-presenting cells (Fife and Bluestone 2008).  Blockade of CTLA-4 binding to CD80/86 
by anti-CTLA-4 antibodies results in markedly enhanced T-cell activation and antitumor activity 
in animal models, including killing of established murine solid tumors and induction of 
protective antitumor immunity.  Therefore, it is expected that treatment with an anti-CTLA-4 
antibody will lead to increased activation of the human immune system, increasing antitumor 
activity in patients with solid tumors.
Pre-clinical data have now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as 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 in adult patients, including metastatic melanoma, squamous and non-squamous cell 
non-small-cell lung cancer, 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.
It is anticipated, based on preliminary efficacy signals for anti-PD-1/PD-L1 antibodies in 
pediatric indications, that immunotherapy agents could also play an important role in the 
treatment of relapsed/refractory solid tumors and hematological malignancies in the pediatric 
population, which are currently lacking.  Presently the following data are available to support use 
of immunotherapy agents in pediatric patients.
A Phase I/II study of pembrolizumab in pediatric patients with advanced melanoma or a PD-L1+ 
advanced, relapsed, or refractory solid tumor or lymphoma.  As of 07 November 2016, 1 patient 
each with HL, adrenocortical carcinoma, mesothelioma, and glioblastoma had partial response 
(PR) for an objective response rate (ORR) of 6.1% (95% confidence interval [CI], 1.7-14.8); 
7 (10.6%) patients had stable disease (SD) for a disease control rate (DCR) of 16.7% (95% CI, 
8.6-27.9).  Median progression-free survival (PFS) and OS were 1.8 months and 9.2 months, 
respectively; 12-month PFS was 10.2% and OS was 40.5% (Geoerger et al 2017a). 
Ipilimumab, an anti CTLA-4 inhibitor is approved by the FDA for the treatment of unresectable 
or metastatic melanoma in adults and pediatric patients (12 years and older) and for the treatment 
of adult and pediatric patients 12 years of age and older with microsatellite instability-high 
(MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer that has progressed 
following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan, in combination with 
nivolumab (USPI).  Ipilimumab in combination with nivolumab is being pursued in a Phase I/II 
study of known pediatric patients with relapsed/refractory solid tumors (Davis et al 2017).
In a Phase I/II study assessing the safety, pharmacokinetic and preliminary activity of 
atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors 
concluded as of 19 July 2016 that the PK and safety profile of atezolizumab is similar to that in 

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a d ults.  T w o i n 5 patie nts wit h H L ha d a P R a n d t he o nl y patient  wit h at ypical r ha b d oi d t u m or 
ha d a n u nc o nfir me d P R. 
T here i s a si g nifica nt u n met me dical nee d f or ne w effect i ve t hera pies f or pe diatric patie nts a n d 
t hese preli mi nar y data s u g gest i m m u n ot hera p y a ge nts a n d c o mbi nati o ns t here of ma y pr o vi de 
alter nati ve effecti ve ca ncer t hera pies f or y o u n g a d ults a n d c hil dre n.  T here is als o str o n g 
r atio nale a n d s u p p ort fr o m t he E M A P D C O a n d cli nical e x perts t o e val uate t he s y ner gist ic 
acti vit y of  c o m bi ne d a nti-P D -L 1 a n d C T L A -4 t a r geti n g t o acti vate t he patie nt’s nati ve i m m u ne 
s yste m a gai nst t heir ca ncer.
2. 2. 2
D ur v al u m a b
D ur val u ma b is a h u ma n m A b o f t he i m m u n o gl o b uli n G 1 ka p pa s u bclass t hat bl oc ks t he 
i nteract i on of P D -L 1 ( b ut n ot P D -L 2) wit h P D -1 o n T -cells a n d C D 8 0 ( B 7. 1) o n I Cs.  It is bei n g 
de vel o pe d b y Astra Ze neca/ Me dI m m u ne f or use i n t he treat me nt of ca ncer.  ( Me dI m m u ne is a 
w h o ll y o w ne d s u bsi diar y of Astra Ze neca; Astra Ze neca/ Me dI m m u ne will be referre d t o as 
Astra Ze neca t hr o u g h o ut t his d oc u me nt.)  T he pr o p ose d mec ha nis m o f act i on f or d ur valu ma b is 
i nterfere nce i n t he i nteracti o n of P D -L 1 wi t h P D- 1 a n d C D 8 0 ( B 7. 1).  Bl oc ka de of P D-L 1/ P D - 1 
a n d P D-L 1/ C D 8 0 i nteracti o ns releases t he i n hi bit i o n of i m m u ne res p o nses, i ncl u di n g t h ose t hat 
ma y res ult i n t u m or eli mi nat i on.  I n vitr o st u dies d e m o nstrate t hat d ur val u ma b a nta g o nizes t he 
i n hi bit or y effect of P D-L 1 o n pri mar y  hu ma n T -cells res ult i n g i n t he rest ore d pr oliferati on of 
i nterfer o n (I F N) -γ (Ste wart et al 2 0 1 5 ).  I n vi v o st u dies ha ve s h o w n t hat d ur val u ma b i n hi bit s 
t u mor gr o wt h i n xe n o graft m o dels via a T- cell-de pe n de nt m ec ha nis m (Ste wart et al 2 0 1 5 ).  
Base d o n t hese data, d ur val u ma b is e x pecte d t o sti m ulate t he patie nt’s a nt itu m or i m m u ne 
res p o nse b y bi n di n g t o P D-L 1 a n d s hift i n g t he bala nce t o war ds a n a ntit u m or res p o nse.  
D ur val u ma b has bee n e n gi neere d t o re d uce a nti b o d y -de pe n de nt ce ll ular c yt ot o xicity a n d 
c o mple me nt -de pe n de nt c y t ot o xicit y. 
T o date, d ur val u ma b has bee n gi ve n t o m ore t ha n 6 0 0 0 a d ult patie nts as part of o n g oi n g st u dies 
eit her as mo n ot hera p y  or i n c o m bi nati on wi t h ot her a ntica ncer a ge nts.  Details o n t he safet y 
pr ofile of  d ur val u ma b mo n ot hera p y  are s u m marize d i n Secti on  4. 3. 1. 2 a n d Secti o n 8. 3. 1 3 .  Refer 
t o t he c urre nt d ur val u ma b I B f or a c o m plete s u m mar y of pre-cli nical a n d cli nical i nf or mat i on 
i ncl u di n g safety,  efficac y, a n d P K.
T here i s a n o n g oi n g st u d y e val uati n g d ur val u ma b m on ot hera p y  in pe diatric pati e nts.  
, a P hase I, o pe n-la bel, si n gle i nstituti o n st u d y  t o assess t he 
safety,  t olera bilit y a n d P K of d ur val u ma b i n pe diatric patie nts wit h rela pse d or refract or y s oli d 
t u mors, l y m p h o m a a n d ce ntral ner v o us s yste m t u m ors, is a n e xter nall y s p o ns ore d, 
i n vesti gat or-i nitiate d si n gle ce nter st u d y at U ni versity of  S o ut her n Calif or nia, L os A n geles, U S C 
Me dical Ce nter.  Patie nts ≥1 2 m o nt hs a n d ≤1 8 y ears of a ge at t he ti me of st u d y e nr oll me nt will 
be a d mi nistere d a starti n g d ose of 1 0 m g/ k g e ver y  2 wee ks ( q 2 w).  T o date, 1 3 c hil dre n (a ge 
ra n ge: 3 t o 1 6 years) ha ve bee n e nr o lle d o nt o t he i n vesti gat or-i nitiate d st u d y e val uati n g 
d ur val u ma b as m o n ot hera p y .  Safet y data fr o m 1 1 e val ua ble patient s ha ve re veale d n o 
d ose -li miti n g t o xicities ( D L Ts).  T he Data Safety M o ni t ori n g B oar d, w hic h c o n ve ne d i n 
Dece m ber 2 0 1 8, di d n ot i n dicate a n y  safet y c o ncer ns a n d rec o m me n de d t he st u d y t o pr ocee d as 
pl a n ne d.  Efficac y data are i nc o m plete at t his t i me, as t his st u d y is still o n g oi n g.  Pla ns are t o 
e nr o ll a n a d diti onal 4 pat ient s o nt o t he st u d y, t o fill t he re mai ni n g a ge-base d c o h orts.
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
2.2.3
Tremelimumab
Tremelimumab is a human IgG2 mAb that is directed against CTLA-4; CD152), a cell surface 
receptor that is expressed primarily on activated T-cells and acts to inhibit their activation.  
Tremelimumab completely blocks the interaction of human CTLA-4 with CD80 and CD86, 
resulting in increased release of cytokines (interleukin-2 and IFN-γ) from human T-cells, 
peripheral blood mononuclear cells and whole blood (Tarhini and Kirkwood 2008).  
Tremelimumab is being developed by AstraZeneca for use in the treatment of cancer. 
Details on the safety profile of tremelimumab monotherapy are summarized in Section 2.3.2.2.  
Refer to the current tremelimumab IB for a complete summary of pre-clinical and clinical 
information including safety, efficacy, and PK available in adult patients.  Tremelimumab 
monotherapy has not been studied in pediatric patients and therefore no clinical data are 
available.  The pre-clinical studies summarized in the IB are considered adequate to support use 
of tremelimumab in pediatric patients, this has been endorsed by the EMA's PDCO.  
2.2.4
Durvalumab in combination with tremelimumab
Because the mechanisms of action of CTLA-4 and PD-1 are non-redundant, targeting both PD-1 
and CTLA-4 pathways may have additive or synergistic activity (Pardoll 2012); therefore, 
AstraZeneca is also investigating the use of durvalumab + tremelimumab combination therapy 
for the treatment of cancer.
To date, more than 3000 adult patients have received the combination using a number of doses 
and dosing schedules.  No pediatric patients have been studied under this combination.  
The clinical safety profile of durvalumab in adult patients has been consistent with 
immune-system activation, and is largely manageable.  Toxicity studies with tremelimumab and 
tremelimumab in combination with durvalumab, or other same-class competitor anti-PD-1 or 
anti-CTLA-4 agents as single agents or in combination in adult patients with solid tumor and 
hematological malignancies indicate that generalized immune activation and consequent 
immune-mediated adverse events (imAEs) are the most likely clinical toxicities.  The target 
organs identified in clinical trials in adult advanced cancer patients are now generally known and 
management guidelines have been established (Weber et al 2012, Kumar et al 2017).  These 
safety risks are expected to be equally relevant for pediatric patients.
Although endocrinopathies are not among the most common imAEs reported in adults, they can 
be very severe and diagnostically challenging, may require endocrinology consultation and 
hormone replacement therapy, and may not be reversible.  One might consider that irreversible 
imAE would be of particular significance to a pediatric population treated with anti-PD-1/PD-L1 
and anti-CTLA-4 therapies.  
Immune checkpoint inhibitors have been shown to enhance ex vivo effector T-cell responses 
from patients with chronic viral, bacterial, or parasitic infection, including human 
immunodeficiency virus (HIV), tuberculosis, and malaria.  Although the data from clinical trials 
in infectious diseases are still sparse, these inhibitors are being considered as potential treatments 
for chronic infections, especially when combined with therapeutic vaccines 

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(D y c k a n d Mills 2 0 1 7 ).  H o we ver, t he ris k of i nfectio n a m o n g a d ul t or p e diatric pat ient s 
recei vi n g i m m u ne c hec k p oi nt bloc ka de is u n k n o w n.  Case re p orts of o p p ort u nist ic i nfecti ons 
a mo n g a d ul t p atie nts wit h mela n o ma recei vi n g t he C T L A -4 i n hi bit or i pili m u ma b ha ve bee n 
descri be d (K yi et al 2 0 1 4 ).  Del Castill o et al., retr os pecti vel y i de ntifie d seri o us i nfecti on i n 7. 3 % 
of  7 4 0 pati e nts at a si n gle i nst ituti o n w h o recei ve d i m m u ne c hec k p o i nt bloc kers.  T he m ai n ris k 
fact ors were recei pt of c ortic oster oi ds a n d/ or i nfli xi ma b (Del  Castillo et al  2 0 1 6). 
Details o n t he safet y pr ofile of d ur val u ma b + tre meli m u ma b c o m bi nat i on t hera p y  are 
s u m marize d i n Secti on 2. 3. 2. 3 .  T he d osi n g strate g y a p plie d f or t his st u d y was base d o n 
si m ulati ons a n d preli mi nar y  P K res ults fr o m st u d y 
 ( please refer t o Secti o n 4. 3. 1
f or details).  Refer t o t he c urre nt e diti ons of t he d ur val u ma b a n d tre meli m u ma b I Bs f or a 
c o mplete s u m mar y  of pre-cli nical a n d cli nical i nf o r mat i on i ncl u di n g safety,  efficac y, a n d P K.
2. 3
Be nefit/ris k assess me nt
M ore detaile d i nf or mat i on a b o ut t he k n o w n a n d e x pecte d be nefits a n d ris ks a n d reas o na bl y 
e x pecte d a d verse e ve nts ( A Es) of d ur val u ma b a n d tre meli m u ma b ma y be f o u n d i n t he res pect i ve
I Bs.
See Secti o n  9. 6. 1 f or i nf or mati o n re gar di n g t he Data Re vi e w C o m mittee ( D R C).
2. 3. 1
P ote nti al be nefits
2. 3. 1. 1
D ur v al u m a b
P D -L 1 is e x presse d i n a br oa d ra n ge of ca ncers wit h a hi g h fre q ue nc y, u p t o 8 8 % i n s o me t y pes 
of  ca ncer.  I n a n u m ber of t hese ca ncers, i ncl u di n g l u n g (M u et al  2 0 1 1), re nal 
(Kra m bec k et al 2 0 0 7 , T h o m ps o n et al  2 0 0 5, T h o m ps o n et al 2 0 0 6 ), pa ncreat ic (L o os et al 2 0 0 8 , 
N o mi et al 2 0 0 7 , Wa n g et al 2 0 1 0 ), a n d o varia n ca ncers (Ha ma nis hi et al 2 0 0 7 ), t he e x pressi on 
of  P D-L 1 i s ass ociate d wit h re d uce d s ur vi val a n d a n u nfa v ora ble pr o g n osis.  O n t he ot her ha n d, 
t he le vels of t u m or -i nfiltrati n g cells, a n d m ore s pecificall y c yt ot o xic T-cells, ha ve bee n 
c orrelate d wit h im pr o ve d pr o g n osis i n a n u m ber of ca ncers i ncl u di n g c ol orectal, mela n o ma, a n d 
l u n g ca ncers (Pa ges et al 2 0 1 0 ), s u g gesti n g t hat a n a ntitu m or i m m u ne res p o nse is be neficial t o 
p atie nts.
T here i s li mite d precli nical data e xa mi ni n g t he e x pressi o n of P D -1 or P D -L 1 i n pe diatric t u m ors.  
H o we ver, e mer gi n g researc h has s h o w n t hat P D -L 1 is e x presse d o n m uri ne e m br y o nal 
r ha b d om y o sarc oma cell li nes (Hi g hfill et al 2 0 1 4 ) a n d o n h u ma n oste osarc o ma cell li nes 
(S he n et al 2 0 1 4 ).  A d diti onall y, P D -1 e x pressi o n o n t u m or -i nfiltrati n g l y m p h oc ytes has bee n 
c orrelate d wit h a d va nce d disease i n patient s wit h oste osarc o ma (Z he n g et al 2 0 1 5) .  Fi nall y, 
u n p u blis he d data has s h o w n t hat P D -L 1 is u pre g ulate d a n d e x presse d o n t u m or -i nfiltrati n g 
l y m p h oc ytes i n a mo us e m o d el  of N B.  T hese earl y data s u g gest a p ote ntial r ole f or P D- 1/ P D -L 1 
i n hi bit or y a ge nts i n pe diatric sarc o ma s a n d N B, w hic h are pre vale nt t u m ors i n pe diatric 
p o p ul at i ons.
T hera pe ut icall y, t here is e mer gi n g data usi n g P D-1/ P D -L 1 pat h wa y  in hi bit ors i n pat ient s wit h 
l y m p h omas, ca ncers t hat cr oss o ver i nt o t he pe diatri c p o p ulat i on.  P D -1 i s o vere x presse d i n 
Ree d -Ster n ber g cells, t he mali g na nt cells o f H L, a n d its bl oc ka de has bee n e xa mi ne d i n a d ults 
a n d s h o w n t o be b ot h t olera ble a n d wit h t hera pe utic acti vit y i n patie nts wit h H L w h o were at 
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D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
least 1 8 years of a ge (A nsell et al 2 0 1 5 ).  I n diff use lar ge B-cell l y m p h o mas ( D L B C L), als o see n 
i n pe diatric patient s, hig h le vels of s o l uble P D -L 1 (s P D -L 1) i n t he bl o o d p orte n ds a p o orer 
pr o g n osi s, s u g gesti n g a p ote ntial t hera pe utic r ole i n patie nts wit h D L B C L (R ossille et al 2 0 1 4 ).
T here i s a n o n g oi n g st u d y e val uati n g d ur val u ma b mo n ot h era p y in pe diatrics (
).  
T his is a P hase I, o pe n -la bel, si n gle i nstitut i on st u d y  t o assess t he safety,  t olera bilit y, a n d P K of 
d ur val u ma b i n pe diatric patie nts wit h rela pse d or refract or y s o li d t u m ors, l y m p h oma, a n d ce ntral 
ner v o us s yste m t u mors. N o efficac y data ha ve bee n retrie ve d fr o m t his st u d y, a n d n o ot her 
st u dies wit h d ur valu ma b ha ve bee n c o n d ucte d i n pe diatric patie nts t o date.
2. 3. 1. 2
D ur v al u m a b + tre meli m u m a b
T he c o m bi nat i on of P D -1/ P D -L 1 i n hi bit i on wi t h bl oc ka de of t he n o n-re d u n da nt an d 
c o mple me ntar y  c hec k p oi nt C T L A-4 i s s u p p orte d b y str o n g pre-cli nical e vi de nce, a n d als o b y 
efficac y r es ults i n a d va nce d mela n o ma pat ient s i n P hase I t o III trials, as ma nifest b y ra pi d, 
d ura ble res p o nses i n a hi g h pr o p orti o n of patie nts (C urra n et al 2 0 1 0 , Lar ki n et al 2 0 1 5 , 
P os t o w et al 2 0 1 5).  
Alt h o u g h t here are preli mi nar y  efficac y si g nals f or a nti-P D -1/ P D -L 1 a nt i b o dies i n pe diatric 
i n dicati ons, pe diatric t u m ors li kel y ha ve si g nifica nt bi o l ogi cal differe nce fr o m t he a d ult t u mors 
w here t here has bee n cli nical act i vity.   C o m bi ni n g a nti-P D -L 1 a n d C T L A -4 t hera p y  c o uld 
t heref ore pr o vi de alter nat i ve t hera p y t o o verc o me t he p ote ntial li mitati ons of si n gle a ge nt 
a nt i-P D -1/ P D -L 1 a ge nts a gai nst pe diatr ic t u m ors t hat ma y ha ve l o w le vels of P D-L 1 e x pressi o n 
or ha ve l o w m ut ati o nal l oa ds a n d p ote ntiall y i na de q uate ne o -a nti ge n e x pressi o n.  F urt her m ore, 
c o m bi nat i on t hera p y , ma y als o res ult i n fe wer a n d less se vere l on g -t er m si de effects i n l o n g-t er m 
s ur vi v ors c o m pare d wit h m ult i-m o dali t y t hera pies t hat i ncl u de c he m ot hera p y 
(J o h n p ulle et al 2 0 1 6, Ra m el yt e et al 2 0 1 7, Metr o et al  2 0 1 7).  A nti-P D -1/ P D -L 1 a n d 
a nt i-C T L A -4 t hera pi es ma y be ass ociate d wit h u nc o m mo n  b ut lo n g- lasti n g e n d ocri ne 
c o mplicat i ons s uc h as h y p o p h ysit is, h y p ot h yr oidis m , a n d dia betes mellit us, wit h s pecial 
sig ni fica nce t o l o n g-t er m s ur vi vi n g pe diatric p o p ulati o ns (B o utr os et al  2 0 1 6).  Caref ul 
e val uat i on of t he f ull safet y pr ofile a n d t ol era bilit y of d ur val u m a b mo n ot h era p y a n d d ur val u ma b 
i n c o m bi nat i on wi t h tr e meli m u ma b a d mi nistere d o n t he e ver y 4 wee k ( q 4 w) sc he d ule will be 
critical t o ulti mate e val uati on of ris k -be nefit treat me nt decisi o ns.
2. 3. 2
O ver all ris ks
M o n ocl o nal  a nti b o dies directe d a gai nst i m m u ne c hec k p oint  pr otei ns, s uc h as P D-L 1 as well as 
t hose di recte d a gai nst P D-1 or C T L A -4, ai m t o b o ost e n d o ge n o us i m m u ne res p o nses directe d 
a gai nst t u m or cells.  B y sti m ulati n g t he i m m u ne s yste m, h o we ver, t here is t he p ote ntial f or 
a d verse effects o n n or mal t iss ues.
M o st a d verse dr u g reacti o ns see n wit h t he i m m u ne c hec k p o i nt i n hi bit or class of a ge nts i n a d ults 
are t h o u g ht t o be d ue t o t he effects of i nfla m mat or y cells o n s pecific t iss ues.  T hese ris ks are 
ge nerall y e ve nts wit h a p ote ntial i nfla m mat or y  or i m m u ne-me diate d me c ha nis m a n d t hat ma y 
re q uir e mor e f re q ue nt mo ni t orin g a n d/ or u ni q ue i nter ve nt i ons s uc h as i m m u n os u p pressa nts 
a n d/ or e n d ocri ne t hera p y.  T hese i m m u ne-me diate d effects ca n occ ur i n nearl y a n y or ga n s yste m, 
a n d are m ost c o m m o nl y  see n as gastr oi ntesti nal ( GI) A Es s uc h as c olitis a n d diarr hea, 
p ne u m o nit is/i nterstitial l u n g disease (I L D), he patic A Es s uc h as li ver e nz y me ele vati ons, s ki n 
e ve nts s uc h as ras h a n d der mat itis, a n d e n d ocri n o pat hies i ncl u di n g h y p o- a n d h y per -t h yr oidis m.
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D ur val u ma b a n d t r e m eli m u m a b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
It is still t o o earl y t o descri be t he s pecific t o xicity pr ofiles f or d ur val u ma b m o n ot hera p y  a n d 
d ur val u ma b i n c o m bi nat i on wi t h tr e meli m u ma b i n pe diatric patie nts.  H o we ver, data fr o m ot her 
i m m u ne c hec k p oi nt i n hi bit ors a n d li mite d data fr o m st u d y 
 ( o n g oi n g st u d y 
e val uat i n g d ur v alu ma b m o n ot h era p y in pe diatrics) ha ve s h o w n safet y pr ofiles i n pe diatric 
pati e nts c o nsiste nt wit h t h ose o bser ve d i n a d ult s:

A t otal o f 1 4 5 pe di atric pat ient s ha ve bee n treate d wit h atez oliz u ma b wit h o ut maj or 
safety c o ncer ns ( pers o nal c o m m u nicat i on, Ra p h ael R o ussea u M D, P h D, 
Ge netec h/ R oc he)

A t otal o f 1 2 5 pati e nts a ge d 1 t o 1 7 years ha ve bee n treate d wit h pe m br o liz u ma b 
wi t ho ut m ajor s af et y  c o ncer ns (Ge oer ger et al 2 0 1 7a )

P e di atric patie nts ha ve bee n treate d wit h i pili m u ma b at hi g her d oses t ha n t he 1 m g/ k g 
tr e meli m u ma b d oses, i ncl u di n g 1 1 patie nts yo u n ger t ha n 1 2 ye ars of a ge 
(Merc ha nt et al
2 0 1 6 )

A t otal o f 3 9 pe di atric pat ient s ha ve bee n treate d with ni v o l u ma b al one or i n 
c o m bi nat i on wi t h ipili m u ma b wit h o ut m ajor safet y c o ncer ns (Da vis et al 2 0 1 7 )

A t otal o f 1 3 pe di atric pat ient s treate d wit h d ur val u ma b, 1 0 m g/ k g q 2 w a n d 1 5 m g/ k g 
q 2 w, s o far s u g gest t he safet y  a n d t olera bility pr ofile is si milar t o t hat descri be d i n 
d ur val u ma b refere n ce safet y i nf or mati on.
T he safet y pr ofile of d ur val u ma b a n d d ur val u ma b i n c o m bi nati o n wit h tre m eli m u ma b is 
e x pecte d t o f oll o w t he sa me patter n as ot her i m m u ne c hec k p o i nt i n hi bit ors i n re gar ds t o i m A Es.
2. 3. 2. 1
D ur v al u m a b
Ris ks wit h d ur val u ma b i ncl u de, b ut are n ot li mite d t o, diarr hea/c o litis, p ne u m onit is/I L D, 
e n d ocri n o pat hies (ie, e ve nts of h y p o p h ysit is, a dre nal ins ufficie nc y , h y per- a n d h y p o -t h yr oidis m, 
a n d t y pe I dia betes mellit us), he pat itis/i ncreases i n tra nsa mi nases, ne p hri tis/i ncreases i n 
creati ni ne, pa ncreat itis, ras h/ der matitis (i ncl u di n g p e m p hi g oi d ), m yo c ar ditis, 
m y osi tis/ p ol y m y ositis, e nce p halit is; ot h er rare or less fre q ue nt i nfla m mat or y e ve nts i ncl u di n g 
i m m u ne t hr o m b oc yt o p e nia a n d ne ur o m usc ular t o xicit ies (e g, Guilla i n-Barré s y n dr o me, 
m yast he nia gra vis), i nf usi o n -r elate d reactio ns, h y perse nsit i vity react i ons, a n d i nfect i ons/seri o us 
i nfecti ons.
F or i nf or mat i on o n all i de nt ifie d a n d p ote ntial ris ks wit h d ur val u ma b, please al wa ys refer t o t he 
c urre nt versi o n of t he d ur val u ma b I B.
I n mo n ot hera p y  cli nical st u dies, A Es re p orte d ver y c o m m o nl y i ncl u de e ve nts s uc h as fat i g ue, 
di arr hea, na usea a n d v o mit i n g, decrease d a p petite, a n d m uscle a n d j oi nt pai n.  As of 
0 3 N o ve m ber 2 0 1 7, a t otal of 5 % t o 1 0 % of a d ult patie nts disc o nt i n ue d t he dr u g d ue t o a n A E.  
Pl ease see t he c urre nt versi o n of t he I B f or a detaile d a n d u p date d s u m mar y of t he m o n ot hera p y  
data i ncl u di n g A Es, seri o us a d verse e ve nts ( S A Es), a n d Nati o nal Ca ncer I nst itute ( N CI) 
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D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
C o m m o n Ter mi n o l og y  Crit eri a for A d verse E ve n ts ( C T C A E) Gra de 3 t o 5 e ve nts re p orte d 
acr oss t he d ur val u ma b pr o gra m.
T he m ajori t y of treat me nt -relate d A Es were ma na gea ble, wit h d ose dela ys, s y m pt o matic 
treat me nt, a n d i n t he case o f e ve nts s us pecte d t o ha ve a n i m m u ne basis, t he use of esta blis he d 
treatme nt  g uideli nes f or i m m u ne -me diate d t o xicit y (see Secti o n  8. 4. 5 ).
Fr o m  re vie w of t he o n g oi n g 
st u d y, t here were n o ne w safety ris ks ide nt ifie d (see 
Secti o n 2. 2. 2 ).
A detaile d s u m mar y  of d ur val u ma b m o n ot hera p y AE data ca n be f o u n d i n t he c urre nt versi o n of 
t he d ur val u ma b I B.
2. 3. 2. 2
Tre meli m u m a b
Ris ks wit h tr e meli m u ma b m o n ot hera p y  incl u de i n a d ults, b ut are n ot li mite d t o, GI effects 
(c olitis, diarr hea, e nter oc olit is, a n d i ntesti nal perf or atio n); e n d ocri ne dis or ders ( h y p o- a n d 
h y pert h y r oidis m, h y p o p h ysit is, a n d a dre nal i ns ufficie nc y); s ki n effects (ras h a n d pruri t us); 
ele vat i ons i n li pase a n d a m ylase a n d cli nical ma nifestati o ns of pa ncreat itis, ot her GI e ve nts (e g, 
ul cerat i ve c olitis, de h y drati on, na usea, a n d v o mit i n g); he patic e ve nts (i ncl u di n g he patitis a n d 
li ver e nz y me ele vati o ns); p ne u m onit is a n d I L D; ner v ous s y st e m e ve nts (i ncl u di n g e nce p halitis, 
p eri p heral  mot or a n d se ns or y  ne ur o pat hies, G uillai n- Barré, a n d pr o xi mal m uscle wea k ness); 
c yt o p e nias (i ncl u di n g t hr o m b oc yt o p e nia, a ne mia, a n d ne utr o pe nia); i nf usi o n- r elate d reactio ns, 
a na p h yla xis, a n d aller gic reac tio ns; re nal  e ve nts (i ncl u di n g re nal fail ure, ac ute ki d ne y i nj ur y, 
ne p hrit is, ne p hr otic s y n dr o me, a n d a ut oi m m u ne ne p hritis); a n d electr ol yte a b n or malities (e g, 
h y p o kal e mia); a ut oi m m u ne diseases (i ncl u di n g a ut oi m m u ne art hritis, Sj o gre n’s s y n dr o me, a n d 
gi a nt cell te m p oral arterit is); h y per gl yce mia a n d dia betes mellit us; a n d p yre xia. 
F or i nf or mat i on o n all i de nt ifie d a n d p ote ntial ris ks wit h tre meli m u ma b, please al wa ys refer t o 
t he c urre nt versi o n of t he tre meli m u ma b I B.
I n mo n ot hera p y  cli nical st u dies i n a d u lts, A Es ty p icall y re p orte d ver y c o m m onl y  incl u de e ve nts 
s uc h as diarr hea, na usea, fat i g ue, pr urit us, decrease d a p petite, ras h, v o miti n g, d ys p nea, 
c o nsti pati o n, c o u g h, p yre xia, a b d o mi nal pai n, decrease d wei g ht, hea dac he, ast he nia, a n d a ne mia.  
A p pr o xi matel y 1 6 % of  patie nts e x perie nce d a n A E t hat res ulte d i n per ma ne nt disc o nti n uati on of 
tr e meli m u ma b, a n d a p pr o xi matel y 4 5 % of patient s e x perie nce d a n S A E.  Please see t he c urre nt 
versi o n of t he I B f or a detaile d s u m mar y of m o n ot hera p y data, i ncl u di n g A Es, S A Es, a n d N CI 
C T C A E Gra de 3 t o 5 e ve nts re p orte d acr oss t he tre meli m u ma b pr o gra m.
A detaile d s u m mar y  of tr e meli m u ma b m o n ot hera p y  AE data ca n be f o u n d i n t he c urre nt versi o n 
of  t he tre meli m u ma b I B. 
2. 3. 2. 3
D ur v al u m a b + tre meli m u m a b
T he safet y of  d ur val u ma b + tr e meli m u ma b c o m bi nati o n t hera p y was i nitiall y e val uate d i n t he 
o n g oi n g d ose escalati o n a n d d ose- e x pa nsi o n St u d y 
i n a d ult patie nts wit h 
n o n- s mall c ell lu n g ca ncer, i s bei n g st u die d i n a n u m ber of ot her o n g oi n g cli nical st u dies i n a 
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D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
n u m ber of di ffere nt i n dicati ons, a n d has t o date s h o w n a ma na gea ble safet y a n d t olera bilit y 
pr ofile.  Please see t he c urre nt versi o n of t he I B f or detaile d i nf or mat i on o n t hese st u dies.
T he t y p es of  ris ks wit h t he c o m bi nati on of d ur val u ma b + tre meli m u ma b ( base d o n a n e q ui vale nt 
d ur val u ma b d ose of 2 0 m g/ k g a n d a tre meli m u ma b d ose of 1 m g/ k g) are si milar t o t h ose f or 
d ur val u ma b a n d tre meli m u ma b m o n ot hera p y .  E mer gi n g data fr o m St u d y  
, fr o m 
ot her st u di es e val uat i n g t he c o m bi nati on, a n d fr o m c o m bi nati o ns of ot he r a ge nts i n t he sa me 
class i n dicate a n i ncrease d fre q ue nc y a n d/ or se verit y of s o me of t hese i m m u ne-me d iate d 
t o xicities. 
F or i nf or mat i on o n all i de nt ifie d a n d p ote ntial ris ks wit h t he d ur val u ma b + tre meli m u ma b 
c o m bi nat i on, pl ease alwa ys refer t o t he c urre n t versi o n of t he d ur val u ma b I B.
I n d ur val u ma b + tre meli m u ma b c o m bi nati on st u dies at t he d ose of d ur val u ma b 2 0 m g/ k g a n d 
tr e meli m u ma b 1 m g/ k g, A Es t y p icall y re p orte d ver y c om m o nl y were fat i g ue, diarr hea, na usea, 
d y s p nea, decrease d a p petite, pr urit us, v o miti n g, a ne mia, c o nsti pati on, c o u g h, a b d o mi nal pai n, 
p y re xia, bac k pai n, art hral gia, h y p ot h yr oidis m , ast he nia, perip heral  e de ma, weig ht decrease d, 
h y p o natre mia, a n d ras h.  Please see t he c urre nt versi o n of t he d ur val u ma b I B f or a detaile d 
s u m mar y of c om bi nat i on t hera p y  data, i ncl u di n g A Es, S A Es, a n d N CI C T C A E Gra de 3 t o 5 
e ve nts re p orte d acr oss t he d ur val u ma b pr o gra m, i ncl u di n g d ur val u ma b i n c o m bi nat i on wi t h 
tr e meli m u ma b.
A p pr o xi matel y  1 5 % of a d ult p atie nts e x perie nce d a n A E t hat res ulte d i n per ma ne nt 
di sc o nti nuat i on of i n vest i gati onal pr o d uct (I P), a n d a p pr o xi matel y 1 5 % of patie nts e x perie nce d 
a n S A E t hat was c o nsi dere d t o be relate d t o d ur val u ma b a n d tre meli m u ma b b y t he st u d y  
I n vesti gat or.
T he d ur val u ma b a n d tre meli m u ma b c o m bi nat i on has n ot y et bee n e val uate d i n t he pe diatric 
p o p ul at i on.  
A detaile d s u m mar y  of d ur val u ma b + tre meli m u ma b c om bi nat i on A E data ca n be f o u n d i n t he 
c urre nt versi o n of t he d ur val u ma b I B.
2. 3. 3
O ver all be nefit/ris k
T he o verall ris k/ be nefit of t his st u d y  has bee n well c o nsi dere d a n d fa v ors t he c o n d uct of t he 
pr o p ose d st u d y .  
T here i s si g nifica nt u n met nee d f or t hera pies f or pe diatric patie nts wit h rela pse d refract or y s oli d 
t u mors a n d he mat ol o gical mali g na ncies a n d i n fact t he patie nts eli gi ble f or t his st u d y  ha ve n o 
via ble t hera pe ut ic o pti o ns.  T he cli nical be nefit ass ociate d wit h i n hi bit i on of t he P D -1/ P D -L 1 
pat h wa y  ( alo n e or c o mbi ne d wi t h in hi bit i on of C T L A -4) is well d oc u me nte d f or a d ult ca ncers.  
Ma n y  p e di atric t u mors bear hall mar ks pre dict i n g se nsiti vity t o i m m u ne c hec k p o i nt i n hi bit or 
t her a pies, i nclu di n g t he prese nce of I C i nfiltrates, e x pressi o n of P D -L 1 i n t u m or a n d/ or 
i nfiltrati n g I C (Ge oer ger et al 2 0 1 7a , Ge oer ger et al 2 0 1 7 b ) a n d hi g h mut ati o n b ur de n i n s o m e 
cases (Mara belle et al 2 0 1 5) .  C hec k p oi nt i n hi bit ors al o ne or i n c o m bi nati on ha ve bee n use d 
safel y i n pe diatric patient s (Da vis et al 2 0 1 7 ), alt ho u g h earl y i n dicat i on s s u g gest t hat at least 
s o me s oli d t u m ors are n ot res p o nsi ve t o c hec k p oi nt i n hi bit or m o n ot hera p y.  T heref ore, t he 
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Clinical Study Protocol - 6.0
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
proposed strategy of combination therapy with durvalumab and tremelimumab warranted.  The 
potential risks of durvalumab, tremelimumab and the combination of these agents are well 
known and mitigation strategies are available.  Overall, the potential benefits to this 
therapeutically underserved pediatric population outweigh the known potential risks based on the 
AEs in patients treated with durvalumab monotherapy and durvalumab + tremelimumab. 
The safety of patients in this study will be assessed by the DRC.
3.
OBJECTIVES AND ENDPOINTS
Table 5
Study objectives
Primary Objective (Dose-finding phase):
Endpoint/Variable:
To determine the adult equivalent 
exposure/MTD/recommended Phase II pediatric 
dose of durvalumab in combination with 
tremelimumab and durvalumab as monotherapy 
following combination therapy. 
Based on PK parameters (including Cmax, Cmin, 
AUC, and others), identify the adult equivalent 
exposure/MTD of durvalumab in combination 
with tremelimumab and durvalumab as 
monotherapy following combination therapy, 
among children and young adults from 
birth to <18 years of age with advanced solid 
tumors, using a q4w dosing schedule. 
Time of RP2D assessment will be at the end of the 
dose-finding phase, when sufficient numbers of 
evaluable samples have been accrued.
To determine the safety profile of durvalumab in 
combination with tremelimumab and durvalumab 
as monotherapy following combination therapy.
Identify the safety and tolerability of durvalumab 
in combination with tremelimumab and 
durvalumab as monotherapy following 
combination therapy at the adult equivalent 
exposure/MTD among children and young adults 
from birth to <18 years of age with advanced solid 
tumors, using a q4w dosing schedule.  Endpoints 
include AEs, vital signs, physical examinations, 
ECGs, and laboratory evaluations.
Primary Objective (Dose-expansion phase):
Endpoint/Variable:
To determine the preliminary antitumor activity 
of durvalumab in combination with 
tremelimumab and durvalumab as monotherapy 
following combination therapy, at the 
recommended dose, using cohort-specific 
response criteria (eg, RECIST 1.1).
Objective response rate as determined by the 
Investigator assessed RECIST 1.1 or alternative 
pre-specified tumor-specific response rates for 
different scoring systems.

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Assess me nt of a ntit u m or acti vit y will be s pecific 
t o t u m or c o h ort, e g, I n vesti gat or assesse d 
R E CI S T 1. 1. 
A d diti o nal efficac y e n d p oi nts t hat will be 
c ollecte d i ncl u de D o R, B o R, D C R, P F S, A P F 1 2, 
a n d A P F 1 8 base d o n R E CI S T 1. 1 assesse d b y t he 
I n vesti gat or, a n d O S, O S 1 2, a n d O S 2 4 as 
a p pr o priate t o eac h i n di vi d ual c o h ort.
Sec o n d ar y O bjecti ve ( D ose -fi n di n g a n d 
D ose -e x p a nsi o n p h ases):
E n d p oi nt/ V ari a ble:
T o descri be t he P K of d ur val u ma b a n d 
tre meli m u ma b i n c o m bi nati o n a n d d ur val u ma b as 
m o n ot hera p y f oll o wi n g c o m bi nati o n t hera p y, i n 
c hil dre n a n d y o u n g a d ults wit h s oli d t u m ors, or 
he mat ol o gical mali g na ncies.
I n di vi d ual d ur val u ma b a n d tre meli m u ma b 
c o nce ntrati o ns i n ser u m, a n d P K para meters 
i ncl u di n g Cma x , Cmi n , A U C, a n d ot her para meters 
w her e a p pr o priate.
T o deter mi ne t he i m m u n o ge nicit y of d ur val u ma b 
a n d tre meli m u ma b i n c o m bi nati o n a n d 
d ur val u ma b as m o n ot hera p y f oll o wi n g
c o m bi nati o n t hera p y, i n c hil dre n a n d y o u n g a d ults 
wit h s oli d t u m ors.
T o deter mi ne t he i m m u n o ge nicit y of d ur val u ma b 
i n c o m bi nati o n wit h tre meli m u ma b a n d 
d ur val u ma b as m o n ot hera p y f oll o wi n g 
c o mbi nati o n t hera p y, i n c hil dre n a n d y o u n g a d ults 
wit h he mat ol o gical mali g na ncies.
T o meas ure effects o n i m m u ne c hec k p oi nt 
i n hi biti o n i n res p o nse t o r o uti ne i m m u nizati o ns 
( d ose-e x pa nsi o n p hase o nl y).
I n di vi d ual a nti b o d y titer meas ure me nts 
 
 
 
 
T o e val uate i m m u ne acti vati o n a n d c o u nts of 
N K -, B- a n d T -cells.
S afet y o bjecti ve:
E n d p oi nt/ v ari a ble:
T o deter mi ne t he safet y pr ofile a n d t olera bilit y of 
patie nts fr o m d ose -e x pa nsi o n c o h ort(s) treate d 
A d verse e ve nts, vital si g ns, p h ysical 
e xa mi nati o ns, E C Gs, a n d la b orat or y e val uati o ns.
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Cli nical St u d y Pr ot oc ol - 6. 0
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D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
wit h d ur val u ma b i n c o m bi nati o n wit h 
tre meli m u ma b wit h a q 4 w d osi n g sc he d ule.
E x pl or at or y o bjecti ve:
E n d p oi nt/ v ari a ble:
T o c ollect bi o mar ker a n d i m m u ne res p o nse data 
i n patie nts treate d wit h d ur val u ma b i n 
c o m bi nati o n wit h tre meli m u ma b a n d d ur val u ma b 
as mo n ot hera p y f oll o wi n g c o mbi nati o n t hera p y .  
T he e n d p oi nts relate d t o ca n di date pre dicti ve 
a n d/ or pr o g n ostic bi o mar kers will f oc us o n 
, 
ac k n o wle d gi n g t hat pe diatric patie nts wit h 
a d va nce d ca ncer ha ve li mitati o ns o n t otal sa m ple 
v ol u mes t hat ca n be har veste d f or c orrelati ve 
st u dies.  If tec h nicall y feasi ble t he c urre nt 
tra nslati o nal pla n will i ncl u de assess me nt of:
I n a d diti o n, a n e x pl orat or y assess me nt relate d t o 
bi o mar kers will be perf or me d base d o n t he 
a vaila bilit y of 
 
s peci me ns t o e xa mi ne t he relati o ns hi p bet wee n a 
patie nt’s healt h a n d 
 
 as well as a n y m o d ulati o ns w hic h ma y 
occ ur d uri n g a n d/ or f oll o wi n g treat me nt relati ve t o 
cli nical o utc o me, as a p plica ble.  If sa m ples are 
a vaila ble, assa ys ma y i ncl u de: 

T o c o m pare R E CI S T 1. 1 wit h ir R E CI S T as 
assess me nt met h o d ol o gies f or cli nical be nefit of 
d ur val u ma b a n d d ur val u ma b i n c o m bi nati o n wit h 
tre meli m u ma b.
Pr o gressi o n -free s ur vi val (a n d O R R) acc or di n g t o 
R E CI S T 1. 1 a n d ir R E CI S T ( N ote: ir R E CI S T will 
o nl y be use d as a n e x pl orat or y e n d p oi nt).
A D A
A n ti-dr u g a nti b o d y; A E A d verse e ve nt; A P F 1 2 / A P F 1 8 Pr o p orti o n of patie nts ali ve a n d pr o gressi o n -free at 
1 2 / 1 8 m o nt hs fr o m first d ose of I P; A U C
Ar ea u n der t he plas ma dr u g c o nce ntrati o n -ti me c ur ve; B o R Best 
o bjecti ve res p o nse; C D
Cl uster of differe ntiati o n; C ma x
Ma xi m u m ser u m c o nce ntrati o n; C mi n
Mi ni m u m ser u m 
C CI
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Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 6
Disease cohorts for dose-finding phase
Cohort
Type of cancer
SARC-1
Bone sarcomas: osteosarcoma or Ewing sarcoma
SARC-2
Soft-tissue sarcomas: rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue 
sarcoma, other sarcomas
NB
Neuroblastoma
STO
Other solid tumors (not represented in the other solid tumor cohorts)
Table 7
Disease cohorts for dose-expansion phase
Cohort
Type of cancer
SARCOMA
Bone sarcomas: osteosarcoma, Ewing sarcoma; 
Soft-tissue sarcomas: rhabdomyosarcoma, non-rhabdomyosarcoma soft-tissue 
sarcoma, other sarcomas
STO
Other solid tumors (not represented in the other solid tumor cohorts)
Note: Patients with soft-tissue sarcomas must account for ≥40% of those enrolled in the SARCOMA cohort.
During the dose-finding phase (I), durvalumab will be given as monotherapy for 1 cycle 
followed by the addition of tremelimumab for the next 4 cycles.  For the dose-expansion phase 
(II), durvalumab will be given in combination with tremelimumab for the first 4 cycles, starting 
on Cycle 1.  When durvalumab is given in combination with tremelimumab, a maximum number 
of four 28-day cycles of tremelimumab will be permitted, followed by durvalumab monotherapy 
administered q4w.  Study treatment will be administered until clinical or confirmed disease 
progression (determined by the Investigator against tumor-specific objective criteria) or until any 
of the other discontinuation criteria are met, whichever comes first.  Tumor-specific objective 
response (OR) criteria are provided in Appendix F for NB, and Appendix E for solid tumors 
(Response Evaluation Criteria in Solid Tumors [RECIST 1.1]).
However, if in the opinion of the Investigator, a patient received clinical benefit from treatment 
with the combination of durvalumab and tremelimumab and subsequently progressed whilst on 
durvalumab maintenance monotherapy, such patients may restart treatment with the combination 
of durvalumab and tremelimumab for 4 cycles.  A patient who meets these criteria should be 
reconsented and receive another 4 cycles of tremelimumab while continuing durvalumab 
treatment.    
The immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) are also provided 
in Appendix G.  Note: The incorporation of the irRECIST appendix in this protocol is only 
meant to serve as a supplement for treating physicians to help in their clinical decision-making in 
situations where tumor response, based on RECIST 1.1, is in doubt.
The study outline is provided in Figure 1.  The objectives and endpoints, as well as the projected 
number of patients who will participate in this study, including the assumptions underlying the 
sample size calculations, are provided in Section 3 and Section 9.2, respectively.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
4.1.1
Dose-finding phase 
The dose-finding phase of the study will be conducted using a modified 3 + 3 design to 
determine whether durvalumab and tremelimumab can be administered safely in children and if 
adult exposures can be achieved.  Dose finding will only be assessed in patients with relapsed or 
refractory solid malignant tumors including osteosarcoma and Ewing sarcoma (SARC-1), 
rhabdomyosarcoma, non-rhabdomyosarcoma, and other sarcomas (SARC-2), NB, other solid 
tumors (STO).  Starting doses of durvalumab and tremelimumab will be 100% of the 
recommended adult dose as a weight-adjusted dose administration.  The dose-finding phase will 
seek to identify the RP2D for durvalumab monotherapy and durvalumab given in combination 
with tremelimumab.  Pediatric patients with relapsed or refractory malignant solid tumors, will 
be enrolled and treated in 2 arms, based on patient weight: Arm A for patients ≥35 kg and Arm B 
for patients <35 kg. 
As seen in Section 4.3.1, available PK data are consistent with simulation-based predictions and 
indicate that administration of an adult weight-adjusted dose to children with body weight 
≥35 kg will result in a PK profile very similar to the observed profile in adults.  These findings 
also suggest that the target engagement and saturation are likely to be similar between adults and 
children.  However, simulation-based predictions indicate that children with body weight <35 kg 
will have exposures that are lower than the predicted profile in adults, thus requiring higher 
doses to reach adult equivalent exposures.  Therefore, during the dose-finding phase of this 
study, the recommended adult weight-adjusted durvalumab and tremelimumab doses will be 
examined in 2 weight-based cohorts separated by a cutoff weight of 35 kg.  Based on emerging 
data during the conduct of the study, cohorts may also be backfilled to provide further 
assessment of safety and PK in specific age groups and to ensure a broad representation of 
ages/weights at a given dose level (DL).
At least 1 patient representing each of the following pediatric age subsets will be enrolled: birth 
to 5 years, 6 to 11 years and 12 to <18 years.  However, patients under 2 years of age will only 
be enrolled after at least 3 pediatric patients older than 2 years of age have been dosed with 
durvalumab and tremelimumab and have cleared the DLT observation period and have been 
evaluated by the DRC.  Additionally, at least 1 day between first patient and subsequent patients 
dosed at each DL is required.

Clinical Study Protocol - 6.0
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Three DLs may be explored in each of the treatment arms (detailed DLs can be seen in Table , 
Table 11, Table 12, and Table 13).  The starting doses (DL 1) will be 100% of the recommended 
adult dose of both durvalumab and tremelimumab administered as weight-adjusted doses.  The 
doses and schedules are as follows:
1.
Cycle 1 (durvalumab monotherapy): durvalumab 20 mg/kg
2.
Cycles 2 to 5 (durvalumab in combination with tremelimumab): durvalumab 20 mg/kg 
and tremelimumab 1 mg/kg (4 cycles administered every 28 days)
3.
From Cycle 6 onwards, treatment will continue until a discontinuation criterion is met, 
with durvalumab monotherapy administered at 20 mg/kg every 28 days.
From Cycle 2 onwards, a treatment delay of up to 14 days is permitted between consecutive 
cycles to manage any side-effects.  If a treatment delay of more than 14 days is required, the start 
of the cycle that had to be delayed must be skipped until the planned Day 1 of the next cycle.  No 
dose reductions are permitted.
The pediatric PK will be considered equivalent to the adult PK when the lower limit of the 
80% CI of the pediatric exposure (as measured by the area under the plasma drug 
concentration-time curve from Day 0 to Day 28 [AUC0-28]) is more than 50% of the adult 
exposure.  Adequate exposure will be declared only if ≥80% (5 of 6 patients at a dose level) 
achieve acceptable adult exposure PK, as defined.  Durvalumab and tremelimumab will be 
escalated sequentially with durvalumab first followed by tremelimumab.
The degree of dose escalation at DLs 2 and 3 will be determined based on the review of all the 
safety and emerging PK data.  It is anticipated that dose ranges of 24 to 40 mg/kg and 1.2 to 
2 mg/kg for durvalumab and tremelimumab, respectively, will be explored in DLs 2 and 3 (the 
maximum dose of durvalumab that will be explored is 40 mg/kg).
Dose escalation will follow a modification of the standard 3 + 3 design. For Arm A 
(weight ≥35 kg), a total of 6 patients will be enrolled into this cohort; additional dose levels will 
only be evaluated if PK data indicate inadequate exposure to that of an adult.  For Arm B 
(weight <35 kg), if none of the 3 patients experience a DLT, then 3 additional patients will be 
treated at the next dose level. If 1 or more patients experience a DLT, the 3 additional patients 
(for a total of 6 patients) will be treated at the same dose level.  Dose escalation will continue 
using the same rules-based approach until at least 2 patients among a cohort of 3 or 6 patients 
experience a DLT, at which time, DLT will be established.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Figure 2
Dose-finding: escalation schema
This figure shows the maximum doses for durvalumab at DLs 2 and 3 (40 mg/kg) and tremelimumab at DL 3 (2 mg/kg).  Lower 
doses may be tested, depending on the obtained PK modeling data.
DL Dose level; NB Neuroblastoma; SARC-1 Osteosarcoma and Ewing sarcoma; SARC-2 Rhabdomyosarcoma, non-
rhabdomyosarcoma, and other sarcomas; STO Solid tumor other.
As indicated in Figure 2, DL 2 will assess an increased dose of durvalumab while holding 
tremelimumab dosing at 1 mg/kg.  
If at DL 1, durvalumab exposure is adequate and tremelimumab exposure is too low, DL 2 can 
be skipped and tremelimumab alone will be escalated to DL 3 with durvalumab dosing staying at 
20 mg/kg (100% of the recommended adult dose). 
Furthermore, based on emerging PK, safety and tolerability data, intermediate DLs may also be 
tested. 
De-escalation for toxicity may occur for durvalumab or tremelimumab to DL -1 with reduced 
doses of 15 mg/kg and 0.75 mg/kg, respectively (See Figure 3).

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
Fi g ure 3
D ose -fi n di n g: de-esc al ati o n sc he m a
D L  D ose le vel
Assess me nts
D uri n g C ycle 1 a n d u nt il C ycle 2 ( Da y 1), safet y,  t olera bilit y, P K, a n d acti vity will be assesse d 
as f o ll ows:
1.
E nc o u ntere d A Es will be re p orte d a n d D L Ts ( defi ne d i n Sect i on 4. 1. 2 ) will be 
i de ntifie d
2.
F o ur d ur val u ma b P K sa m ples (ta ke n pre d ose a n d e n d -of  -i nf usi on o n Da y 1 a n d o n 
D a y  8 a n d Da y 1 5) will  be o btai ne d a n d
3.
T hree sa m ples will be ta ke n o n Da y  1 ( pre- a n d p ost d ose) a n d Da y 8 t o deter mi ne 
.
D uri n g C ycle 2, safet y,  t olera bility,  P K, a n d acti vity will be assesse d as f o ll ows:
1.
E nc o u ntere d A Es will be re p orte d a n d D L Ts will be i de nt ifie d
2.
T w o d ur val u ma b P K sa m ples (ta ke n pre d ose a n d at t he e n d of i nf usi o n o n Da y  1) will 
be o btai ne d
3.
F o ur tre m eli m u ma b P K sa m ples (ta ke n pre d ose a n d e n d -of  -i nf usi on o n Da y 1 a n d o n 
D a y  8 a n d Da y 1 5) will be o btaine d a n d
4.
O ne sa m ple will be ta ke n o n Da y  1 prior t o d osi n g of tre meli m u ma b t o deter mi ne 
.
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Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
4.1.2
Definition of dose-limiting toxicities and stopping criteria
Dose-limiting toxicities will be determined during Cycles 1 and 2 of the dose-finding phase 
using CTCAE version 5.  Toxicities that occur during the first 28 day cycle and meet the criteria 
below will be assessed for attribution to durvalumab monotherapy.  Any of the below listed AEs 
encountered between Cycle 1 Day 1 and Cycle 2 Day 28 (ie, 56 day DLT monitoring period for 
combination therapy) and in the opinion of the Investigator is thought to be attributable to 
durvalumab or/and tremelimumab, given a reasonable possibility based on temporal exposure to 
IP and for which an alternate etiology does not exist or cannot be identified, will be classified as 
DLTs:

Grade 5 toxicity

Hematological toxicity: Any Grade ≥3 (including febrile neutropenia Grade ≥3) except 
for the following:
o
Grade 3 thrombocytopenia that does not result in a bleeding event or does 
not require platelet transfusion
o
Grade 3 neutropenia that resolves to Grade ≤2 within 7 days.

Non-hematological toxicity:  
o
Any Grade 4 imAE
o
Any ≥ Grade 3 colitis
o
Any Grade 3 or 4 noninfectious pneumonitis
o
Any Grade 2 pneumonitis that does not resolve within 5 days to ≤ Grade 1 
after initiation of maximal supportive care (including use of steroids)
o
Any Grade 3 imAE, excluding colitis or pneumonitis, that does not 
downgrade to Grade 2 within 3 days after onset of the event despite optimal 
medical management including systemic corticosteroids and does not 
downgrade to ≤Grade 1 or baseline within 14 days of onset
o
Liver transaminase elevation >5 × upper limit of normal (ULN) or total 
bilirubin (TBL) >3 × ULN.  For patients with liver metastases at baseline, 
transaminase elevation >8 × ULN will constitute a DLT
o
Grade 4 vomiting, diarrhea, electrolyte abnormality, or systemic reaction
o
Grade 3 toxicity lasting >7 days despite optimal supportive care
o
Any ≥ Grade 3 non-imAE, except for the exclusions listed below
o
Any Grade 3 immune-mediated peripheral neuropathy or other 
immune-mediated neurotoxicity
o
Grade ≥3 inflammatory reactions.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
The definition of DLTs excludes the following conditions:

Grade 3 fatigue lasting ≤7 days.

Grade 3 endocrine disorder (pituitary and/or adrenal insufficiency) that is managed 
with or without systemic corticosteroid therapy and/or hormone replacement therapy 
and the patient is asymptomatic.

Grade 3 hypothyroidism adequately treated with hormone replacement therapy.

Grade 3 inflammatory reaction attributed to a local antitumor response (eg, 
inflammatory reaction at sites of metastatic disease, lymph nodes, etc.).

Concurrent vitiligo or alopecia of any AE grade.

Grade 3 infusion-related reaction (first occurrence and in the absence of steroid 
prophylaxis) that resolves within 6 hours with appropriate clinical management.

Grade 3 fever (fever greater than 40ºC [>104ºF] for ≤24h in duration).

Any grade lymphopenia.

Isolated Grade 3 electrolyte abnormalities that are not associated with clinical signs or 
symptoms and are reversed with appropriate maximal medical intervention (including 
supplementation) within 7 days of initiating supplementation.
Immune-related adverse events are defined as AEs of immune nature (ie, inflammatory) in the 
absence of a clear alternative etiology.  In the absence of clinical abnormality, repeat laboratory 
testing must be conducted to confirm significant laboratory findings prior to designation as a 
DLT.
Guiding principles:
1.
While the rules outlined above dictate the classification of AEs as DLTs, any other 
AEs that are observed during the observation period may be defined as a DLT in 
consultation with the DRC; after having taken into consideration the emerging safety 
profile of durvalumab and tremelimumab.
2.
The NCI CTCAE (version 5.0) will be used for AEs reporting and its severity will be 
graded on a scale from 1 to 5 provided for each AE term.
3.
An immune-mediated AE is defined as an AE that is associated with exposure to 
durvalumab or/and tremelimumab and is consistent with an immune-mediated 
mechanism of action after alternate etiologies have been considered and excluded. 

Clinical Study Protocol - 6.0
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
4.
In the absence of clinical findings, repeat laboratory testing must be conducted to 
confirm the clinical significance of abnormal laboratory test result before it is 
classified as a DLT.
Patient dosing or study enrollment may be halted in the dose-finding phase until the toxicity data 
can be further studied.  If DLTs occur in ≥2/6 patients on a given cohort, enrollment will be 
placed on hold and the DRC will be required to fully evaluate the available information prior to 
further patient enrollment.  Upon review, a decision will be made to resume, stop or modify the 
study.  If ≥2 DLTs occur at DL -1, the study may be prematurely stopped.
In the dose-expansion phase, enrollment in a disease-specific cohort will be halted and the DRC 
will be required to fully evaluate the available information prior to further patient enrollment if 
≥3/9 patients have an AE or SAE that would be considered a DLT based on criteria established 
in the dose-finding phase.  Upon review, a decision will be made to resume, stop or modify the 
study.
4.1.3
Determining a recommended Phase II dose 
A DRC will be established prior to the initiation of the study to review all the data, with a 
primary emphasis on safety and PK, to establish RP2D to be further explored in the 
dose-expansion phase of the study.  Dose escalation decisions and determination of RP2D will 
mainly consider safety assessments from at least 3 patients followed up for 4 cycles, to include a 
single cycle of durvalumab and 3 cycles of the combination of durvalumab and tremelimumab 
(for a total of 120 days).  More details on the DRC constitution are described in Section 9.6.1.
The key considerations to be followed by the DRC during the dose-finding phase of the study are 
outlined in Table .
Table 8
Key considerations for dose escalation decisions
#DLTs
Pharmacokinetics
Decision/Outcome
0 out of 3-5
Equivalent to adult exposure
(5 out of 6 patients)
Declare tolerated and observe for 4 
cycles, and if <2 patients with DLTs are 
observed during the first 4 cycles of 
study drug, enter dose-expansion stage 
OR
1 out of 6
Less than 80% of adult exposure
(≤2 patients)
Declare tolerated and move to next DL
1 out of 3
Increase number of patients to 6
≥2
Declare not tolerated; if observed on 
DL 1, move to DL -1
DL Dose level; DLT Dose-limiting toxicity.

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4.1.4
Dose-expansion phase
During dose-expansion, patients will be monitored for safety according to the same criteria 
employed during the dose-finding phase (although events will not be considered DLTs during 
dose-expansion).  Additionally, 4 cycles of safety information are required prior to opening the 
initial dose-expansion cohorts.  See Section 4.1.2 for stopping criteria.
The dose-expansion phase will be conducted using a Simon 2-stage optimal design with an 
additional provision to include 1 mixed disease cohort (other malignant solid tumors).
Once the RP2D has been established, patients will be recruited to each of the following cohorts:
1.
SARCOMA (bone sarcomas: osteosarcoma and Ewing sarcoma; soft-tissue sarcomas 
[≥40% of enrollment]: rhabdomyosarcoma, non-rhabdomyosarcoma, and other 
sarcomas)
2.
STO (other solid tumors).
For the SARCOMA cohort, the initial stage will allow 11 evaluable patients, to be dosed in this 
disease-specific cohorts. If 2 or more responses in either of these cohorts are observed, additional 
patients will be accrued, as part of the second stage, into the corresponding expansion cohort; 
15 patients will be accrued into the SARCOMA expansion cohort for a total of 26 evaluable 
patients. If there has been ≤1 objective response in either cohort, at the time that evaluable 
patients (11 patients) dosed in the initial stage who have been followed for at least 3 cycles have 
been assessed, the cohort will be discontinued for lack of benefit.
For the STO cohort, 10 evaluable patients will be enrolled into this mixed-disease cohort; Simon 
rules are not applicable for this cohort.
4.1.5
Study Conduct Mitigation During Study Disruptions Due to Cases of Civil Crisis, 
Natural Disaster, or Public Health Crisis
The guidance given below supersedes instructions provided elsewhere in this clinical study 
protocol (CSP) and should be implemented only during cases of civil crisis, natural disaster or 
public health crisis (eg, during quarantines and resulting site closures, regional travel restrictions, 
and considerations if site personnel or study participants become infected with severe acute 
respiratory syndrome coronavirus 2 [SARS-CoV-2] or similar pandemic infection), which would 
prevent the conduct of study-related activities at study sites, thereby compromising the study site 
staff or the participant’s ability to conduct the study.  The Investigator or designee should contact 
the study Sponsor to discuss whether the mitigation plans below should be implemented.
To ensure continuity of the clinical study during a civil crisis, natural disaster, or public health 
crisis, changes may be implemented to ensure the safety of study participants, maintain 
compliance with Good Clinical Practice (GCP), and minimize risks to study integrity.  Where 

Cli nical St u d y Pr ot oc ol - 6. 0
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D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
all o wa ble b y  lo c al  healt h a ut h orities, et hics c o m mittees, healt h care pr o vi der g ui deli nes (e g, 
h os pi t al p olicies) or lo c al  g o ver n me nt, t hese c ha n ges ma y i ncl u de t he f oll o wi n g o pti o n:

O btai ni n g c o nse nt f or t he mit i gati on pr oce d ures ( n ote, i n t he case of ver bal c o nse nt, 
t he i nf or me d c o nse nt f or m [I C F] s h o ul d be si g ne d at t he partici pa nt’s ne xt c o ntact 
wi t h t he st u d y sit e).

Rescree ni n g: A d dit i onal rescree ni n g f or scree n fail ure a n d t o c o nfir m eli gi bilit y t o 
parti ci pate i n t he cli nical st u d y ca n be perf or me d i n previ o usl y  scree ne d partici pa nts. 
T he I n vesti gat or s h o ul d c o nfir m t his wit h t he desi g nate d me dical m o nit or. 

T el e me dici ne visit: Re m ote c o ntact wit h t he partici pa nts usi n g telec o m m u nicat i ons 
tec h n ol og y  incl u di n g p h o ne calls, virt ual or vi de o visit s, a n d mo bil e healt h de vices.
F or f urt her details o n st u d y  c o n d uct d uri n g ci vil crisis, nat ural disaster, or p u blic healt h crisis, 
refer t o A p pe n di x K.
4. 2
Scie ntific r ati o n ale f or st u d y desi g n
T he d ose -fi n di n g p hase of t he st u d y will be c o n d ucte d t o deter mi ne w het her a d ult P K e x p os ure 
le vels ca n be ac hie ve d b y t he a d mi nistratio n of  t he a d ult rec o m me n de d d ose of b ot h d ur val u ma b 
a n d tre meli m u ma b t o pe diatric patie nts.  F urt her m ore, si m ulat i ons a n d preli mi nar y  P K res ults 
fr om t he o n g oi n g 
st u d y s h o w t hat c hil dre n wei g hi n g ≥3 5 k g are pre dicte d t o ha ve 
e x p os ure le vels c o nsiste nt wit h a d ult patie nts, w hereas c hil dre n wit h a b o d y  wei g ht < 3 5 k g are 
pre di cte d t o ha ve a p pr o xi matel y 2 -f ol d l ower e x p os ure t ha n t h ose o bser ve d i n a d ults 
( Sectio n 4. 3. 1. 1 ).  O verall, 3 D Ls ma y be e x pl ore d i n t his st u d y, wit h 2 ar ms se parate d b y a 
c utoff b o d y  wei g ht of 3 5 k g, base d o n t hese P K fi n di n gs.  
4. 3
J u stific ati o n f or d ose
4. 3. 1
D ur v al u m a b a n d tre meli m u m a b d ose a n d tre at me nt re gi me n j ustific ati o n
4. 3. 1. 1
D ur v al u m a b + tre meli m u m a b c o m bi n ati o n t her a p y d ose r ati o n ale
T he d ur val u ma b + tre meli m u ma b c o m bi nat i on t hera p y  d oses a n d re gi me n selecte d f or t his st u d y 
are base d o n t he g oal of selecti n g a n o pti mal c o m bi nat i on d ose of d ur val u ma b a n d 
tr e meli m u ma b t hat w o uld yiel d s ustai ne d 
 de m o nstrate pr o misi n g 
efficac y, a n d ha ve a n acce pta ble safety pr ofile . 
P h ar m ac o ki netics/ P h ar m ac o d y n a mics d at a
D ur val u ma b :
St u d y  p atie nts will ini tiall y recei ve t he rec o m me n de d a d ult weig ht- a djuste d d ose of 2 0 m g/ k g I V 
d ur val u ma b q 4 w ( ma xi m u m d ur val u ma b d ose t o be e x pl ore d is 4 0 m g/ k g).  Base d o n t he 
si m ulati ons a n d preli mi nar y  P K res ults fr o m st u d y
, c hil dre n ≥3 5 k g are pre dicte d 
t o ha ve e x p os ure le vels c o nsiste nt wit h a d ult patie nts.  H o we ver, si m ulati ons als o i n dicate d t hat 
pati e nts < 3 5 k g i n wei g ht are e x pecte d t o ha ve a p pr o xi matel y  2 t o 1 0- f ol d l ower e x p os ure t ha n 
t hose o bser ve d i n a d ults de pe n di n g o n wei g ht.  T he mi ni m u m acce pta ble A U C 0 -2 8 f or t his 
C CI
C CI
C CI

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Of 11 patients evaluable for safety assessment, no DLTs have been reported.  The safety and 
tolerability for the 11 patients evaluated so far are similiar to that seen in the adult population in 
terms of imAEs.
The starting dose of 10 mg/kg was selected based on the manageable safety and tolerability 
profile seen in adults (in which no maximum tolerated dose [MTD] was identified) and 
mathematical PK modeling. 
4.3.1.3
Rationale for 4 cycles of combination therapy followed by durvalumab 
monotherapy
Long-term follow-up on melanoma patients treated with ipilimumab, an anti-CTLA-4 targeting 
antibody (dosed q3w for 4 doses and then discontinued), shows that adult patients responding to 
ipilimumab derive long-term benefit, with a 3-year OS rate of approximately 22%.  Furthermore, 
the survival curve in this population reached a plateau at 3 years and was maintained through 
10 years of follow-up (Schadendorf et al 2013). Following the data obtained from adults, the 
same treatment schedule will be applied in this study for the pediatric population.
The durvalumab + tremelimumab combination regimen will be administered for 4 doses q4w 
followed by durvalumab monotherapy q4w until PD or unless other specific discontinuation 
criteria are met. 
4.4
End of study definition
Without regard to the present study, the primary completion date of the study for the purpose of 
the primary analysis, will occur approximately 6 months following enrollment of the last patient 
(See Section 9.5.1).  End of study is defined as the completion of the 90-day safety follow-up 
period for the last patient who is no longer receiving study treatment (i.e., last subject, last visit 
[LSLV]. .
A patient is considered to have completed the study when the 90-day safety follow-up period has 
been completed following their last dose of study treatment.
Patients may be withdrawn from the study if the study itself is stopped.  The study will be 
stopped if, in the judgment of AstraZeneca, study patients are placed at undue risk because of 
clinically significant findings.
See Appendix A 6 for guidelines for the dissemination of study results.
5.
STUDY POPULATION
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 in order to be assigned to a study intervention.  Under no circumstances can there be 

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target lesions (TLs), unless there are no other lesions suitable for biopsy (reassessment 
after biopsy may be required).
5.
Lansky play performance scale ≥50 (Appendix J) for patients ≥1 and <16 years of age 
and Karnofsky performance status score ≥50 (Appendix I) for patients ≥16 years of 
age (patients <1 year of age are exempt from this criterion).
6.
At least 1 lesion, not previously irradiated, that can be accurately evaluated or 
measured by RECIST 1.1 (Appendix E), INRC for NB (Appendix F).  Tumor 
radiological assessments must be performed within 21 days prior to first dose. Lesions 
in a previously irradiated field can be used as measurable disease, provided that there 
has been demonstrated progression in the lesion
Or
Have evaluable disease following methods used in common clinical practice. 
7.
No prior exposure to immune checkpoint inhibitors or genetically engineered cellular 
therapies including, but not limited to, other anti-CTLA-4, anti-PD-1, anti-PD-L1,
anti-PD-L2 antibodies and chimeric antigen receptor T-cell therapy (CAR-T) or other 
cell therapies, excluding therapeutic anticancer vaccines.  Exposure to other 
investigational agents may be permitted after discussion with the Sponsor or designee.
8.
Adequate organ and marrow function, independent of transfusion for at least 7 days 
prior to screening and independent of growth factor support for at least 14 days prior 
to screening, as defined below: 

Hemoglobin ≥9.0 g/dL

Absolute neutrophil count ≥1.0 × 109/L

Platelet count ≥75 × 109/L
o
For patients with marrow involvement, criteria established for the 
hematology malignancies will apply, including a provision for platelet 
count ≥50 × 109/L

Serum bilirubin ≤1.5 × the ULN.  In case of patients with confirmed Gilbert’s 
syndrome, who will be allowed in consultation with their physician, the upper 
limit will be ≤3.0 × ULN

Alanine transaminase (ALT) and aspartate transaminase (AST) ≤3 × ULN; for 
patients with hepatic metastases, ALT and AST ≤5 × ULN

Inclusion of patients with concomitant transaminases + bilirubin elevations should 
be discussed with the Sponsor or designee

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
Creatinine for age within local laboratory ranges.  If abnormal creatinine for age 
based on local laboratory ranges, inclusion can be based on a calculated creatinine 
clearance using the Schwartz pediatric equation, radioisotope measured 
glomerular filtration rate (GFR) of ≥70 mL/min/1.73m2, or by 24-hour urine 
collection.
9.
Must have a life expectancy of at least 3 months.
Sex
10.
Male or female.
5.2
Exclusion criteria (All Patients)
Medical conditions 
1.
History of allogeneic organ transplantation. Patients who have previously received an 
autologous bone marrow transplant are eligible (eg, after discussion with Sponsor or 
designee).
2.
Active or prior documented autoimmune or inflammatory disorders (including 
inflammatory bowel disease [eg, colitis or Crohn’s disease], diverticulitis [with the 
exception of a prior resolved episode of diverticulosis], celiac disease or other serious 
GI chronic conditions associated with diarrhea, systemic lupus erythematosus, 
Wegener syndrome [granulomatosis with polyangiitis]; myasthenia gravis, Graves’ 
disease, rheumatoid arthritis, hypophysitis, uveitis, etc), autoimmune myocarditis, and 
autoimmune pneumonitis.  The following are exceptions to this criterion:

Patients with vitiligo or alopecia

Patients with hypothyroidism (eg, following Hashimoto syndrome) stable on 
hormone replacement  

Psoriasis that does not require systemic therapy

Patients with celiac disease controlled by diet alone. 
3.
Uncontrolled intercurrent illness, including but not limited to, ongoing or active 
infection, symptomatic congestive heart failure, cardiac arrhythmia, ILD, or 
psychiatric illness or social situations that would limit compliance with study 
requirements, substantially increase risk of incurring AEs from IP, or compromise the 
ability of the patient to give written informed consent.
4.
History of primary immunodeficiency. 
5.
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 (known positive hepatitis B virus [HBV] surface 

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CONFIDENTIAL AND PROPRIETARY
antigen [HBsAg] result), hepatitis C, or 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 hepatitis C virus 
(HCV) antibody are eligible only if polymerase chain reaction is negative for HCV 
ribonucleic acid (RNA).
6.
Any unresolved toxicity NCI CTCAE version 5.0 Grade ≥2 from previous anticancer 
therapy with the exception of alopecia, vitiligo, lymphopenia and the laboratory values 
defined in the inclusion criteria 

Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis and 
may be included after consultation with the Study Physician.

Persistent toxicities (CTCAE Grade ≥2) caused by previous anticancer therapy, 
excluding alopecia. Patients with toxicity not reasonably expected to be 
exacerbated by treatment with durvalumab or tremelimumab in the opinion of the 
Investigator (eg, hearing loss, gastrostomy tube), may be included 
7.
Patients with clinically active brain metastases (known or suspected), spinal cord 
compression, and choloromas are excluded, unless these conditions have been 
previously treated and are considered stable.  Stable brain metastases are defined as no 
change on computed tomography (CT) scan or magnetic resonance imaging (MRI) 
scan for a minimum of 2 months AND no clinical requirement for steroids above 
physiologic replacement dose.
8.
History of leptomeningeal carcinomatosis, or involvement of any other anatomic area 
that, in the opinion of the Investigator, may cause significant symptoms if an 
inflammatory reaction occurs.
9.
Known allergy or hypersensitivity to any of the IPs or any of the IP excipients. 
10.
Any condition that, in the opinion of the Investigator, would interfere with evaluation 
of the IP or interpretation of patient safety or study results.
Prior/concomitant therapy
11.
Receipt of the last dose of an anticancer therapy (chemotherapy, immunotherapy, 
endocrine therapy, targeted therapy, biologic therapy, tumor embolization, or mAbs) 
≤28 days or 5 half-lives of the drug and a minimum of 7 days, whichever is shorter, 
prior to the first dose of IP.  If sufficient washout time has not occurred due to the 
schedule or PK properties of an agent, a longer washout period will be required, as 
agreed by AstraZeneca and the Investigator.
12.
Any concurrent chemotherapy, IP, biologic, or hormonal therapy for cancer treatment.  
Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone 
replacement therapy) is acceptable.

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Durvalumab and tremelimumab
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13.
Receipt of any radiotherapy or hormonal therapy for cancer treatment within 30 days 
prior to first dose of IP.
14.
Receipt of any investigational anticancer therapy within 28 days or 5 half-lives, 
whichever is longer, prior to the first dose of study treatment.
15.
Receipt of live attenuated vaccine within 30 days prior to the first dose of IP.  Note: 
Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to 
30 days after the last dose of IP. 
16.
Major surgical procedure (as defined by the Investigator) within 28 days prior to the 
first dose of IP.  Note: Local surgery of isolated lesions for palliative intent is 
acceptable.
17.
Current or prior use of immunosuppressive medication within 14 days before the first 
dose of durvalumab or tremelimumab.  The following are exceptions to this criterion:

Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra-articular 
injection).

Systemic corticosteroids at physiologic doses as replacement therapy, not to 
exceed 10 mg/m2/day of prednisone or its equivalent.

Steroids as premedication for hypersensitivity reactions (eg, CT scan 
premedication).
Prior/concurrent clinical study experience 
18.
Previous IP assignment in the present study.
19.
Concurrent enrollment in another clinical study, unless it is an observational 
(non-interventional) clinical study or during the follow-up period of an interventional 
study.
Other exclusions
20.
Female patients who are pregnant or breastfeeding or male or female patients of 
reproductive potential who are not willing to employ highly 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 therapy.  A patient is 
considered to be of childbearing potential if, in the opinion of the Investigator, she is 
biologically capable of having children and is sexually active.   
21.
Non-sterilized male patients who are sexually active with a female partner of 
childbearing potential who are not willing to employ male condom plus spermicide 
from screening to 90 days after the last dose of durvalumab monotherapy or 180 days 
after the last dose of durvalumab + tremelimumab combination therapy.  

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Durvalumab and tremelimumab
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22.
Judgment by the Investigator that the patient should not participate in the study if the 
patient is unlikely to comply with study procedures, restrictions, and requirements. 
5.3
Lifestyle restrictions
The following restrictions apply while the patient is receiving IP and for the specified times 
before and after:
1.
Female patient of childbearing potential

If in the opinion of the Investigator, the patient is biologically capable of having 
children and is sexually active, they will be considered of childbearing potential. 

Female patients of childbearing potential who are not abstinent and intend to be 
sexually active with a non-sterilized male partner, and in accordance with local 
regulations, must use at least 1 highly effective method of contraception (Table ) 
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. 
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 ).

If a patient’s partner becomes pregnant during or within 90 days after the last dose 
of durvalumab/180 days after the last dose of durvalumab in combination with 
tremelimumab, the partner or partner’s parent/guardian is asked to sign the 
"Informed Consent Form for Pregnant Partners of Study Patients" and provide 
information about the pregnancy accordingly.

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Durvalumab and tremelimumab
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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 .  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 9
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.
3.
All patients: Patients should not donate blood or blood components while participating 
in this study and through 180 days after receipt of the final dose of 
durvalumab + tremelimumab combination therapy or 90 days after receipt of the final 
dose of durvalumab or until alternate anticancer therapy is started. 
4.
Restrictions relating to concomitant medications are described in Section 6.4.
5.4
Screen failures
Screen failures are patients who have provided informed consent to participate in the study but 
on screening are found not to fulfill the eligibility criteria for the study, and therefore must not be 
assigned to study treatment.  These patients should have the reason for study withdrawal 
recorded as “eligibility criteria not fulfilled” (ie, patient does not meet the required 
inclusion/exclusion criteria).  This reason for study withdrawal is only valid for screen failures.  
Patients may be rescreened a single time, if the screening failure was due to a temporary 
condition.  Any rescreening of patients must be done in consultation of the Sponsor’s Study 
Physician and any decision must be captured in the patient’s medical notes. 

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If a patie nt w h o has faile d scree ni n g is rescree ne d, a ne w E-c o de must n ot be assi g ne d.  Patie nts 
will rec o nfir m t heir c o nse nt t o partici pate i n t he st u d y  b y resi g ni n g a n d dati n g t heir ori gi nal 
c o nse nt for m (s), ne xt t o t heir origi nal  si g nat ure a n d date.  All assess me nts 
 
 m ust be re peate d f or rescree ni n g, u nless t he y are wit hi n 2 8 da ys of 
i nitial d ose.
A mi ni mal set of scree n fail ure i nf or mat i on is re q uire d t o e ns ure tra ns pare nt re p orti n g o f scree n 
fail ure patie nts t o meet t he C o ns oli date d Sta n dar ds of Re p orti n g Trials p u blis hi n g re q uire me nts 
a n d t o res p o n d t o q ueries fr o m re g ulat or y a ut h orities.  Mi ni mal i nf or mat i on i ncl u des 
d e m o gra p h y , scree n fail ure details, eli gibili t y crit eria, a n d a n y S A Es.
6.
S T U D Y T R E A T M E N T S
St u d y  treat me nt is defi ne d as a n y I P(s) (i ncl u di n g mar kete d pr o d uct c o m parat or a n d place b o) or 
me dical de vice(s) i nte n de d t o be a d mi nistere d t o a st u d y  patient  acc or din g t o t he st u d y  pr ot oc ol.  
St u d y  treat me nt i n t his st u d y r efers t o d ur valu ma b a n d tre meli m u ma b.
6. 1
Tre at me nts a d mi nistere d
6. 1. 1
D ose a n d tre at me nt re gi me ns
6. 1. 1. 1
D ose -fi n di n g p h ase 
T he patie nt’s wei g ht at baseli ne is t o be use d f or s u bse q ue nt treat me nt c y cle d ose calc ulat i ons 
u nless t here is a ≥1 0 % c ha n ge i n t he meas ure d wei g ht at t he be gi n ni n g o f a ne w treat me nt c ycle.
St u d y  treat me nt will c o nsist of t he c o m bi nat i on of d ur val u ma b a n d tre meli m u ma b, a d mi nistere d 
at 3 pla n ne d D Ls as descri be d i n  Ta ble , Ta ble 1 1 , a n d Ta ble 1 2 ( de-escalat i on d oses t o D L -1 
are f o u n d i n  Ta ble 1 3 ).  Treat me nt will be a d mi nistere d o n 2 8 -d a y  ( 4 wee k) c y cles.  F or t he 
d ose -fi n di n g p hase, C ycle 1 will al wa ys start wit h a d mi nistrati o n of d ur val u ma b o nly ; 
s u bse q ue ntl y, d uri n g C ycles 2 t o 5 (f or a t otal of 4 c ycles), tre meli m u ma b will be 
c o -a d mi nistere d wit h d ur val u ma b.  Starti n g wit h C ycle 6, treat me nt c o nsists of d ur val u ma b 
m o n ot hera p y  o nl y a n d c o nti n ues u ntil cli nical or ra di ol ogi cal pr o gressio n  or u ntil e vi de nce of 
u nacce pta ble t o xicit y, wi t hdra wal of c o nse nt or a n ot her disc o nt i n uati o n criteri o n is met.
H o we ver, if i n t he o pi ni o n of t he I n vest i gat or, a patie nt recei ve d cli nical be nefit fr o m treat me nt 
wi t h t he c o m bi nati on of d ur val u ma b a n d tre meli m u ma b a n d s u bse q ue ntl y pr o gresse d w hilst o n 
d ur val u ma b mai nte na nce m o n ot hera p y , s uc h patie nts ma y restart treat me nt wit h t he c o m bi nati on 
of  d ur val u ma b a n d tre meli m u ma b f or 4 c y cles.  A patie nt w h o meets t hese criteria s h o ul d be 
rec o nse nte d a n d recei ve a n ot her 4 c ycles o f tr e meli m u ma b w hile c o nt i n ui n g d ur val u ma b 
treat me nt.  Retreat me nt wit h a n a d dit i onal c o m bi nati o n re gi me n ma y o nl y occ ur o nce (f or a 
si n gle ti me).
Fr o m  C ycle 2 o n war ds, a treat me nt d ela y of u p t o 1 4 d a y s is per mitte d bet wee n c o nsec uti ve 
c ycles t o ma na ge a n y si de-effects.  If a treat me nt dela y of m ore t ha n 1 4 da ys is re q uire d, t he start 
of  t he c ycle t hat ha d t o be dela ye d m ust be s ki p pe d u ntil t he pla n ne d Da y 1 of  t he ne xt c ycle.  N o 
d ose re d ucti o ns are per mitte d t hr o u g h o ut t he st u d y peri o d.
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 10
Planned dose level 1
Dose Level 1
Drug
Cycle 1
Cycles 2-5
Cycle 6 onwards
Durvalumab
20 mg/kg
20 mg/kg
20 mg/kg
Tremelimumab
NA
1 mg/kg
NA
NA Not applicable.
Table 11
Planned dose level 2
Dose Level 2
Drug
Cycle 1
Cycles 2-5
Cycle 6 onwards
Durvalumab
40 mg/kg
40 mg/kg
40 mg/kg
Tremelimumab
NA
1 mg/kg
NA
Dose level 2 may be skipped with progression directly to dose level 3 (see details in the dose level 2 description in 
Section 6.1.1.1).
NA Not applicable.
Table 12
Planned dose level 3
Dose Level 3
Drug
Cycle 1
Cycles 2-5
Cycle 6 onwards
Durvalumab
40 mg/kg
40 mg/kg
40 mg/kg
Tremelimumab
NA
2 mg/kg
NA
NA Not applicable.
Table 13
Planned dose level -1
Dose Level -1
Drug
Cycle 1
Cycles 2-5
Cycle 6 onwards
Durvalumab
15 mg/kg
15 mg/kg
15 mg/kg
Tremelimumab
NA
0.75 mg/kg
NA
NA Not applicable.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY

Dose Level 1:  Patients will receive the equivalent adult weight-based dose of both 
durvalumab and tremelimumab, as listed in Table .

Dose Level 2:  Patients will receive a tremelimumab dose that remains constant to that 
of DL 1 (1 mg/kg).  However, there will be a planned dose escalation for durvalumab 
to increase the dose to a maximum of 40 mg/kg (reflecting a 100% increase from the 
starting dose).  If data from the PK modeling obtained from patients treated at DL 1 
suggests that adequate exposure levels will require less than a doubling of the dose, 
then an appropriate dose between 24 mg/kg and 40 mg/kg may be evaluated instead of 
40 mg/kg.  If data from the PK modeling obtained from patients treated at DL 1 
suggests that adequate exposure level have not been obtained and a higher dose may 
be needed to achieve such an exposure, the dose escalation plan may be adjusted to 
incorporate subsequent dose increases.
o
If at DL 1 durvalumab exposure is adequate and tremelimumab exposure is 
too low, DL 2 can be skipped and tremelimumab alone will be escalated to 
DL 3 with durvalumab dosing remaining at the initial dose of 20 mg/kg. 

Dose Level 3:  Patients will receive adjusted doses of both durvalumab and 
tremelimumab; the dose of durvalumab will be determined from PK modeling data 
obtained from DL 2.  There will be a planned dose escalation for tremelimumab to 
increase the dose to 2 mg/kg (reflecting a 100% increase from the starting dose).  If 
data from the PK modeling obtained from patients treated at DL 1 suggests that 
adequate exposure level will require less than a doubling of the dose, then an 
appropriate dose between 1.2 mg/kg and 2 mg/kg may be evaluated instead of 
2 mg/kg.  If data from the PK modeling obtained from patients treated at DL 1 
suggests that adequate exposure level have not been obtained and a higher dose may 
be needed to achieve such an exposure, the dose escalation plan may be adjusted to 
incorporate subsequent dose increases.   

Dose Level -1:  In the event of toxicity, patients will be treated at a reduced dose of 
both durvalumab and tremelimumab at doses of 15 mg/kg (durvalumab) and 
0.75 mg/kg (tremelimumab) to reflect 25% reduction from the starting dose.
6.1.1.2
Dose-expansion phase
Patients will be treated with the combination of durvalumab and tremelimumab using the RP2D 
of each agent, based on data obtained from the dose-finding phase.  Durvalumab and 
tremelimumab will be administered concurrently on an every 28-day (4 weeks) cycle for a total 
of 4 cycles (Cycles 1 to 4); subsequently, durvalumab is continued on an every 28-day cycle as 
monotherapy until clinical or confirmed PD, or other discontinuation criteria is met, whichever 
comes first.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
However, if in the opinion of the Investigator, a patient received clinical benefit from treatment 
with the combination of durvalumab and tremelimumab and subsequently progressed whilst on 
durvalumab maintenance monotherapy, such patients may restart treatment with the combination 
of durvalumab and tremelimumab for 4 cycles.  A patient who meets these criteria should be 
reconsented and receive another 4 cycles of tremelimumab while continuing durvalumab 
treatment.  Retreatment with an additional combination regimen may only occur once (for a 
single time).
6.1.2
Study Drug Administration
During Cycles 1 and 2 of the dose-finding phase, durvalumab is infused over 120 minutes 
(2 hours).  Starting with Cycle 3, if tolerated, the durvalumab infusion time may be reduced to 
60 minutes (1 hour).  Tremelimumab infusions will be administered over 60 minutes (1 hour) 
during all treatment cycles.

During the dose-expansion phase, all durvalumab infusions will be administered over 
60 minutes (1 hour)
On days when both durvalumab and tremelimumab are scheduled (Cycles 2 to 5 in dose-finding 
phase and Cycles 1 to 4 in dose-expansion phase), the tremelimumab infusion is to be 
administered first followed by a 1-hour interval (maximum 2 hours) before the start of the 
durvalumab infusion.

Refer to Section 8.2.3 (Vital signs) for details on required vital signs and observation 
periods
Both durvalumab and tremelimumab infusions are to be administered using a 0.2 or 0.22 µm 
low-protein binding in-line filter.
No other drugs are to be infused through the same line or port while study infusions are being 
administered.
The IV tubing is flushed with a volume of saline equal to the priming volume of the 
administration set used after the contents of the IV bag or IV syringe are fully administered, 
according to institutional policy to ensure the full dose is administered.
The study infusion may be interrupted for an infusion reaction and when permitted, is restarted at 
a slower (ie, 50%) infusion rate.  In instances where the total dose cannot be completed using an 
8 hour hang time, a new infusion bag must be prepared to complete the study infusion.
6.1.3
Study Drug Preparation
AstraZeneca will supply durvalumab (MEDI4736) and tremelimumab to be used according to 
Table 14. 

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Table 14
Study treatments
Treatment 1
Treatment 2
Study treatment name
Durvalumab (MEDI4736)
Tremelimumab
Dosage formulation:
500- or 120-mg vial solution 
(50 mg/mL)
400- or 25-mg vial solution 
(20 mg/mL)
Route of administration 
IV
IV
Dosing instructions:
Section 6.1.1.1 (dose-finding).
Section 6.1.1.2 (dose-expansion).
Section 6.1.1.1 (dose-finding).
Section 6.1.1.2 (dose-expansion).
Packaging and labeling
Study treatment will be provided 
in 500- or 120-mg vials.  Each 
vial will be labeled in accordance 
with GMP Annex 13 and per 
country regulatory requirement.a
Study treatment will be provided 
in 400- or 25-mg vials.  Each vial 
will be labeled in accordance with 
GMP Annex 13 and per country 
regulatory requirement.a
Provider
AstraZeneca
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. 
GMP Good Manufacturing Practice, IV intravenous.
For patients >20 kg, both durvalumab and tremelimumab doses can be prepared and 
administered either by an infusion bag or as a syringe, according to local practices. For patients 
≤20 kg, doses should be prepared in a syringe with suggested final volumes based on weight 
ranges, as listed in Table 15, and administered via a syringe pump. 
Table 15
Syringe administration volumes for patients ≤20 kg
Weight (kg)
Total syringe volume range (mL)
2.4–5.0
15
5–10
15–20
10–15
20–30
15–20
30–50

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
6.1.3.1
Durvalumab (MEDI4736)
Durvalumab is supplied by AstraZeneca as a 500- or 120 mg vial formulated as solution 
containing 50 mg/mL durvalumab, 26 mM histidine/histidine hydrochloride, 275 mM trehalose 
dihydrate, and 0.02% weight/volume (w/v) polysorbate 80; the final pH of the solution is 6.0.  
The nominal fill volume is 10.0 mL for the 500 mg vial and 2.4 mL for the 120 mg vial.  
Investigational product 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 the original packaging until use to prevent prolonged exposure to 
light.
The starting DL, using a weight-based approach, will be 20 mg/kg; during the dose-finding 
phase, 2 additional DLs of durvalumab will be evaluated (Table , Table 11, and Table 12).  The 
patient’s weight at baseline is to be used for subsequent treatment dosing calculations unless 
there is a ≥10% change in the measured weight.  The dose will be prepared using an IV bag 
(polyvinyl chloride [PVC] or non-PVC) or a syringe, according to local practices, and 
administered via a standard infusion or syringe pump.
The dose of durvalumab for administration must be prepared by the Investigator’s or site’s 
pharmacist (or designee) using aseptic technique. Total time from needle puncture of the 
durvalumab vial to the start of administration should not exceed: 

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature.
The durvalumab vial size (120 mg or 500 mg) should be selected based on: 1) availability and 2) 
calculated durvalumab dose volume.  It is recommended that for small durvalumab volumes 
(2.4 mL or less), the 120 mg vial size may be used; and for larger volumes (greater than 2.4 
mL), the 500-mg vial size may be used.  A combination of vial sizes may be used depending on 
the dose volume in order to minimize drug wastage (eg, for a dose volume of 11.0 mL, one 
500 mg and one 120 mg vial may be used).
Durvalumab will be diluted in 0.9% sodium chloride (normal saline [NS]) to a final 
concentration between 1 and 20 mg/mL, and administered with IV tubing containing a 0.2 μm or 
0.22 μm low-protein binding in-line filter; acceptable configurations include an IV set containing 
an in-line filter or the attachment of a separate filter to the distal end of the IV tubing.  
Preparation of durvalumab doses for administration with an IV bag
Intravenous bag preparation
Dose calculation
The volume (in mL) of durvalumab to be added to an IV bag containing 0.9% sodium chloride is 
calculated as follows:
Dose level (mg/kg) × patient weight (kg) / 50 (mg/mL of durvalumab)

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Example:

Dose: 20 mg/kg

Patient weight: 80 kg

Dose for patient: 20 (mg/kg) × 80 (kg) = 1600 (mg)

Dose volume:  1600 (mg) / 50 (mg/mL) = 32.0 mL

Add the durvalumab dose volume into an infusion bag (PVC or non-PVC) containing 
0.9% sodium chloride (NS); mix the solution using gentle inversion.  Do not shake.  

Final products are prepared at a concentration between 1 and 20 mg/mL.

Infusions should be administered immediately after preparation; however, once 
prepared, infusions can be stored for up to 24 hours under refrigeration and 4 hours at 
room temperature.  Once the infusion has started, the hang-time of the infusion should 
not exceed 8 hours.

Sites are to follow local practices for final IV bag preparation, including attachment of 
IV tubing (PVC or non-PVC) and priming (if applicable), and to ensure the IV 
infusion set connected to the IV infusion bag contains a 0.2 or 0.22 µm low-protein 
binding in-line filter.
Preparation of durvalumab doses for administration with an IV syringe
Intravenous syringe preparation
The volume (in mL) of durvalumab to be added to an IV syringe containing 0.9% sodium 
chloride is calculated as follows:
Dose level (mg/kg) × patient weight (kg) / 50 (mg/mL of durvalumab)
Example:

Dose: 20 mg/kg

Patient weight: 10 kg

Dose for patient: 20 (mg/kg) × 10 (kg) = 200 (mg)

Dose: 200 (mg) / 50 (mg/mL) = 4.0 mL

Withdraw the durvalumab dose volume into a suitable size syringe.  Prepare a separate 
syringe containing required amount of sodium chloride 0.9% (NS) to achieve the total 
syringe volume.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY

Transfer the durvalumab solution into the NS syringe; once capped (or secured with an 
attached needle), mix the solution using a gentle inversion.  Do not shake.

Final products are prepared at a concentration between 1 and 20 mg/mL.

Infusions should be administered immediately after preparation; however, once 
prepared, infusions can be stored for up to 24 hours (refrigeration) and 4 hours (room 
temperature.  Once the infusion has started, the hang-time of the infusion should not 
exceed 8 hours.

Sites are to follow local practices for final preparation, including attachment of IV 
tubing (PVC or non-PVC) and priming (if applicable), and to ensure the IV 
administration set connected to the IV syringe contains a 0.2 or 0.22 μm low-protein 
binding in-line filter.
6.1.3.2
Tremelimumab
Tremelimumab will be supplied by AstraZeneca as a 400- or 25 mg vial solution containing 
20 mg/mL tremelimumab, 20 mM histidine/histidine hydrochloride, 222 mM trehalose 
dihydrate, 0.27 mM disodium edetate dihydrate, and 0.02% w/v polysorbate 80; the final pH of 
the solution is 5.5.  The nominal fill volume is 20.0 mL for the 400-mg vial and 1.25 mL for the 
25-mg vial.  Investigational product 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 container until use to prevent prolonged 
exposure to light.
The starting dose, using a weight-based approach, is 1 mg/kg; during the dose-finding phase, 
1 additional DL will be evaluated (Table , Table 11, and Table 12).  The patient’s weight at 
baseline is to be used for subsequent dosing calculations unless there is a ≥10% change in the 
measured weight.  The dose will be prepared using an IV bag (PVC or non-PVC) or as a syringe 
and administered via a standard infusion pump.  Tremelimumab will be diluted in 0.9% sodium 
chloride (NS) to a final concentration between 0.10 and 10 mg/mL, and administered through an 
IV infusion line containing a 0.2 μm or 0.22 μm low-protein binding in-line filter; acceptable 
configurations include an IV set containing an in-line filter or the attachment of a separate filter 
to the distal end of the IV tubing. 
The dose of tremelimumab for administration must be prepared by the Investigator’s or site’s 
pharmacist (or designee) using aseptic technique.  Once a vial has been punctured (ie, at time of 
preparation) the final (diluted) preparation is to be stored as follows:

24 hours at 2°C to 8°C (36°F to 46°F)

4 hours at room temperature. 
The tremelimumab vial size (25 mg or 400 mg) should be selected based on: 1) availability and 
2) calculated tremelimumab dose volume.  It is recommended that for small tremelimumab 
volumes (1.25 mL or less), the 25 mg vial size may be used; and for larger volumes (greater 
than 1.25 mL), a combination of 25 mg and the 400 mg vial sizes may be used.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Preparation of tremelimumab doses for administration with an IV bag
IV bag preparation
Dose calculation
The volume (in mL) of tremelimumab to add is calculated as follows:
Dose level (mg/kg) × patient weight (kg) / 20 (mg/mL tremelimumab)
Example:

Dose: 1 mg/kg

Patient weight: 80 kg

Dose for patient: 1 (mg/kg) × 80 (kg) = 80 (mg)

Dose to be added into infusion bag: 80 (mg) / 20 (mg/mL) = 4.0 mL

Add tremelimumab dose volume into an infusion bag (PVC or non-PVC) containing 
0.9% sodium chloride (NS); mix the solution using gentle inversion.  Do not shake.

Final products are prepared at a concentration between 0.1 and10 mg/mL.

Infusions should be administered immediately after preparation; however, infusions 
once prepared, can be stored for up to 24 hours (refrigeration) and 4 hours (room 
temperature).  Once the infusion has started, the hang-time of the infusion should not 
exceed 8 hours.

Sites are to follow local practices for final preparation, including attachment of IV 
tubing (PVC or non-PVC) and priming (if applicable), and to ensure the IV set 
connected to the IV infusion bag contains a 0.2 or 0.22 µm low-protein binding in-line 
filter.
Preparation of tremelimumab doses for administration with an IV syringe
IV syringe preparation
Dose calculation
The volume (in mL) of tremelimumab to add is calculated as follows:
Dose level (mg/kg) × patient weight (kg) / 20 (mg/mL tremelimumab)

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Example:

Dose: 1 mg/kg

Patient weight: 10 kg

Dose for patient: 1 (mg/kg) × 10 (kg) = 10 (mg)

Dose: 10 (mg) / 20 (mg/mL) = 0.5 mL

Withdraw tremelimumab dose volume into a suitable size syringe.  Prepare a separate 
syringe containing required amount of 0.9% sodium chloride (NS) to achieve the total 
syringe volume.

Transfer the tremelimumab solution into the NS syringe; once capped (or secured with 
an attached needle), mix the solution using gentle inversion.  Do not shake.

Final products are prepared at a concentration between 0.1 and 10 mg/mL.

Infusions should be administered immediately after preparation; however, infusions 
once prepared, can be stored for up to 24 hours under refrigeration and 4 hours at 
room temperature.  Once the infusion has started, the hang-time of the infusion should 
not exceed 8 hours. 

Sites are to follow local practices for final preparation, including attachment of IV 
tubing (PVC or non-PVC) and priming (if applicable), to ensure the IV set connected 
to the IV syringe contains a 0.2 or 0.22 μm low-protein binding in-line filter.
6.1.4
Duration of treatment and criteria for restarting treatment with durvalumab in 
combination with tremelimumab
All treatment will be administered beginning on Day 1 until clinical progression or confirmed 
radiological progression (refer to Appendix E for solid tumors, Appendix F for NB, other 
malignancies will be analyzed based on the best response assessed by the Investigator) unless 
there is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met.  
If during the durvalumab monotherapy component of the treatment (after the 4 cycles of 
durvalumab + tremelimumab, where applicable), a patient’s disease progresses, re-administration 
of durvalumab in combination with tremelimumab for another 4 cycles may be considered, 
following the conditions below:

Patients who complete the 4 dosing cycles of the combination of durvalumab and 
tremelimumab portion of the regimen (with clinical benefit per Investigator judgment), 
but subsequently have evidence of defined PD, with or without confirmation, during 
the durvalumab monotherapy portion of the combination regimen may restart 
treatment with the combination once (4 cycles only).  After this, durvalumab 
monotherapy will resume, if the Investigator judges there is clinical benefit to the 
patient.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
6.1.5
Storage
The Investigator, or an approved representative (eg, pharmacist), will ensure that both 
durvalumab and tremelimumab are stored in a secured area, under refrigerated temperature (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 study product storage requirements reflected on the product label.
In the situation where the site is required to maintain a study supply of protocol-specified rescue 
medications (eg, infliximab, mycophenolate), proper storage requirements must be maintained in 
accordance with published information provided on the product packaging.  Additionally, sites 
will be required to maintain temperature logs for such medications, when provided by the 
Sponsor.
6.2
Measures to minimize bias: randomization and blinding
6.2.1
Patient enrollment and randomization
This study will not be randomized.  Patients will be assigned to a treatment regimen based on 
study phase and disease type (see Section 4.1). Interactive Response Technology 
(IRT)/Randomization and Trial Supply Management (RTSM) will only be used for the 
dose-expansion phase.  The dose-finding phase will be manually supplied/managed.
At screening/baseline (Days -28 to -1), the Investigator or suitably trained designee will:
1.
Obtain signed informed consent from the potential patient’s parent(s)/legally 
authorized representative(s) before any study-specific procedures are performed.  
When applicable and as per local regulations, assent will be provided by patients.
2.
Assign potential patient a unique 7-digit enrollment code (E-code) beginning with ‘E#’ 
after written informed consent has been obtained.  The E-code (EWWXXYZZ) will 
consist of a 2-digit country number (WW), a 2-digit site number (XX), a 1-digit study 
number (Y) and a 2-digit patient number (ZZ, starting with 01) issued by the study 
center in order of informed consent taken.
3.
Determine patient eligibility.  See Sections 5.1 and 5.2 for inclusion and exclusion 
criteria, respectively.
Patients may be enrolled but not treated.  If the patient is not treated or withdraws from 
participation in the study, then his/her enrollment code cannot be reused and they cannot re-enter 
into the study.  Refer to Section 5.4 (Screen failures) for conditions for rescreening.
Patients must not be treated unless all eligibility criteria have been met (Sections 5.1 and 5.2).

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
The IRT/RTSM will be used to track drug supply, patient assignment and kit assignment in the 
dose-expansion phase.  The dose-finding phase will be manually supplied/managed 
(management procedures will be provided in a separate document).
6.2.2
Procedures for handling incorrectly enrolled patients
Patients who fail to meet the eligibility criteria should not, under any circumstances, receive 
study medication.  There can be no exceptions to this rule.  Patients who are enrolled, but 
subsequently found not to meet all the eligibility criteria must not be initiated on treatment, and 
must be withdrawn from the study.
Where a patient does not meet all the eligibility criteria but is incorrectly started on treatment, 
the Investigator should inform the AstraZeneca Study Physician immediately, and a discussion 
should occur between the AstraZeneca Study Physician and the Investigator regarding whether to 
continue or discontinue the patient from treatment.  The AstraZeneca Study Physician must 
ensure all decisions are appropriately documented and that the potential benefit/risk profile 
remains positive for the patient.  
6.2.3
Methods for ensuring blinding
This is an open-label study, no blinding methods will be applied. 
6.3
Treatment compliance
Any change from the dosing schedule, dose delays/interruptions, and dose discontinuations must 
be recorded in the case report form (CRF).
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 screening until the end of the clinical treatment phase of the study including 90 days since the 
last dose of IP. 
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.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Restricted, prohibited, and permitted concomitant medications are described in Table 16 and 
Table 17.  Refer also to the TMGs (see Section 8.4.5). 
Table 16
Prohibited concomitant medications
Prohibited medication/class of drug:
Usage:
Any investigational anticancer therapy other 
than those under investigation in this study.
Should not be given concomitantly whilst the patient 
is on study treatment.
mAbs against CTLA-4, PD-1, or PD-L1 other 
than those under investigation in this study.
Should not be given concomitantly whilst the patient 
is on study treatment.
Any concurrent chemotherapy, radiotherapy, 
immunotherapy, or biologic or hormonal 
therapy for cancer treatment other than those 
under investigation in this study. 
Should not be given concomitantly whilst the patient 
is on study treatment. (Concurrent use of hormones 
for non-cancer-related conditions [eg, insulin for 
diabetes and hormone replacement therapy] is 
acceptable.  Local treatment of isolated lesions, 
excluding TLs, for palliative intent is acceptable [eg, 
by local surgery or radiotherapy]).
Live attenuated vaccines. 
Should not be given from 30 days prior to the first 
dose of IP until 30 days after the last dose of IP.
Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/m2/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 immune-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).
Drugs with laxative properties and herbal or 
natural remedies for constipation.
Should be used with caution through to 90 days after 
the last dose of tremelimumab during the 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 medication/class of drug:
Usage:
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 1st generation EGFR 
TKIs) has been reported when durvalumab has been 
given concomitantly.
Herbal and natural remedies which may have 
immune-modulating effects.
Should not be given concomitantly unless agreed by 
the Sponsor or designee.
AE Adverse event; CTLA-4 Cytotoxic T-lymphocyte-associated antigen 4; EGFR Epidermal growth factor 
receptor; IP Investigational product; IT intrathecal; mAb Monoclonal antibody; PD-1 Programmed cell death 
1; PD-L1 Programmed cell death ligand 1; TL target lesion; TKI Tyrosine-kinase inhibitor. 
Table 17
Supportive medications
Supportive medication/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-TLs, etc]).
Should be used, when necessary, for all patients.
Inactivated viral vaccine preparations, such as 
the influenza vaccine.
Permitted.
TL target lesion. 
6.4.1
Background medication
Not applicable. 
6.4.2
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 CRF.

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6.4.3
Durvalumab drug-drug interactions
There is no information to date on drug-drug interactions with durvalumab either pre-clinically 
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 
mechanism of action 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.
6.4.4
Tremelimumab drug-drug interactions
No formal drug-drug interaction studies have been conducted with tremelimumab.  However, in 
renal cell carcinoma studies, acute renal failure has been reported with the combination of 
tremelimumab and sunitinib.  It is unknown whether a similar reaction will be observed when 
tremelimumab is combined with other tyrosine kinase inhibitors.  More information is available 
in the product IB.
6.4.5
Rescue medication
As a result of imAEs that could potentially be experienced by patients on durvalumab, steroids 
and other immunosuppressant rescue medication has to be made 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, 
controlled, and administered by the pharmacist and stored according to the labeled storage 
conditions, with temperature excursions reported accordingly by the pharmacist. 
6.5
Dose modification
Dose delays are permitted for IO therapy (see TMGs).  
6.6
Continued Access to Study Intervention After the Final DCO: Patient 
Management
After the final DCO for this study, AstraZeneca will continue to supply durvalumab to patients 
who are receiving treatment with clinical benefit; treatment will continue until evidence of PD as 
judged by the investigator or until the patients meets any other discontinuation criteria, as 
defined in Section 7.1. Patients will continue to receive durvalumab infusions, administered on 
an every 28-day schedule.  Routine safety monitoring (i.e., labs, vital signs) will be performed as 
standard of care procedures, per the site’s local practices. Patients will be continued to be 
monitored for treatment-related immune mediated toxicity, specifically attributed to study 
treatment. In the event of a treatment-related immune adverse event, Investigators should 
continue to consult the toxicity management guidelines (TMGs) in place for Durvalumab. (see 
Section 8.4.5.) 

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Tumor assessments will be performed according to the sites local imaging schedule. 
See section 8.3.14 for SAE and AESI reporting requirements for patients remaining on treatment 
after DCO.
The schedule of activities for patients receiving ongoing treatment after the final DCO is 
reflected in Table 4.
Research studies/activities intended for collection at the time of progression, as an end-of-
treatment visit, or during the follow-up period (currently reflected in tables 1, 2 and 3) are no 
longer required; therefore, the following studies/activities are now waived: blood sample for 
vaccine antibody titer, Durvalumab PK sample, Tremelimumab PK sample, Durvalumab ADA 
sample, Tremelimumab ADA sample, recording of concomitant medications, and non-
serious/non-imAE assessments. 
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 
participant(s) to alternative supply, where possible.
7.
DISCONTINUATION OF TREATMENT AND SUBJECT 
WITHDRAWAL 
7.1
Discontinuation of study treatment
An individual patient will not receive any further IP (durvalumab + tremelimumab combination 
therapy or durvalumab monotherapy) if any of the following occur in the patient in question:

Withdrawal of consent from further treatment with IP.  The patient or parent(s)/legal 
guardian(s)/legally authorized representative is, at any time, free to discontinue 
treatment, without prejudice to further treatment.  A patient who discontinues 
treatment is normally expected to continue to participate in the study (eg, for safety 
and survival 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 TMGs (see 
Section 8.4.5).

Pregnancy or intent to become pregnant.

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
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.

Clinical progression or confirmed radiological progression (refer to Appendix E for 
solid tumors, Appendix F for NB; other malignancies will be analyzed based on the 
best response assessed by the Investigator) and Investigator determination that the 
patient is no longer benefiting from treatment with IP.
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 or his/her parent(s)/legally authorized representative(s) who decides to 
discontinue IP will always be asked about the reason(s) for discontinuation and the presence of 
any AE.  The patient should continue attending subsequent study visits, and data collection 
should continue according to the study protocol.  If the patient or his/her parent(s)/legally 
authorized representative(s) 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 his/her parent(s)/legally authorized 
representative(s), a contact with a relative or treating physician, or information from medical 
records.  The approach taken should be recorded in the medical records.  A patient or his/her 
parent(s)/legally authorized representative(s) 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 are permanently 
discontinued will enter follow-up (see the SoAs). 
Patients who permanently discontinue drug for reasons other than objective PD should continue 
to have OR assessments performed every 8 weeks ± 1 week relative to the date of the first dose
until PD plus an additional follow-up assessment or death (whichever comes first) as defined the 
SoAs.
If a patient is discontinued for PD, then the patient should have 1 additional follow-up 
assessment performed preferably at the next (and no later than the next) scheduled imaging visit, 
and no less than 4 weeks after the prior assessment of PD.
All patients will be followed for survival until the end of the study. 
Patients or his/her parents/legally authorized representatives who decline to return to the site for
evaluations should be contacted by telephone as indicated in the SoAs as an alternative. 
Patients who have permanently discontinued from further receipt of IP will need to be 
discontinued from the IRT/RTSM (Note that IRT/RTSM will only be used for the 
dose-expansion phase.  Dose-finding phase will be manually supplied/managed).

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7.2
Lost to follow-up
Patients will be considered lost to follow-up only if no contact has been established by the time 
the study is completed (see Section 4.3.1.3), such that there is insufficient information to 
determine the patient’s status at that time.  Patients who refuse to continue participation in the 
study, including telephone contact, should be documented as “withdrawal of consent” rather than 
“lost to follow-up.”  Investigators should document attempts to re-establish contact with missing 
patients throughout the study period.  If contact with a missing patient is re-established, the 
patient should not be considered lost to follow-up and evaluations should resume according to 
the protocol.
In order to support key end points of PFS and OS analyses, the survival status of all patients in 
the full analysis set (FAS) and the safety analysis set (SAS) 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 or his/her parents/legally authorized representatives 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.) 
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 or his/her parent(s)/legally authorized 
representative(s) 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 or his/her parent(s)/legally authorized representative(s) 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 or his/her parent(s)/legally authorized representative(s) withdraws consent, they will 
be specifically asked if they are withdrawing consent to:

All further participation in the study including any further follow-up (eg, survival 
contact telephone calls)

Withdrawal to the use of any samples (see Section 8.8.7).

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8.
STUDY ASSESSMENTS AND PROCEDURES
Study procedures and their timing are summarized in the SoA.  The schedule for study 
procedures for the dose-finding and dose-expansion phases are presented in Table 1 and Table 2
respectively.  The schedule of study procedures for patients who have discontinued all study 
treatments (durvalumab monotherapy or durvalumab and tremelimumab combination therapy) in 
the dose-finding or the dose-expansion are presented in Table 3.  
The Investigator will ensure that data are recorded on the electronic CRF.  The Web Based Data 
Capture system will be used for data collection and query handling. 
The Investigator ensures the accuracy, completeness, legibility, and 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 electronic CRFs.  A copy of the completed 
electronic CRFs will be archived at the study site.
Immediate safety concerns should be discussed with the Sponsor or designee 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 a 
screening log to record details of all patients screened and to confirm eligibility or record reasons 
for screening failure, 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.
Enrollment/screening period
All screening evaluations must be completed and reviewed to confirm that potential patients 
meet all eligibility criteria.  The screening procedures (presented in Table 1 and Table 2) will be 
completed within 28 days of signing the ICF and before durvalumab infusion on Cycle 1 Day 1 
(radiological assessments to be completed within 21 days before on Cycle 1 Day 1).  The 
Investigator will maintain a screening log to record details of all patients screened and to confirm 
eligibility or record reasons for screening failure, as applicable.  At screening, consenting 
patients are assessed to ensure that they meet eligibility criteria (Sections 5.1 and 5.2).  Patients 
who do not meet these criteria must not be started on treatment.  Patients will be considered to be 
in the screening period until all screening visit assessments are completed and eligibility is 
confirmed.  Patients will be considered to be in the dose-finding period after the first dose of 
durvalumab has been administered.

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Dose-finding phase
Descriptions of the procedures for this period are included in the SoA for the dose-finding phase 
of the study (Table 1).  
Patients will receive durvalumab monotherapy on Cycle 1 Day 1 and will be closely monitored 
for 28 days for safety and tolerability (DLT observational period 1) attending clinic visits on
Days 8 and 15. Starting on Cycle 2, patients will receive durvalumab + tremelimumab in 
combination on Day 1 and attend clinic visits on Days 8 and 15.  Cycle 2 Day 1 to Day 28 is the 
second DLT observational period; the total DLT observational period is 56 days or 2 cycles.  
Starting at Cycle 3, patients will have a scheduled visit only on Day 1 of the treatment cycle.  
From Cycle 6 onwards, patients will receive durvalumab monotherapy until progression.
Dose-expansion phase
Once a RP2D has been confirmed, patients will be recruited to the dose-expansion phase and will 
follow the procedures for this period in Table 2.  All patients will receive durvalumab + 
tremelimumab in combination on Day 1 of Cycles 1, 2, 3, and 4.  From Cycle 5, patients will 
receive durvalumab monotherapy until progression. 
Off-treatment follow-up
Patients should be discontinued from study treatment if any discontinuation criteria are fulfilled, 
(Section 7.1).  The assessments to be carried out during follow-up are detailed in Table 3.  Any 
SAEs and/or non-serious AEs ongoing at the time of treatment discontinuation or which have 
occurred during the follow-up period must be followed up (in accordance with Section 8.3.3).  
Appropriate safety evaluations should be repeated and/or additional tests performed at any time 
when clinically indicated, or at the discretion of the Investigator, until resolution, unless, in the 
Investigator’s opinion, the condition is unlikely to resolve due to the patient’s underlying 
disease.  If the patient is lost to follow-up, then this should be noted in the CRF.  Survival will be 
collected every 2 months for all patients (Section 8.1.2).
Volume of blood and prioritization of laboratory sampling
For a patient weighing less than 6 kg, the following parameters for blood volume collection 
should apply:

Maximum blood volume in 24 hours: 2 mL/kg.

Maximum blood volume in 8 weeks: 8 mL/kg.
The total volume of blood that will be drawn as maximum per day (Cycle 1 Day 1) and for the 
60-day period encompassing Cycle 1 and Cycle 2 has been carefully assessed across the weight 
range 6 kg to 55 kg to stay below the World Health Organisation blood limit guidelines 
(Table 18; Howie 2011).  Pediatric tubes/microcontainers should be used, whenever possible, for 
blood collection.  If there is any difficulty obtaining specimens or the local blood volume limits 
are met at any one time for any patient, the order of sampling priority should be followed as 

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Table 18
Volume of blood to be collected (by weight and including World Health 
Organisation limits)
Total blood volume (TBV): 80 mL/kga
Weight (kg)
6
10
20
35
55
TBV (mL)
480
800
1600
2800
4400
WHO limits per 24 hours: 1–5% TBV
Sick kids: 3.8% TBV
WHO limits per 8 weeks: up to 10% TBV
Dose-finding phase
Max volume (mL) 
per 24 hours
(% TBV)
12.5
(2.6)
12.5
(1.6)
20.5
(1.3)
20.5
(0.73)
20.5
(0.47)
Volume (mL) per 
8 weeks
(%TBV)
32
(6.6)
32
(4)
56
(3.5)
56
(2)
56
(1.27)
Volume (mL) 
from Cycle 3 until 
progression
Safety labs (chemistry/hematology/TSH) at each cycle: 4 mL
Research labs (according to Schedule of Activities): up to 14.5 mL (+3.5 mL for 
tumor markers with each tumor assessment) between Cycles 3 and 12
EOT (mL)
4
4
4
4
4
Dose-expansion phase
Max volume (mL) 
per 24 hours
(% TBV)
20
(2.9)
20
(2.5)
28
(1.7)
28
(1)
28
(0.63)
Volume (mL) per 
8 weeks
(%TBV)
38
(7.9)
40.5
(5)
64.5
(4)
64.5
(2.3)
64.5
(1.5)
Volume (mL) 
from Cycle 3 until 
progression
Safety labs (chemistry/hematology/TSH) at each cycle: 4 mL
Research labs (according to Schedule of Activities): up to 6 mL (+3.5 mL for tumor 
markers with each tumor assessment) between Cycles 3 and 12
EOT (mL)
4
7.5
7.5
7.5
7.5
a 
WHO range: 75–80 mL/kg (beyond neonatal period); maximum of 105 mL/kg from birth to 1 month.
EOT end of treatment; Max maximum; TBV total blood volume; TSH thyroid-stimulating hormone; WHO World Health 
Organisation.
8.1
Efficacy assessments 
Efficacy assessments of ORR, duration of response (DoR), DCR, and PFS will be derived (by 
AstraZeneca) using the response criteria defined below.  Overall survival will also be assessed 
for each individual patient.

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Tumor assessments will be done in accordance with the type of tumor: NB (Appendix F), other 
solid tumors (Appendix E).  
Radiological assessments will be made following routine clinical practice procedures during 
screening and then every 8 weeks (relative to the date of Cycle 1 Day 1), until radiological 
progression.  For patients who achieve an objective response (CR, PR) or stable disease and for 
whom the response is still evident at 12 months, subsequent tumor assessments are to occur 
every 16 weeks.  Unscheduled assessments can be performed at any time during the study, as 
clinically indicated, based on signs and symptoms.  Disease progression requires confirmation, 
the confirmatory scan should occur preferably at the next scheduled visit and no earlier than 
4 weeks after the initial assessment of PD in the absence of clinically significant deterioration.  
Treatment will continue between the initial assessment of progression and confirmation for 
progression.
Tumor assessments will be made during screening/baseline and at regular (follow-up) intervals 
during study treatment.  Pelvic imaging is recommended only when primary or metastatic 
disease in the pelvic region is likely.  Any other areas of disease involvement should be 
additionally imaged based on the signs and symptoms of individual patients.  It is important to 
follow the tumor assessment schedule as closely as possible (refer to the SoAs).  If an 
unscheduled assessment is performed (eg, to investigate clinical signs/symptoms of progression) 
and the patient has not progressed, every attempt should be made to perform the subsequent 
assessments at the next scheduled visit.  Treatment continues until clinical 
progression/deterioration or confirmed radiological progression, and scanning/tumor assessments 
continue throughout treatment until radiological progression plus an additional follow-up scan (if 
clinically feasible).
Screening/Baseline imaging should be performed no more than 21 days before start of study 
treatment, and ideally should be performed as close as possible to and prior to the start of study 
treatment.  Definitions of lesions, methods of assessments and response types are defined in 
Appendix F for NB, Appendix E for other solid tumors (RECIST 1.1)
8.1.1
Central reading of scans
All images, including unscheduled visit scans, will be collected on an ongoing basis and sent to 
an AstraZeneca appointed contract research organization (CRO) for quality control check 
(QCC).  Guidelines for image acquisition, de-identification, storage at the investigative site as 
source data and transfer to the imaging CRO will be provided in a separate document.
A blinded independent central review (BICR) of images will be performed at the discretion of 
AstraZeneca.  Results of these independent reviews will not be communicated to Investigators, 
and results of Investigator radiological assessments will not be shared with the central reviewers.  
The management of patients will be based in part upon the results of the radiological assessment 
conducted by the Investigator.  Further details of the BICR will be documented in the 
Independent Review Charter, (also referred to as ‘Imaging Charter’).

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8.1.2
Survival assessments
Assessments for survival must be made 30 days, 2 months, 3 months, 4 months, and every 
2 months following treatment discontinuation (Table 3).  Survival information may be obtained 
via telephone contact with the patient or the patient’s family, or by contact with the patient’s 
current physician.  The details of first and subsequent therapies for cancer, after discontinuation 
of treatment, will be collected. 
In addition, patients on treatment or in survival follow-up will be contacted following the DCO 
for survival analyses to provide complete survival data.  These contacts should generally occur 
within 7 days of the DCO.
8.2
Safety assessments
Planned time points for all safety assessments are provided in the SoA.
8.2.1
Physical examinations
Full and targeted physical examinations will be performed according to the assessment schedules 
(see the SoAs) and in unscheduled visits.  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 and weight will be measured at screening, and q4w (on dosing days 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. 
8.2.2
Clinical safety laboratory assessments
Blood and urine samples for determination of clinical chemistry, hematology, and urinalysis will 
be taken at the times indicated in the assessment schedules and as clinically indicated (see the 
SoAs). 
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 
(performed only on female patients of childbearing potential) 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 CRF.
The laboratory variables to be measured are presented in Table 19 (clinical chemistry), Table 20
(hematology), and Table 21 (urinalysis).
Other safety tests to be performed at screening include assessment for hepatitis B surface 
antigen, hepatitis C antibodies, and HIV antibodies.  

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The following laboratory variables will be measured:
Table 19
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 TBL must be conducted and assessed concurrently.  If TBL 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 
are 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 the Schwartz pediatric equation, 
radioisotope measured GFR, or by 24-hour urine collection. 
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.  
TSH will be collected every 4 weeks.
f
Free T4 or free T3 will only be measured if TSH is abnormal or if there is a clinical suspicion of an AE related 
to the endocrine system.  Free T4 can be collected with or without free T3.
AE Adverse event; ALT Alanine aminotransferase; AST Aspartate aminotransferase; GFR glomerular filtration 
rate; T3 Triiodothyronine; T4 Thyroxine; TBL total bilirubin; TSH Thyroid-stimulating hormone.

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Table 20
Hematology
Absolute neutrophil counta
Absolute lymphocyte counta
Hemoglobin
Platelet count
Total white cell count
Coagulationb
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.
b
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.
Table 21
Urinalysis
Bilirubin
Ketones
Blood
pH
Color and appearance
Protein
Glucose
Specific gravity
Note: Urinalysis should be done at the visits shown in Table 1 (for dose-finding) and Table 2 (for dose-expansion).
Note: Microscopy should be used as appropriate to investigate white blood cells and use the high power field for red 
and white blood cells. 
Results for LFTs, electrolytes, full blood count, urea, and creatinine must be available before 
commencing an infusion (within 3 days) and reviewed by the treating physician or Investigator 
prior to dosing.
If a patient shows an AST or ALT ≥3 × ULN together with TBL ≥2 × ULN, refer to Appendix D
for further instructions on cases of increases in liver biochemistry and evaluation of Hy’s Law.  
These cases should be reported as SAEs if, after evaluation, they meet the criteria for a Hy’s law 
case or if any of the individual liver test parameters fulfill any of the SAE criteria. 
All patients should have further chemistry profiles performed at 30 days (±3 days) after 
permanent discontinuation of IP (see Table 3).
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded on the CRF.  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 IP 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.

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8.2.3
Vital signs
Vital signs (blood pressure [BP], pulse, temperature, and respiration rate) will be evaluated 
according to the SoAs.  Peripheral oxygen saturation will be measured at screening/baseline and 
at clinic visits, in accordance with the SoA, along with the remaining vital signs.
Patients will be monitored and vital signs collected/recorded in CRF as presented in the bulleted 
list below:

Based on a 120-minute infusion (durvalumab):

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 60 minutes during the infusion (halfway through infusion) 

At the end of the infusion (approximately 120 minutes ± 5 minutes).

Based on a 60-minute infusion (durvalumab and tremelimumab):

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.
Dose-finding phase
Vital signs will be obtained and documented prior to, mid-infusion, and end of infusion for the 
following:

Cycle 1 Day 1: Durvalumab infusion.

Cycle 2 Day 1: Tremelimumab and durvalumab infusion.
For Cycle 3 onwards, only at the beginning of the first 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.
For the observation period:

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
Cycle 1 Day 1 : 1 hour after completion of durvalumab infusion.

Cycle 2 Day 1 to Cycle 4 Day 1: 1 hour between tremelimumab and durvalumab.

Cycle 2 Day 1: 1 hour after completion of tremelimumab and durvalumab infusions.
Dose-expansion phase
Vital signs will be obtained and documented prior to, mid-infusion and end of infusion for the 
following:

Cycle 1 Day 1: Tremelimumab and durvalumab infusion.
For Cycle 2 onwards, only at the beginning of first 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.
For the observation period:

Cycle 1 Day 1: 1 hour between tremelimumab and durvalumab;

For Cycle 2 onwards: if no infusion reaction, observation period may be waived 
allowing durvalumab to be administered immediately after tremelimumab.

Cycle 2 Day 1: 1 hour after completion of tremelimumab and durvalumab infusions.
Situations in which vital signs 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.
8.2.4
Tanner staging
Tanner staging (Appendix H) will also be assessed at Cycle 1 Day 1 and subsequently at visits 
where radiological efficacy assessments are made (see Section 8.1).
8.2.5
Electrocardiograms
Single resting 12-lead electrocardiograms (ECGs) will be recorded at screening and as clinically 
indicated throughout the study (see the SoAs).  ECGs should be obtained after the patient has 
been in a supine position for 5 minutes and recorded while the patient remains in that position.
In case of clinically significant ECG abnormalities, including a QTcF value >470 ms calculated 
using Fridericia’s formula, an additional 12-lead ECG should be obtained over a brief period (eg, 
30 minutes) to confirm the finding. 

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Situations in which ECG results should be reported as AEs are described in Section 8.3.7.
8.2.6
Early patient review for safety
Patients should be attending scheduled visits on Cycle 1 Day 15 and Cycle 2 Day 15.  It is also 
recommended patients are contacted on Cycle 3 Day 15 to ensure early identification and 
management of toxicities.  
8.2.7
Performance status
Karnofsky performance status (Appendix I) will be assessed in patients ≥16 years of age and 
Lansky play performance scale (Appendix J) will be assessed in patients ≥1 and <16 years of age 
at the times specified in the assessment schedules in line with the SoA.
Any significant change from baseline or screening must be reported as an AE.
8.2.8
Other safety assessments
8.2.8.1
Other 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 TMGs (see 
Section 8.4.5) 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 CRF.  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 TMGs 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

Signs and symptoms (cough, shortness of breath, and pyrexia, etc) including 
auscultation for lung field will be assessed.

Saturation of peripheral oxygen (resting and exertion)

High-resolution CT

Other items

When pneumonitis (ILD) is suspected during study treatment, the following 
markers should be measured where possible:

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(i)
ILD Markers (KL-6, SP-D) and β-D-glucan
(ii)
Tumor markers: particular tumor markers which are related to PD 
(iii)
Additional clinical chemistry: c-reactive protein, lactate dehydrogenase. 
8.3
Collection of adverse events
The Principal Investigator (PI) 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 B.
Adverse events will be reported by the patient or parent(s)/legally authorized representative(s). 
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 
Adverse events 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 or durvalumab + 
tremelimumab.  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 IP then it should be reported as an AE or SAE as 
applicable.
All SAEs will be recorded and reported to the Sponsor or designee within 24 hours, as indicated 
in Appendix B.  The Investigator will submit any updated SAE data to the Sponsor or designee 
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 or designee.
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 B.
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 SAE/non-serious AEs/AEs of special interest (AESI; as defined 

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in Section 8.3.13), 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 visit 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 or durvalumab + tremelimumab), 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:

Adverse event (verbatim)

The date when the AE started and stopped

The maximum NCI CTCAE grade reported

Changes in NCI CTCAE grade (report only the maximum NCI 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

Outcome.
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

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
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 NCI 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 investigational product?’
For SAEs, causal relationship will also be assessed for other medication and study procedures.  
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 B to the Clinical 
Study Protocol.
8.3.6
Adverse events based on signs and symptoms
All AEs spontaneously reported by the patient or parent(s)/legally authorized representative(s),
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 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, vital signs, physical examination findings, or ECG 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.
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).  In the 

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absence of clinical signs or symptoms, clinically relevant deteriorations in non-mandated 
parameters should be reported as AE(s).
Deterioration of a laboratory value, which is unequivocally due to PD, 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, 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 TBL ≥2 × ULN may need to be reported as 
SAEs.  Please refer to Appendix D for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s Law.
8.3.9
Disease under study 
Events which are unequivocally due to disease under study 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 disease 
under study 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 PD 
and not an AE.  Events, which are unequivocally due to PD, 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 IP, must be reported as follows:

Death clearly resulting from PD should be reported to the Study Physician at the next 
monitoring visit and should be documented in the CRF in the Statement of Death 
page.  It should not be reported as an SAE.

Where death is not due (or not clearly due) to progression of the disease under study, 
the AE causing the death must be reported to the Study Physician as an SAE within 24 
hours.  It should also be documented in the Statement of Death page in the CRF.  The 

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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 CRF.  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 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 IP 
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.
Adverse events of special interest for durvalumab ± tremelimumab include but are not limited to 
events with a potential inflammatory or immune-mediated mechanism and which may require 
more frequent monitoring and/or interventions such as steroids, immunosuppressants and/or 
hormone replacement therapy.  These AESIs are being closely monitored in clinical studies with 
durvalumab monotherapy and combination therapy.  An imAE is defined as an AESI that is 
associated with drug exposure and is consistent with an immune-mediated mechanism of action 
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 regards to an event being an imAE, the Investigator 
should promptly contact the Study Physician.
AESIs observed with durvalumab ± tremelimumab include:

Diarrhea/colitis and intestinal perforation

Pneumonitis/ILD

Endocrinopathies (ie, events of hypophysitis/hypopituitarism, adrenal insufficiency, 
hyper- and hypo-thyroidism and type I diabetes mellitus)

Hepatitis/transaminase increases

Nephritis/blood creatinine increases

Pancreatitis/serum lipase and amylase increases

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
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, neuromuscular 
toxicities (eg, Guillain-Barré syndrome, myasthenia gravis) 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 and tremelimumab IBs.  More specific guidelines for their evaluation and 
treatment are described in detail in the TMGs (see Section 8.4.5).  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 IP/study regimen by the reporting Investigator.
8.3.14
Safety data to be collected following the final DCO of the study
For patients continuing to receive durvalumab treatment after final DCO and database closure, it 
is recommended that patients continue their scheduled treatment visits and Investigators continue 
to monitor the patient’s safety laboratory results in accordance with standard of care procedures, 
reflecting local practices. AE and SAE data will be collected, but only SAEs and AESI data will 
be reported. All data after the final DCO and database closure will be recorded in the patient’s 
notes, but with the exception of SAEs and AESIs, will not otherwise be reported for the purposes 
of this study.
All SAEs and AESIs that occur in patients still receiving durvalumab treatment (or within the 90 
days following the last dose of durvalumab or until initiation of subsequent anti-cancer therapy), 
post the final DCO and database closure) must be reported as detailed in Section 8.4.1.
Additional details will be provided to the investigators with instructions for using an alternative 
process ( eg. a non-electronic data capture mechanism) to report these events
8.4
Safety reporting and medical management
8.4.1
Reporting of serious adverse events
All SAEs have to be reported, whether or not considered causally related to the IP, or to the 
study procedure(s).  All SAEs will be recorded in the CRF.  

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If any SAE occurs in the course of the study, then Investigators or other site personnel inform the 
appropriate AstraZeneca representatives within 1 day (ie, immediately but no later than 
24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all the 
necessary information is provided to the AstraZeneca Patient Safety data entry site within 
1 calendar day of initial receipt for fatal and life-threatening events and within 5 calendar
days of initial receipt for all other SAEs.
For fatal or life-threatening AEs where important or relevant information is missing, active 
follow-up is undertaken immediately.  Investigators or other site personnel inform AstraZeneca 
representatives of any follow-up information on a previously reported SAE within 1 calendar day 
(ie, immediately but no later than 24 hours of when he or she becomes aware of it).
Once the Investigators or other site personnel indicate an AE is serious in the electronic data 
capture (EDC) system, an automated email alert is sent to the designated AstraZeneca 
representative. 
If the EDC system is not available, then the Investigator or other study site staff reports a SAE to 
the appropriate AstraZeneca representative by telephone.  The AstraZeneca representative will 
advise the Investigator/study site staff how to proceed. 
This study will use EDC for SAE submission.  If we are talking of back-up method when EDC is 
down, then it will be using SAE or relevant form to be scanned and emailed to the appropriate 
AstraZeneca representative or faxed.
For further guidance on the definition of a SAE, see Appendix B of the Clinical Study Protocol.
Reporting of serious adverse events and adverse events of special interest for patients 
receiving treatment following the final DCO.
.
The timeframe,for SAE reporting to the AstraZeneca representative remains the same during the 
post-DCO period
Adverse events of special interest are to be reported at the time of diagnosis of the event.
8.4.2
Pregnancy
All pregnancies and outcomes of pregnancy should be reported to AstraZeneca except for:

If the pregnancy is discovered before the study patient has received any IP. 
If a pregnancy is reported, the Investigator should inform the Sponsor within 24 hours of 
learning of the pregnancy.

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Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs.
8.4.2.1
Maternal exposure
If a patient becomes pregnant during the course of the study, the IP should be discontinued 
immediately.
Pregnancy itself is not regarded as an AE unless there is a suspicion that the IP under study may 
have interfered with the effectiveness of a contraceptive medication.  Congenital 
abnormalities/birth defects and spontaneous miscarriages should be reported and handled as 
SAEs.  Elective abortions without complications should not be handled as AEs.  The outcome of 
all pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth 
or congenital abnormality) should be followed up and documented even if the patient was 
discontinued from the study.
If any pregnancy occurs in the course of the study, then the Investigator or other site personnel 
informs the appropriate AstraZeneca representatives within 1day (ie, immediately but 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 within 1 or 5 calendar 
days for SAEs (see Section 8.4.1) and within 30 days for all other pregnancies.
The same timelines apply when outcome information is available.
The PREGREP module in the CRF is used to report the pregnancy and the PREGOUT is used to 
report the outcome of the pregnancy. 
8.4.2.2
Paternal exposure 
Male patients should refrain from fathering a child or donating sperm during the study and for 
90 days after the last dose of durvalumab + tremelimumab combination or after the last dose of 
durvalumab monotherapy.  
Pregnancy of the patient’s partner is not considered to be an AE.  However, the outcome of all 
pregnancies (spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or 
congenital abnormality) occurring from the date of the first dose until 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.

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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 or tremelimumab
Use of durvalumab or tremelimumab 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 overdose 
of durvalumab or tremelimumab, 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 IP 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 a SAE, the standard reporting timelines apply, see Section 8.3.2.  
For other overdoses, reporting must occur within 30 days.
8.4.4
Medication error, Drug Abuse, and Drug Misuse
If an event of medication error, drug abuse or drug misuse occurs during the study, then the 
Investigator or other site personnel informs the appropriate AstraZeneca representatives within 1 
day (ie, immediately but no later than 24 hours of when he or she becomes aware of it).
The designated AstraZeneca representative works with the Investigator to ensure that all relevant 
information is completed within 1 (Initial Fatal/Life-Threatening or follow-up 
Fatal/Life-Threatening) or 5 (other serious initial and follow-up) calendar days if there is an SAE 
associated with the medication error, drug abuse, or misuse (see Section 8.3.2) and within 30 
days for all other events.
8.4.4.1
Medication error
For the purposes of this clinical study a medication error is an unintended failure or mistake in 
the treatment process for an IMP or AstraZeneca NIMP that either causes harm to the patient or 
has the potential to cause harm to the patient.
The full definition and examples of Medication Error can be found in Appendix B.

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8.4.4.2
Drug Abuse
Drug abuse is the persistent or sporadic intentional, non-therapeutic excessive use of IMP or 
AstraZeneca NIMP for a perceived reward or desired non-therapeutic effect.
The full definition and examples of drug abuse can be found in Appendix B.
8.4.4.3
Drug Misuse
Drug misuse is the intentional and inappropriate use (by a study participant) of IMP or 
AstraZeneca NIMP for medicinal purposes outside of the authorised product information, or for 
unauthorised IMPs or AstraZeneca NIMPs, outside the intended use as specified in the protocol 
and includes deliberate administration of the product by the wrong route.
The full definition and examples of Drug Misuse can be found in Appendix B.
8.4.5
Management of IP-related toxicities 
The following general guidance should be followed for management of toxicities.

Treat each of the toxicities with maximum supportive care (including holding the 
agent suspected of causing the toxicity if required).

If the symptoms promptly resolve with supportive care, consideration should be given 
to continuing 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. 
8.4.5.1
Specific toxicity management and dose modification information – Durvalumab 
and durvalumab + tremelimumab
Comprehensive TMGs have been developed to assist Investigators with the recognition and 
management of toxicities associated with use of the immune-checkpoint inhibitors, durvalumab 
[MEDI4736] (PD-L1 inhibitor) and tremelimumab (CTLA-4 inhibitor).  Given the similar 
underlying mechanism of toxicities observed with these 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 anti-cancer 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 

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use local practice guidelines and consult local references for the management of toxicities 
observed with other anti-cancer 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.  
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 and tremelimumab should be 
permanently discontinued (see Section 7.1 of this protocol and the TMGs).
Following the first dose of IP, subsequent administration of durvalumab and tremelimumab can 
be modified based on toxicities observed as described in the TMGs.  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 + tremelimumab regimen by the reporting 
Investigator.
8.5
Pharmacokinetics and anti-drug antibodies
8.5.1
Collection of pharmacokinetic samples and determination of drug concentration
Blood samples will be taken at the time points presented in the SoA (Table 1 and Table 2 for 
dose-finding and dose-expansion, respectively).  It is essential that the actual time and date of 
collection of each blood sample (whether collected as per protocol or not) will be recorded in the 
CRF.  If a patient is receiving durvalumab + tremelimumab combination therapy, because 
tremelimumab is infused before durvalumab the following principles will be followed when 
these samples are scheduled:

Predose samples for tremelimumab PK will be taken before tremelimumab is infused.  
Predose samples for durvalumab PK will be taken before durvalumab is infused.  
During the combination period, predose samples for durvalumab PK should ideally be 
taken in the interval following tremelimumab administration and before durvalumab is 
infused.  However, sampling prior to tremelimumab infusion is also acceptable, if 
considered necessary for logistical/operational reasons.

End of infusion sample for tremelimumab PK will be taken after tremelimumab is 
infused.

End of infusion sample for durvalumab PK will be taken after durvalumab is infused.

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End of infusion PK samples should be taken within 10 minutes of the completion of IP infusion.

In the dose-finding phase only, an end of treatment tremelimumab sample is required 
for patients at the EoT visit who have received only a single dose (cycle) of 
tremelimumab in combination with durvalumab (i.e treatment discontinuation after 
cycle 2). Preferably, this sample should be collected approximately 30 days after the 
final tremelimumab infusion, but can be collected at any time beyond the final 
(day 15) tremelimumab PK sample collection.
Samples will be collected, labeled, stored, and shipped as detailed in the Laboratory Manual.  
Samples for determination of durvalumab and tremelimumab concentration in serum will be 
analyzed by a designated third party on behalf of AstraZeneca. 
Full details of the analytical method used will be described in a separate Bioanalytical Validation 
Report.
8.5.2
Collection of samples to measure for the presence of ADAs and ADA-neutralizing 
antibodies
The presence of ADA will be assessed in serum samples taken according to the SoAs (Table 1
and Table 2 for dose-finding and dose-expansion, respectively).  
Samples will be measured for the presence of ADAs and ADA-neutralizing antibodies for both 
IPs (durvalumab and tremelimumab) using validated assays.  Tiered analysis will be performed 
to include screening, confirmatory, and titer assay components, and positive negative cut points 
previously statistically determined from drug-naïve validation samples will be employed.
8.5.3
Storage and destruction of pharmacokinetic/anti-drug antibody samples
Durvalumab and tremelimumab PK and ADA samples will be destroyed within 5 years of CSR 
finalization.
Pharmacokinetic and ADA samples may be disposed of or destroyed and anonymized by 
pooling.  Additional analyses may be conducted on the anonymized, pooled PK samples to 
further evaluate and validate the analytical method.  Results from such analyses may be reported 
separately from the CSR.
Incurred sample reproducibility analysis, if any, will be performed alongside the bioanalysis of 
the test samples.  The results from the evaluation will not be reported in the CSR but separately 
in a Bioanalytical Validation Report.
Any residual back-up PK samples may be used for future exploratory biomarker research (in this 
case, residual back-up PK samples will be shipped to an AstraZeneca-assigned Biobank; see 
details in the Laboratory Manual).
8.6
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.

Cli nical St u d y Pr ot oc ol - 6. 0
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D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
M a n a ge me nt of bi o m ar ker d at a
T he bi o mar ker data will ha ve u n k n o w n cli nical si g nifica nce.  Astra Ze neca will n ot pr o vi de 
bi o mar ker rese arc h res ults t o patie nts, t heir fa mil y me m bers, a n y i ns ura nce c o m pa n y, a n 
e mpl o y er, cli nical st u d y I n vestigat or, ge neral  p h ysicia n, or a n y ot her t hir d part y, u nless re q uire d 
t o d o s o b y la w.  T he patie nt’s sa m ples will n ot be use d f or a n y p ur p ose ot her t han t h ose 
descri be d i n t he st u d y  pr ot o c ol.
I n di vi d ual patient s will n ot be i de ntifie d i n a n y re p ort or p u blicati on res ult i n g fr o m t his w or k.  
T he data a n d res ults of t his researc h ma y  be re vie we d wit h c olla b orat ors a n d p u blis he d, b ut 
neit her t he patie nt’s na me n or a n y  ot her pers o nal ide nt ifiers will a p pear i n a n y p u blicati on or 
re p ort.
8. 8. 4
St or a ge, re -use a n d destr ucti o n of bi o m ar ker s a m ples
S a m ples will  be st ore d f or a ma xi m u m of 1 5 years fr o m t he e n d o f st u d y, after w hic h t he y will 
be destr o y e d.  S u m maries a n d a nal yses f or e x pl orat or y bio m ar kers will be d oc u me nte d i n a 
se parate a nal ysis pla n a n d will be re p orte d o utsi de t he C S R i n a se parate re p ort.  T he res ults of 
t his bio m ar ker researc h ma y be p o ole d wit h bio m ar ker data fr o m ot her st u dies i n v o l vi n g 
d ur val u ma b or tre m eli m u ma b t o ge nerate h yp ot heses t o be teste d i n f ut ure researc h.
8. 8. 5
L a beli n g a n d s hi p me nt of bi ol o gic al s a m ples
T he PI will e ns ure t hat sa m ples are la bele d a n d s hi p pe d i n acc or da nce wit h t he La b orat or y  
Ma n ual a n d t he Bi o l ogical  S u bsta nce, Cate g or y B, Re g ulat i ons ( materials c o ntai ni n g or 
s us pecte d t o c o ntai n i nfect i ous s u bsta nces t hat d o n ot meet Cate g or y  A crit eria) ; see A p pe n di x C
“I A T A [I nter nati o nal Airli ne Tra ns p ortati o n Ass ociat i on] 6. 2 G ui da nce D oc u me nt.”
A n y sa m ples i de nt ifie d as I nfecti ous Cate g or y  A mat erials will n ot be s hi p pe d, a n d n o f urt her 
sa m ples will be ta ke n fr o m t he i n v o l ve d patient s u nless a gree d u p o n wit h Astra Ze neca a n d 
a p pr o priate la beli n g, s hi p me nt, a n d c o ntai n me nt pr o visi o ns are a p pr o ve d.
C CI

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For the dose-expansion phase, the SARCOMA cohort mentioned in Section 4.1.4 will follow a 
Simon 2-stage optimal design.  An ORR ≤10% will not be considered clinically meaningful. 
In the SARCOMA cohort, the Simon 2-stage design will have a type I error rate set at 
0.1 (1-sided) and power of at least 85%.  Based on the assumption that the ORR for the null 
hypothesis is 10% and the true ORR for the SARCOMA cohort is 30%, then the SARCOMA 
cohort will require a total of 26 evaluable patients (with the requirement that ≥40% of the 
patients enrolled must have soft-tissue sarcomas), with 11 evaluable patients required in the first 
stage.  If fewer than 2 responses are observed in the first 11 evaluable patients, then the cohort 
will be closed for lack of benefit.  If 2 or more responses are observed out of the first 
11 evaluable patients, then an additional 15 evaluable patients will be enrolled, for a total of 
26 evaluable patients.  
For a cohort that enrolls the maximum total of evaluable patients for that particular cohort 
(26 patients in the SARCOMAcohort), if fewer than 5 responses are observed out of the 
maximum total of evaluable patients, then no further investigation of this cohort will be done; if 
5 or more responses are observed out of the maximum total of evaluable patients, then the null 
hypothesis will be rejected for this cohort and further investigation will be warranted. 
The STO cohort is planned to recruit 10 evaluable patients.  This sample size is based on 
practical, rather than formal considerations, as no formal hypothesis testing is planned for this 
cohort. 
With the above considerations, the sample size for evaluable patients in the dose-expansion 
phase is expected to range from21 to 36. Assuming that about 20% of patients may not be 
evaluable for ORR, the total number of patients dosed in the dose-expansion phase may range 
from approximately 25 to 43.
9.3
Populations for analyses
Definitions of the analysis sets for each outcome variable are provided in Table 22.

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Table 22
Summary of outcome variables and analysis populations
Outcome variable
Populations
Efficacy Data
ORR (primary for dose-expansion phase)
Evaluable for response analysis 
set
(Sensitivity analysis on FAS)
PFS, OS, BoR, APF12, APF18, OS12, OS24
FAS (ITT population)
DoR 
Evaluable for response analysis 
set (restricted to responders 
only)
DCR
Evaluable for response analysis 
set
(Sensitivity analysis on FAS)
Demography
FAS  (ITT population)
PK data
PK analysis set
Safety Data
Exposure
SAS
AEs
SAS
Laboratory measurements
SAS
Vital Signs
SAS
DLTs (primary for dose-finding phase)
DLT evaluable analysis set
AE Adverse event; APF12 / APF18 Proportion of patients alive and progression-free at 12 / 18 months from first 
dose of IP; BoR Best objective response; DCR Disease control rate; DLT Dose-limiting toxicity; 
DoR Duration of response; FAS Full analysis set; ITT Intention-to-treat; OS Overall survival; 
OS12 / OS24 Proportion of patients alive at 12 / 24 months from first dose of IP; PFS Progression-free 
survival; PK Pharmacokinetics; SAS Safety analysis set.
9.3.1
Full analysis set
The FAS will include all patients who were assigned to treatment and received at least 1 dose of 
study treatment.  The FAS (or subset of the FAS specified below) will be used for all efficacy 
analyses.  
9.3.2
Evaluable for response analysis set
The subset of patients in the FAS who had measurable disease at baseline.
9.3.3
Safety analysis set
The SAS will consist of all patients who received at any amount of study treatment.  Safety data 
will be summarized using the SAS according to the treatment received.

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9. 3. 4
D ose -li miti n g t o xicit y e v al u a ble a n al ysis set
T he D L T e val ua ble a nal ysis set is a s u bset of t he Safet y a nal ysis set f or t he d ose -fi n di n g p hase 
of  t he st u d y.  It incl u des all pat ient s e nr olle d i n t he d ose-fi n di n g p hase of t he st u d y w h o recei ve 
t he pr ot oc ol-assi g ne d treat me nt wit h d ur val u ma b + tre meli m uma b a n d c o m plete t he safet y 
f oll ow- u p t hr o u g h t he D L T e val uat i on peri o d ( C y cle 1 + C ycle 2) or e x perie nce a D L T d uri n g 
t he D L T e val uati o n peri o d. 
9. 3. 5
P h ar m ac o ki netic a n al ysis set
All patie nts w h o recei ve at least 1 d ose of I P per t he pr ot oc ol f or w h o m a n y p ost dose data are 
a vaila ble a n d w h o d o n ot vi o late or de viate fr o m t he pr ot oc ol i n wa ys t hat w o ul d si g nifica nt l y 
affect t he P K a nal yses will be i ncl u de d i n t he P K a nal ysis set.  T he p o p ulati o n will be defi ne d b y 
t he St u d y P h ysicia n, P har mac o ki neticist, a n d Stat isticia n pri or t o a n y a nal yses bei n g perf or me d.
9. 3. 6
Ot her a n al ysis sets
Ot her a nal ysis sets, s uc h as 
, ma y be defi ne d if 
dee m e d necessar y.  T hese will be s u bsets of t he S A S a n d will i ncl u de patient s w h o pr o vi de d 
s ufficie nt data f or i ncl usi o n i n t he c orres p o n di n g a nal yses.  M ore details will be pr o vi de d i n t he 
S A P.
9. 4
O u tc o me me as ures f or a n al yses
9. 4. 1
C alc ul ati o n or deri v ati o n of effic ac y v ari a bles
9. 4. 1. 1
R E CI S T 1. 1 a n d I N R C -b ase d e n d p oi nts
T he a nal ysis of t he pri mar y  e n d p oi nt, O R R, a n d t he a nal yses of t he sec o n dar y e n d p oi nts, P F S, 
D o R, a n d D C R, will be base d o n t he site I n vest i gat or assess me nts usi n g R E CI S T 1. 1 f or s oli d 
t u mors (A p pe n di x E )a n d I N R C f or N B (A p pe n di x F ).  I n a d ditio n, O S, a n ot her sec o n dar y  
e n d p o i nt, will als o be e val uate d. 
I n vesti g at or R E CI S T 1. 1 a n d I N R C-b a se d assess me nts
All R E CI S T 1. 1 ( or I N R C) assess me nts, w het her sc he d ule d or u nsc he d ule d, will be i ncl u de d i n 
t he calc ulat i ons.  T his is als o re gar dless of w het her a patie nt disc o nt i n ues st u d y treat me nt or 
recei ves a n ot her a ntica ncer t hera p y. 
At  eac h visit, pati e nts will be pr o gra m mat icall y assig ne d a R E CI S T 1. 1 (A p pe n di x E ) visit 
res p o nse of c om p lete res p o nse ( C R), P R, S D, or P D de pe n di n g o n t he stat us of t heir disease 
c o mpare d wi t h baseli ne a n d pre vi o us assess me nts.  Baseli ne will be assesse d wit hi n t he 2 1 da ys 
pri or t o fi rst d ose.  If a patie nt has ha d a t u mor assess me nt t hat ca n n ot be e val uate d, t he n t he 
pati e nt will be assi g ne d a visit res p o nse of N E ( u nless t here is e vi de nce o f pr o gressi o n i n w hic h 
case t he res p o nse will be assi g ne d as P D).  T he c orres p o n di n g criteria f or  A p pe n di x F f or N B.
P r o gressi o n-free s ur vi val a n d O R R b y ir R E CI S T criteria will als o be perf or me d f or e x pl orat or y 
p ur p oses o nl y.
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9.4.1.2
Primary endpoint: Objective response rate
Objective response rate (per RECIST 1.1or INRC, using Investigator assessments) is defined as 
the percentage of patients with at least 1 visit response of CR or PR that is subsequently 
confirmed on another scan not less than 4 weeks after visit observed response.  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.
9.4.1.3
Progression-free survival 
Progression-free survival (per RECIST 1.1or INRC, as assessed by the site Investigator) will be 
defined as the time from the date of first dose of IP until the date of objective disease progression 
or death (by any cause in the absence of progression) regardless of whether the patient withdraws 
from therapy or receives another anticancer therapy prior to progression (ie, date of event or 
censoring – date of first dose of IP + 1).  Patients who have not progressed or died at the time of 
analysis will be censored at the time of the latest date of assessment from their last evaluable 
RECIST 1.1 (or INRC) assessment.  However, if the patient progresses or dies after 2 or more 
missed visits, the patient will be censored at the time of the latest evaluable RECIST 1.1 (or 
INRC) assessment prior to the 2 missed visits.  If the patient has no evaluable visits or does not 
have baseline data, they will be censored at Day 1 unless they die within 2 visits of baseline, then 
they will be treated as an event with date of death as the event date.
The PFS time will always be derived based on scan/assessment dates and not visit dates.
RECIST 1.1 (or INRC) assessments/scans contributing towards a particular visit may be 
performed on different dates.  The following rules will be applied:

For Investigator assessments, the date of progression will be determined based on the 
earliest of the RECIST 1.1 (or lymphoma criteria or INRC) assessment/scan dates of 
the component that indicates progression.

When censoring a patient for PFS, the patient will be censored at the latest of the 
assessment/scan dates contributing to a particular overall visit assessment.
Additionally, PFS will also be assessed using irRECIST data for exploratory purposes only.
9.4.1.4
Overall survival
Overall survival is defined as the time from the date of first dose of IP until death due to any 
cause.  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. 
Note: Survival calls will be made following the date of DCO for the analysis (these contacts 
should generally occur within 7 days of the DCO).  If patients are confirmed to be alive or if the 
death date is post the DCO date, these patients will be censored at the date of DCO.  Death dates 
may be found by checking publicly available death registries.

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9.4.1.5
Duration of response
Duration of response (per RECIST 1.1,or INRC, using Investigator assessment) will be defined 
as the time from the date of first documented response (which is subsequently confirmed) until 
the first date of documented progression or death in the absence of disease progression (ie, date 
of PFS event or censoring - date of first response + 1).  The end of response should coincide with 
the date of progression or death from any cause used for the RECIST 1.1 (or INRC) PFS 
endpoint. 
The time of the initial response will be defined as the latest of the dates contributing towards the 
first visit response of CR or PR.  If a patient does not progress following a response, then their 
DoR will be censored at the PFS censoring time.  Duration of response will not be defined for 
those patients who do not have documented response.
9.4.1.6
Best objective response
Best objective response (BoR) is calculated based on the overall visit responses from each 
RECIST 1.1 (or INRC) assessment.  It is the best response a patient has had during their time in 
the study up until RECIST 1.1 (or INRC) progression or the last evaluable assessment in the 
absence of RECIST 1.1 (or lymphoma criteria or INRC) progression.
Categorization of BoR for solid tumors will be based on RECIST 1.1 (Appendix E) using the 
following response categories: CR, PR, SD, PD, and NE.  
For NB, the categories will be based on INRC (Appendix F) and they are CR, PR, minor 
response (MR), SD, PD, and NE (applicable for the dose-finding phase only).
Complete response or PR must be confirmed.  Best objective response will be determined 
programmatically based on RECIST 1.1 (or lymphoma criteria or INRC) using all Investigator 
assessments up until the first progression event.  For patients whose progression event is death, 
BoR will be calculated based upon all evaluable RECIST 1.1 (or INRC) assessments prior to 
death.
For patients who die with no evaluable RECIST 1.1 (or INRC) assessments, if the death occurs 
≤119 days (ie, 2 × 8 weeks + 7 days) after first dose of IP, then BoR will be assigned to the 
progression (PD) category.  For patients who die with no evaluable RECIST 1.1 (or INRC) 
assessments, if the death occurs >119 days (ie, 2 × 8 weeks + 7 days) after the date of first dose 
of IP, then BoR will be assigned to the NE category. 
Progression events that have been censored due to them being >119 days after the last evaluable 
assessment will not contribute to the BoR derivation.
9.4.1.7
Disease control rate
Disease control rate at 16 or 24 weeks will be defined as the proportion of patients who achieve 
best response of CR or PR, respectively, or who have SD for at least 16 weeks −7 days or 24 
weeks - 7 days, respectively, after start of treatment.  

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9.4.1.8
Proportion alive and progression free at 12 and 18 months
Proportion of patients alive and progression-free at 12 months from first dose will be defined as 
the Kaplan-Meier (KM) estimate of PFS (per RECIST 1.1) at 12 months.  Similarly, APF18 will 
be defined as KM estimate of PFS (per RECIST 1.1) at 18 months.
9.4.1.9
Overall survival at 12 and 24 months
OS12 will be defined as KM estimate of OS at 12 months.  Similarly, OS24 will be defined as 
KM estimate of OS at 24 months.
9.4.2
Calculation or derivation of safety variables
9.4.2.1
Adverse events
Safety and tolerability will be assessed in terms of AEs (including SAEs), deaths, laboratory 
data, vital signs, ECGs, physical examinations and exposure.  These will be collected for all 
patients.  Data from all cycles of treatment will be combined in the presentation of safety data.  
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.
Adverse events observed up until 90 days following discontinuation of the immunotherapy 
agents (ie, the last dose of durvalumab, tremelimumab or durvalumab + tremelimumab) or until 
the initiation of the first subsequent therapy following discontinuation of treatment (whichever 
occurs first) will be used for the reporting of the AE summary tables.  This will more accurately 
depict AEs attributable to study treatment only as a number of AEs up to 90 days following 
discontinuation of the immunotherapy agents are likely to be attributable to subsequent therapy.  
However, to assess the longer term toxicity profile, AE summaries will also be produced 
containing AEs observed up until 90 days following discontinuation of the immunotherapy 
agents (ie, without taking subsequent therapy into account).  Any events in this period that occur 
after a patient has received further therapy for cancer (following discontinuation of study 
treatment) will be flagged in the data listings. 
The SAS will be used for reporting of safety data.
A separate data listing of AEs occurring more than 90 days after discontinuation of IP will be 
produced.  These events will not be included in AE summaries.
9.4.2.2
Safety assessments
For the change from baseline summaries for vital signs, laboratory data, ECGs and physical 
examinations, the baseline value will be the latest result obtained prior to the start of study 
treatment. 
QTcF will be derived during creation of the reporting database using the reported ECG values 
(RR and QT) using the following formula:
QTcF = QT/RR^ (1/3) where RR is in seconds

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Efficacy data will be summarized and analyzed based on the FAS and, where appropriate, on the 
evaluable for response analysis set. 
Results of all statistical analyses will be presented using a 90% CI, unless otherwise stated. 
The primary analysis cut off will be defined at approximately 6 months after enrollment of the 
last patient.  At this point, data analysis will be performed and the CSR will be written.  After 
this, patients still in the study will continue to be followed and a CSR addendum may be issued 
for OS and safety data collection.
The following table (Table 23) presents the analyses planned for the efficacy endpoints.  All 
tumor-related endpoints will be analyzed using Investigator RECIST 1.1 assessments.
Table 23
Pre-planned statistical analyses to be conducted
Endpoints analyzed
Notes
Objective response rate
Exact 90% 2-sided CI (Mid-P) 
Duration of response 
Median estimated from KM curve
Disease control rate 
Exact 90% 2-sided CI (Mid-P)
Best objective response 
n (%) of patients in each response category
Progression-free survival 
Median estimated from KM curve 
Overall survival
Median estimated from KM curve
Proportion alive and 
progression-free at 12 months
90% 2-sided CI estimated from KM curve
Proportion alive and 
progression-free at 18 months
90% 2-sided CI estimated from KM curve
Proportion alive at 12 months
90% 2-sided CI estimated from KM curve
Proportion alive at 24 months 
90% 2-sided CI estimated from KM curve
CI Confidence interval; KM Kaplan-Meier.
9.5.1.1
Primary endpoint: objective response rate
The ORR will be based on the programmatically derived RECIST 1.1 (or INRC) using the 
Investigator tumor data.  The point estimate and 90% CI (2-sided) of the ORR will be presented.  
The CI will be calculated using an exact Mid-P method.  This analysis will be performed on the 
evaluable for response analysis set. 
Summaries will be produced that present the number and percentage of patients with a tumor 
response (CR/PR).
Sensitivity analysis will be performed for tumor response (CR/PR) on FAS and "unconfirmed 
CR/PR" on evaluable for response analysis set.

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CONFIDENTIAL AND PROPRIETARY
Objective response rate by irRECIST criteria will be presented as described above for 
exploratory purposes only.
9.5.1.2
Duration of response
Kaplan-Meier plots of DoR based on programmatically derived RECIST 1.1 (or INRC) 
responses using the Investigator tumor assessments will be presented.  The median DoR will also 
be summarized calculated from the KM curve.  Only patients who have a confirmed response 
will be included in this summary table.
9.5.1.3
Disease control rate
For DCR, the point estimate and 90% CI (2-sided) will be presented.  The CI will be calculated 
using an exact Mid-P method.
Sensitivity analysis will be performed for tumor response (CR/PR) on FAS and "unconfirmed 
CR/PR" on evaluable for response analysis set.
9.5.1.4
Best objective response
Overall visit response data will be listed for all patients (ie, the FAS).  For each cohort (and each 
DL within cohort in the dose-finding phase), BoR will be summarized by n (%) for each 
category (CR, PR, SD, PD, and NE or INRC categories).  No formal statistical analyses are 
planned for BoR.
9.5.1.5
Progression-free survival
Progression-free survival will be summarized using the KM curve, from which the median PFS 
will be estimated.  In addition, KM plots will be presented.  Summaries of the number of 
percentage of patients experiencing a PFS event and the type of event (RECIST 1.1 , INRC or 
death) will also be provided.  The analysis will be performed on the FAS.
Progression-free survival by irRECIST criteria will be presented as described above for 
exploratory purposes only.
9.5.1.6
Overall survival
Kaplan-Meier plots as well as summaries of the number and percentage of patients who have 
died, those still in survival follow-up, those lost to follow-up, and those who have withdrawn 
consent will be provided along with the median OS for each cohort (and DL within cohort where 
applicable).
9.5.1.7
Proportion alive and progression-free at 12 and 18 months
The proportion of patients alive and progression-free at 12 months, APF12, and its 90% CI will 
be summarized (using the KM curve) and presented by cohort.
The proportion of patients alive and progression-free at 18 months, APF18, will be summarized 
as APF12.

Cli nical St u d y Pr ot oc ol - 6. 0
Astra Ze neca
D ur val u ma b a n d tre meli m u ma b
C O N FI D E N TI A L A N D P R O P RI E T A R Y
9. 5. 6
Bi o m ar ker d at a
Vacci ne a nt i b o d y titer data will be liste d b y patient . 
9. 5. 7
Met h o ds f or m ulti pli cit y c o ntr ol
N ot a p plica ble f or t his st u d y .
9. 6
I nteri m a n al yses 
N o f or m al int eri m a nal ysis f or efficac y is pla n ne d f or t his st u d y.  H o we ver, O R R will be 
e val uate d o n a n o n g oi n g basis f or t he first 1 1 e val ua ble pat ient s i n t he S A R C O M A c o h ort t o 
c o mplete Sta ge 1 of t he Si m o n 2 -sta ge o pti mal desi g n (see Secti o n 4. 1. 4).
9. 6. 1
D at a Re vie w C o m mittee
A D R C will be esta blis he d pri or t o t he i nit iati on of t he st u d y  a n d will re vie w t he safety a n d P K 
data.  T he D R C me m bers hi p will c o m pr ise of partici pat i n g I n vesti gat ors a n d represe ntati ves 
fr om b ot h Astra Ze neca ( P har mac o vi gila nce Scie ntists f or d ur val u ma b a n d tre meli m u ma b, P K 
S ci e nt ist, St u d y P h ysicia n a n d Bi ost atisticia n) a n d I Q VI A ( St u d y P h ysicia n, Safety P h ysicia n 
a n d Bi ostatisticia n).  O n a case- b y- case basis, t he D R C ma y a ls o see k a d vice fr o m pe diatric 
o nc ol o gi sts wit h t he re q uire d site s pecializati on e x perti se. 
W o r ki n g r ules, i ncl u di n g t he ti mi n g of pla n ne d meeti n gs, will be descri be d i n t he D R C c harter.  
I n s u m mar y, rec o m me n dati ons a n d decisi o ns will be ma de t hr o u g h c o ns e ns us of o pi ni o n 
a mo n gst t he D R C m e m bers wit h all decisio n s bei n g d oc u me nte d a n d distri b ute d t o D R C 
me m bers.  A d dit i onall y, ‘a d-h oc’ D R C meet i n gs ma y be c o n ve ne d, if re q uire d, a n y time d uri n g 
t he c o n d uct of t he st u d y.
T he ke y  tas ks of t he D R C me m bers will be t o re vie w t he data rec or de d i n t he cli nical data base i n 
c o nju nct i on wi t h t he P K data t o:
1.
Deter mi ne w het her D L Ts ha ve occ urre d
2.
Deci de w het her a d dit i on al  patient s s h o ul d be a d de d t o a c o h ort
3.
Rec o m me n d de -escalat i n g a d ose t hat was p o orl y t olerate d or escalat i n g a d ose if P K 
e x p os ures i nferi or t o t h ose o bser ve d i n a d ults, were ac hie ve d
4.
Declare t hat d ose fi n di n g is c o m plete
C CI

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
5.
Recommended a RP2D to be explored in the dose-expansion phase of the study
6.
Perform a benefit/risk assessment at the completion of safety data analysis for children 
<1 year old prior to enrolling a patient less than 1 year old; notify local health 
authority of decision, if applicable, as per local requirements
7.
Put enrollment on hold
8.
End the study.
During the dose-expansion phase, the DRC will review safety, tolerability, PK, and efficacy data 
to make consensual decisions on cohort expansion or closure, and end the study, among others.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
10.
REFERENCES
Alexandrov et al 2013
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures 
of mutational processes in human cancer. Nature 2013;500:415-21.
Ansell et al 2015
Ansell SM, Lesokhin AM, Borrello I, Halwani A, Scott EC, Gutierrez M, et al. PD-1 blockade 
with nivolumab in relapsed or refractory Hodgkin's lymphoma. N Engl J Med. 2015;372:311-9.
Boutros et al 2016
Boutros C, Tarhini A, Routier E, Lambotte O, Ladurie FL, Carbonnel F, et al. Safety profiles of 
anti-CTLA-4 and anti-PD-1 antibodies alone and in combination. Nat Rev Clin Oncol. 
2016;13:473-86.
Brahmer et al 2012
Brahmer JR, Tykodi SS, Chow LQ, Hwu WJ, Topalian SL, Hwu P, et al. Safety and activity of 
anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 2012;366:2455-65.
Curran et al 2010
Curran MA, Montalvo W, Yagita H, Allison JP. PD-1 and CTLA-4 combination blockade 
expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma 
tumors. Proc Natl Acad Sci USA 2010;107:4275-80.
Del Castillo et al 2016
Del Castillo M, Romero FA, Esther Argüello E, Kyi C, Postow MA, Redelman-Sidi G. The 
spectrum of serious infections among patients receiving immune checkpoint blockade for the 
treatment of melanoma. Clin Infect Dis. 2016;63:1490-3.
Davis et al 2017
Davis KL, Fox E, Reid JM, Liu X, Minard CG, Weigel B, et al. ADVL1412: Initial results of a 
phase I/II study of nivolumab and ipilimumab in pediatric patients with relapsed/refractory solid 
tumors – A COG study. J Clin Oncol 2017;35(suppl): abstr 10526. 
Dyck and Mills 2017
Dyck L, Mills KHG, Immune checkpoints and their inhibition in cancer and infectious diseases, 
Eur J Immunol. 2017;47:765-79.
Dunn et al 2004
Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol 
2004;22:329-60.
Fife and Bluestone 2008
Fife BT, Bluestone JA. Control of peripheral T-cell tolerance and autoimmunity via the CTLA-4 
and PD-1 pathways. Immunol Rev 2008;224:166-82.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Geoerger et al 2017a
Geoerger B, Kang HJ, Yalon-Oren M, Marshall LV, Vezina C, Pappo AS, et al. Phase 1/2 
Keynote-051 study of pembrolizumab (pembro) in pediatric patients (pts) with advanced 
melanoma of a PD-L1 + advanced, relapsed, or refractory solid tumor or lymphoma. J Clin 
Oncol. 2017;35(Suppl):abstr 10525.
Geoerger et al 2017b
Geoerger B, Karski EE, Zwaan CM, Casanova M, Marshall LV, DuBois SG, et al. A phase I/II 
study of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors 
(iMATRIX-Atezolizumab). J Clin Oncol. 2017;35(Suppl):abstr 10524.
Hamanishi et al 2007
Hamanishi J, Mandai M, Iwasaki M, Okazaki T, Tanaka Y, Yamaguchi K, et al. Programmed 
cell death 1  ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of 
human ovarian cancer. Proc Natl Acad Sci USA 2007;104:3360-5.
Highfill et al 2014
Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, et al. Disruption of 
CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy. Sci Transl Med. 
2014;6:237ra67.
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 
2005;65:1089-96.
Howie 2011
Howie SRC. Blood sample volumes in child health research: review of safe limits. Bull World 
Health Organ 2011;89(1):46–53. Available from: URL: 
http://www.ncbi.nim.gov/pubmed/21346890.
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.
Johnpulle et al 2016
Johnpulle RA, Conry RM, Sosman JA, Puzanov I, Johnson DB. Responses to immune 
checkpoint inhibitors in nonagenarians. Oncoimmunology. 2016;5:e1234572.
Keir et al 2008
Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. 
Annu Rev Immunol 2008;26:677-704.

Clinical Study Protocol - 6.0
AstraZeneca
Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Krambeck et al 2007
Krambeck AE, Dong H, Thompson RH, Kuntz SM, Lohse CM, Leibovich BC, et al. Survivin 
and b7-h1 are collaborative predictors of survival and represent potential therapeutic targets for 
patients with renal cell carcinoma. Clin Cancer Res 2007;13:1749-56.
Kumar et al 2017
Kumar V, Chaudhary N, Garg M, Floudas CS, Soni P and Chandra AB. Current diagnosis and 
management of immune related adverse events (irAEs) Induced by immune checkpoint inhibitor 
therapy. Front Pharmacol. 2017;8:49.
Kyi et al 2014
Kyi C, Hellmann MD, Wolchok JD, Chapman PB, Postow MA. Opportunistic infections in 
patients treated with immunotherapy for cancer. J Immunother Cancer. 2014;2:19.
Larkin et al 2015
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, et al. Combined 
nivolumab and ipilimumab or monotherapy in untreated melanoma. N Engl J Med 
2015;373:23-34.
Loos et al 2008
Loos M, Giese NA, Kleeff J, Giese T, Gaida MM, Bergmann F, et al. Clinical significance and 
regulation of the costimulatory molecule B7-H1 in pancreatic cancer. Cancer Letters 
2008;268:98-109.
Marabelle et al 2015
Marabelle A, Gray J. Tumor-targeted and immune-targeted monoclonal antibodies: Going from 
passive to active immunotherapy. Pediatr Blood & Cancer 2015;62:1317–25.
Merchant et al 2016
Merchant MS, Wright M, Baird K, Wexler LH, Rodriguez-Galindo C, Bernstein D, et al. Phase I 
Clinical Trial of Ipilimumab in Pediatric Patients with Advanced Solid Tumors. Clin Cancer Res. 
2016;15;22:1364-70.
Metro et al 2017
Metro G, Ricciuti B, Brambilla M, Baglivo S, Soli I, Minenza E, et al. The safety of nivolumab 
for the treatment of advanced non-small cell lung cancer. Expert Opin Drug Saf. 
2017;16:101-109.
Mu et al 2011
Mu CY, Huang A, Chen Y, Chen C, Zhang XG. High expression of PD-L1 in lung cancer may 
contribute to poor prognosis and tumor cells immune escape through suppressing tumor 
infiltrating dendritic cell maturation. Med Oncol 2011;28:682-8.
Nomi et al 2007
Nomi T, Sho M, Akahori T, Hamada K, Kubo A, Kanehiro H, et al. Clinical significance and 
therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human 
pancreatic cancer. Clin Cancer Res 2007;13:2151-7.

Clinical Study Protocol - 6.0
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Okazaki and Honjo 2007
Okazaki T, Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application. Int Immunol 
2007;19:813-24.
Okudaira et al 2009
Okudaira K, Hokari R, Tsuzuki Y, Okada Y, Komoto S, Watanabe C, et al. Blockade of B7-H1 
or B7-DC induces an antitumor effect in a mouse pancreatic cancer model. Int J Oncol 
2009;35:741-9.
Pages et al 2010
Pages F, Galon J, Dieu-Nosjean MC, Tartour E, Sautes-Fridman C, Fridman WH. Immune 
infiltration in human tumours: a prognostic factor that should not be ignored. Oncogene 
2010;29:1093-102.
Pardoll 2012
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 
2012;12:252-64.
Postow et al 2015
Postow MA, Chesney J, Pavlick AC, Robert C, Grossmann K, McDermott D, et al. Nivolumab 
and ipilimumab versus ipilimumab in untreated melanoma. N Engl J Med 2015;372:2006-17.
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;515:558-62.
Qin et al 2016
Qin A, Coffey DG, Warren EH, Ramnath N. Mechanisms of immune evasion and current status 
of checkpoint inhibitors in non-small cell lung cancer. Cancer Med 2016;5:2567-78.
Ramelyte et al 2017
Ramelyte E, Schindler SA, Dummer R. The safety of anti PD-1 therapeutics for the treatment of 
melanoma. Expert Opin Drug Saf. 2017;16:41-53.
Rizvi et al 2015
Rizvi NA, Brahmer JR, Ou S-HJ, Segal NH, Khleif S, Hwu W-J. Safety and clinical activity of 
MEDI4736, an anti-programmed cell death-ligand-1 (PD-L1) antibody, in patients with nonsmall 
cell lung cancer (NSCLC). J Clin Oncol 2015;33:Abstract 8032.
Rossille et al 2014
Rossille D, Gressier M, Damotte D, Maucort-Boulch D, Pangault C, Semana G, et al. High level 
of soluble programmed cell death ligand 1 in blood impacts overall survival in aggressive diffuse 
large B-Cell lymphoma: results from a French multicenter clinical trial. Leukemia. 
2014;28:2367-75.

Clinical Study Protocol - 6.0
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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
Schadendorf et al 2013
Schadendorf D, Hodi FS, Robert C, et al. Pooled analysis of long-term survival data from phase 
II and phase III trials of ipilimumab in metastatic or locally advanced, unresectable melanoma 
[abstract 24]. Presented at European Cancer Congress 2013 (ECCO-ESMO-ESTRO); 
27 September to 01 October 2013; Amsterdam, The Netherlands. 
Segal et al 2015
Segal NH, Ou S-HI, Balmanoukian AS, Fury MG, Massarelli E, Brahmer JR, et al. Safety and 
efficacy of MEDI4736, an anti-PD-L1 antibody, in patients from a squamous cell carcinoma of 
the head and neck (SCCHN) expansion cohort. J Clin Oncol 2015;33:Abstract 3011.
Shen et al 2014
Shen JK, Cote GM, Choy E, Hornicek FJ, and Duan Z. Targeting programmed cell death ligand 
1 in osteosarcoma: an auto-commentary on therapeutic potential. Oncoimmunology. 
2014;3:e954467.
SIOPE briefing, 2015
Why children and adolescents with cancer are still missing out on potentially life-saving 
treatments, despite the Paediatric Regulation SIOPE Briefing Addressed to Members of the 
European Parliament ENVI Committee June 16th 2015. Available at: SIOPE: 
http://www.siope.eu/wpcontent/uploads/2013/06/SIOPE_briefing_Paediatric_Regulation_June_2
015.pdf.  Accessed 13 April 2017.
Stewart et al 2015
Stewart R, Morrow M, Hammond SA, Mulgrew K, Marcus D, Poon E, et al. Identification and 
characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer 
Immunol Res 2015;3:1052-62.
Tarhini and Kirkwood 2008
Tarhini AA, Kirkwood JM. Tremelimumab (CP-675,206): a fully human anticytotoxic 
T lymphocyte-associated antigen 4 monoclonal antibody for treatment of patients with advanced 
cancers. Expert Opin Biol Ther 2008;8:1583-93.
Thompson et al 2005
Thompson RH, Gillet MD, Cheville JC, Lohse CM, Dong H, Webster WS, et al. Costimulatory 
molecule B7-H1 in primary and metastatic clear cell renal cell carcinoma. Cancer 
2005;104:2084-91.
Thompson et al 2006
Thompson RH, Kuntz SM, Leibovich BC, Dong H, Lohse CM, Webster WS, et al. Tumor 
B7-H1 is associated with poor prognosis in renal cell carcinoma patients with long-term follow-
up. Cancer Res 2006;66:3381-5.
Topalian et al 2012
Topalian SL, Hodi FS, Brahmer JR, Gettinger SN, Smith DC, McDermott DF, et al. Safety, 
activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 
2012;366:2443-54.

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CONFIDENTIAL AND PROPRIETARY
Wang et al 2010
Wang L, Ma Q, Chen X, Guo K, Li J, Zhang M. Clinical significance of B7-H1 and B7-1 
expressions in pancreatic carcinoma. World J Surg 2010;34:1059-65.
Weber et al 2012
Weber JS, Kahler KC, and Hauschild A Management of immune-related adverse events and 
kinetics of response with ipilimumab. J Clin Oncol 30:2691-7.
Zhang et al 2008
Zhang C, Wu S, Xue X, Li M, Qin X, Li W, et al. Anti-tumor immunotherapy by blockade of the 
PD-1/PD-L1 pathway with recombinant human PD-1-IgV. Cytotherapy 2008;10:711-9.
Zheng et al 2015
Zheng W, Xiao H, Liu H, and Zhou Y. Expression of programmed death 1 is correlated with 
progression of osteosarcoma. APMIS 2015;123:102-7.

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Durvalumab and tremelimumab
CONFIDENTIAL AND PROPRIETARY
11.
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS

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 4 1 9ec 0 0 0 0 1-cs p- v 6
D oc u me nt Title:
D 4 1 9 E C 0 0 0 0 1 Cli nical St u d y Pr ot oc ol versi o n 6
D oc u me nt I D:
Versi o n L a bel:
7. 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
1 5- Dec- 2 0 2 2 1 2: 0 5 U T C
A ut h or A p pr o val
1 5- Dec- 2 0 2 2 1 2: 2 8 U T C
C o nte nt A p pr o val
1 5- Dec- 2 0 2 2 1 4: 5 2 U T C
C o nte nt A p pr o val
1 5- Dec- 2 0 2 2 1 4: 1 4 U T C
C o nte nt A p pr o val
C CI
C CI
P P D
P P D
P P D
P P D