Multicenter Phase II Trial of Durvalumab (MEDI4736) With Trastuzumab and Pertuzumab Combination in HER2-Enriched and HER2-Amplified Breast Cancer (DTP Trial)
Phase: PHASE2
Conditions: Breast Cancer
Sponsor: The Methodist Hospital Research Institute

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 1 of 109 
  
Investigational Drug  
Durvalumab (MEDI4736) 
AZ Study Number 
ESR-18-13489; 
v4_12Nov18 
HMRI Version  
Number 
14.0 
HMRI Date 
September 10, 2024 
IRB Number 
Pro00020917 
IND Number 
Exempt 
 
 
Multicenter Phase II Trial of Durvalumab (MEDI4736) with Trastuzumab 
and Pertuzumab Combination in HER2-Enriched and HER2-Amplified 
Breast Cancer (DTP Trial) 
 
Sponsor: Houston Methodist Cancer Center and Houston Methodist Research Institute 
PROTOCOL SYNOPSIS 
Clinical Protocol  
Study Title: Multicenter Phase II Trial of Durvalumab (MEDI4736) with Trastuzumab and 
Pertuzumab  
Combination in HER2-Enriched and HER2-Amplified Breast Cancer (DTP Trial) 
Protocol Number: PRO00020917 
Clinical Phase: II 
Study Duration: 36 months 

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 2 of 109 
  
Study Treatment: 
Durvalumab (MEDI4736) will be supplied as a 500-mg vial solution for infusion after dilution. 
Trastuzumab is supplied as 420 mg multiple-dose or 150 mg single-dose vials for IV administration.  
Pertuzumab is supplied as 420 mg/14 mL (30 mg/mL) single-dose vials for IV administration. 
Research Hypothesis: 
A more selected patient population with highly human epidermal growth factor receptor 2 
(HER2)dependent breast cancer and the addition of durvalumab will increase the pathological response 
(pCR, RCB 0 and RCB 1) rate of neoadjuvant dual HER2 blockade (without chemotherapy).  
Objectives:  
Primary Objective: 
1. Determination of the pathologic response rate [residual cancer burden (RCB)- 0, and RCB 1] in the 
breast of durvalumab with trastuzumab and pertuzumab combination in patients with HER2-enriched 
and HER2-amplified breast cancer. 
Secondary Objectives: 
1. 
Estimation of the RCB 0 and RCB 1 rate in the breast of durvalumab with trastuzumab and 
pertuzumab combination in patients whose tumors have <5% and ≥5% tumor-infiltrating lymphocytes 
(TILs). 
2. 
Estimation of the RCB 0 and RCB 1 rate in the breast of durvalumab with trastuzumab and 
pertuzumab combination in patients with PD-L1−positive (≥1% tumor or stroma) and PD-L1−negative 
tumors (<1% tumor or stroma). 
3. 
Determination of the 3-year disease-free survival (DFS) rate of durvalumab with trastuzumab 
and pertuzumab combination in patients with HER2-enriched and HER2-amplified breast cancer (only 
for patients who achieve RCB 0 and RCB 1). 
4. 
Determination of the safety and toxicity of durvalumab with trastuzumab and pertuzumab 
combination in patients with HER2-enriched and HER2-amplified breast cancer, as assessed by the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v5. 
Exploratory Objective: 
− 
 Evaluation of the correlative molecular and genetic biomarkers of response and resistance to 
durvalumab with trastuzumab and pertuzumab combination in patients with HER2-enriched and 
HER2amplified breast cancer. 
 

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 3 of 109 
  
Study Design: 
This is a multicenter Phase II study evaluating the efficacy and safety of durvalumab with trastuzumab 
and pertuzumab combination in patients with HER2-enriched and HER2-amplified breast cancer. The 
primary endpoint will be the RCB 0 and RCB 1 rate in the breast of durvalumab with trastuzumab and 
pertuzumab combination. The study will be conducted using a Simon’s optimal two-stage design, and 
approximately 39 patients will be enrolled. Trastuzumab, pertuzumab, and durvalumab will be 
administered for 6 21-day cycles.  
Patients will undergo breast MRI and biopsy after completion of 6 cycles of neoadjuvant therapy. 
Patients who have been determined based on biopsy to have achieved RCB 0 and RCB 1 will undergo 
surgery (within 30 days of the final dose of study treatment). Following surgery, RCB 0 and RCB 1  
patients will continue to receive the combination of trastuzumab, pertuzumab, and durvalumab plus 
standard-of-care treatment to complete 1 year. Patients who have been determined based on biopsy to 
not have achieved RCB 0 and RCB 1 will undergo continued neoadjuvant treatment with targeted 
therapy and chemotherapy per physician’s choice. Correlative studies will include tissue and blood-
based molecular and genetic biomarkers of response and resistance to the regimen. 
Number of Centers: 1 
(1) Houston Methodist Hospital TMC 
Number of Patients: 39 
Study Population: Female patients aged ≥18 years with HER2-enriched and HER-amplified breast 
cancer. 
 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date 1 0 Se pte m ber 2 0 2 4 
Pa ge 4  of 1 0 9 
  
I ncl usi o n Criteri a: 
1.  
Ca pa ble of gi vi n g si g ne d i nf or me d c o nse nt w hic h i ncl u des c o m plia nce wit h t he re q uire me nts 
a n d restricti o ns liste d i n t he i nf or me d c o nse nt f or m a n d i n t his pr ot oc ol. Writte n i nf or me d c o nse nt a n d 
a n y l ocall y re q uire d a ut h orizati o n (e. g., Healt h I ns ura nce P orta bilit y a n d Acc o u nta bilit y Act) w ill be 
o btai ne d fr o m t he patie nt/le gal re prese ntati ve pri or t o perf or mi n g a n y pr ot oc ol-relate d pr oce d ures, 
i ncl u di n g scree ni n g e val uati o ns. 
2.  
Fe male a ge d > 1 8 years at t he ti me of st u d y e ntr y.  
3.  
Hist ol o gicall y c o nfir me d H E R 2 -e nric he d ( b y Ma m ma pri nt/ Bl ue Pri nt) a n d H E R 2-a m plifie d 
(E R B B 2  m R N A > 7. 5 - 1 0)5 7 H E R 2 o vere x pressi n g breast ca ncer.  
4.  
Estr o ge n rece pt or ( E R) a n d pr o gester o ne rece pt or ne gati ve ( E R a n d pr o gester o ne rece pt or 
ne gati vit y are defi ne d as ≤1 0 % I H C stai ni n g).  
5.  
Pri mar y t u m or greater t ha n 1 c m dia meter, meas ure d b y cli nical e xa mi nati o n a n d 
ma m m o gra p h y or ec h o gra p h y,  
6.  
A n y n o dal stat us  
7.  
Bilateral breast ca ncers t hat i n di vi d uall y meet eli gi bilit y criteria are all o we d.  
8.  
Easter n C o o perati ve O nc ol o g y Gr o u p ( E C O G) perf or ma nce stat us of 0 or 1.  
9.  
Life e x pecta nc y > 6 m o nt hs.  
1 0.  
A de q uate or ga n a n d marr o w f u ncti o n as defi ne d bel o w:  
 He m o gl o bi n ≥1 0. 0 g/ d L wit h n o bl o o d tra nsf usi o n i n t he past 2 8 da ys  
 A bs ol ute ne utr o p hil c o u nt ≥1. 5 × 1 0 9/ L 
 Platelet c o u nt ≥1 0 0 × 1 0 9/ L 
 Ser u m t otal bilir u bi n ≤1 × i nstit uti o nal u p per li mit of n or mal ( U L N; I n t he case of 
k n o w n Gil bert's s y n dr o me, a hi g her ser u m t otal bilir u bi n [ < 1. 5 × U L N] is all o we d),  
 As partate tra nsa mi nase/ala ni ne tra nsa mi nase ≤2. 5 × i nstit uti o nal U L N  
 Al kali ne p h os p hatase ≤1. 5 × i nstit uti o nal U L N  
 Creati ni ne ≤1. 5 m g/ d L  
1 1.  
Baseli ne left ve ntric ular ejecti o n fracti o n ≥5 0 %, as meas ure d b y m ulti gate d ac q uisiti o n 
( M U G A) sca n or ec h ocar di o gra m ( E C H O). 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date 1 0 Se pte m ber 2 0 2 4 
Pa ge 5  of 1 0 9 
  
1 2.  
E vi de nce of p ost me n o pa usal stat us or ne gati ve ser u m pre g na nc y test f or pre me n o pa usal 
patie nts. Ne gati ve ser u m β -h u ma n c h ori o nic g o na d otr o pi n pre g na nc y test wit hi n 7 da ys pri or t o t he first 
d ose of st u d y treat me nt f or pre me n o pa usal patie nts. W o me n will be c o nsi dere d p ost me n o pa usal if t he y 
ha ve bee n a me n orr heic f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical ca use. T he f oll o wi n g a ge- s pecific 
re q uire me nts a p pl y:  
 W o me n < 5 0 years of a ge w o ul d be c o nsi dere d p ost me n o pa usal if t he y ha ve bee n 
a me n orr heic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of e x o ge n o us h or m o nal 
treat me nts a n d if t he y ha ve l utei nizi n g h or m o ne a n d f ollicle-sti m ulati n g h or m o ne  
le vels  i n  t he  p ost me n o pa usal  ra n ge  f or  t he  i nstit uti o n  or  u n der we nt  s ur gical  
sterilizati o n ( bilateral o o p h orect o m y or h ysterect o m y).  
 W o me n  ≥5 0  years  of  a ge  w o ul d  be  c o nsi dere d  p ost me n o pa usal  if  t he y  ha ve  bee n 
a me n orr heic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of all e x o ge n o us h or m o nal 
treat me nts, ha d ra diati o n-i n d uce d me n o pa use wit h last me nses > 1 year a g o, ha d 
c he m ot hera p y-i n d uce d  me n o pa use  wit h  last  me nses  > 1  year  a g o,  or  u n der we nt  
s ur gical  sterilizati o n  ( bilateral  o o p h orect o m y,  bilateral  sal pi n gect o m y,  or  
h ysterect o m y).  
1 3.  
Willi n g t o pr o vi de bi o ps y tiss ues as re q uire d b y t he st u d y.  
 Patie nt is willi n g a n d a ble t o c o m pl y wit h t he pr ot oc ol f or t he d urati o n of t he st u d y 
i ncl u di n g u n der g oi n g treat me nt a n d sc he d ule d visits a n d e xa mi nati o ns i ncl u di n g 
f oll o w- u p. 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date 1 0 Se pte m ber 2 0 2 4 
Pa ge 6  of 1 0 9 
  
 
E xcl usi o n Criteri a:  
1.  
Partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal pr o d uct wit hi n 2 8 da ys pri or t o t he 
first d ose of st u d y treat me nt. 
2.  
C o nc urre nt e nr ol me nt i n a n ot her cli nical st u d y, u nless it is a n o bser vati o nal ( n o n -i nter ve nti o nal) 
cli nical st u d y or d uri n g t he f oll o w - u p peri o d of a n i nter ve nti o nal st u d y. 
3.  
U nres ol ve d or u nsta ble a d verse e ve nts ( A Es) fr o m pri or a d mi nistrati o n of a n ot her i n vesti gati o nal 
dr u g.  
  
4.  
A n y c o nc urre nt c he m ot hera p y, ra diati o n t hera p y, i m m u n ot hera p y, or bi ol o gic t hera p y f or ca ncer 
treat me nt. 
5.  
Maj or s ur gical pr oce d ure (as defi ne d b y t he i n vesti gat or) wit hi n 2 8 da ys pri or t o t he first d ose of 
st u d y treat me nt.  
6.  
Hist or y of all o ge neic or ga n tra ns pla ntati o n.  
7.  
Acti ve or pri or d oc u me nte d a ut oi m m u ne or i nfla m mat or y dis or ders (i ncl u di n g i nfla m mat or y 
b o wel  disease  [e. g., c olitis or Cr o h n's disease], di vertic ulitis [ wit h t he  e xce pti o n  of di vertic ul osis], 
s yste mic  l u p us  er yt he mat os us,  Sarc oi d osis  s y n dr o me,  or  We ge ner  s y n dr o me  [ gra n ul o mat osis  wit h  
p ol ya n giitis,  Gra ves'  di sease,  r he u mat oi d  art hritis,  h y p o p h ysitis,  u veitis,  etc]).  T he  f oll o wi n g  are  
e xce pti o ns t o t his criteri o n: 
 Patie nts wit h vitili g o or al o pecia  
 Patie nts wit h h y p ot h yr oi dis m (e. g., f oll o wi n g Has hi m ot o s y n dr o me) sta ble o n 
h or m o ne re place me nt  
 A n y c hr o nic s ki n c o n diti o n t hat d oes n ot re q uire s yste mic t hera p y  
 Patie nts wit h o ut acti ve disease i n t he last 5 years ma y be i ncl u de d b ut o nl y after 
c o ns ultati o n wit h t he st u d y p h ysicia n 
8.  
Hist or y of acti ve pri mar y i m m u n o deficie nc y.  
9.  
Acti ve i nfecti o n i ncl u di n g t u berc ul osis  (cli nical e val uati o n t hat i ncl u des cli nical hist or y, p h ysical 
e xa m a n d ra di o gra p hic fi n di n gs, a n d t u berc ul osis testi n g i n li ne wit h l ocal practice), he patitis B ( k n o w n 
p ositi ve H B V s urface a nti ge n [ H Bs A g] res ult), he patitis C, or h u ma n i m m u n o deficie nc y vir us ( p ositi ve 
HI V 1/ 2 a nti b o dies). Patie nts wit h a past or res ol ve d H B V i nfecti o n ( defi ne d as t he prese nce of he patitis 
B c ore a nti b o d y [a nti -H Bc] a n d a bse nce of he patitis B s urface a nti ge n [ H Bs A g]) are eli gi ble. Pati e nts 
p ositi ve f or he patitis C ( H C V) a nti b o d y are eli gi ble o nl y if p ol y merase c hai n reacti o n is ne gati ve f or  
H C V R N A.  
 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date 1 0 Se pte m ber 2 0 2 4 
Pa ge 7  of 1 0 9 
  
1 0.  
C urre nt or pri or use of i m m u n os u p pressi ve me di cati o n wit hi n 1 4 d a ys pri or t o t he first 
d ose of st u d y treat me nt. T he f oll o wi n g are e xce pti o ns t o t his criteri o n: 
 I ntra nasal, i n hale d, t o pical ster oi ds, or l ocal ster oi d i njecti o ns (e. g., i ntra-artic ular 
i njecti o n) 
 S yste mic c ortic oster oi ds at p h ysi ol o gic d oses n ot t o e xcee d 1 0 m g/ da y of 
pre d nis o ne or its e q ui vale nt  
 Ster oi ds as pre me dicati o n f or h y perse nsiti vit y reacti o ns  
1 1.  
Recei pt of li ve atte n uate d vacci ne wit hi n 3 0 da ys pri or t o t he first d ose of st u d y treat me nt. N ote: 
Patie nts, if e nr olle d, s h o ul d n ot recei ve li ve vacci ne w hile recei vi n g st u d y treat me nt a n d u p t o 3 0 da ys 
after t he last d ose of st u d y treat me nt. 
1 2.  
Patie nts w h o are pre g na nt or breastfee di n g or patie nts of re pr o d ucti ve p ote ntial w h o are n ot 
willi n g t o e m pl o y effecti ve birt h c o ntr ol fr o m scree ni n g t o 7 m o nt hs after t he last d ose of st u d y treat me nt.  
1 3.  
K n o w n aller g y or h y perse nsiti vit y t o a n y of t he st u d y dr u gs or a n y of t he st u d y dr u g e xci pie nts.  
1 4.  
Patie nts wit h a mea n Q T i nter val of greater t ha n or e q ual t o 4 7 0 ms calc ul ate d fr o m 3 
E K Gs  
1 5.  
Patie nts  wit h  u n derl yi n g  car di o vas c ular  c o n diti o ns  t hat  ha ve  rece ntl y  u n der g o ne  
i nter ve nti o ns i ncl u di n g: car diac ve ntric ular arr h yt h mia re q uiri n g me dicati o n, hist or y of sec o n d 
or t hir d de gree A V bl oc ks, m y ocar dial i nfarcti o n wit h t he pre vi o us year, c o n gest i ve heart fail ure, 
a n d u nsta ble a n gi na 
1 6.  
Patie nts wit h a L V E F less t ha n 5 0 %  

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 8 of 109 
  
 
Study Treatment, Dose and Mode of Administration: 
Trastuzumab will be administered as 8 mg/kg IV loading dose, followed by 6 mg/kg IV every 3 weeks 
(Q3W). Pertuzumab will be administered as 840 mg IV loading dose, followed by 420 mg Q3W.  
Durvalumab will be administered at a fixed dose of 1120 mg IV Q3W.  
Study Assessments and Criteria for Evaluation: 
Safety Assessments: 
AEs, physical exam, vital signs, ECOG performance status, electrocardiogram, MUGA acquisition scan 
or ECHO, hematology, clinical chemistry, and thyroid-stimulating hormone. 
Efficacy Assessments: 
Responders will be defined as having: 1.) pCR (RCB 0) and 2.) RCB 0 and 1.  
Response will be analyzed according to TIL level (<5% vs. ≥5%) and programmed cell death-ligand 1 
status (positive vs. negative)  
3-year DFS rate will also be calculated.  

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 9 of 109 
  
Statistical Methods and Data Analysis: 
This Phase II trial will be conducted using a Simon’s minimax two-stage design. A null response rate of 
35% is assumed.16 The target response rate for the regimen will be 52%. When the probability of 
accepting a “bad” regimen (i.e., response rate ≤35%) is 0.10 (i.e., alpha) and the probability of rejecting 
a “good” regimen (i.e., response rate ≥52%) is 0.20 (i.e., beta or 1 – power), Simon’s minimax design 
requires 15 patients in the first stage. If 4 or fewer patients respond to the regimen, the study will be 
stopped and the regimen will be declared as ineffective. If at least 5 of the first 15 patients respond, 24 
additional patients will be entered on the study to reach a total of 39 patients. At the end of the second 
stage, the regimen will be rejected if the response rate is less than or equal to 17 out of 39 patients and 
will be accepted otherwise.  
As a measure of safety, an initial cohort of 3 patients will be followed for toxicity through the first cycle 
of trastuzumab, pertuzumab, and durvalumab. If no more than 1 of 3 patients experience toxicity, then 3 
more patients will be enrolled. If no more than 1 of 6 patients experience toxicity, then the study will be 
fully opened. Toxicity will be defined as any treatment-related death and any ≥ Grade 3 toxicity 
excluding alopecia and constitutional symptoms (as assessed by the NCI CTCAE v5). Additionally, 
toxicity after the first 6 patients will be monitored based on a beta-binomial model, assuming a priori 
that the probability of toxicity p is distributed beta (1, 1). Study accrual will be suspended and the safety 
profile of the combination will be reviewed by the safety monitoring committee if Pr  (p > .30 | data) > 
0.95. This stopping rule yields the following stopping bounds where the numerator represents the number 
of events needed to suspend accrual and the denominator represents the number treated at that point in 
the study: 7/12, 8/14, 9/17, 10/20, 11/22, 12/25, 13/28, 14/30, 15/33, and 16/36.  
 
At the end of the study, the response rate and its associated 95% Wilson score confidence interval (CI) 
will be reported. The overall toxicity rate and CI will be reported, and the toxicity profile of the regimen 
will be summarized. 

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 10 of 109 
  
 
 
SCHEDULE OF STUDY ASSESSMENTS 
Period 
Screeninga Baselineb 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOT 
Week 
Week 
Week 
Week 
Week 
Week 
 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
 
Scheduling 
Window (days) 
-28 to -7 
-7 to -1 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Examc 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
ECOG Performance 
Status 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
12-Lead ECGd 
Xq 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
MUGA Scan or 
ECHOd 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Hematologye 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Clinical Chemistryf 
X 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
TSH (reflex free T3 
or free T4)g 
 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 

Clinical Study Protocol 
Drug Substance Durvalumab (MEDI4736) 
AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 11 of 109 
  
SCHEDULE OF STUDY ASSESSMENTS 
Period 
Screeninga Baselineb 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
EOT 
Week 
Week 
Week 
Week 
Week 
Week 
 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
1 
2 
3 
 
Scheduling 
Window (days) 
-28 to -7 
-7 to -1 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
±5 
 
aPTT and INRh 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B and C 
and HIVi 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum Pregnancy 
(βhCG)j 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysisk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mammograml 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Breast Ultrasoundl 
 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
Breast MRIl 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Biopsym 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Blood Collection for 
Circulating DNAn 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Trastuzumabo 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
Pertuzumabo 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date 1 0 Se pte m ber 2 0 2 4 
Pa ge 1 2  of 1 0 9 
  
S C H E D U L E O F S T U D Y A S S E S S M E N T S  
Peri o d  
Scree ni n g a B aseli ne b 
C y cle 1  
C y cle 2  
C y cle 3  
C y cle 4  
C ycle 5  
C ycle 6  
E O T  
Wee k  
Wee k  
Wee k  
Wee k  
Wee k  
Wee k  
 
1  
2  
3  
1  
2  
3  
1  
2  
3  
1  
2  
3  
1  
2  
3  
1  
2  
3  
 
Sc he d uli n g 
Wi n d o w ( d a ys)  
-2 8 t o -7 
-7 t o -1 
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
± 5  
 
D ur val u ma b o 
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
X  
 
 
 
A Es a n d S A Es p 
 
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
A b br e viati o ns: A E = a d verse e ve nt; A L P = al kali ne p h os p hatase; A L T = ala ni ne tra nsa mi nase; A N C = a bs ol ute ne utr o p hil c o u nt; a P T T = acti vate d 
partial t hr o m b o plasti n ti me; A S T = as partate tra nsa mi nase; -h C G  = beta-h u ma n c h ori o nic g o na d otr o pi n; B U N = bl o o d urea nitr o ge n; E C G = 
electr ocar di o gra m;  E C H O  =  ec h ocar di o gra m;  E C O G  =  Easter n  C o o perati ve  O nc ol o g y  Gr o u p;  E O T  =  e n d  of  treat me nt;  HI V  =  h u ma n  
i m m u n o deficie nc y vir us; I N R = i nter nati o nal n or malize d rati o; I V = i ntra ve n o us; L D H = lactate de h y dr o ge nase; M C H = mea n c or p usc ular 
he m o gl o bi n; M C H C = mea n c or p usc ular he m o gl o bi n c o nce ntrati o n; M C V = mea n c or p usc ular v ol u me; M RI = ma g netic res o na nce i ma gi n g ; 
M U G A = m ulti gate d ac q uisiti o n; p C R = pat h ol o gical c o m plete res p o nse; P D -L 1 = pr o gra m me d cell deat h -li ga n d 1; Q 3 W = e ver y 3 wee ks; R B C 
= re d bl o o d cell; S A E = seri o us a d verse e ve nt; T 3 = trii o d ot h yr o ni ne; T 4 = t h yr o xi ne; T B = t otal bilir u bi n; TI L = t u m or- i nfiltrati n g l y m p h oc yte; 
T S H = t h yr oi d -sti m ulati n g h or m o ne; W B C = w hite bl o o d cell.  
A wi n d o w of ± 5 da ys is all o we d f or st u d y visits a n d assess me nts/ pr oce d ures (e xce pt as ot her wise s pecifie d).  Patie nts will u n der g o s ur ger y 
wit hi n 3 0 da ys of t he fi nal d ose of st u d y treat me nt. E O T is defi ne d as 7 t o 1 0 da ys after t he fi nal d ose of st u d y treat me nt.  
a. Wit hi n 2 8 da ys pri or t o t he C ycle 1, Da y 1 d ose of trast uz u ma b, pert uz u ma b, a n d d ur val u ma b.  
b.  Wit hi n 7 da ys pri or t o t he C ycle 1, Da y 1 d ose of trast uz u ma b, pert uz u ma b, a n d d ur val u ma b.  O nl y scree ni n g pr oce d ures n ot per f or me d wit hi n 
7 da ys of d osi n g are re q uire d at baseli ne.  
c. P h ysical e xa m will be perf or me d at scree ni n g/ baseli ne, bef ore e ver y c ycle, a n d at E O T. P h ysical e xa m will i ncl u de vital si g n ( bl o o d press ure, 
res pirat or y rate, p ulse, a n d oral or te m p oral te m perat ure) a n d wei g ht meas ure me nts. Hei g ht will be meas ure d at scree ni n g o nl y. 

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d. A 12-lead ECG and MUGA scan or ECHO will be performed at screening, after Cycle 2, at EOT, and when clinically indicated. The same 
method (MUGA scan or ECHO) must be used throughout the duration of the study. Twelve-lead ECG will be obtained after the patient has 
been rested in a supine position for at least 5 minutes in each case. Any clinically significant abnormalities detected require triplicate ECG 
results. Triplicate ECG will be performed at Screening and mean QT interval will be calculated. 
e. Hematology assessments (hemoglobin, hematocrit, RBCs, platelets, MCH, MCHC, MCV, WBCs, absolute differential WBC count 
[neutrophils, lymphocytes, monocytes, eosinophils, and basophils], and ANC) will be performed at screening/baseline, before every cycle, at 
EOT, and when clinically indicated.  
f. Clinical chemistry assessments (glucose, albumin, sodium, potassium, calcium, carbon dioxide, chloride, BUN, creatinine, TB, total protein, 
ALP, AST, ALT, magnesium, LDH, uric acid, and amylase) will be performed at screening/baseline, before every cycle, at EOT, and when 
clinically indicated. 
g. TSH will be measured at baseline, before every cycle, at EOT, and when clinically indicated. If TSH is measured within 14 days prior to Cycle 
1, Day 1, it does not need to be repeated at Cycle 1, Day 1. Free T3 or free T4 will only be measured if TSH is abnormal or if there is clinical 
suspicion of an AE related to the endocrine system. 
h. aPTT and INR will be performed at baseline and when clinically indicated. 
i. Hepatitis B and C and HIV testing will be performed at screening. 
j. For women of childbearing potential, the results of a serum β-hCG pregnancy test must be negative within 7 days prior to the administration 
of the first dose of study treatment. If the screening serum β-hCG pregnancy test is performed more than 7 days before dosing, it must be 
repeated at baseline, with results known to be negative prior to the administration of the first dose of study treatment.  β-hCG pregnancy testing 
is to be repeated as clinically indicated. 
k. Urinalysis by dipstick will be performed at baseline and when clinically indicated. 
l. Mammogram and breast ultrasound will be performed at baseline. Mammogram and breast ultrasound performed as standard of care can be 
used for baseline if performed within 90 days prior to the Cycle 1, Day 1 dose of trastuzumab, pertuzumab, and durvalumab. Mammogram and 
breast ultrasound will be repeated after Cycle 3 (+/- 3 days) and EOT.  Breast MRI will be performed at baseline and EOT. Breast MRI 
performed as standard of care can be used for baseline if performed within 60 days prior to the Cycle 1, Day 1 dose of trastuzumab, pertuzumab, 
and durvalumab. 
m. Tumor biopsy will be performed at baseline and EOT.  Diagnostic biopsy may be used in lieu of repeat baseline biopsy, and collected for study 
purposes. Tissue will also be collected at the time of surgery. Banked tumor tissue obtained as part of the patient’s standard of care and 
collected biopsy and surgical tissues will be used for determination of pathological response, PD-L1 expression, and TILs and correlative 
studies. 
n. Blood samples for analysis of circulating DNA will be collected at baseline, after Cycle 2 (± 3 days), and at EOT and will be used for evaluation 
of correlative molecular and genetic biomarkers. 
o. Trastuzumab, pertuzumab, and durvalumab will be administered for 6 21-day cycles (18 weeks).  Trastuzumab, pertuzumab, and durvalumab 
will be administered sequentially as separate IV infusions on Day 1 at each cycle. Patients will be observed for 30−60 minutes after each 

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infusion. Trastuzumab will be the first infusion, followed by pertuzumab and then durvalumab. Trastuzumab will be administered as 8 mg/kg 
IV loading dose, followed by 6 mg/kg IV Q3W. Pertuzumab will be administered as 840 mg IV loading dose, followed by 420 mg IV Q3W. 
Durvalumab will be administered at a fixed dose of 1120 mg IV Q3W. Note: All assessments on infusion days are to be performed prior to 
infusion. Results of hematology and clinical chemistry results must be available before commencing an infusion. Patients who have been 
determined based on biopsy to have achieved pCR (RCB 0) or RCB 0 and 1 after completion of 6 cycles of neoadjuvant therapy will undergo 
surgery. Following surgery, RCB 0 and RCB 1 patients will continue to receive the trastuzumab, pertuzumab, and durvalumab (1120 mg Q3W) 
regimen plus standard-of-care treatment to complete 1 year. Follow-up will be provided every 12 weeks, as per standard-of-care, and will 
include physical exam, Echo, ECG, and labs (Clinical Chemistry, Hematology and TSH).  Patients who have been determined based on biopsy 
to not have achieved p RCB 0 and RCB 1 after completion of 6 cycles of neoadjuvant therapy will undergo continued neoadjuvant treatment 
with targeted therapy and chemotherapy per physician’s choice.  
p. AEs and SAEs will be captured from the time of informed consent signing up to and including 30 days after the last treatment dose. 
q.  Triplicate ECG will be performed at Screening and mean QT interval will be calculated. 

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Contents 
Clinical Protocol ......................................................................................................................... 1 
LIST OF TABLES ................................................................................................................... 18 
LIST OF APPENDICES .......................................................................................................... 18 
ABBREVIATIONS AND DEFINITION OF TERMS ............................................................ 20 
1 
BACKGROUND .............................................................................................................. 24 
1.1 
Human epidermal growth factor receptor 2 and breast cancer ...................................... 24 
1.2 
Neoadjuvant therapy for HER2-positive breast cancer ................................................. 24 
1.2.1 
HER2 enriched breast tumor subtype and response to HER2 dual blockade 
without chemotherapy ...................................................................................................... 25 
1.3 
Immunotherapies ........................................................................................................... 26 
1.4 
Durvalumab (MEDI4736) ............................................................................................. 27 
1.4.1 
Durvalumab non-clinical and clinical experience .............................................. 27 
1.5 
Research hypothesis ...................................................................................................... 27 
1.6 
Rationale for conducting this study ............................................................................... 28 
1.6.1 
Rationale for fixed dosing .................................................................................. 28 
1.6.2 
Rationale for Q3W dosing .................................................................................. 29 
1.7 
Benefit/risk and ethical assessment ............................................................................... 29 
1.7.1 
Potential benefits ................................................................................................ 29 
1.7.2 
Overall risks ........................................................................................................ 30 
1.7.3 
Overall benefit-risk ............................................................................................. 31 
2 
OBJECTIVES ................................................................................................................... 31 
2.1 
Primary objective ........................................................................................................... 31 
2.2 
Secondary objectives ..................................................................................................... 31 
2.3 
Exploratory objective .................................................................................................... 32 
3 
ENDPOINTS .................................................................................................................... 32 
3.1 
Primary endpoint ........................................................................................................... 32 
3.2 
Secondary endpoints ...................................................................................................... 32 
3.3 
Exploratory endpoint ..................................................................................................... 33 

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4 
STUDY DESIGN ............................................................................................................. 33 
4.1 
Overview of study design .............................................................................................. 33 
4.2 
Study schema ................................................................................................................. 33 
5 
PATIENT SELECTION ................................................................................................... 34 
5.1 
Inclusion criteria ............................................................................................................ 34 
5.2 
Exclusion criteria ........................................................................................................... 36 
5.3 
Withdrawal of patients from study treatment and/or study ........................................... 38 
5.3.1 
Permanent discontinuation of study treatment ................................................... 38 
5.3.2 
Withdrawal of consent ........................................................................................ 39 
6 
STUDY TREATMENT .................................................................................................... 40 
6.1 
Dosing and administration ............................................................................................. 40 
6.2 
Durvalumab ................................................................................................................... 41 
6.2.1 
Formulation/packaging/storage .......................................................................... 41 
6.2.2 
Preparation .......................................................................................................... 41 
6.2.3 
Monitoring of dose administration ..................................................................... 42 
6.2.4 
Accountability and dispensation ......................................................................... 42 
6.3 
Toxicity management guidelines ................................................................................... 43 
6.3.1 
Durvalumab ........................................................................................................ 43 
6.3.2 
Trastuzumab and pertuzumab ............................................................................. 44 
7 
Restrictions during the study and concomitant treatment(s) ............................................ 46 
7.1 
Restrictions during the study ......................................................................................... 46 
7.1.1 
Contraception ..................................................................................................... 46 
7.2 
Concomitant treatment(s) .............................................................................................. 48 
7.2.1 
Permitted concomitant medications.................................................................... 49 
7.2.2 
Prohibited concomitant medications .................................................................. 49 
8 
STUDY PROCEDURES .................................................................................................. 50 
8.1 
Schedule of study procedures ........................................................................................ 50 
8.1.1 
Screening phase .................................................................................................. 51 
8.1.2 
Baseline phase .................................................................................................... 53 

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8.1.3 
Treatment phase .................................................................................................. 54 
8.1.4 
Other procedures................................................................................................. 57 
9 
ASSESSMENT OF SAFETY .......................................................................................... 57 
9.1 
Safety parameters .......................................................................................................... 57 
9.1.1 
Definition of adverse events ............................................................................... 57 
9.1.2 
Definition of serious adverse events ................................................................... 58 
9.1.3 
Definition of adverse events of special interest (AESIs) .................................... 58 
9.2 
Assessment of safety parameters ................................................................................... 59 
9.2.1 
Assessment of severity ....................................................................................... 59 
9.2.2 
 Assessment of relationship ................................................................................ 60 
9.3 
Recording of adverse events and serious adverse events .............................................. 60 
9.3.1 
 Study recording period and follow-up for adverse events and serious adverse 
events 62 
9.3.2 
Causality collection ............................................................................................ 62 
9.3.3 
 Relationship to protocol procedures .................................................................. 62 
9.3.4 
Adverse events based on signs and symptoms ................................................... 63 
9.3.5 
Adverse events based on examinations and tests ............................................... 63 
9.3.6 
 Hy’s Law ........................................................................................................... 63 
9.3.7 
 Disease progression ........................................................................................... 64 
9.3.8 
New cancers ........................................................................................................ 64 
9.3.9 
Deaths ................................................................................................................. 64 
9.3.10 
Reporting of serious adverse events ................................................................... 65 
9.3.11 
Reporting of deaths to AstraZeneca ................................................................... 66 
9.3.12 
Other events requiring reporting......................................................................... 67 
10  STATISTICAL METHODS ........................................................................................... 69 
11 ETHICAL AND REGULATORY REQUIREMENTS ................................................... 71 
11.1  Ethical conduct of the study ......................................................................................... 71 
11.2  Ethics and regulatory review ........................................................................................ 71 
11.3  Patient confidentiality ................................................................................................... 72 
11.4 Informed consent ........................................................................................................... 72 

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12 STUDY MANAGEMENT ............................................................................................... 73 
12.1 Training of study site personnel .................................................................................... 73 
12.2 Monitoring of the study ................................................................................................. 73 
13 DATA MANAGEMENT ................................................................................................. 74 
14 LIST OF REFERENCES ................................................................................................. 75 
 
 
LIST OF TABLES 
Table 1. Dose Modifications for Left Ventricular Dysfunction................................................39 
Table 2. Highly Effective Methods of Contraception (<1% Failure Rate) ...............................41 
Table 3. Supportive Medications...............................................................................................42 
Table 4. Prohibited Concomitant Medications..........................................................................42 
Table 5. Hematology Laboratory Tests.....................................................................................44 
Table 6. Clinical Chemistry Laboratory Tests ..........................................................................44 
Table 7. Urinalysis Tests...........................................................................................................45 
Table 8. Operating Characteristics for Toxicity Monitoring Rule............................................59 
LIST OF FIGURES 
Figure 1. Study schema .............................................................................................................29 
LIST OF APPENDICES 
Appendix 1. Dosing 
Modification 
and 
Toxicity 
Management 
Guidelines 
for 
ImmuneMediated,  
Infusion-Related,  
and  
Non-Immune–Mediated 
 Reactions  
(MEDI4736)  
Appendix 2.   ECOG Performance Status Scale 

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ABBREVIATIONS AND DEFINITION OF TERMS 
The following abbreviations and special terms are used in this study Clinical Study Protocol. 
Abbreviation or 
special term 
Explanation 
ADCC 
Antibody-dependent cell-mediated cytotoxicity 
AE 
Adverse event 
AESI 
Adverse event of special interest 
ALP 
Alkaline phosphatase 
ALT 
Alanine transaminase 
ANC 
Absolute neutrophil count 
Anti-HBc 
Hepatitis B core antibody 
AST 
Aspartate transaminase 
β-hCG 
Beta-human chorionic gonadotropin 
BUN 
Blood urea nitrogen 
CI 
Confidence interval 
CRF 
Case report form 
CTLA-4 
Cytotoxic T-lymphocyte-associated antigen-4 
DFS 
Disease-free survival 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal growth factor receptor 
EOT 
End of treatment 

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ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
 
Abbreviation or 
special term 
Explanation 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HER2 
Human epidermal growth factor receptor 2 
HIV 
Human immunodeficiency virus 
HR 
Hormone receptor 
IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICH 
International Council on Harmonization 
IHC 
Immunohistochemical  
ILD 
Interstitial lung disease 
imAE 
Immune-mediated adverse event 
IRB 
Institutional review board 
IV 
Intravenous(ly) 
LDH 
Lactate dehydrogenase 
LH 
Luteinizing hormone 

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LVEF 
Left ventricular ejection fraction 
mAb 
Monoclonal antibody 
MedDRA 
Medical Dictionary for Regulatory Activities 
MCH 
Mean corpuscular hemoglobin 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MRI 
Magnetic resonance imaging 
MUGA 
Multigated acquisition 
NCI CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse  
Events  
NSCLC 
Non-small cell lung cancer 
pCR 
Pathological complete response 
 
Abbreviation or 
special term 
Explanation 
PD 
Progressive disease 
PD-1 
Programmed cell death-1 
PD-L1 
Programmed cell death-ligand 1 
PD-L2 
Programmed cell death-ligand 2 
PI3KCA 
Phosphatidylinositol-4,5-bisphosphonate 3-kinase catalytic subunit alpha 
PK 
Pharmacokinetic(s) 
PTEN 
Phosphatase and tensin homolog 
Q2W 
Every 2 weeks 

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Q3W 
Every 3 weeks 
QD 
Once daily 
RBC 
Red blood cell 
SAE 
Serious adverse event 
TB 
Total bilirubin 
TIL 
Tumor-infiltrating lymphocyte 
TSH 
Thyroid-stimulating hormone 
ULN 
Upper limit of normal 
U.S. 
United States  
WBC 
White blood cell 
 
 

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1 BACKGROUND 
1.1 Human epidermal growth factor receptor 2 and breast cancer 
Human epidermal growth factor receptor 2 (HER2) amplification or overexpression occurs in 
approximately 20–25% of breast cancers. HER2 is a tyrosine kinase receptor belonging to the 
HER family that also includes epidermal growth factor receptor (EGFR; HER1), HER3, and 
HER4. HER2 is activated by either heterodimerization with other ligand-bound HER family 
members or, when overexpressed, by ligand-independent homodimerization. HER2 functions 
as a driver oncogene in HER2-overexpressing tumors.1,2 HER2 overexpression is associated 
with aggressive disease, relatively poor prognosis, and worse clinical outcomes.  
1.2 Neoadjuvant therapy for HER2-positive breast cancer 
Neoadjuvant therapy is standard of care for patients with locally advanced, inflammatory, or 
inoperable primary breast cancer. Neoadjuvant therapy is used to downstage tumors, thereby 
potentially rendering them suitable for breast-conserving surgery. Clinical studies have shown 
that pathological complete response (pCR) to neoadjuvant therapy is strongly correlated with 
survival and prognosis in breast cancer patients.3-5 Breast cancer patients who achieve pCR to 
neoadjuvant therapy, particularly those with HER2-positive breast cancers, are known to have 
better disease-free survival (DFS) and overall survival compared with those with residual 
disease.6-8 The addition of the anti-HER2 monoclonal antibody (mAb) trastuzumab to 
neoadjuvant chemotherapy has been shown to improve pCR rate in patients with HER2-positive 
locally advanced breast cancer.9-11 Because of the complex and redundant signaling pathways 
of the HER family, dual anti-HER2 therapies have been developed to more completely block 
signaling from HER2 and its related HER family members. Multiple large randomized clinical 
trials have demonstrated that dual HER2-targeted therapies are synergistic and result in 
improved efficacy. 
Dual HER2 blockade with trastuzumab and pertuzumab in combination with taxane-based 
chemotherapy is the current neoadjuvant approach for patients with HER2-positive breast 
cancer. Pertuzumab is an anti-HER2 mAb that targets the extracellular dimerization domain of 
HER2 to block ligand-dependent heterodimerization of HER2 with other HER family members, 
including EGFR, HER3, and HER4. The multicenter, open-label, randomized Phase II 
NeoSphere study (NCT00545688) demonstrated that combining neoadjuvant trastuzumab and 
docetaxel with pertuzumab significantly improved pCR rate compared with trastuzumab plus 
docetaxel, pertuzumab plus docetaxel, and trastuzumab and pertuzumab in patients with locally 
advanced, inflammatory, or early HER2-positive breast cancer (45.8% vs. 29%, 24%, and 
16.8%, respectively).12 However, not all HER2-positive breast cancers respond to 
HER2targeted therapy and many that initially respond later develop resistance. Therefore, novel 
strategies are needed to overcome this intrinsic/acquired resistance.  

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1.2.1 HER2 enriched breast tumor subtype and response to HER2 dual 
blockade without chemotherapy  
The potential of using dual HER2 blockade without chemotherapy in the treatment of 
HER2positive breast cancer has been demonstrated in several clinical studies. Development of 
such chemotherapy-free regimens would be of particular importance for patients who are unable 
to tolerate cytotoxic drugs and would spare a subset of patients the short and long-term toxicities 
associated with cytotoxic-based therapy. In the trastuzumab and pertuzumab without 
chemotherapy arm of the NeoSphere study, 16.8% (18/107) of patients achieved pCR after 12 
weeks of neoadjuvant treatment.12 We conducted a multicenter Phase II study of neoadjuvant 
lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with 
HER2-overexpressing breast cancer.13 Patients received trastuzumab (4 mg/kg intravenous [IV] 
loading dose, followed by 2 mg/kg every 3 weeks [Q3W]) and lapatinib (1000 mg orally once 
daily [QD]) for 12 weeks. Patients with estrogen receptor (ER)-positive tumors also received 
letrozole. Sixty-four patients were evaluable for response. The overall pCR rate (i.e., absence 
of all invasive cancer) was 53% (34/64). The pCR rate was 40% (10/25) in the ER-negative 
cohort and 21% (8/39) in the ER-positive cohort. In the multicenter, randomized Phase II UK 
EPHOS-B study (NCT01104571), 127 patients with newly diagnosed HER2-positive breast 
cancer were randomized to receive no treatment (control group; n = 29), trastuzumab only (n = 
32), or trastuzumab and lapatinib in combination (n = 66) for 11 days before surgery.14 Of the 
66 patients treated with the trastuzumab and lapatinib combination, 7 (10.6%) had their tumors 
disappear (pCR) and 11 (16.7%) had minimal residual disease (<5 mm invasive tumor). In 
contrast, none of the patients in the control and trastuzumab only groups achieved pCR and 
none of the patients in the control group and 1 patient in the trastuzumab only group had 
minimal residual disease. Together, these findings suggest that a proportion of HER2-positive 
tumors are responsive to HER2-targeted combination therapies alone. Importantly, results of 
the nonrandomized, open-label Phase II PAMELA study (NCT01973660) indicated that the 
PAM50 HER2-enriched subtype is a strong predictor of sensitivity to dual HER2 blockade 
without chemotherapy in patients with HER2-positive early breast cancer.15 Patients (n = 151) 
were treated with dual HER2 blockade consisting of lapatinib (1000 mg QD) and trastuzumab 
(6 mg/kg Q3W) for 18 weeks. Hormone receptor (HR)-positive patients also received endocrine 
therapy (letrozole or tamoxifen). pCR rate was significantly higher in patients with 
HER2enriched tumors compared with those with non-HER2-enriched tumors (40.6% vs. 
10.0%; p = 0.0004). Furthermore, pCR rate was 43.1% in patients with HR-negative disease 
and 18.2% in those with HR-positive disease (p = 0038). Combined HER2-enriched 
subtype/ERBB2-high mRNA level was shown to be a strong predictor of pCR following dual 
HER2 blockade without chemotherapy; pCR rates in HER2-enriched/ERBB2-high, non-HER2-
enriched/ERBB2-high,  
HER2-enriched/ERBB2-low, and non-HER2-enriched/ERBB2-low groups were 45.0%,  
16.1%, 10.8%, and 6.7%, respectively.16,17 

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1.3 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.18  
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 
(CD279) is expressed on the surface of activated T-cells.19 It has 2 known ligands: PD-L1 (B7-
H1; CD274) and PD-L2 (B7-DC; CD273).20 PD-1 and PD-L1/PD-L2 belong to the family of 
immune checkpoint proteins that act as coinhibitory factors, which can halt or limit the 
development of T-cell responses. 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.21 Importantly, 
PD-L1 is commonly overexpressed on tumor cells or on non-transformed cells in the tumor 
microenvironment.22 PD-L1 expressed on the tumor cells binds to PD-1 on 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 PD-L1 
inhibits the interaction of PD-L1 with PD-1 and CD80 receptors expressed on immune cells. 
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 non-clinical and clinical studies of 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,20,23-27with responses that tend to be more pronounced in 
patients with PD-L1–expressing tumors.28-30 In addition, high mutational burden (e.g., in 
bladder carcinoma31) may contribute to the responses seen with immunotherapy. 
Preclinical data have now been added to a wealth of clinical data showing that blockade of 
negative regulatory signals to T-cells such as cytotoxic T-lymphocyte antigen-4 (CTLA-4) and 
PD-L1 has promising clinical activity. The anti–CTLA-4 agent ipilimumab was granted United 
States (U.S.) Food and Drug Administration (FDA) approval for the treatment of metastatic 
melanoma and is currently under investigation for several other malignancies, whereas 

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nivolumab and pembrolizumab, two anti–PD-1 agents, and atezolizumab, an anti–PD-L1 agent, 
have been granted approvals by agencies such as the U.S. FDA and European Medicines 
Agency for the treatment of a number of malignancies including metastatic melanoma, 
squamous and non-squamous cell non-small cell lung cancer (NSCLC) 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. 
1.4 Durvalumab (MEDI4736) 
Durvalumab (MEDI4736) is a human mAb of the immunoglobulin G1 kappa subclass that 
inhibits binding of PD-L1 and is being developed by AstraZeneca/MedImmune for use in the 
treatment of cancer (MedImmune is a wholly owned subsidiary of AstraZeneca; 
AstraZeneca/MedImmune will be referred to as AstraZeneca throughout this document). 
Durvalumab is approved for the treatment of patients with locally advanced or metastatic 
urothelial carcinoma who have disease progression during or following platinum-containing 
chemotherapy, or who have disease progression within 12 months of neoadjuvant or adjuvant 
treatment with platinum-containing chemotherapy. Durvalumab is also approved for the 
treatment of patients with unresectable, Stage III NSCLC whose disease has not progressed 
following concurrent platinum-based chemotherapy and radiation therapy.  
1.4.1 Durvalumab non-clinical and clinical experience 
The non-clinical and clinical experience is fully described in the most current version of the 
durvalumab Investigator’s Brochure (IB).  
The proposed mechanism of action for durvalumab is interference in the interaction of PD-L1 
with PD-1 and CD80 (B7.1). Blockade of PD-L1/PD-1 and PD-L1/CD80 interactions releases 
the inhibition of immune responses, including those that may result in tumor elimination. In 
vitro studies demonstrate that durvalumab antagonizes the inhibitory effect of PD-L1 on 
primary human T-cells, resulting in the restored proliferation of interferon-γ.32 In vivo studies 
have shown that durvalumab inhibits tumor growth in xenograft models via a T-cell−dependent 
mechanism.32 Based on these data, durvalumab is expected to stimulate the patient’s antitumor 
immune response by binding to PD-L1 and shifting the balance toward an antitumor response.  
To date, durvalumab has been given to more than 6000 patients as part of ongoing studies either 
as monotherapy or in combination with other anticancer agents. Details on the safety profile of 
durvalumab monotherapy are summarized in Section 1.7.2.1. Refer to the current durvalumab 
IB for a complete summary of non-clinical and clinical information including safety, efficacy, 
and pharmacokinetics (PK).  
1.5 Research hypothesis 
A more selected patient population with highly HER2-dependent breast cancer and the addition 
of durvalumab will increase the pCR rate of neoadjuvant dual HER2 blockade with trastuzumab 
and pertuzumab (without chemotherapy).  

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1.6 Rationale for conducting this study 
Clinical studies have demonstrated the superiority of dual HER2 blockade over single-agent 
blockade in achieving a more comprehensive inhibition of the various HER2 dimers. Despite 
the efficacy of dual HER2 blockade, many HER2-positive breast cancers fail to respond and 
those that initially respond eventually develop resistance. As de novo and acquired resistance 
still remain a significant clinical challenge, novel combination strategies are needed to 
overcome resistance.  
Clinical studies have indicated the potential of using dual HER2 blockade without 
chemotherapy in the treatment of HER2-positive breast cancer, particularly HER2-enriched and 
HER2-amplified breast cancer (see Section 1.2.1 − HER2-enriched breast tumor subtype and 
response to HER2 dual blockade without chemotherapy).12-17 As several studies have indicated 
the relevance of the immune system in the response to HER2-targeted therapy, dual HER2 
blockade in combination with immunotherapy may represent a valid approach. In addition to 
direct binding to HER2, trastuzumab and pertuzumab also induce antibody-dependent 
cellmediated cytotoxicity (ADCC) through the interaction of the Fc portion of 
trastuzumab/pertuzumab with Fcγ receptors on immune cells.33,34 ADCC has been linked to the 
in vitro/in vivo and clinical responses to trastuzumab.35-41 Notably, the HER2-enriched subtype 
of HER2-positive breast cancer has been shown to have the highest rate of immune response to 
trastuzumab treatment.42 HER2-positive breast tumors have also been shown to contain high 
levels of tumor-infiltrating lymphocytes (TILs) and this has been shown to be associated with 
increased pCR rates to neoadjuvant HER2-targeted therapy.43-46  
Resistance to HER2-targeted therapy in vitro has been correlated with increased PD-L1 
expression.47 In the NeoSphere trial, PD-L1 expression was associated with a lower pCR rate 
to trastuzumab and pertuzumab (odds ratio = 0.30; 95% confidence interval [CI]: 0.15–0.61; p 
= 0.0007).48 Intratumoral CD8+ T-cells were found to be significantly associated with pCR to 
anti-HER2 neoadjuvant therapy in patients with HER2-positive breast cancer.49 Furthermore, 
all patients with intratumoral CD8+ T-cells and no PD-L1 expression (tumor/immune cells) 
achieved pCR. The efficacy of combined HER2 and PD-1 targeting in HER2-positive breast 
cancer has been demonstrated in the metastatic setting. In the Phase Ib/II PANACEA trial 
(KEYNOTE-014; NCT02129556), the combination of trastuzumab and pembrolizumab 
achieved an overall response rate of 15.2% and a disease control rate of 24% in 58 patients with 
trastuzumab-resistant metastatic breast cancer.50 Together, these studies indicate the 
contribution of the immune system in the response/resistance to HER2-targeted therapies. Given 
the involvement of PD-L1 in the resistance to HER2-targeted therapy, PD-L1 blockade may 
offer a rational approach to circumvent the resistance to and improve the efficacy of 
HER2targeted therapy.  
1.6.1 Rationale for fixed dosing 
A population PK model was developed for durvalumab using monotherapy data from a Phase I 
study in patients with solid tumors (Study 1108; n = 292; doses = 0.1 to 10 mg/kg every 2 weeks 

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[Q2W] or 15 mg/kg Q3W). Population PK analysis indicated only minor impact of body weight 
on the PK of durvalumab (coefficient of ≤0.5). The impact of body weight-based (10 mg/kg 
Q2W) and fixed dosing (750 mg Q2W) of durvalumab was evaluated by comparing predicted 
steady state PK concentrations (5th, median, and 95th percentiles) using the population PK 
model. A fixed dose of 750 mg was selected to approximate 10 mg/kg (based on median body 
weight of ~75 kg). A total of 1000 patients were simulated using body weight distribution of 
40–120 kg. Simulation results demonstrate that body weight-based and fixed dosing regimens 
yield similar median steady state PK concentrations with slightly less overall between-patient 
variability with the fixed dosing regimen.  
Similar findings have been reported by others.51-54 Wang and colleagues investigated 12 mAbs 
and found that fixed and body size-based dosing perform similarly, with fixed dosing being 
better for 7 of 12 antibodies.52 In addition, they investigated 18 therapeutic proteins and peptides 
and showed that fixed dosing performed better for 12 of 18 in terms of reducing the 
betweenpatient variability in PK/pharmacodynamics parameters.53 
A fixed dosing approach is preferred by the prescribing community due to ease of use and 
reduced dosing errors. Given the expectation of similar PK exposure and variability, we 
considered it feasible to switch to fixed dosing regimens.  
1.6.2 Rationale for Q3W dosing 
The planned dose of trastuzumab for this study is 8 mg/kg IV loading dose, followed by 6 mg/kg 
IV Q3W. The planned dose of pertuzumab is 840 mg IV loading dose, followed by 420 mg IV 
Q3W. These are the approved doses for the neoadjuvant treatment of HER2-positive breast 
cancer.  Given that trastuzumab and pertuzumab should be dosed Q3W, Q3W dosing will also 
be used for durvalumab. The planned dose of durvalumab for this study is 1120 mg IV Q3W.  
1.7 Benefit/risk and ethical assessment 
1.7.1 Potential benefits 
Preclinical and clinical data have demonstrated a role of PD-L1 in the resistance to 
HER2targeted therapy39-41 and therefore, PD-L1 blockade could be an effective strategy to 
overcome treatment resistance. HER2-enriched tumors with HER2 amplification have been 
found to benefit most from anti-HER2 therapy and to elicit a strong immune response to anti-
HER2 therapy.38 Addition of durvalumab may potentiate the immune response to neoadjuvant 
trastuzumab and pertuzumab, leading to better treatment outcomes (i.e., pCR). This is highly 
significant given the association of pCR with long-term survival in HER2-positive patients. 
The impact of PD-L1 status and TILs on response (pCR) to the durvalumab with trastuzumab 
and pertuzumab combination will be assessed. Furthermore, biopsied tumor tissues and blood 
samples (circulating DNA) will be evaluated for molecular and genetic biomarkers of response 
and resistance to durvalumab with trastuzumab and pertuzumab combination. Together, this 

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information will be important in identifying patients most likely to benefit from the durvalumab 
with trastuzumab and pertuzumab combination. 
1.7.2 Overall risks 
mAbs directed against immune checkpoint proteins, such as PD-L1 and PD-1, aim to boost 
endogenous immune responses directed against tumor cells. By stimulating the immune system, 
however, there is the potential for adverse effects on other tissues. 
Most adverse drug reactions seen with the immune checkpoint inhibitor class of agents are 
thought to be due to the effects of inflammatory cells on specific tissues. These risks are 
generally events with a potential inflammatory or immune-mediated mechanism and which may 
require more frequent monitoring and/or unique interventions such as immunosuppressants 
and/or endocrine therapy. These immune-mediated effects can occur in nearly any organ system 
and are most commonly seen as gastrointestinal adverse events (AEs) such as colitis and 
diarrhea, pneumonitis/interstitial lung disease (ILD), hepatic AEs such as hepatitis and liver 
enzyme elevations, skin events such as rash and dermatitis, and endocrinopathies including 
hypothyroidism and hyperthyroidism. 
1.7.2.1 Durvalumab 
Risks with durvalumab include, but are not limited to, diarrhea/colitis and intestinal perforation, 
pneumonitis/ILD, endocrinopathies (hypothyroidism and hyperthyroidism, type I diabetes 
mellitus(which may present as diabetic ketoacidosis), Diabetes insipidus, hypophysitis, and 
adrenal insufficiency), hepatitis/increases in transaminases, nephritis/increases in creatinine, 
pancreatitis/increases in amylase and lipase, rash/pruritus/dermatitis,  (including pemphigoid), 
myocarditis, Encephalitis, myositis/polymyositis, Immune thrombocytopenia, non-infective 
encephalitis, cytokine release syndrome , uveitis, and immune-mediated arthritis.  Other rare or 
less frequent inflammatory events including neurotoxicities, neuromuscular toxicities (e.g., 
Guillain-Barré syndrome, myasthenia gravis), infusion-related reactions, subcutaneouss 
injection site reaction, hypersensitivity reactions, and infections/serious infections.   
Further information on these risks can be found in the current version of the durvalumab IB. 
For information on all identified and potential risks with durvalumab, please always refer to the 
current version of the durvalumab IB. 
In monotherapy clinical studies, AEs (all grades) reported very commonly (≥10% of patients) 
are fatigue, nausea, decreased appetite, dyspnea, cough, constipation, diarrhea, vomiting, back 
pain, pyrexia, asthenia, anemia, arthralgia, peripheral edema, headache, rash, and pruritus. 
Approximately 9% of patients experienced an AE that resulted in permanent discontinuation of 
durvalumab and approximately 6% of patients experienced a serious AE (SAE) that was 
considered to be related to durvalumab by the study investigator. 

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The majority of treatment-related AEs were manageable with dose delays, symptomatic 
treatment, and in the case of events suspected to have an immune basis, the use of established 
treatment guidelines for immune-mediated AEs (imAEs; Appendix 1).  
A detailed summary of durvalumab monotherapy AE data can be found in the current version 
of the durvalumab IB. 
1.7.3 Overall benefit-risk 
Durvalumab has shown significant activity and manageable toxicity in urothelial carcinoma and 
NSCLC. Durvalumab in combination with chemotherapy has also shown promising efficacy in 
the neoadjuvant setting in triple negative breast cancer. Preliminary results of a Phase I/II 
neoadjuvant study (NCT02489448) showed that the addition of durvalumab to chemotherapy 
(weekly nab-paclitaxel followed by dose-dense doxorubicin and cyclophosphamide) increased 
pCR rate (71% [5/7 patients]) compared with the historical rate of 35−40% with chemotherapy 
alone.55  
Phase I study data showed that there were no dose-limiting toxicities with the combination of 
durvalumab (1120 mg IV Q3W) and trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg 
IV Q3W) in patients with HER2-positive metastatic breast cancer, and the recommended Phase 
2 dose was the standard full doses of both agents.56 
The study will be conducted using a Simon’s optimal two-stage design. This design allows for 
early study termination for futility and therefore, minimizes the number of patients exposed to 
an intervention that is probably ineffective. 
2 OBJECTIVES 
2.1 Primary objective 
1. Determination of pathologic response (pCR (RCB 0) and RCB 1) rate in the breast of 
durvalumab with trastuzumab and pertuzumab combination in patients with HER2-enriched and 
HER2-amplified breast cancer. 
2.2 Secondary objectives 
1. 
Estimation of the RCB 0 and RCB 1 rate in the breast of durvalumab with trastuzumab 
and pertuzumab combination in patients whose tumors have <5% and ≥5% TILs. 
2. 
Estimation of the RCB 0 and RCB 1 rate in the breast of durvalumab with trastuzumab 
and pertuzumab combination in patients with PD-L1−positive (≥1% tumor or stroma) and 
PDL1−negative tumors (<1% tumor or stroma). 

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3. 
Determination of the 3-year DFS rate of durvalumab with trastuzumab and pertuzumab 
combination in patients with HER2-enriched and HER2-amplified breast cancer (only for 
patients who achieve RCB 0 and RCB1). 
4. 
Determination of the safety and toxicity of durvalumab with trastuzumab and 
pertuzumab combination in patients with HER2-enriched and HER2-amplified breast cancer, 
as assessed by the National Cancer Institute Common Terminology Criteria for Adverse Events 
(NCI CTCAE) v5. 
2.3 Exploratory objective 
1. Evaluation of the correlative molecular and genetic biomarkers of response and resistance to 
durvalumab with trastuzumab and pertuzumab combination in patients with HER2-enriched and 
HER2-amplified breast cancer, including but not limited to phosphatidylinositol-
4,5bisphosphate 3-kinase catalytic subunit alpha (PI3KCA) and phosphatase and tensin 
homolog (PTEN). 
3 ENDPOINTS 
3.1 Primary endpoint  
1. 
Pathologic response (RCB 0 and RCB 1) rate in the breast of durvalumab with 
trastuzumab and pertuzumab combination in patients with HER2-enriched and HER2-amplified 
breast cancer.  
3.2 Secondary endpoints 
1. 
Pathologic response (RCB 0 and RCB 1) rate in the breast of durvalumab with 
trastuzumab and pertuzumab combination in patients whose tumors have <5% and ≥5% TILs. 
2. 
Pathologic response (RCB 0 and RCB 1)  rate in the breast of durvalumab with 
trastuzumab and pertuzumab combination in patients with PD-L1−positive (≥1% tumor or 
stroma) and PDL1−negative tumors (<1% tumor or stroma). 
3. 
Three-year DFS rate of durvalumab with trastuzumab and pertuzumab combination in 
patients with HER2-enriched and HER2-amplified breast cancer (only for patients who achieve 
RCB 0 and RCB 1). DFS will be calculated from the date of surgery to the date of first event 
(second primary cancer, locoregional relapse, distant relapse, or death from any cause). 
4. 
Safety and toxicity of durvalumab with trastuzumab and pertuzumab combination in 
patients with HER2-enriched and HER2-amplified breast cancer, as assessed by the NCI 
CTCAE v5. Toxicity will be defined as any treatment-related death or any ≥ Grade 3 AE 
excluding alopecia and constitutional symptoms. 

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3.3 Exploratory endpoint 
1 
Correlative molecular and genetic biomarkers of response and resistance to durvalumab 
with trastuzumab and pertuzumab combination in patients with HER2-enriched and HER2-
amplified breast cancer, including but not limited to PI3KCA and PTEN. If sufficient tissue is 
available, next-generation sequencing will be done to identify potential molecular correlates of 
the treatment regimen. 
4 STUDY DESIGN 
4.1 Overview of study design 
This is a multicenter Phase II study evaluating the efficacy and safety of durvalumab with 
trastuzumab and pertuzumab combination in patients with HER2-enriched and HER2-amplified 
breast cancer. The primary endpoint will be the pathologic response rate (RCB 0 and RCB 1) 
rate in the breast of the regimen. The study will be conducted using a Simon’s minimax twostage 
design, and approximately 39 patients will be enrolled. Trastuzumab, pertuzumab, and 
durvalumab will be administered for 6 21-day cycles. Patients will undergo breast MRI and 
biopsy after completion of 6 cycles of neoadjuvant therapy. Patients who have been determined 
based on biopsy to have achieved pathologic response (RCB 0 and RCB 1) will undergo surgery 
(within 30 days of the final dose of study treatment). Following surgery, RCB 0 and RCB 1 
patients will continue to receive the combination of trastuzumab, pertuzumab, and durvalumab 
plus standard-of-care treatment to complete 1 year. Patients who have been determined based 
on biopsy to not have achieved RCB 0 and RCB 1 will undergo continued neoadjuvant treatment 
with targeted therapy and chemotherapy per physician’s choice. Correlative studies will include 
tissue and blood-based molecular and genetic biomarkers of response and resistance to the 
regimen. 
4.2 Study schema 
Figure 1.  

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5 PATIENT SELECTION  
5.1 Inclusion criteria 
For inclusion in the study, patients must fulfill all of the following criteria: 
1. Capable of giving signed informed consent which includes compliance with the requirements 
and restrictions listed in the informed consent form (ICF) and in this protocol. Written 
informed consent and any locally required authorization (e.g., Health Insurance Portability 
and Accountability Act) will be obtained from the patient/legal representative prior to 
performing any protocol-related procedures, including screening evaluations.  
2. Female aged >18 years at the time of study entry. 
3. Histologically confirmed HER2-enriched (by Mammaprint/BluePrint) and HER2-amplified 
(ERBB2 mRNA >7.5-10)57 HER2 overexpressing breast cancer.  
4. ER and progesterone receptor negative (ER and progesterone receptor negativity are defined 
as ≤10% IHC staining). 
5. Primary tumor greater than 1 cm diameter, measured by clinical examination and 
mammography or echography. 
6. Any nodal status. 
7. Bilateral breast cancers that individually meet eligibility criteria are allowed. 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 3 5  of 1 0 9 
 
8.  Easter n C o o per ati ve O nc ol o g y Gr o u p ( E C O G) p erf or ma nce stat us of 0 or 1 ( A p pe n di x 2). 
9.  Life e x pecta nc y > 6 m o nt hs. 
1 0.  A de q uate or g a n a n d marr o w f u ncti o n as defi ne d b el o w:  
 He m o gl o bi n ≥1 0. 0 g/ d L wit h n o bl o o d tra nsf usi o n i n t he past 2 8 da ys 
 A bs ol ute ne utr o p hil c o u nt ( A N C) ≥1. 5 × 1 0 9/ L 
 Platelet c o u nt ≥1 0 0 × 1 0 9/ L 
 Ser u m t otal bilir u bi n ( T B) ≤1 × i nstit uti o nal u p per li mit of n or mal ( U L N; I n 
t he cas e of k n o w n  Gil bert's s y n dr o me,  a hi g her s er u m T B [ < 1. 5  × U L N]  is 
all o we d),  
 As partate tra ns a mi nase ( A S T)/ala ni ne tra nsa mi nase ( A L T) ≤2. 5 × i nstit uti o nal  
U L N  
 Al kali ne p h os p hatase ( A L P) ≤1. 5 × i nstit uti o nal U L N  
 Creati ni ne ≤1. 5 m g/ d L  
1 1.  Baseli ne  left  ve ntric ular  ejecti o n  fracti o n  ( L V E F)  ≥5 0 %,  as  meas ure d  b y  m ulti gate d 
ac q uisiti o n ( M U G A) sca n or ec h ocar di o gra m ( E C H O).  
1 2.  E vi de nce of p ost me n o p a usal stat us or ne gati ve s er u m pre g n a nc y test f or pre me n o pa us al 
patie nts. Ne gati ve s er u m β -h u ma n c h ori o nic g o n a d otr o pi n ( β -h C G) pre g na nc y test wit hi n 7 
da ys pri or t o t he first d ose of st u d y treat me nt f or pre me n o pa usal patie nts. W o me n w ill be 
c o nsi dere d  p ost me n o pa usal  if  t he y  ha ve  bee n  a me n orr h eic  f or  1 2  m o nt hs  wit h o ut  a n  
alter nati ve me dical ca us e. T he f oll o wi n g a ge- s p ecific re q uire me nts a p pl y:  
 W o me n < 5 0 years of a g e w o ul d b e c o nsi dere d p ost me n o pa usal if t h e y h a ve 
bee n a me n orr h eic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of e x o g e n o us 
h or m o nal treat me nts a n d if t he y ha ve l utei nizi n g h or m o ne ( L H) a n d f ollicle -
sti m ulati n g  h or m o ne  ( F S H)  le vels  i n  t he  p ost me n o pa usal  ra n ge  f or  t he  
i nstit uti o n  or  u n der we nt  s ur gical  sterilizati o n  ( bilateral  o o p h orect o m y  or  
h ysterect o m y).  

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 3 6  of 1 0 9 
 
 W o me n ≥5 0 years of a g e w o ul d be c o nsi dere d p ost me n o pa usal if t he y ha ve 
bee n a me n orr hei c f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of all e x o g e n o us 
h or m o nal treat me nts, ha d ra diati o n -i n d uce d me n o pa use wit h last me nses > 1 
year a g o, ha d c he m ot hera p y -i n d uce d me n o pa us e wit h last me nses > 1 year a g o, 
or  u n der we nt  s ur gical  sterilizati o n  ( bilateral  o o p h orect o m y,  bilateral  
sal pi n gect o m y, or h ysterect o m y). 
1 3.  Willi n g t o pr o vi de bi o ps y tiss ues as re q uire d b y t he st u d y. 
1 4.  Patie nt is willi n g a n d a bl e t o c o m pl y wit h t he pr ot oc ol f or t he d urati o n of t h e st u d y i ncl u di n g 
u n der g oi n g treat me nt a n d sc he d ule d visits a n d e x a mi nati o ns i ncl u di n g f oll o w- u p. 
5. 2  E xcl usi o n criteri a  
Patie nts s h o ul d n ot e nter t he st u d y if a n y of t he f oll o wi n g e xcl usi o n criteria are f ulfille d: 
1.  Partici pati o n i n a n ot her cli nical st u d y wit h a n i n vesti gati o nal pr o d uct wit hi n 2 8 da ys pri or t o 
t he first d ose of st u d y treat me nt. 
2.  C o nc urre nt e nr ol me nt  i n  a n ot her  cli nical  st u d y,  u nless  it  is  a n  o bser vati o nal  ( n o n -
i nter ve nti o nal) cli nical st u d y or d uri n g t he f oll o w- u p peri o d of a n i nter v e nti o nal st u d y. 
3.  U nres ol ve d or u nsta bl e A Es fr o m pri or a d mi nistrati o n of a n ot her i n vesti gati o nal dr u g.  
  
4.  A n y c o nc urre nt c h e m ot hera p y, r a diati o n t hera p y, i m m u n ot hera p y, or bi ol o gic t hera p y f or 
ca ncer treat me nt.  
5.  Maj or s ur gical pr o ce d ur e (as defi ne d b y t he i n v esti gat or) wit hi n 2 8 da ys pri or t o t h e first 
d ose of st u d y treat me nt.  
6.  Hist or y of all o ge neic or g a n tra ns pla ntati o n. 
7.  Acti ve or pri or d o c u me nt e d a ut oi m m u ne or i nfla m mat or y dis or ders (i ncl u di n g i nfla m mat or y 
b o wel  diseas e  [ e. g.,  c olitis  or  Cr o h n's  disease],  di vertic ulitis  [ wit h  t he  e xce pti o n  of  
di vertic ul osis], s yste mic l u p us er yt he mat os us, Sarc oi d osis s y n dr o me, or We ge ner s y n dr o me 
[ gra n ul o mat osis  wit h  p ol ya n giitis,  Gra ves'  disease,  r h e u mat oi d  art hritis,  h y p o p h ysitis,  
u veitis, etc]). T he f oll o wi n g are e x ce pti o ns t o t his criteri o n: 
 Patie nts wit h vitili g o or al o pecia  

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 3 7  of 1 0 9 
 
 Patie nts wit h h y p ot h yr oi dis m (e. g., f oll o wi n g Has hi m ot o s y n dr o me) sta ble o n 
h or m o ne re place me nt  
 A n y c hr o nic s ki n c o n diti o n t hat d oes n ot re q uire s yste mic t hera p y 
 Patie nts wit h o ut acti ve disease i n t he last 5 years ma y be i ncl u de d b ut o nl y 
after c o ns ultati o n wit h t he st u d y p h ysicia n 
 Patie nts wit h celiac disease c o ntr olle d b y diet al o n e  
8.  U nc o ntr olle d  i nterc urre nt  ill ness  i ncl u di n g  b ut  n ot  li mite d  t o  o n g oi n g  or  acti ve  i nfecti o n, 
s y m pt o matic c o n gesti ve heart fail ure, u nc o ntr olle d h y perte nsi o n, u nsta ble a n gi na pect oris, 
car diac  arr h yt h mia,  i nterstitial  l u n g  disease,  seri o us  c hr o nic  gastr oi nte sti nal  c o n diti o ns  
ass ociate d wit h diarr h ea, or ps yc hiatric ill ness/s ocial sit uati o ns t hat w o ul d li mit c o m plia nce 
wit h st u d y re q uire me nt, s u bsta ntiall y i ncrease t he ris k of i nc urri n g  A Es, or c o m pr o mise t he 
a bilit y of t he patie nt t o gi ve writte n i nf or me d c o n s e nt. 
9.  Hist or y of a n ot her pri mar y mali g na nc y e x ce pt f or: 
 Mali g na nc y treate d wit h c urati ve i nte nt a n d wit h n o k n o w n acti ve disease ≥5 
years bef ore t he first d ose of st u d y treat me nt a n d of l o w p ote ntial ris k f or 
rec urre nce 
 A de q uatel y  tr eate d  n o n -mela n o ma  s ki n  ca n cer  or  le nti g o  mali g na  wit h o ut 
e vi de nce of disease  
 A de q uatel y treate d carci n o ma i n sit u wit h o ut e vi de nce of dis ease. 
1 0.  Hist or y of acti ve pri mar y i m m u n o deficie nc y.  
1 1.  Acti ve i nfecti o n i ncl u di n g t u berc ul osis (cli nical e val uati o n t hat i ncl u des cli nical hist or y, 
p h ysical e xa m a n d ra di o gra p hic fi n di n gs, a n d t u berc ul osis testi n g i n li ne wit h l ocal practice), 
he p atitis B  ( k n o w n p ositi ve H B V s urface a nti ge n ( H Bs A g) res ult), he p atitis C , or h u m a n  
i m m u n o deficie nc y vir us ( p ositi ve HI V 1/ 2 a nti b o dies). Patie nts wit h a past or res ol ve d 
H B V i nfecti o n ( defi ne d as t he prese nce of he p atitis B c ore a nti b o d y [a nti- H Bc] a n d a bse nce 
of he patitis B s urf ace a nti ge n [ H Bs A g]) are eli gi ble. Patie nts p ositi ve f or h e patitis C ( H C V) 
a ntib o d y are eli gi ble o nl y if p ol y merase c h ai n reacti o n is ne gati ve f or H C V R N A. 
1 2.  C urre nt or pri or use of i m m u n os u p pressi ve me dicati o n wit hi n 1 4 da ys pri or t o t he first d ose 
of st u d y treat me nt. T he f oll o wi n g are e xce pti o ns t o t his criteri o n: 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 3 8  of 1 0 9 
 
 I ntr a nasal,  i n hale d,  t o pical  ster oi ds,  or  l ocal  ster oi d  i njecti o ns  (e. g.,  
i ntraartic ular i njecti o n) 
 S yste mic c ortic oster oi ds at p h ysi ol o gic d oses n ot t o e xcee d 1 0 m g/ da y of 
pre d nis o ne or its e q ui val e nt 
 Ster oi ds as pre me dicati o n f or h y pers e nsiti vit y reacti o ns  
1 3.  Recei pt of li ve atte n uate d vacci ne wit hi n 3 0 da ys pri or t o t he first d ose of st u d y treat me nt. 
N ote: Patie nts, if e nr olle d, s h o ul d n ot recei ve li ve vacci ne w hile recei vi n g st u d y treat me nt 
a n d u p t o 3 0 da ys after t he last d ose of st u d y treat me nt. 
1 4.  Patie nts w h o ar e pr e g na nt or br eastfee di n g or pati e nts of re pr o d u cti ve p ote ntial w h o are n ot 
willi n g t o e m pl o y effecti ve birt h c o ntr ol fr o m scree ni n g t o 7 m o nt hs after t he last d ose of 
st u d y treat me nt. 
1 5.  K n o w n  aller g y  or  h y perse nsiti vit y  t o  a n y  of  t he st u d y  dr u gs  or  a n y  of  t he  st u d y  dr u g 
e xci pie nts. 
1 6.  Patie nts wit h a meas ure me nt of t he mea n Q T i nter val of greater or e q ual t o 4 7 0 ms calc ulate d 
fr o m 3 E K Gs 
1 7.  Patie nts  w h o  ha ve  u n d erl yi n g  car di o vasc ular  c o n diti o ns  t hat  ha ve  rece ntl y  u n der g o ne  
i nter ve nti o ns  i ncl u di n g:  car diac  ve ntric ular  arr h yt h mia  re q uiri n g  me di cati o n,  hist or y  of  
sec o n d or t hir d de gree A V bl oc ks, m y ocar dial i nfarcti o n wit hi n t he pre vi o us year, co n gesti v e 
heart f ail ure, a n d u nsta bl e a n gi na 
1 8.  Patie nts wit h a L V E F less t ha n 5 0 %  
Pr oce d ures f or wit h dra w al of i nc orr ectl y e nr olle d patie nts are prese nte d i n Secti o n 5. 3. 
5. 3  Wit h dr a w al of p atie nts fr o m st u d y tre at me nt a n d/ or st u d y  
5. 3. 1  Per m a ne nt disc o nti n u ati o n of st u d y tre at me nt  
A n i n di vi d ual patie nt will n ot recei ve a n y f urt her st u d y treat me nt if a n y of t he f oll o wi n g occ ur 
i n t he patie nt i n q uesti o n: 
1.  Patie nt or le gal re pr ese nt ati ve wit h dra ws c o ns e nt  
2.  L ost t o f oll o w- u p 

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3. AE that, in the opinion of the investigator or sponsor, contraindicates further dosing 
4. Patient is determined to have met one or more of the exclusion criteria for study participation 
at study entry and continuing investigational therapy might constitute a safety risk. Patients 
who fail to meet the selection criteria should not be enrolled. When patients who do not meet 
the selection criteria in error or incorrectly started on study treatment, or where patients 
subsequently fail to meet the study criteria post-initiation, the patient should have their study 
treatment stopped and be withdrawn from the study. 
5. Confirmed positive serum (β-hCG) pregnancy test or intent to become pregnant 
6. Any AE that meets criteria for discontinuation as defined in Section 6.3 and Appendix 1 
7. Dose interruption that exceeds 3 weeks 
8. Grade ≥3 infusion reaction 
9. Patient non-compliance that, in the opinion of the investigator or sponsor, warrants 
withdrawal; e.g., refusal to adhere to scheduled visits 
10. Initiation of alternative anticancer therapy including another investigational agent 
11. Confirmed radiographic disease progression and investigator determination that the patient 
is no longer benefiting from the study treatment  
When a patient is permanently discontinued from receiving the study treatment prior to study 
completion, all applicable activities scheduled for the final study visit should be performed at the 
time of withdrawal. The patient will continue to be followed for safety unless consent is 
withdrawn or the patient is lost to follow-up or enrolled in another clinical study.  
5.3.2 Withdrawal of consent 
Patients are free to withdraw from the study at any time (study treatment and assessments) 
without prejudice to further treatment. 
Patients who withdraw consent for further participation in the study will not receive any further 
study treatment or further study observation. Note that the patient may be offered additional tests 
or tapering of treatment to withdraw safely. 
A patient who withdraws consent will always be asked about the reason(s) for withdrawal and 
the presence of any AE. The investigator will follow up AEs outside of the clinical study.  

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An individual patient will not receive any further study treatment if any of the following occur 
in the patient in question: 
• 
An AE that, in the opinion of the investigator or AstraZeneca, contraindicates further 
dosing 
• 
Pregnancy or intent to become pregnant 
• 
Non-compliance with the study protocol that, in the opinion of the investigator or 
AstraZeneca, warrants withdrawal from study treatment (e.g., refusal to adhere to 
scheduled visits) 
• 
Initiation of alternative anticancer therapy including another investigational agent 
• 
Clinical progression, i.e. investigator determination that the patient is no longer 
benefiting from the study treatment, with or without radiographic progression 
• 
Any AE that meets criteria for discontinuation as defined in the Dosing Modification and 
Toxicity Management Guidelines (Appendix 1) 
6 STUDY TREATMENT 
6.1 Dosing and administration 
Trastuzumab, pertuzumab, and durvalumab (MEDI4736) will be given for 6 cycles unless there 
is unacceptable toxicity, withdrawal of consent, or another discontinuation criterion is met. Cycle 
length will be 21 days. Trastuzumab, pertuzumab, and durvalumab will be administered 
sequentially as separate IV infusions on Day 1 at each cycle. Trastuzumab will be the first 
infusion, followed by pertuzumab and then durvalumab. Patients will be observed for 30-60 
minutes after each infusion.  
Trastuzumab: 
• 
Loading dose as 8 mg/kg IV infusion over 90 minutes 
• 
Subsequent doses as 6 mg/kg IV infusion over 30–90 minutes Q3W Pertuzumab: 
• 
Loading dose as 840 mg IV infusion over 60 minutes 
• 
Subsequent doses as 420 mg IV infusion over 30–60 minutes Q3W 
Durvalumab: 1120 mg IV infusion over 60 minutes Q3W 

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Results of hematology and clinical chemistry results must be available before commencing an 
infusion. 
Patients will undergo breast MRI and biopsy after completion of 6 cycles of neoadjuvant therapy. 
Patients who have been determined based on biopsy to have achieved RCB 0 and RCB 1 will 
undergo surgery (within 30 days of the final dose of study treatment). Following surgery, RCB 
0 and RCB 1 patients will continue to receive the trastuzumab, pertuzumab, and durvalumab 
(1120 mg Q3W) regimen plus standard-of-care treatment to complete 1 year. Patients who have 
been determined based on biopsy to not have achieved RCB 0 and RCB 1will undergo continued 
neoadjuvant treatment with targeted therapy and chemotherapy per physician’s choice.  
6.2 Durvalumab 
6.2.1 Formulation/packaging/storage 
Durvalumab (MEDI4736) will be supplied by AstraZeneca as a 500-mg vial solution for infusion 
after dilution. The solution contains 50 mg/mL durvalumab (MEDI4736), 26 mM 
histidine/histidine-hydrochloride, 275 mM trehalose dihydrate, and 0.02% weight/volume (w/v) 
polysorbate 80; it has a pH of 6.0 and a density of 1.054 g/mL.  The nominal fill volume is 10.0 
mL.   
Investigational product vials are stored at 2°C to 8°C (36°F to 46°F) and must not be frozen. 
Drug product should be kept in original packaging until use to prevent prolonged light exposure.  
6.2.2 Preparation 
6.2.2.1 Preparation of durvalumab doses for administration with an IV bag 
The dose of durvalumab (MEDI4736) for administration must be prepared using aseptic 
technique. Total time from needle puncture of the durvalumab (MEDI4736) vial to the start of 
administration should not exceed:  
• 
24 hours at 2°C to 8°C (36°F to 46°F) 
• 
4 hours at room temperature 
A dose of 1120 mg will be administered using an IV bag containing 0.9% (w/v) saline or 5% 
(w/v) dextrose, and delivered through an IV administration set with a 0.2- or 0.22-μm filter.  Add 
22.4 mL of durvalumab (MEDI4736) (i.e., 1120 mg of durvalumab [MEDI4736]) to the IV bag. 
The IV bag size should be selected such that the final concentration is within 1 to 15 mg/mL. 
Mix the bag by gently inverting to ensure homogeneity of the dose in the bag. 

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Standard infusion time is 1 hour. In the event that there are interruptions during infusion, the total 
allowed infusion time should not exceed 8 hours at room temperature.  
Do not coadminister other drugs through the same infusion line. 
The IV line will be flushed with a volume of IV diluent equal to the priming volume of the 
infusion set used after the contents of the IV bag are fully administered, or complete the infusion 
according to institutional policy to ensure the full dose is administered.  
If either preparation time or infusion time exceeds the time limits, a new dose must be prepared 
from new vials.  Durvalumab (MEDI4736) does not contain preservatives, and any unused 
portion must be discarded.  
6.2.3 Monitoring of dose administration 
Patients will be monitored before, during, and after the infusion (30-60 minutes). 
In the event of a ≤ Grade 2 infusion-related reaction, the infusion rate of durvalumab may be 
decreased by 50% or interrupted until resolution of the event (up to 4 hours) and re-initiated at 
50% of the initial rate until completion of the infusion. For patients with a ≤ Grade 2 infusion-
related reaction, subsequent infusions may be administered at 50% of the initial rate. 
Acetaminophen and/or an antihistamine (e.g., diphenhydramine) or equivalent medications per 
institutional standard may be administered at the discretion of the investigator. If the infusion-
related reaction is Grade 3 or higher in severity, durvalumab will be discontinued. The standard 
infusion time is 1 hour, however, if there are interruptions during infusion, the total allowed time 
from infusion start to completion of infusion should not exceed 4 hours at room temperature, 
with maximum total time at room temperature not exceeding 4 hours (otherwise requires new 
infusion preparation). For management of patients who experience an infusion reaction, please 
refer to the Dosing Modification and Toxicity Management Guidelines in Appendix 1. 
As with any antibody, allergic reactions to dose administration are possible. Appropriate drugs 
and medical equipment to treat acute anaphylactic reactions must be immediately available, and 
study personnel must be trained to recognize and treat anaphylaxis. The study site must have 
immediate access to emergency resuscitation teams and equipment in addition to the ability to 
admit patients to an intensive care unit if necessary. 
6.2.4 Accountability and dispensation 
The study drug provided for this study (durvalumab) is for use as directed in the study protocol. 
It is the investigator’s/institution’s responsibility to establish a system for handling 
investigational products so as to ensure that: 

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• 
Deliveries of such products from AstraZeneca are correctly received by a responsible person 
• 
Such deliveries are recorded 
• 
Such products are handled and stored safely and properly as stated on the label 
• 
Such products are only dispensed to study patients in accordance with the protocol 
The investigational staff will account for investigational product dispensed and returned. 
At the end of the study, it must be possible to reconcile delivery records with records of usage 
and destroyed/returned stock. Records of usage should include identification of the person to 
whom the investigational product was dispensed, the quantity and date of dispensing and unused 
investigational product returned to the investigator. This record is in addition to any drug 
accountability information recorded on the case report form (CRF). Any discrepancies must be 
accounted for on the appropriate forms. Certificates of delivery and return must be signed, 
preferably by the investigator or qualified designee or a pharmacist. 
6.3 Toxicity management guidelines  
Any toxicity observed during the course of the study can be managed by interruption of the dose 
of study treatment. Dose reductions for trastuzumab, pertuzumab, and durvalumab are not 
permitted. Repeat dose interruptions are allowed as required, for a maximum of 3 weeks on 
each occasion. If an interruption of longer than 3 weeks is required, the patient should be 
withdrawn. When a patient withdraws prior to study completion, all applicable activities 
scheduled for the final study visit should be performed at the time of withdrawal. Any AEs that 
are present at the time of withdrawal should be followed as described in Section 8.1.4.1.   
6.3.1 Durvalumab  
Guidelines for the management of imAEs, infusion-related reactions, and non-imAEs for 
durvalumab are provided in the durvalumab Dosing Modification and Toxicity Management 
Guidelines in Appendix 1. The most current version of the durvalumab Toxicity Management 
Guidelines is also available through the following link: https://tmg.azirae.com.   
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. 

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In addition, there are certain circumstances in which durvalumab should be permanently 
discontinued (see Dosing Modification and Toxicity Management Guidelines in Appendix 1). 
Following the first dose, subsequent administration of durvalumab can be modified based on 
toxicities observed as described in the Dosing Modification and Toxicity Management 
Guidelines in Appendix 1. These guidelines apply to AEs considered causally related to 
durvalumab by the reporting investigator. 
All toxicities will be graded according to the NCI CTCAE v5.  
6.3.2 Trastuzumab and pertuzumab 
Left ventricular dysfunction 
Trastuzumab and pertuzumab can result in subclinical and clinical cardiac failure manifesting as 
decreased LVEF and congestive heart failure. Dose modifications for left ventricular dysfunction 
are shown in Table 1. 
 
 

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Table 1: Dose Modifications for Left Ventricular Dysfunction 
Withhold trastuzumab and pertuzumab for 
an LVEF decrease to: 
Resume trastuzumab and pertuzumab if 
LVEF has recovered to: 
Either 
Either 
<40% 
40−45% with a fall of 
≥10% points below 
pretreatment value 
>45% 
40−45% with a fall of 
<10% points below 
pretreatment value 
<50% with a fall of ≥10% points below  
Either 
pretreatment value 
≥50% 
<10% points below 
pretreatment value 
LVEF = left ventricular ejection fraction.  
Infusion-related reactions  
Pertuzumab administration can result in infusion-related reactions. Common reactions include 
pyrexia, chills, fatigue, headache, hypersensitivity, asthenia, and vomiting. The majority of 
reactions are Grade 1 or 2, with less than 1% being Grade 3 or 4. 
  
• 
Decrease the rate of infusion for mild or moderate infusion reactions 
• 
Interrupt the infusion in patients with dyspnea or clinically significant hypotension 
• 
Discontinue infusion for severe or life-threatening infusion reactions  
Trastuzumab administration can result in serious and fatal infusion-related reactions and 
pulmonary toxicity. Symptoms usually occur during or within 24 hours of trastuzumab 
administration.  
• 
Interrupt infusion for dyspnea or clinically significant hypotension 
• 
Discontinue infusion for anaphylaxis, angioedema, interstitial pneumonitis, or acute 
respiratory distress syndrome. 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 4 6  of 1 0 9 
 
7  Restricti o ns d uri n g t he st u d y a n d c o nc o mit a nt tre at me nt(s)  
7. 1  Restricti o ns d uri n g t he st u d y  
7. 1. 1  C o ntr ace pti o n  
T he  f oll o wi n g  restricti o ns  a p pl y  w hile  t he  patie nt  is  recei vi n g  st u d y  treat me nt  a n d  f or  t he  
s pecifie d ti mes bef ore a n d after: 
Fe male p atie nt of c hil d beari n g p ote ntial  
 Fe male patie nts of c hil d beari n g p ote ntial w h o are n ot a bsti ne nt a n d i nte n d t o 
be se x uall y acti ve wit h a n o n -sterilize d male p art n er m ust use at least 1 hi g hl y  
effecti ve  met h o d  of  c o ntrace pti o n  ( Ta ble  2)  fr o m  t he  ti me  of  scree ni n g  
t hr o u g h o ut t he t otal d urati o n of t he st u d y treat me nt a n d 7 m o nt hs after t he l ast 
d ose of st u d y treat me nt. N o n -sterilize d m ale part ners of a fe m ale patie nt of 
c hil d beari n g p ote ntial m ust use male c o n d o m pl us s per mici de t hr o u g h o ut t his 
peri o d. Cessati o n of birt h c o ntr ol after t his p oi nt s h o ul d be disc usse d wit h a 
res p o nsi ble  p h ysicia n.  Peri o dic  a bsti ne nce,  t he  r h yt h m  met h o d,  a n d  t he  
wit h dra wal  met h o d  are  n ot  acce pta ble  met h o ds  of  birt h  c o ntr ol.  Fe male  
patie nts s h o ul d als o refrai n fr o m breastfee di n g t hr o u g h o ut t his peri o d. 
Fe males of c hil d beari n g p ote ntial are defi ne d as t h ose w h o are n ot s ur gicall y sterile (i. e., bilateral 
sal pi n gect o m y, bilateral o o p h orect o m y, or c o m pl ete h ysterect o m y) or p ost me n o pa usal.   
W o me n will be c o nsi dere d p ost me n o pa usal if t he y ha ve b ee n a me n orr heic f or 1 2 m o nt hs wit h o ut 
a n alter nati ve m e dical ca use.  T he f oll o wi n g a ge-s pecific re q uire me nts a p pl y: 
  
 W o me n < 5 0 years of a g e w o ul d be c o nsi dere d p ost me n o pa usal if t he y ha ve 
bee n a m e n orr h eic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of e x o ge n o us 
h or m o nal  treat me nts  a n d  if  t he y  ha ve  L H  a n d  F S H  le vels  i n  t he  
p ost me n o pa usal ra n ge f or t he i nstit uti o n. 
 W o me n ≥5 0 y ears of a g e w o ul d b e c o nsi dere d p ost me n o pa usal if t h e y ha ve 
bee n a me n orr heic f or 1 2 m o nt hs or m ore f oll o wi n g cessati o n of all e x o ge n o us 
h or m o nal treat me nts, ha d ra diati o n -i n d uce d me n o pa use wit h last me nses > 1 
year a g o, ha d c he m ot hera p y -i n d uce d me n o pa use wit h last me nses > 1 year a g o, 
or  u n der we nt  s ur gical  sterilizati o n  ( bilateral  o o p h orect o m y,  bilateral  
sal pi n gect o m y, or h ysterect o m y). 
Hi g hl y effecti ve met h o ds of c o ntrace pti o n, defi n e d as o ne t hat res ults i n a l o w fail ure rate (i. e., 
less t ha n 1 % p er y ear) w he n use d c o nsiste ntl y a n d c orrectl y are d escri b e d i n Ta ble 2. N ote t hat 
s o me c o ntrace pti o n met h o ds are n ot c o nsi dere d hi g hl y effecti ve (e. g., mal e or fe male c o n d o m 

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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). 
 
 

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Table 2: Highly Effective Methods of Contraception (<1% Failure Rate) 
 
Barrier/Intrauterine Methods 
Hormonal Methods 
 
Copper T intrauterine device Implants: 
Etonogestrel-releasing 
implants: 
Levonorgestrel-
releasing intrauterine system  
e.g., Implanon® or Norplant®  
(e.g., Mirena®)a 
Intravaginal: Ethinylestradiol/etonogestrel- 
releasing intravaginal devices: e.g.,  
NuvaRing®  
Injection: Medroxyprogesterone injection: 
e.g., Depo-Provera®  
Combined Pill: Normal and low dose 
combined oral contraceptive pill 
Patch: 
Norelgestromin/ethinylestradiolreleasi
ng transdermal system: e.g., Ortho  
Evra®  
Minipill: Progesterone-based oral 
contraceptive pill using desogestrel: 
Cerazette® is currently the only highly  
effective progesterone-based contraceptive 
pill 
 
aThis is also considered a hormonal method. 
Blood donation 
Patients should not donate blood while participating in this study and for 3 months after the last 
dose of study treatment. 
7.2 Concomitant treatment(s) 
All medications that the investigator considers necessary for a patient’s welfare may be 
administered at the discretion of the investigator in keeping with the community standards of 
medical care. All concomitant medication will be recorded in the CRF including all prescription, 
over-the-counter, and IV medications and fluids. If changes occur during the study period, 
documentation of drug dosage, frequency, route, and date may also be included in the CRF. 

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All concomitant medications received within 28 days before the first dose of study treatment and 
30 days after the last dose of study treatment should be recorded. All concomitant medications 
should be recorded in the CRF including supportive care drugs and the drugs used to treat AEs 
or chronic diseases as well as non-drug supportive interventions. The use of any natural/herbal 
products or other traditional remedies should be discouraged, but use of these products, as well 
as use of all vitamins, nutritional supplements, and all other concomitant medications must be 
recorded in the CRF. 
7.2.1 Permitted concomitant medications 
Table 3: Supportive Medications 
Supportive medication/class of drug: 
Usage: 
Concomitant  
medications  
or  
treatments 
(e.g., 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) 
Should be used, when necessary, for all 
patients 
Inactivated viruses, such as those in the influenza 
vaccine 
Permitted 
 
7.2.2 Prohibited concomitant medications 
Table 4: 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 while 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 while the patient is 
on study treatment 
Any 
concurrent 
chemotherapy, 
immunotherapy, or biologic therapy for cancer 
treatment other than those under investigation 
in this study 
Should not be given concomitantly while the patient is 
on study treatment.  

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Immunosuppressive medications including, but 
not limited to, systemic corticosteroids at doses 
exceeding 10 mg/day of prednisone or 
equivalent, methotrexate, azathioprine, and 
tumor necrosis factor-α blockers 
Should not be given concomitantly or used for 
premedication prior to durvalumab infusions. The 
following are allowed exceptions: 
• 
Use of immunosuppressive medications for 
the management of study treatment-related 
AEs 
• 
Short-term premedication for prophylaxis of 
trastuzumab/pertuzumab 
hypersensitivity 
reactions 
• 
Use in patients with contrast allergies 
• 
Use of inhaled, topical, and intranasal  
corticosteroids  
A temporary period of steroids will be allowed if 
clinically indicated and considered to be essential for 
the management of non−immunotherapy-related 
events experienced by the patient (e.g., chronic 
obstructive pulmonary disease, nausea, etc). 
EGFR 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. 
Live attenuated vaccines 
Should not be given through 30 days after the last dose 
of study treatment 
Herbal and natural remedies that may have 
immune-modulating effects 
Should not be given concomitantly  
EGFR TKI = epidermal growth factor receptor tyrosine kinase inhibitor; mAb = monoclonal antibody. 
8 STUDY PROCEDURES 
8.1 Schedule of study procedures 
Before study entry, throughout the study, and following study drug discontinuation, various 
clinical and diagnostic laboratory evaluations are outlined. The purpose of obtaining these 
detailed measurements is to ensure adequate safety and tolerability assessments. Clinical 
evaluations and laboratory studies may be repeated more frequently if clinically indicated. The 
Schedule of Assessments during screening/baseline, treatment, and end of treatment (EOT) 
phases is provided following the Protocol Synopsis. 

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8.1.1 Screening phase 
Screening procedures will be performed up to 28 days before Cycle 1, Day 1. All patients must 
first read, understand, and sign the institutional review board (IRB)-approved ICF before any 
study-specific screening procedures are performed. After signing the ICF, completing all 
screening procedures, and being deemed eligible for entry, patients will be enrolled in the study. 
Procedures that are performed prior to the signing of the ICF and are considered standard of care 
may be used as screening assessments if they fall within the 28-day screening window, unless 
otherwise specified.  
The following assessments and procedures should be performed within 28 days prior to the first 
dose of study treatment: 
• 
Informed consent 
• 
Review of eligibility criteria 
• 
Medical history and demographics 
• 
Review of prior/concomitant medications  
• 
Physical exam  
• 
ECOG performance status 
• 
Vitals signs (blood pressure, respiratory rate, pulse, oral or temporal temperature), 
weight, and height  
• 
12-lead electrocardiogram (ECG) 
• 
MUGA scan or ECHO. The same method must be used throughout the duration of the 
study. 
• 
Clinical laboratory tests for: o Hematology (Table 5) o Clinical chemistry (Table 6) 
o Serum (β-hCG) pregnancy test (for women of childbearing potential only) 
o Hepatitis B and C and HIV 
• 
AEs must be captured from the time of consent 
Findings from medical history (obtained at screening) and physical exam shall be given a 
baseline grade according to the procedure for AEs. Increases in severity of preexisting 
conditions during the study will be considered AEs, with resolution occurring when the grade 
returns to the ≤ Grade 1 or baseline. 
 
 

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Table 5: Hematology Laboratory Tests 
Basophils 
MCV 
Eosinophils 
Hematocrit 
Monocytes  
Hemoglobin 
Neutrophils 
Platelet count 
Lymphocytes 
RBC count 
MCH 
Total WBC count 
MCHC 
ANC 
ANC = absolute neutrophil count; MCH = mean corpuscular hemoglobin; MCHC = 
mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC 
= red blood cell; WBC = white blood cell. 
 
 
Table 6: Clinical Chemistry Laboratory Tests 
Albumin 
Glucose 
ALP 
LDH 
ALT 
Uric acid 
AST 
Potassium 
BUN 
Sodium 
Chloride  
TB 
Creatinine 
Carbon dioxide 
Total 
protein 
Amylase 
Calcium 

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 5 3  of 1 0 9 
 
A L P  =  al kali ne  p h os p hatase;  A L T  =  ala ni ne  tra nsa mi nase;  A S T  =  as partate 
tra nsa mi nase; B U N = bl o o d urea nitr o ge n; L D H = lactate de h y dr o ge nase; T B = t otal 
bilir u bi n.  
 
8. 1. 2  B aseli ne p h ase  
T he f oll o wi n g assess me nts a n d pr oce d ures s h o ul d be perf or m e d wit hi n 7 da ys pri or t o t he first 
d ose of st u d y treat me nt: 
• 
P h ysical  e xa m  i ncl u di n g  vital  si g n  ( bl o o d  press ure,  res pirat or y  rate,  p ulse,  oral  or  
te m p oral te m perat ure) a n d wei g ht meas ure m e nts 
• 
E C O G perf or ma nce stat us  
• 
T h yr oi d-sti m ulati n g h or m o ne ( T S H)  C li nical la b orat or y tests f or: 
o  He mat ol o g y ( Ta ble 5) o  Cli nical c he mistr y ( Ta ble 6)  
o  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  will  be  
perf or me d at baseli ne a n d w he n cli nicall y  
o  Uri nal ysis b y di pstic k will be perf or m e d at b aseli ne a n d w h e n cli nicall y  i n dicate d 
( Ta ble 7) 
• 
Ma m m o gra m,  breast  ultras o u n d,  a n d  breast  ma g netic  res o na n ce  i ma gi n g  ( M RI).  
Ma m m o gra m  a n d  breast  ultras o u n d  perf or me d  as  sta n dar d  of  care  ca n  be  use d  f or  
baseli ne if perf or me d wit hi n 9 0 da ys pri or t o t he C ycle 1, Da y 1 d os e of trast uz u ma b, 
pert uz u ma b, a n d d ur v al u ma b. Breast M RI perf or me d as sta n dar d of care ca n be use d f or 
baseli ne if perf or me d wit hi n 6 0 da ys pri or t o t he C ycle 1, Da y 1 d os e of trast uz u ma b, 
pert uz u ma b, a n d d ur val u ma b. 
• 
C ore bi o ps y a n d c ollecti o n of t u m or tiss ue 
• 
Researc h bl o o d c ollecti o n f or circ ul ati n g D N A 
O nl y scree ni n g pr o ce d ur es n ot perf or me d wit hi n 7 da ys pri or t o t he first d ose of st u d y treat me nt 
are r e q uire d at baseli ne.  
T a ble 7: Uri n al ysis Tests a 
 
Bilir u bi n  
p H  
Bl o o d 
Pr otei n  

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Glucose 
Specific gravity 
Ketones 
Color and appearance 
 
aMicroscopy should be used as appropriate to investigate white blood cells and use the high-power field for red 
blood cells. 
8.1.3 Treatment phase  
Assessments will be performed at the time points specified in the Schedule of Assessments. A 
window of ± 5 days is allowed for study visits and assessments (except as otherwise specified). 
EOT is defined as 7 to 10 days after the last dose of study treatment. Note: All assessments on 
infusion days are to be performed prior to infusion. Results of hematology and clinical chemistry 
results must be available before commencing an infusion. 
8.1.3.1 Adverse event monitoring 
The investigator or qualified designee will assess each patient to evaluate for potential new or 
worsening AEs from the time of ICF signing through 30 days after the last dose of study 
treatment. AEs will be graded and recorded throughout the study and during the follow-up period 
according to the NCI CTCAE v5. Toxicities will be characterized in terms of seriousness, 
causality, toxicity grading, and action taken with regard to the study treatment.  
Refer to Section 9 for detailed information regarding the assessment and recording of AEs. 
8.1.3.2 Physical exam 
Physical exam including vital sign (blood pressure, respiratory rate, pulse, oral or temporal 
temperature) and weight measurements will be performed before every cycle and at EOT.  
8.1.3.3 ECOG performance status 
ECOG performance status assessment will be performed before every cycle and at EOT.  
8.1.3.4 12-Lead ECG and MUGA scan or ECHO 
Twelve-lead ECG will be performed after Cycle 2, at EOT, and when clinically indicated. 
Resting 12-lead ECGs will 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, 2 additional 12-lead ECGs should be 
obtained over a brief period (e.g., 30 minutes) to confirm the finding.   

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Situations in which ECG results should be reported as AEs are described in Section 9.3.5. 
MUGA scan or ECHO will be performed after Cycle 2, at EOT, and when clinically indicated.  
The same method must be used throughout the duration of the study. 
8.1.3.5 Tumor imaging and disease assessment  
Mammogram and breast ultrasound will be repeated after Cycle 3 (+/- 3 days) and EOT, as per 
standard of care. 
Breast MRI will be performed at EOT. 
8.1.3.5.1 Response Evaluation Criteria in Solid Tumors 1.1 
The Response Evaluation Criteria in Solid Tumors 1.1 will be used to assess treatment response. 
All measurable lesions (up to 5 measurable lesions [2/organ]) representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. A sum of 
the longest diameter for all target lesions will be calculated and reported as the baseline sum 
longest diameter.  
• 
Complete Response (CR) 
Disappearance of all target lesions.  
• 
Partial Response (PR) 
At least a 30% decrease in the sum of the longest diameter of target lesions, using the baseline 
sum longest diameter as a reference. 
• 
Stable Disease (SD)  
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive 
disease (PD), using the smallest sum longest diameter recorded since treatment start as a 
reference. 
• 
PD 
At least a ≥20% increase in the sum of the longest dimensions of the target lesions taking as a 
reference the smallest sum longest diameter recorded since treat start, or the appearance of one 
or more new lesions. In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm. 
• 
Clinical PD 
Patients who in the opinion of the treating principal investigator have clinical evidence of PD 
may be classified as having PD. 

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8.1.3.6 Laboratory procedures/assessments 
8.1.3.6.1 Hematology and clinical chemistry 
Hematology and clinical chemistry will be performed before every cycle, at EOT, and when 
clinically indicated. Hematology and clinical chemistry assessments to be performed are listed 
in Tables 5 and 6 (Section 8.1.1 − Screening phase). 
Any clinically significant abnormal laboratory values should be repeated as clinically indicated 
and recorded in the CRF. Situations in which laboratory safety results should be reported as AEs 
are described in Section 9.3.5. 
If a patient shows an AST or ALT ≥3 × ULN together with TB ≥2 × ULN, refer to Appendix 1 
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.  
8.1.3.6.2 Thyroid-stimulating hormone 
TSH will be measured before every cycle, at EOT, and when clinically indicated. If TSH is 
measured within 14 days prior to Cycle 1, Day 1, it does not need to be repeated at Cycle 1, Day 
1.  
Free triiodothyronine or free thyroxine will only be measured if TSH is abnormal or if there is a 
clinical suspicion of an AE related to the endocrine system.  
8.1.3.7 Correlative studies 
Correlative studies will include tissue and blood-based evaluation of molecular and genetic 
biomarkers of response and resistance to durvalumab with trastuzumab and pertuzumab 
combination. 
8.1.3.7.1  Tumor tissue collection 
All patients will have biopsy at EOT. Tissue will also be collected at the time of surgery. 
Collected biopsy and surgical tissues will be used for determination of pathological response and 
correlative studies. RNA will be extracted from de-identified tissue blocks collected during the 
trial and provided to IDIBAPS Hospital Clinic Barcelona for additional correlative studies at the 
following address: 
IDIBAPS Hospital Clinic Barcelona 
Casanova 143 
08036 Barcelona 

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8.1.3.7.2 Blood collection for plasma circulating DNA analysis 
Blood sample collection for plasma circulating DNA analysis will be performed after Cycle 2 
and at EOT.  
8.1.4 Other procedures 
8.1.4.1 Safety follow-up  
The safety follow-up visit should be conducted approximately 30 days after the last dose of study 
treatment or before the initiation of a new anticancer therapy, whichever comes first. All AEs 
that occur prior to the safety follow-up visit should be recorded. Patients with an AE of > Grade 
1 will be followed until the resolution of the AE to ≤ Grade 1 or baseline. SAEs that occur within 
30 days of EOT should also be followed and recorded.   
8.1.4.2 Disease-free survival follow-up 
Mammogram and breast ultrasound will be performed post-surgery (± 7 days) per standard of 
care until second primary cancer, relapse, death, or withdrawal of consent. Computed 
tomography will be performed when clinically indicated. 
9 ASSESSMENT OF SAFETY 
The principal investigator is responsible for ensuring that all staff involved in the study are 
familiar with the content of this section. 
9.1 Safety parameters 
9.1.1 Definition of adverse events 
The International Council on Harmonization (ICH) Guideline for Good Clinical Practice (GCP) 
E6(R1) defines an AE as: 
Any untoward medical occurrence in a patient or clinical investigation patient administered a 
pharmaceutical product and which does not necessarily have a causal relationship with this 
treatment. An AE can, therefore, be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
An AE includes but is not limited to any clinically significant worsening of a patient’s preexisting 
condition. An abnormal laboratory finding (including ECG finding) that requires an action or 
intervention by the investigator, or a finding judged by the investigator to represent a change 
beyond the range of normal physiologic fluctuation, should be reported as an AE. 

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AEs may be treatment emergent (i.e., occurring after initial receipt of investigational product) or 
non-treatment emergent. A non−treatment-emergent AE is any new sign or symptom, disease, 
or other untoward medical event that begins after written informed consent has been obtained 
but before the patient has received investigational product.  
Elective treatment or surgery or preplanned treatment or surgery (that was scheduled prior to the 
patient being enrolled into the study) for a documented preexisting condition, that did not worsen 
from baseline, is not considered an AE (serious or non-serious). An untoward medical event 
occurring during the prescheduled elective procedure or routinely scheduled treatment should be 
recorded as an AE or SAE. 
The term AE is used to include both serious and non-serious AEs. 
9.1.2 Definition of serious adverse events 
A SAE is an AE occurring during any study phase (i.e., screening, run-in, treatment, wash-out, 
follow-up), at any dose of the study drugs that fulfills one or more of the following criteria: 
• 
Results in death 
• 
Is immediately life threatening 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization  
• 
Results in persistent or significant disability or incapacity  
• 
Is a congenital abnormality or birth defect in offspring of the patient 
• 
Is an important medical event that may jeopardize the patient or may require 
medical intervention to prevent one of the outcomes listed above 
o Medical or scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in this 
situation. Examples of medically important events are 
intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions 
that do not result in hospitalizations; or development of 
drug dependency or drug abuse. 
The causality of SAEs (their relationship to all study treatment/procedures) will be assessed by 
the investigator(s) and communicated to AstraZeneca. 
9.1.3 Definition of adverse events of special interest (AESIs) 
An AE of special interest (AESI) is one of scientific and medical interest specific to the 
understanding of durvalumab and may require close monitoring. An AESI may be serious or 
nonserious.  

Cli nical St u d y Pr ot oc ol  
Dr u g S u bsta nce D ur val u ma b ( M E DI 4 7 3 6)  
A Z St u d y N u m ber E S R -1 8 -1 3 4 8 9; v 4 _ 1 2 N o v 1 8 
H M RI Versi o n N u m ber 1 4 . 0 
H M RI Date  1 0 Se pte m ber 2 0 2 4 
Pa ge 5 9  of 1 0 9 
 
If t he i n vesti gat or has a n y q uesti o ns i n re gar ds t o a n e ve nt bei n g a n i m A E, t he i n vesti gat or s h o ul d 
pr o m ptl y c o ntact Astra Z e neca.  
A E SIs o bser ve d wit h d ur val u ma b i ncl u de: 
• 
Diarr hea / C olitis a n d i ntesti nal perf orati o n  
• 
P ne u m o nitis / I L D  
• 
He patitis / Tra nsa mi nase i ncreas es  
• 
E n d ocri n o pat hies  (i. e.,  e ve nts  of  h y p o p h ysitis/ h y p o pit uitaris m,  a dre nal  
i ns ufficie nc y,  h y p ert h yr oi dis m  a n d  h y p ot h yr oi dis m,  a n d  t y pe  I  dia b etes  
mellit us)  
• 
Ras h / Der matitis  
• 
Ne p hritis / Bl o o d creati ni ne i ncreases  
• 
Pa ncreatitis  / Ser u m li pase a n d a m ylase i n creases   
• 
M y ocar ditis 
• 
M y ositis / P ol y m y ositis  
• 
Ne ur o pat h y / Ne ur o m usc ular t o xicit y (e. g., G uillai n -Barré, m yast he nia gra vis) 
 Intesti nal Perf orati o n  
• 
Ot her i nfla m mat or y res p o nses t hat are rare / less fre q u e nt wit h a p ote ntial 
i m m u ne-me diate d  eti ol o g y  i ncl u de,  b ut  are  n ot  li mite d  t o,  pericar ditis,  
sarc oi d osis, u veitis a n d ot her e ve nts i n v ol vi n g t he e ye, s ki n, he mat ol o gical, 
a n d r he u mat ol o gical e ve nts. 
I n  a d diti o n,  i nf usi o n-r elate d  r eacti o ns  a n d  h y perse nsiti vit y/a na p h ylactic  reacti o ns  wit h  a  
differe nt u n d erl yi n g p har mac ol o gical eti ol o g y are als o c o nsi dere d A E SIs. 
F urt her i nf or mati o n o n t h ese ris ks ( e. g., prese nti n g s y m pt o ms) 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. M ore s pecific g ui d eli nes f or t heir e val uati o n a n d treat me nt are des cri be d 
i n detail i n t he D osi n g M o dificati o n a n d T o xicit y Ma na ge me nt G ui deli nes i n A p pe n di x 1. T hese 
g ui deli nes a p pl y t o A Es c o nsi dere d ca usall y relate d t o d ur val u ma b b y t he re p orti n g i n vesti gat or.  
9. 2  Assess me nt of s afet y p ar a meters  
9. 2. 1  Assess me nt of se verit y  
Assess me nt of se v erit y is o ne of t h e res p o nsi bilities of t he i n vesti gat or i n t h e e val u ati o n of A Es 
a n d S A Es. Se verit y will be gra de d acc or di n g t o t he N CI C T C A E v 5. 
It is i m p orta nt t o disti n g uis h bet wee n seri o us criteria a n d se verit y of a n A E. Se verit y is a meas ure 
of i nte nsit y w hereas seri o us ness is defi ne d b y t he criteria i n Secti o n 9. 1. 2. A Gra de 3 A E nee d 
n ot necessaril y be c o nsi d ere d a n S A E. F or e x a m ple, a Gra de 3 hea d ac h e t hat persists f or se v eral 

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hours may not meet the regulatory definition of an SAE and would be considered a non-serious 
event, whereas a Grade 2 seizure resulting in a hospital admission would be considered an SAE. 
9.2.2  Assessment of relationship 
A guide to the interpretation of the causality question is found in the Dosing Modification and 
Toxicity Management Guidelines in Appendix 1. 
9.3 Recording of adverse events and serious adverse events 
AEs and SAEs will be collected from the time of the patient signing the ICF until the follow-up 
period is completed (30 days after the last dose of study treatment). If an event that starts post 
the defined safety follow-up period noted above is considered to be due to a late onset toxicity 
to study treatment then it should be reported as an AE or SAE, as applicable. 
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient for as long as the event is ongoing.  Every effort should be made to obtain a resolution 
for all events, even if the events continue after the patient has discontinued study treatment or 
the study has completed. 
Any AEs that are unresolved at the patient’s last study visit are followed up by the investigator 
for as long as medically indicated, 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. 
The following variables will be collected for each AE: 
In addition, the following variables will be collected for SAEs, as applicable: 
• 
AE (verbatim) 
• 
The date when the AE started and stopped 
• 
The maximum CTCAE grade reported 
• 
Changes in CTCAE grade 
• 
Whether the AE is serious or not 
• 
Investigator causality rating against the study treatment (yes or no) 

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• 
Action taken with regard to study treatment 
• 
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 fulfilled 
• 
Date of hospitalization 
• 
Date of discharge 
• 
Probable cause of death 
• 
Date of death 
• 
Whether an autopsy was performed 
• 
Causality assessment in relation to study procedure(s) 
• 
Causality assessment in relation to other medication, as explained in 
Section 9.2.2 
• 
Description of the SAE 
The grading scales found in the NCI CTCAE v5 will be utilized for all events with an assigned 
CTCAE grading. A copy of the CTCAE v5 can be downloaded from the Cancer Therapy 
Evaluation Program website (http://ctep.cancer.gov). 
Events, which are unequivocally due to disease progression, should not be reported as an AE 
during the study. 

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9.3.1  Study recording period and follow-up for adverse events and serious 
adverse events 
AEs and SAEs will be recorded from time of signature of informed consent, throughout the 
treatment period, and the follow-up period (30 days after the last dose of study treatment).  
During the course of the study, all AEs and SAEs should be proactively followed up for each 
patient. Every effort should be made to obtain a resolution for all events, even if the events 
continue after discontinuation/study completion. 
The investigator is responsible for following all SAEs until resolution, until the patient returns 
to baseline status, or until the condition has stabilized with the expectation that it will remain 
chronic, even if this extends beyond study participation. 
9.3.2 Causality collection 
The investigator will assess causal relationship between the study treatment 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 study treatment?” 
For SAEs, causal relationship will the study treatment and study procedures will also be assessed. 
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 the Dosing Modification and 
Toxicity Management Guidelines in Appendix 1. 
9.3.3  Relationship to protocol procedures 
The investigator is also required to provide an assessment of the relationship of SAEs to protocol 
procedures on the SAE report form. This includes both non−treatment-emergent (i.e., SAEs that 
occur prior to the administration of study treatment) and treatment-emergent SAEs. A 
protocolrelated SAE may occur as a result of a procedure or intervention required during the 
study (e.g., blood collection). The following guidelines should be used by the investigator to 
assess the relationship of SAEs to the protocol: 
• 
Protocol related: The event occurred due to a procedure or intervention that was 
described in the protocol for which there is no alternative etiology present in the 
patient’s medical record. 

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• 
Not protocol related: The event is related to an etiology other than the procedure or 
intervention that was described in the protocol. The alternative etiology must be 
documented in the study patient’s medical record. 
9.3.4 Adverse events based on signs and symptoms 
All AEs spontaneously reported by the patient or reported in response to the open question from 
the study personnel: “Have you 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. 
9.3.5 Adverse events based on examinations and tests 
Deterioration as compared to baseline in protocol-mandated laboratory values and vital signs 
should, therefore, only be reported as AEs if they fulfill any of the SAE criteria or are the reason 
for discontinuation of study treatment. 
If deterioration in a laboratory value or vital sign is associated with clinical signs and symptoms, 
the sign or symptom will be reported as an AE and the associated laboratory result or vital sign 
will be considered as additional information. Whenever possible, the reporting investigator 
should use the clinical rather than the laboratory term (e.g., anemia versus low hemoglobin 
value). In the absence of clinical signs or symptoms, clinically relevant deteriorations in non-
mandated parameters should be reported as AEs. 
Deterioration of a laboratory value that is unequivocally due to disease progression should not 
be reported as an AE/SAE. 
Any new or aggravated clinically relevant abnormal medical finding at a physical exam as 
compared with the baseline assessment will be reported as an AE. 
9.3.6  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 TB ≥2 × ULN may need to be reported as 
SAEs. Please refer to Appendix 1 for further instruction on cases of increases in liver 
biochemistry and evaluation of Hy’s law. 

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9.3.7  Disease progression 
Disease progression can be considered as a worsening of a patient’s condition attributable to the 
disease for which the study treatment 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 
metastasis to the primary cancer under study should be considered as disease progression and 
not an AE. Events that are unequivocally due to disease progression should not be reported as an 
AE during the study. 
9.3.8 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 study treatment and have been 
identified after the patient’s inclusion in this study. 
9.3.9 Deaths 
All deaths that occur during the study treatment period, or within the protocol-defined follow-up 
period after the administration of the last dose of study drug, must be reported as follows: 
• 
Death clearly resulting from disease progression should be reported to the sponsor and 
AstraZeneca. The event 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 
 
sponsor (CTOMgmt@houstonmethodist.org)  
and  
AstraZeneca  
(AEMailboxClinicalTrialTCS@astrazeneca.com) as an SAE within 24 hours. It 
should also be documented in the Statement of Death page in the CRF. The report 
should contain a comment regarding the coinvolvement of disease progression, 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 postmortem may be 
helpful in the assessment of the cause of death, and if performed, a copy of the 
postmortem 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 (30 days after the 
administration of the last dose of study treatment) should be documented in the Statement of 
Death page. If the death occurred as a result of an event that started after the defined safety follow 

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upperiod and the event is considered to be due to a late onset toxicity to study treatment, then it 
should also be reported as an SAE. 
AstraZeneca/MedImmune 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. 
Follow-up of unresolved adverse events 
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, but without further recording in the CRF. After 
30 days, only patients with ongoing study treatment-related SAEs will continue to be followed 
for safety. 
AstraZeneca/MedImmune 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. 
Post-study events 
After the patient has been permanently withdrawn from the study, there is no obligation for the 
investigator to actively report information on new AEs or SAEs occurring in former study 
patients after the 30-day safety follow-up period. However, if an investigator learns of any SAEs, 
including death, at any time after the patient has been permanently withdrawn from study, and 
he/she considers there is a reasonable possibility that the event is related to the study treatment, 
the investigator should notify the study sponsor and AstraZeneca/MedImmune Drug Safety. 
9.3.10 Reporting of serious adverse events 
All SAEs will be reported, whether or not considered causally related to the study treatment or 
to the study procedure(s). The reporting period for SAEs is the period immediately following the 
time that written informed consent is obtained through 30 days after the last dose of study 
treatment or until the initiation of alternative anticancer therapy. The investigator or qualified 
designee are responsible for informing the FDA (via the Houston Methodist Research Institute 
Office of Regulatory Affairs & Translational Management) and IRB of the SAE as per local 
requirements. 
The investigator or qualified designee must inform the FDA, via a MedWatch/AdEERs form, of 
any serious or unexpected AEs that occur in accordance with the reporting obligations of 21 CFR 
312.32. This will be done through the Houston Methodist Research Institute Office of Regulatory 
Affairs & Translational Management. A copy of the MedWatch/AdEERs report must be sent to 
the Houston Methodist Research Institute Office of Regulatory Affairs & Translational 
Management (pamendoza@houstonmethodist.org; fax line: 713-793-7001). The investigator or 
qualified 
designee 
will 
concurrently 
forward 
all 
such 
reports 
to 
the 
sponsor 

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(CTOMgmt@houstonmethodist.org) and AstraZeneca. A copy of the MedWatch/AdEERs report 
must be emailed to AstraZeneca (AEMailboxClinicalTrialTCS@astrazeneca.com) at the time 
the event is reported to the FDA. It is the responsibility of the investigator to compile all 
necessary information and ensure that the FDA receives a report according to the FDA reporting 
requirement timelines and to ensure that these reports are also submitted to the sponsor and 
AstraZeneca at the same time. 
* A cover page should accompany the MedWatch/AdEERs form indicating the following: 
• 
“Notification from an Investigator-Sponsored Study” 
• 
The investigator’s name and address 
• 
The study name/title and AstraZeneca ISS reference number (ESR-18-13489) 
* 
The investigator must also indicate, either in the SAE report or the cover page, the 
causality of events in relation to all study medications and if the SAE is related to disease 
progression. 
* 
Send the SAE report and accompanying cover page by way of email to AstraZeneca’s 
designated mailbox: AEMailboxClinicalTrialTCS@astrazeneca.com 
The SAE report should also be sent to the Houston Methodist Research Institute Office of 
Regulatory Affairs & Translational Management at: RATM@houstonmethodist.org fax line: 
713-793-7001 
If a non-serious AE becomes serious, this and other relevant follow-up information must also be 
provided to the sponsor (CTOMgmt@houstonmethodist.org), AstraZeneca, the FDA (via the 
Houston Methodist Research Institute Office of Regulatory Affairs & Translational 
Management), and the IRB. 
SAEs that do not require expedited reporting to the FDA still need to be reported to AstraZeneca 
preferably using the MedDRA coding language for SAEs. This information should be reported 
on a monthly basis and under no circumstance less frequently than quarterly.  
9.3.11 Reporting of deaths to AstraZeneca 
All deaths that occur during the study, or within the protocol-defined 30-day post-last dose of 
study treatment safety follow-up period must be reported to AstraZeneca as follows: 
• 
Death that is clearly the result of disease progression should be 
documented but should not be reported as an SAE. 

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• 
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 AstraZeneca 
as an SAE within 24 hours (see Section 9.3.10 for further details). The 
report should contain a comment regarding the coinvolvement of 
progression of disease, if appropriate, and should assign main and 
contributory causes of death.  
• 
Deaths with an unknown cause should always be reported as a SAE. 
  
Deaths that occur following the protocol-defined safety follow-up period (30 days after the last 
dose of study treatment) will be documented as events for DFS analysis, but will not be reported 
as an SAE. However, if an investigator learns of any SAEs, including death, at any time after the 
patient has been permanently withdrawn from study, and he/she considers there is a reasonable 
possibility that the event is related to the study treatment, the investigator should notify the 
sponsor and AstraZeneca/MedImmune Drug Safety. 
9.3.12 Other events requiring reporting 
9.3.12.1 
Overdose 
An overdose is defined as a patient receiving a dose of durvalumab in excess of that specified in 
the IB, unless otherwise specified in this protocol. 
Any overdose of durvalumab, with or without associated AEs/SAEs, in a study patient is required 
to be reported within 24 hours of knowledge of the event to the sponsor 
(CTOMgmt@houstonmethodist.org) and AstraZeneca/MedImmune Patient Safety or designee 
using the designated Safety emailbox (AEMailboxClinicalTrialTCS@astrazeneca.com). If the 
overdose results in an AE, the AE must also be recorded as an AE (Section 9.3). Overdose does 
not automatically make an AE serious, but if the consequences of the overdose are serious, for 
example death or hospitalization, the event is serious and must be recorded and reported as an 
SAE (Section 9.3.10).  
There is currently no specific treatment in the event of an overdose of durvalumab. The 
investigator will use clinical judgment to treat any overdose. 
9.3.12.2 
Hepatic function abnormality 
Hepatic function abnormality in a study patient that fulfills the biochemical criteria of a potential  
Hy’s Law case, with or without associated clinical manifestations, is required to be reported as 
“hepatic function abnormal” within 24 hours of knowledge of the event to the sponsor  

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(CTOMgmt@houstonmethodist.org) and AstraZeneca Patient Safety using the designated Safety 
emailbox (AEMailboxClinicalTrialTCS@astrazeneca.com), unless a definitive underlying 
diagnosis for the abnormality (e.g., cholelithiasis or bile duct obstruction) that is unrelated to the 
study treatment has been confirmed. The criteria for a potential Hy’s Law case is AST or ALT 
≥3 × ULN together with TB ≥2 × ULN at any point during the study following the start of study 
treatment irrespective of an increase in ALP. 
• 
If the definitive underlying diagnosis for the abnormality has been established and is 
unrelated to the study treatment, the decision to continue dosing of the study patient will 
be based on the clinical judgment of the investigator. 
• 
If no definitive underlying diagnosis for the abnormality is established, dosing of the 
study patient must be interrupted immediately. Follow-up investigations and inquiries 
must be initiated by the investigational site without delay. 
Each reported event of hepatic function abnormality will be followed by the investigator and 
evaluated by the sponsor and AstraZeneca/MedImmune.  
9.3.12.3 
Pregnancy 
9.3.12.3.1  Maternal exposure 
If a patient becomes pregnant during the course of the study, the study treatment should be 
discontinued immediately.  
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study treatment may 
have interfered with the effectiveness of a contraceptive medication. Congenital abnormalities 
or birth defects and spontaneous miscarriages should be reported and handled as SAEs. Elective 
abortions without complications should not be handled as AEs. The outcome of all pregnancies 
(spontaneous miscarriage, elective termination, ectopic pregnancy, normal birth, or congenital 
abnormality) should be followed up and documented even if the patient was discontinued from 
the study.  
If any pregnancy occurs in the course of the study, then the investigator or other site personnel 
should inform the sponsor and appropriate AstraZeneca representatives within 1 day, i.e., 
immediately, but no later than 24 hours of when he or she becomes aware of it.  
The designated AstraZeneca representative will work with the investigator to ensure that all 
relevant information is provided to the AstraZeneca Patient Safety data entry site within 1 to 5 
calendar days for SAEs and within 30 days for all other pregnancies.  

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The same timelines apply when outcome information is available.  
10  STATISTICAL METHODS 
This Phase II study will be conducted using a Simon’s minimax two-stage design. A null 
response rate of 35% is assumed.16 The target response rate for the regimen will be 52%. When 
the probability of accepting a “bad” regimen (i.e., response rate ≤35%) is 0.10 (i.e., alpha) and 
the probability of rejecting a “good” regimen (i.e., response rate ≥52) is 0.20 (i.e., beta or 1 – 
power), Simon’s minimax design requires 15 patients in the first stage. If 4 or fewer patients 
respond to the regimen, the study will be stopped and the regimen will be declared as ineffective. 
If at least 5 of the first 15 patients respond, 24 additional patients will be entered on the study to 
reach a total of 39 patients. At the end of the second stage, the regimen will be rejected if the 
response rate is less than or equal to 17 out of 39 patients and will be accepted otherwise. This 
design yields a type I error rate of α = 0.096 (targeted rate of 0.10) and power of 80.1% (targeted 
power of 80%) when the true response rate is 0.52. When the true response rate is 35% (i.e., null 
hypothesis is true), the probability of stopping the study early (i.e., after the first stage) is 35.2%. 
On the other hand, if the true response rate is 52%, the probability of stopping the study early is 
only 4.3%. The expected sample size is 30.6 if the response rate is 35% and 38.0 if the true 
response rate is 52%. If there are 4 or fewer responders in the first 15 patients, the probability of 
achieving a significant result at the end of stage 2 is only 0.0002 (the futility rate), assuming the 
observed data in stage 1 provides a reasonable estimate of the response rate.   
As a measure of safety, an initial cohort of 3 patients will be followed for toxicity through the 
first cycle of trastuzumab, pertuzumab, and durvalumab. If no more than 1 of 3 patients 
experience toxicity (i.e., if 2 of the first 3 patients experience toxicity, the study will stop 
immediately), then 3 more patients will be enrolled. If no more than 1 of 6 patients experience 
toxicity (again, the study would stop if 2 of the first 6 patients experience toxicity), then the study 
will be fully opened. Toxicity will be defined as any treatment-related death or any ≥ Grade 3 
AE excluding alopecia and constitutional symptoms (as assessed by the NCI CTCAE v5). 
Additionally, toxicity after the first 6 patients will be monitored based on a beta-binomial model, 
assuming a priori that the probability of toxicity p is distributed beta(1, 1). Study accrual will be 
suspended and the safety profile of the combination will be reviewed by the safety monitoring 
committee if Pr(p > .30 | data) > 0.95. This stopping rule yields the following stopping bounds 
where the numerator represents the number of events needed to suspend accrual and the 
denominator represents the number treated at that point in the study: 7/12, 8/14, 9/17, 10/20, 
11/22, 12/25, 13/28, 14/30, 15/33, and 16/36. Scenario 1 of the operating characteristics table 
(Table 8) indicates that the probability of stopping the study early for toxicity is low when the 
combination is safe; that is, the study has an 11% chance of stopping early when the true toxicity 

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rate is 10%. The study has an 89.9% chance of stopping for toxicity if the true toxicity rate is 
45% and on average would take only 4 patients to arrive at that conclusion. 
 
 

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Table 8: Operating Characteristics for Toxicity Monitoring Rule 
Scenario True Pr(toxicity) Pr(stop early) 
Median No. of Patients 
(25%, 75%) 
1 
0.10 
00.1116 
39 (39, 39) 
2 
0.20 
00.3366 
39 (5, 39) 
3 
0.30 
00.5954 
6 (4, 39) 
4 
0.45 
00.8988 
4 (3, 6) 
5 
0.60 
00.9952 
3 (2, 4) 
At the end of the study, the response rate and its associated 95% Wilson score CI will be reported. 
With 39 patients, the response rate CI will be no wider than 29.9 percentage points. The overall 
toxicity rate and CI will be reported, and the toxicity profile of the regimen will be summarized. 
This trial was designed using PASS 13.0.8 and the Multc99 software developed by the 
Biostatistics Department of the University of Texas MD Anderson Cancer Center. 
11 ETHICAL AND REGULATORY REQUIREMENTS 
11.1  Ethical conduct of the study 
This study will be conducted in full conformance with the ICH E6 guideline for GCP and the 
principles of the Declaration of Helsinki. The study will comply with U.S. FDA regulations and 
applicable local, state, and federal laws.  
11.2  Ethics and regulatory review 
The protocol and ICF will be submitted to the FDA and IRB for review and approval. Approval 
of both the protocol and ICF must be obtained before any patient is enrolled in the study. Any 
amendment to the protocol and ICF will require review and approval by the FDA and IRB before 
implementation. The patient or her legally acceptable representative should be informed in a 
timely manner if new information becomes available that may be relevant to the patient’s 
willingness to continue participation in the study. The communication of this information will 
be provided and documented via a revised consent form or addendum to the original consent 
form that captures the patient’s dated signature or by the patient’s legally acceptable 
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11.3  Patient confidentiality 
The sponsor maintains confidentiality standards by coding each patient enrolled in the study 
through assignment of a unique patient identification number. Patient medical information 
obtained by this study is confidential and may be disclosed to third parties only as permitted by 
the ICF signed by the patient, unless permitted or required by law. Data generated by this study 
must be available for inspection upon request by representatives of the U.S. FDA and other 
national and local health authorities and the IRB. 
Extra precautions are taken to preserve confidentiality and prevent genetic data being linked to 
the identity of the patient. In exceptional circumstances; however, certain individuals might see 
both the genetic data and the personal identifiers of a patient. For example, in the case of a 
medical emergency, an AstraZeneca Physician or an investigator might know a patient’s identity 
and also have access to her genetic data. Also, regulatory authorities may require access to the 
relevant files, although the patient’s medical information and the genetic files would remain 
physically separate. 
11.4 Informed consent 
The investigator or qualified designee will obtain documented consent from each potential 
patient prior to participating in the study. The ICF will be FDA and IRB approved and the 
patient will be asked to read and review the document. The investigator will explain the 
research study to the patient and answer any questions that may arise. All patients will receive 
a verbal explanation in terms suited to their comprehension of the purposes, procedures, and 
potential risks of the study and of their rights as research participants. Patients will have the 
opportunity to carefully review the written ICF and ask questions prior to signing. Patients 
should have the opportunity to discuss the study with their surrogates or think about it prior to 
agreeing to participate. Consent must be documented by the patient’s dated signature or by the 
patient’s legally acceptable representative’s (LAR) dated signature on the ICF along with the 
dated signature of the person conducting the consent discussion. Patients may withdraw 
consent at any time throughout the course of the study. A copy of the signed and dated ICF will 
be given to the patients for their records. The rights and welfare of the patients will be 
protected by emphasizing to them that the quality of their medical care will not be adversely 
affected if they decline to participate in this study. In the event that time and distance are of 
concern and it will prevent the potential patient and/or their LAR from being present to sign the 
consent form in person, Informed consent can be orally obtained by a delegated member of the 
research team by telephone, or through a Houston Methodist-vetted system enabling a virtual 
‘face to face’ discussion, provided that one additional person monitors the process and there is 
written documentation in the research record including confirmation of the person consenting, 

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their name and their relationship to the patient; the date and time consent was given; the 
protocol for which the consent was given. 
A copy of the Full IRB approved consent must be transmitted to the potential subject or LAR 
prior to initiating the consent process. If relying on telephone consent, the participant or LAR 
must sign the consent and can either mail or scan and send the consent electronically to the 
research team. The research team will sign and return a final, signed copy to the participant or 
LAR. Research procedures cannot begin before the informed consent is fully documented.11.5 
Changes to the protocol and informed consent form 
Any change or addition to this protocol that significantly affects patient safety, the scope of the 
investigation, or the scientific quality of the study requires approval by the FDA and IRB.  
Examples of amendments requiring such approval are:  
• 
increases in drug dose or duration of patient exposure  
• 
significant changes in the study design (e.g., addition or deletion of a control group) 
• 
increase in the number of invasive procedures 
• 
addition or deletions of a test procedure required for safety monitoring 
These requirements for approval should in no way prevent any immediate action from being 
taken by the investigator in the interests of preserving the safety of all patients included in the 
study. The FDA and IRB must be informed of any immediate protocol changes implemented by 
the investigator for safety reasons. Amendments affecting administrative aspects of the study do 
not require formal protocol amendments but do require IRB approval.  
12 STUDY MANAGEMENT 
12.1 Training of study site personnel 
Before the first patient is entered into the study, the investigator or qualified designee will review 
and discuss the requirements of the clinical study protocol with the investigational staff at the 
primary and participating sites. 
Proper handling and shipment of biological samples will be reviewed and discussed with 
investigators and investigational staff at the other participating centers. 
12.2 Monitoring of the study 
An independent research monitor will conduct periodic monitoring visits during study conduct 
to ensure GCP are being followed, to confirm the investigational team is adhering to the protocol, 
and to confirm data are being accurately and timely recorded in the CRFs. The investigator and 

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sponsor will allow the monitor direct access to source documents to perform this verification. 
The monitor will report his/her observations/findings to the IRB. 
13 DATA MANAGEMENT 
CRFs will be designed and utilized to capture all patient data. An electronic database will be 
designed to store patient CRFs. The investigational staff will ensure that data are recorded in the 
CRF as specified in the study protocol. Data quality control will be performed regularly by the 
investigational staff to ensure timely, accurate, and complete patient data collection as well as 
protocol compliance. Queries will be generated and resolved prior to the generation of interim 
and final summary reports.    
 

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4. von Minckwitz G, et al. S3-2: neoadjuvant chemotherapy adapted by interim response 
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5. Ritger LS, et al. Neoadjuvant chemotherapy adaptation and serial MRI response monitoring 
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6. von Minckwitz G, et al. Definition and impact of pathologic complete response on prognosis 
after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 
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7. Houssami N, et al. Meta-analysis of the association of breast cancer subtype and pathologic 
complete response to neoadjuvant chemotherapy. Eur J Cancer 2012:48:3342-54. 
8. Kim MM, et al. Pathologic complete response to neoadjuvant chemotherapy with 
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Appendix 1 
Dosing Modification and Toxicity Management Guidelines (TMGs) for  
Durvalumab Monotherapy, Durvalumab in Combination with other Products, or 
Tremelimumab Monotherapy – August 2024  
 
General Considerations Regarding Immune-Mediated Reactions 
 
These guidelines are provided as a recommendation to support investigators in the management of potential 
immunemediated adverse events (imAEs).  
Immune-mediated events can occur in nearly any organ or tissue, therefore, these guidelines may not include all the possible 
immune-mediated reactions. Investigators are advised to take into consideration the appropriate practice guidelines and other 
society guidelines (e.g., National Comprehensive Cancer Network (NCCN), European Society of Medical Oncology (ESMO)) 
in the management of these events. Refer to the section of the table titled “Other -Immune-Mediated Reactions” for general 
guidance on imAEs not noted in the “Specific Immune-Mediated Reactions” section. Early identification and management of 
imAEs is essential to ensure safe use of the study drug. Monitor patients closely for symptoms and signs that may be clinical 
manifestations of underlying imAEs. Patients with suspected imAEs should be thoroughly evaluated to rule out any alternative 
etiologies (e.g., disease progression, concomitant medications, infections). In the absence of a clear alternative etiology, all 
such events should be managed as if they were immune-mediated. Institute medical management promptly, including specialty 
consultation as appropriate. In general, withhold study drug/study regimen for severe (Grade 3) imAEs. Permanently 
discontinue study drug/study regimen for life-threatening (Grade 4) imAEs, recurrent severe (Grade 3) imAEs that require 
systemic immunosuppressive treatment, or an inability to reduce corticosteroid dose to 10 mg or less of prednisone or 
equivalent per day within 12 weeks of initiating corticosteroids. Based on the severity of the imAE, durvalumab and/or 
tremelimumab should be withheld and corticosteroids administered. Upon improvement to Grade ≤ 1, corticosteroid 
should be tapered over ≥ 28 days. More potent immunosuppressive agents should be considered for events not responding to 
systemic steroids. Alternative immunosuppressive agents not listed in this guideline may be considered at the discretion of the 
investigator based on clinical practice and relevant guidelines. With long-term steroid and other immunosuppressive use, 
consider the need for glucose monitoring. 
Dose modifications of study drug/study regimen should be based on severity of treatment-emergent toxicities graded per NCI 
CTCAE version in the applicable study protocol. 
 
Considerations for Prophylaxis for Long Term use of Steroids for Patients Receiving Immune Checkpoint Inhibitor 
Immunotherapy 
• Infection Prophylaxis: Pneumocystis jirovecii pneumonia (PJP), antifungal and Herpes Zoster reactivation 
• Gastritis: Consider prophylaxis for patients at high risk of gastritis (e.g. NSAID use, anticoagulation) when  
   the patient is taking steroid therapy 
• Osteoporosis: Consider measures for prevention and mitigation of osteoporosis  
 
AE Adverse event; CTC Common Toxicity Criteria; CTCAE Common Terminology Criteria for Adverse Events; imAE 
immune-mediated adverse event; NCI National Cancer Institute; NCCN National Comprehensive Cancer Network; ESMO 
European Society for Medical Oncology 
 
 

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Relevant Society Guidelines for Management of imAEs 
 
These society guidelines are provided as references to serve in support of best clinical practice and the TMGs. Please 
note, these were the current versions of these guidelines at the time of updating TMGs. Please refer to the most up to date 
version of these guidelines. 
 
1. Brahmer JR, et al. Society for Immunotherapy of Cancer (SITC) clinical practice guideline on immune checkpoint inhibitor-
related adverse events. J Immunother 
Cancer 2021, version 1.2;9:e002435 
2. Schneider BJ, et al. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor 
therapy: American Society of 
Clinical Oncology (ASCO) Guideline Update. J Clin Oncol 2022;39(36):4073-4126. 
3. Haanen J, et al. Management of toxicities from immunotherapy: European Society for Medical Oncology (ESMO) clinical 
practice guideline for diagnosis, 
treatment, and follow-up. Annals Oncol 2022;33(12):1217-1238. 
4. Sangro B, et al. Diagnosis and management of toxicities of immune checkpoint inhibitors in hepatocellular carcinoma. J 
Hepatol 2020;72(2):320-341. 
5. Thompson JA, et al. National Comprehensive Cancer Network Guidelines: Management of immunotherapy-related 
toxicities version 2.2023. Published December 
7, 2022. 
 
 
Pediatric Considerations Regarding Immune-Mediated Reactions 
Dose Modifications 
Toxicity Management 
The criteria for permanent discontinuation of study 
drug/study regimen based on CTCAE grade/severity is 
the same for pediatric patients as it is for adult patients, 
as well as to permanently discontinue study drug/study 
regimen if unable to reduce corticosteroid ≤ a dose 
equivalent to that required for corticosteroid 
replacement therapy within 12 weeks of initiating 
corticosteroids.  
− 
All recommendations for specialist consultation should 
occur with a pediatric specialist in the specialty 
recommended. 
− 
The recommendations for steroid dosing (i.e., mg/kg/day) 
provided for adult patients should also be used for 
pediatric patients. 
− 
The recommendations for IVIG and plasmapheresis use 
provided for adult patients may be considered for 
pediatric patients. 
− 
The infliximab 5 mg/kg IV one time dose recommended 
for adults is the same as recommended for pediatric 
patients ≥ 6 years old. For subsequent dosing and dosing 
in children < 6 years old, consult a pediatric specialist. 
− 
For pediatric dosing of mycophenolate mofetil, consult a 
pediatric specialist. 

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− 
With long-term steroid and other immunosuppressive use, 
consider need for PJP prophylaxis, gastrointestinal 
protection, and glucose monitoring. 
 
 
 

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Specific Immune-Mediated Reactions 
Adverse Events 
Severity Grade 
of the Event  
Dose Modifications 
Toxicity Management 
Pneumonitis/Interstitial  
Lung Disease (ILD) 
Any Grade 
(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the  
CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology with similar clinical 
presentation (e.g infection,progressive disease).  
- Monitor patients for signs (e.g. tachypnoea) and 
symptoms of pneumonitis or ILD (new onset or 
worsening shortness of breath or cough). 
Evaluate patients with imaging and pulmonary 
function tests, including other diagnostic 
procedures as described below.  
- Suspected pneumonitis should be confirmed 
with radiographic imaging and other infectious 
and disease-related etiologies excluded, and 
managed as described below. 
- Initial work-up may include clinical evaluation, 
monitoring of oxygenation via pulse oximetry 
(resting and exertion), laboratory work-up 
(including clinically relevant culture specimens 
to rule out infection),  and high- resolution CT 
scan. 
- Consider Pulmonary and Infectious Diseases 
consults. 
 
Grade 1 
No dose modifications 
required. However, 
consider holding study 
drug/study regimen dose 
as clinically appropriate 
and during diagnostic 
work-up for other 
etiologies. 
For Grade 1  
- Monitor and closely follow up in 2 to 4 days for 
clinical symptoms, pulse oximetry (resting and 
exertion), and laboratory work-up, and then as 
clinically indicated. 

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Grade 2 
Hold study drug/study 
regimen dose until 
Grade 2 resolution to 
Grade ≤1. 
• If toxicity improves 
to Grade ≤1, then the 
decision to reinitiate 
study drug/study 
regimen will be 
based upon treating 
physician’s clinical 
judgment and after 
completion of 
steroid taper (<10 
mg prednisone or 
equivalent). 
For Grade 2 
- Monitor symptoms daily and consider 
hospitalization as clinically indicated. 
- Consider Pulmonary and Infectious Diseases 
Consults; 
- Promptly start systemic steroids (e.g., 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent). 
- Consider HRCT or chest CT with 
contrast.Repeat imaging study as clinically 
indicated.  
- If no improvement within 2 to 3 days, additional 
workup should be considered and prompt 
treatment with IV methylprednisolone 2 to 4 
mg/kg/day started. 
- If no improvement within 2 to 3 days 
despite IV methylprednisolone at 2 to 4 
mg/kg/day, promptly start 
immunosuppressive therapy. such as 
tumor necrosis factor (TNF) inhibitors 
(e.g., infliximab at 5 mg/kg IV once, may 
be repeated at 2 and 6 weeks after initial 
dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: It is important to rule out sepsis 
and refer to infliximab label for general 
guidance before using infliximab. 
-  Consider, as necessary, discussing with 
clinical study lead. 
 
Grade 3 or 4 
Permanently discontinue 
study drug/study regimen 
 
For Grade 3 or 4 
- Hospitalize the patient 
- Promptly initiate empiric IV 
methylprednisolone 1 to  4 mg/kg/day or 
equivalent 
- Obtain Pulmonary and Infectious Diseases 
Consults; consider discussing with Clinical 
Study Lead, as needed 
- Supportive care (e.g. oxygen) 
- If no improvement within 2 days, additional 
workup should be considered and prompt 
treatment with additional immunosuppressive 
therapy such as TNF inhibitors (e.g., 
infliximab at 5 mg/kg IV, may be repeated at 2 
and 6 weeks after initial dose at the discretion 
of the treating provider or relevant practice 
guidelines). Caution: rule out sepsis and refer 
to infliximab label for general guidance before 
using infliximab. 
Diarrhea/Colitis 
Any Grade 
General Guidance 
- For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 

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(Refer to NCI  
CTCAE  
applicable version 
in study protocol  
for defining the 
CTCAE 
grade/severity) 
progression, other medications, or infections), 
including testing for Clostridium difficile toxin, 
etc. 
- Monitor for symptoms that may be related to 
diarrhea/enterocolitis (abdominal pain, 
cramping, or changes in bowel habits such as 
increased frequency over baseline or blood in 
stool) or related to bowel perforation (such as 
sepsis, peritoneal signs, and ileus). 
- Consider further evaluation with imaging study 
with contrast.  
- Consult a gastrointestinal (GI) specialist for 
consideration of further workup. 
- WHEN SYMPTOMS OR EVALUATION 
INDICATE AN INTESTINAL 
PERFORATION IS SUSPECTED, 
CONSULT A SURGEON EXPERIENCED 
IN ABDOMINAL SURGERY 
IMMEDIATELY WITHOUT ANY 
DELAY.  
- PERMANENTLY DISCONTINUE STUDY 
DRUG FOR ANY GRADE OF 
INTESTINAL PERFORATION. 
- Steroids should be considered in the absence of 
clear alternative etiology, even for low-grade 
events, in order to prevent potential 
progression to higher grade events, including 
intestinal perforation. 
- Use analgesics carefully; they can mask 
symptoms of perforation and peritonitis. 
Grade 1 
No dose modifications 
For Grade 1 
- Monitor closely for worsening symptoms. 
- Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), loperamide, and other supportive 
care measures. 
- If symptoms persist, consider checking 
lactoferrin and/or calprotectin; if positive, treat 
as Grade 2 below. If negative and no infection, 
continue Grade 1 management. 
Grade 2 
Hold study drug/study 
regimen until 
resolution to Grade ≤1 
- If toxicity improves to 
Grade ≤1, then study 
drug/study regimen 
can be resumed after 
completion of steroid 
taper (<10 mg 
For Grade 2 
- Consider symptomatic treatment, including 
hydration, electrolyte replacement, dietary 
changes (e.g., American Dietetic Association 
colitis diet), and loperamide and/or 
budesonide. 
- Consider further evaluation with imaging study 
with contrast. 
- Consider consult of a gastrointestinal (GI) 
specialist for consideration of further workup. 
- Promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 

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prednisone, or 
equivalent) 
- If no improvement within 3 days despite 
therapy with 2 to 2 mg/kg IV prednisone 
equivalent reconsult GI specialist and, if 
indicated promptly start additional 
immunosuppressant agent such as infliximab at 
5 mg/kg IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider or relevant practice guidelines. 
Caution: it is important to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab 
- If perforation is suspected, consult a 
surgeon experienced in abdominal surgery 
immediately without any delay. 
- Consider, as necessary, discussing with 
Clinical Study Lead if no resolution to Grade 
≤1 in 3 to 4 days. 
 
Grade 3 or 4 
Grade 3 
 
For patients 
treated with durvalumab 
monotherapy, hold 
study drug/study 
regimen until resolution 
to Grade ≤1; study 
drug/study regimen can 
be resumed after 
completion of steroid 
taper (<10 mg 
prednisone per day, or 
equivalent). 
− 
 
For 
patients treated with 
durvalumab in 
combination with other 
products (not 
tremelimumab), 
decision to be 
made at the discretion 
of the study 
investigator, in 
discussion with 
AstraZeneca Clinical 
Study Lead. 
For patients treated 
with durvalumab in 
combination with 
tremelimumab or 
tremelimumab 
monotherapy: 
A. 
Permanently 
discontinue 
- Urgent GI consult and imaging and/or 
colonoscopy as appropriate.  
- Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
- Monitor stool frequency and volume and 
maintain hydration. 
- If still no improvement within 2 days, continue 
steroids and promptly add further 
immunosuppressants. (e.g., infliximab at 5 
mg/kg IV, may be repeated at 2 and 6 weeks 
after initial dose at the discretion of the treating 
provider or relevant practice guidelines). 
Caution: Ensure GI consult to rule out bowel 
perforation and refer to infliximab label for 
general guidance before using infliximab. 
- If perforation is suspected, consult a 
surgeon experienced in abdominal surgery 
immediately without any delay. 

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tremelimumab for 
Grade 3 
diarrhea/colitis. 
HOLD durvalumab 
until resolution to 
Grade ≤ 1; 
durvalumab alone can 
be resumed after 
completion of steroid 
taper (<10 mg 
prednisone per day or 
equivalent) 
B. 
Permanently 
discontinue both 
durvalumab and 
tremelimumab for 
1) Grade 4 
diarrhea/colitis or 2) 
Any grade of intestinal 
perforation 
Grade 4  Permanently 
discontinue study 
drug/study regimen. 
Hepatitis  
Infliximab should not be 
used for management of 
immune-related hepatitis 
 
 
Any Grade  
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g. viral hepatitis, 
disease progression, concomitant medications) 
- Monitor and evaluate transaminases (aspartate 
aminotransferase [AST], alanine 
aminotransferase [ALT], alkaline phosphatase 
[ALP]) and total bilirubin. 
ALT or AST < 3x 
ULN or total 
bilirubin <1.5. x 
ULN 
- No dose modification  
- If it worsens, then 
consider holding 
therapy. 
- 
Continue transaminase and total 
bilirubin monitoring per protocol. 
ALT or AST > ≤ 
3 x ULN or total 
bilirubin ≤ 1.5 x 
ULN 
Hold study drug/study 
regimen 
dose 
until ALT or AST 
≤ 3 x ULN or total 
bilirubin ≤ 1.5 x 
ULN. 
Resume 
study drug/study 
regimen 
after 
completion 
of 
steroid taper (<10 
mg prednisone or 
equivalent). 
Regular and frequent checking of transaminases 
and total bilirubin (e.g., every 1 to 2 
days) until transaminases and total bilirubin 
elevations improve or resolve. 
-   Consider checking creatinine phosphokinase 
(CPK) and aldolase (to rule out myositis) 
- If no resolution to ALT or AST ≤ 3 x ULN 
or total bilirubin ≤ 1.5 x ULN in 1 to 2 
days, consider discussing with Clinical Study 
Lead, as needed. 
PLEASE SEE shaded 
area immediately 
below this section to 
find guidance for 
management of 
“Hepatitis (elevated 
LFTS)” in 
hepatocellular 
carcinoma (HCC) or 
secondary tumor 
involvement of the 
liver with abnormal 
baseline values 
[BLV]) 

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AZ Study Number ESR-18-13489; v4_12Nov 18 
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HMRI Date 10 September 2024 
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- − Permanently 
discontinue study 
drug/study regimen 
for any case meeting 
Hy’s law laboratory 
criteria (AST  or 
ALT  >3 ×  ULN     
AND bilirubin >2 × 
ULN without initial 
findings of cholestasis 
(i.e., elevated ALP) 
and in the absence of 
any alternative cause. 
- If event is persistent (>2 to 3 days) or worsens, 
promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent. 
ALT or AST > 5 
<10 x ULN  
- Hold study drug/study 
regimen.  
- Resume study 
drug/study regimen if 
elevations downgrade 
to ALT or AST ≤ 3 x 
ULN or total bilirubin 
≤ 1.5 x ULN after 
completion of steroid 
taper (<10 mg 
prednisone, or 
equivalent). 
- If in combination 
with tremelimumab, 
do not restart 
tremelimumab. 
- 
Promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day 
or equivalent. 
- 
Check CPK and aldolase (to rule out 
myositis) 
- 
Perform Hepatology Consult,  
abdominal  workup, and imaging as 
appropriate. 
- 
If still no improvement within 2 to 3 
days despite 1 to 2 mg/kg/day 
methylprednisolone IV or equivalent, 
promptly start treatment with an 
additional immunosuppressant.(e.g.,   
mycophenolate   mofetil 
- 
0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult or 
relevant practice guidelines). Discuss 
with Clinical Study Lead if 
mycophenolate is not available. 
Infliximab should NOT be used. 
Concurrent 
ALT or 
AST > 3 x 
ULN and 
total 
bilirubin 
> 2 x ULN 
 
 
ALT or AST 
> 10 x ULN OR 
total bilirubin > 3 
x ULN 
Permanently discontinue 
study drug/study 
regimen. 
− 
Promptly 
initiate 
empiric 
IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
−     If still no improvement within 2 to 3 days 
despite 
1 
to 
2 
mg/kg/day 
methylprednisolone 
IV 
or 
equivalent, 
promptly start treatment with an additional 
immunosuppressant.(e.g.,   mycophenolate   
mofetil 
0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult or 
relevant practice guidelines). Discuss with 
Clinical Study Lead if mycophenolate is 
not available. Infliximab should NOT be 
used. 

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AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 89 of 109 
 
- − Perform Hepatology Consult, abdominal 
workup, and imaging as appropriate. 
Hepatitis 
(elevated transaminases 
and total bilirubin) 
 
Infliximab should not be 
used for management of 
immune-related hepatitis 
 
 
Any Elevations 
of AST, ALT, or 
T. Bili as 
Described Below 
General Guidance 
For Any Elevations Described 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., viral 
hepatitis, disease progression, concomitant 
medications, worsening of liver cirrhosis [e.g., 
portal vein thrombosis]). 
- Monitor and evaluate AST, ALT, ALP, and T. 
Bili. 
- For hepatitis B (HBV) + patients: evaluate 
quantitative HBV viral load, quantitative 
Hepatitis B surface antigen (HBsAg), or 
Hepatitis B envelope antigen (HBsAg). 
- − For hepatitis C (HCV) + patients: evaluate 
quantitative HCV viral load. 
- Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or 
starting antiviral HBV medications if HBV 
viral load is >2000 IU/ml. 
- Consider consulting Hepatology or Infectious 
Diseases specialists regarding changing or 
starting antiviral HCV medications if HCV 
viral load has increased by ≥2-fold. 
- For HCV+ with Hepatitis B core antibody 
(HBcAb)+: Evaluate for both HBV and HCV 
as above. 
See instructions at bottom of 
shaded area if transaminase 
rise not isolated but (at any 
time) occurs in setting of 
either increasing bilirubin or 
signs of DILI/Liver 
decompensation. 
Isolated AST or 
ALT > ULN and 
≤ 2.5 x BLV  
- No dose modifications. 
- If ALT/AST elevations 
represents significant 
worsening based on 
investigator 
assessment, then treat 
as described for 
elevations in the row 
below.  
- For all transaminase 
elevations , see 
instructions at bottom 
of shaded area if 
transaminase rise if not 
isolated but (at any 
time) occurs in setting 
of either increasing 
bilirubin or signs of 
DILI/Liver 
decompensation 
 
THIS shaded area is 
guidance only for 
management of 
“Hepatitis (elevated 
LFTs)” in HCC 
patients (or secondary 
tumour involvement of 
the liver with 
abnormal baseline 
values [BLV]) 

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HMRI Version Number 14.0 
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ALT or AST > 
2.5- ≤ 5 x BLV 
and ≤ 20 x ULN 
- Hold study drug/study 
regimen dose until 
resolution to AST or 
ALT ≤2.5×BLV  
- If toxicity worsens, 
then treat as described 
for elevations in the 
rows below. If toxicity 
improves to AST or 
ALT ≤2.5×BLV, 
resume stud drug/study 
regimen after 
completion of steroid 
taper (<10 mg 
prednisone,or 
equivalent). 
- 
Regular and frequent checking of 
Transaminases and total bilirubin (e.g., every 1 
to 3 days) until elevations of these are 
improving or resolved. 
− Recommend consult hepatologist; consider 
abdominal ultrasound, including Doppler 
assessment of liver perfusion. 
− Consider, as necessary, discussing with 
Clinical Study Lead. 
− If event is persistent (>2 to 3 days) or worsens, 
and investigator suspects toxicity to be an 
imAE, start prednisone 1 to 2 mg/kg/day PO or 
IV equivalent. 
− If still no improvement within 2 to 3 days 
despite 1 to 2 mg/kg/day of prednisone PO or 
IV equivalent, consider additional workup. If 
still no improvement within 2 to 3 days despite 
2mg/kg/day of IV methylprednisolone, 
consider additional abdominal workup 
(including liver biopsy) and imaging (i.e., liver 
ultrasound), and consider starting additional 
immunosuppressants. (e.g., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with hepatology consult or 
relevant practice guidelines). Discuss Clinical 
Study Lead if mycophenolate mofetil is not 
available.  
Infliximab should NOT be used. 
ALT or AST >5-7 
x BLV and ≤ 20 x 
ULN  
OR concurrent 
2.5-5 x BLV and 
≤ 20 x ULN AND 
total bilirubin > 
1.5 - < 2 x ULN 
- Withold durvalumab 
and permanently 
discontinue 
tremelimumab 
- Resume study 
drug/study regimen if 
elevations downgrade 
to AST or ALT ≤2.5 × 
BLV and after 
completion of steroid 
taper (<10 mg 
prednisone, or 
equivalent). 
- Permanently 
discontinue study 
drug/study regimen if 
the elevations do not 
downgrade to AST or 
ALT ≤2.5 × BLV 
within 14 days 
- 
Regular and frequent checking of LFTs (e.g., 
every 1-2 days) until elevations of these are 
improving or resolved. 
- 
Consult hepatologist (unless investigator is 
hepatologist); obtain abdominal ultrasound, 
including Doppler assessment of liver 
perfusion; and consider liver biopsy. 
- 
Consider discussing with Clinical Study Lead, 
as needed. 
- 
If investigator suspects toxicity to be 
immunemediated, promptly initiate empiric IV 
methylprednisolone at 1 to 2 mg/kg/day or 
equivalent. 
- 
If no improvement within 2 to 3 days despite 1 
to 2 mg/kg/day methylprednisolone IV or 
equivalent, obtain liver biopsy (if it has not 
been done already) and promptly start 
treatment with an additional 
immunosuppressant. (e.g., mycophenolate 
mofetil 0.5 – 1 g every 12 hours then taper in 
consultation with a hepatologist or relevant 
practice guidelines). Discuss with Study 

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HMRI Version Number 14.0 
HMRI Date 10 September 2024 
Page 91 of 109 
 
Clinical Lead if mycophenolate is not 
available. 
Infliximab should NOT be used. 
ALT or AST > 7 x 
BLV OR > 20 
ULN whichever 
occurs first OR 
bilirubin > 3 ULN 
Permanently discontinue 
study drug/study 
regimen 
Same as above 
(except recommend obtaining liver biopsy 
early) 
 
Nephritis and/or renal 
dysfunction 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity 
General Guidance 
For Any Grade 
− Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, infections, recent IV contrast, 
medications, fluid status). 
− Consider consulting a nephrologist.  
− Consider imaging studies to rule out any 
alternative etiology.  
− Monitor for signs and symptoms that may be 
related to changes in renal function (e.g., 
routine urinalysis, elevated serum BUN and 
creatinine, decreased creatinine clearance, 
electrolyte imbalance, decreased urine output, 
or proteinuria). 
− Follow urine protein/creatinine ratio every 3-7 
days.  
Grade 1 
- No dose modifications 
For Grade 1 
− Monitor serum creatinine weekly and any 
accompanying symptoms. 
− 
If creatinine returns to baseline, resume 
its regular monitoring per study 
protocol. 
− 
If creatinine worsens, depending on the 
severity, treat as Grade 2, 3, or 4. 
− Consider hydration, electrolyte replacement, 
and diuretics, as clinically indicated. 
− Consider nephrologist consult if not resolved 
within 14 days, or earlier as clinically 
indicated.  
Grade 2 
Hold study drug/study 
regimen until resolution 
to Grade ≤1 or baseline.  
- If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume study 
drug/study regimen 
For Grade 2 
- 
Consider including hydration, electrolyte 
replacement, and diuretics as clinically 
indicated. . 
- 
Follow urine protein/creatinine ratio every 3-7 
days  
- 
Carefully monitor serum creatinine as 
clinically warranted. 

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after completion of 
steroid taper (<10 
mg prednisone, or 
equivalent). 
- 
Consult nephrologist and consider renal biopsy 
if clinically indicated. 
- 
Start prednisone  1 to 2 mg/kg/day if other 
causes are ruled out 
- 
If event is persistent beyond 5 days or worsens, 
increase to prednisone up to 2 mg/kg/day PO 
or IV equivalent. 
- 
If event is not responsive within 3 to 5 days or 
worsens despite prednisone at 1 to 2 mg/kg/day 
PO or IV equivalent, consider additional 
workup. When event returns to baseline, 
resume study drug/study regimen and routine 
serum creatinine monitoring per study 
protocol. 
 
Grade 3 or 4 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 3 or 4 
- 
Carefully monitor serum creatinine daily 
- 
Follow urine protein/creatinine ratio every 3-7 
days  
- 
Consult nephrologist and consider renal biopsy 
if clinically indicated 
- 
Promptly start prednisone 1 to 2 mg/kg/day PO 
or IV equivalent 
- 
If event is not responsive within 3 to 5 days of 
steroids or worsens despite prednisone at 1 to 2 
mg/kg/day PO or IV equivalent, consider 
additional workup and prompt treatment with 
an immunosuppressant. 
 
Dermatologic Adverse 
Events (Including 
Pemphigoid) 
Any Grade 
(Refer to NCI 
CTCAE applicable 
version in study 
protocol for 
definition of 
severity/grade  
depending on type 
of skin rash) 
General Guidance 
For Any Grade 
- 
Patients should be thoroughly evaluated to rule 
out any alternative etiology. 
- 
Monitor for signs and symptoms of dermatitis 
(rash and pruritus). 
HOLD STUDY DRUG IF GRADE 3 
PEMPHIGOID OR SEVERE CUTANEOUS 
ADVERSE REACTION (SCAR) IS 
SUSPECTED.  
- 
PERMANENTLY DISCONTINUE STUDY 
DRUG IF SCAR, OR GRADE 3 PEMPIGOID 
IS CONFIRMED. 
Grade 1 
No dose 
modifications. 
For Grade 1 
- 
Consider symptomatic treatment, including 
oral antipruritics (e.g., diphenhydramine or 

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AZ Study Number ESR-18-13489; v4_12Nov 18 
HMRI Version Number 14.0 
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hydroxyzine) and topical therapy e.g., 
emolient, lotion, or institutional standard). 
 
Grade 2 
For persistent (>1 week) 
Grade 2 events, hold 
scheduled study 
drug/study regimen until 
resolution to Grade ≤1 or 
baseline. 
− If toxicity improves to 
Grade ≤1 or baseline, 
then resume drug/study 
regimen after completion 
of steroid taper (<10 mg 
prednisone, or 
equivalent). 
- 
For Grade 2 
- 
Consider dermatology consult and skin biopsy, 
as indicated. 
- 
Consider symptomatic treatment, including 
oral antipruritics (e.g.,diphenhydramine or 
hydroxyzine) and topical therapy 
- 
Consider moderate-strength topical steroid. 
- 
If no improvement of rash/skin lesions occurs 
within 1 week or is worsening despite 
symptomatic treatment and/or use of moderate 
strength topical steroid, consider discussing 
with Clinical Study Lead, as needed, and 
promptly start systemic steroids such as 
prednisone 1 to 2 mg/kg/day PO or IV 
equivalent. 
Grade 3 
For Grade 3 
− Hold study 
drug/study regimen 
until resolution to 
Grade ≤1or 
baseline. 
− If toxicity improves 
to Grade ≤1 or 
baseline, then 
resume drug/study 
regimen after 
completion of 
steroid taper (<10 
mg prednisone, or 
equivalent). 
For Grade 3 
- 
Reconsult a dermatologist. Consider skin 
biopsy (preferably more than 1) as clinically 
feasible. 
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
- 
Consider hospitalization. 
- 
Monitor the extent of rash [Rule of Nines]. 
- 
Consider, as necessary, discussing with 
Clinical Study Lead. 
Grade 4 
For Grade 4 
Permanently 
discontinue study 
drug/study regimen. 
For Grade 4 
- 
Reconsult a dermatologist. Consider skin 
biopsy (preferably more than 1) as clinically 
feasible. 
- 
Promptly initiate empiric IV 
methylprednisolone 1 to 2 mg/kg/day or 
equivalent. 
- 
Consider hospitalization. 
- 
 Monitor the extent of rash [Rule of Nines]. 

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- 
Consider, as necessary, discussing with 
Clinical Study Lead. 
 
 
Endocrinopathy 
 
(e.g., hyperthyroidism, 
thyroiditis, hypothyroidism, 
type 1 diabetes mellitus, 
hypophysitis, 
hypopituitarism, and adrenal 
insufficiency) 
Any Grade 
Depending on type 
of 
endocrinopathy, 
refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression including brain metastases, or 
infections).  
- Consider consulting an endocrinologist for 
endocrine events. 
-  Consider discussing with Clinical Study Lead, 
as needed. 
- Monitor patients for signs and symptoms of 
endocrinopathies. (Nonspecific symptoms 
include headache, fatigue, behaviour changes, 
mental status changes, photophobia, visual field 
cuts, vertigo, abdominal pain, unusual bowel 
habits, polydipsia, polyuria, hypotension, and 
weakness.) 
- Depending on the suspected endocrinopathy, 
monitor and evaluate thyroid function tests: 
thyroid stimulating hormone (TSH), free T3 and 
free T4 and other relevant endocrine and related 
labs (e.g., blood glucose and ketone levels, 
hemoglobin A1c (HgA1c)).If a patient 
experiences an AE that is thought to be possibly 
of autoimmune nature (e.g., thyroiditis, 
pancreatitis, hypophysitis, or diabetes insipidus), 
the investigator should send a blood sample for 
appropriate autoimmune antibody testing. 
- Investigators should ask subjects with 
endocrinopathies who may require prolonged or 
continued hormonal replacement, to consult 
their primary care physicians or 
endocrinologists about further monitoring and 
treatment after completion of the study. 
 
Grade 1 
No dose 
modifications. 
For Grade 1 
- Monitor patient with appropriate endocrine 
function tests. 
- For suspected hypophysitis/hypopituitarism, 
consider consulting an endocrinologist to guide 
assessment of early-morning  
adrenocorticotropin hormone (ACTH), cortisol, 
TSH and free T4; also consider gonadotropins, 
sex hormones, and prolactin levels, as well as 
cosyntropin stimulation test (though it may not 

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be useful in diagnosing early secondary adrenal 
insufficiency). 
- If TSH < 0.5 × LLN, or TSH >2 × ULN, or 
consistently out of range in 2 subsequent 
measurements, include free T4 at subsequent 
cycles as clinically indicated and consider 
consultation of an endocrinologist. 
 
Grade 2, 3, or 4 
- For Grade 2-4 
endocrinopathies other 
than hypothyroidism 
and type 1 diabetes 
mellitus (T1DM), 
consider holding study 
drug/study regimen 
dose until acute 
symptoms resolve. 
- − Study drug/study 
regimen can be 
resumed once patient 
stabilizes and after 
completion of steroid 
taper (<10 mg 
prednisone, or 
equivalent). 
− Patients with  
endocrinopathies  who 
may require prolonged or 
continued steroid 
replacement (e.g., 
adrenal insufficiency) 
can be retreated with 
study drug/study regimen 
if the patient is clinically 
stable as per investigator 
or treating physician’s 
clinical judgement. 
For Grade 2-4 
- Consult endocrinologist to guide evaluation of 
endocrine 
function 
and, 
as 
indicated 
by 
suspected 
endocrinopathy and as clinically 
indicated, consider pituitary scan. 
- For all patients with abnormal endocrine work 
up, except those with isolated hypothyroidism or 
T1DM, and as guided by an endocrinologist, 
consider short- term corticosteroids (e.g., 1 to 2 
mg/kg/day methylprednisolone or IV equivalent) 
and prompt initiation of treatment with relevant 
hormone replacement. 
- Isolated hypothyroidism may be  treated with 
replacement therapy, without study drug/study 
regimen 
interruption, 
and 
 
without 
corticosteroids. 
- Isolated T1DM may be treated with 
appropriate diabetic therapy, and without 
corticosteroids. Only hold study drug/study 
regimen in setting of hyperglycemia when 
diagnostic workup  is positive for diabetic 
ketoacidosis. 
- For patients with  normal  endocrine  workup 
(laboratory assessment or magnetic resonance 
imaging (MRI) scans), repeat laboratory 
assessments/MRI as clinically indicated. 
 
Amylase/Lipase increased 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
General Guidance 
For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g. disease 
progression, viral infection, concomitant 
medications, substance abuse). 

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CTCAE 
grade/severity) 
- For modest asymptomatic elevations in serum 
amylase and lipase, corticosteroid treatment is 
not indicated as long as there are no other signs 
or symptoms of pancreatic inflammation. 
- Assess for signs/symptoms of pancreatitis 
- Consider appropriate diagnostic testing (e.g., 
abdominal CT with contrast, MRCP if clinical 
suspicion of pancreatitis and no radiologic 
evidence on CT) 
- If isolated elevation of enzymes without 
evidence of pancreatitis, continue 
immunotherapy. Consider other causes of 
elevated amylase/lipase 
- If evidence of pancreatitis, manage according to 
pancreatitis recommendations 
 
Grade 1 
No dose 
modifications. 
Grade 2, 3, or 4 
For Grade 2,3, or -4  
In consultation with 
relevant gastroenterology 
specialist consider 
continuing study 
drug/study regimen if no 
clinical/radiologic 
evidence of pancreatitis ± 
improvement in 
amylase/lipase. 
 
 
Acute Pancreatitis 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology. 
- Consider Gastroenterology referral. 
 
Grade 2 
Consider holding 
study drug/regimen 
Grade 2 
- Consider IV hydration. 
- Consider Gastroenterology referral 
Grade 3, or 4 
For Grade 3 
Hold study drug/study 
regimen until resolution 
of elevated enzymes and 
no radiologic findings  
If no elevation in 
enzymes or return to  
Baseline values, then 
resume study drug/study 
regimen after. completion 
of steroid taper (<10 mg 
prednisone, or 
equivalent). 
For Grade 4 
For Grade 3, or 4 
- Promptly start systemic steroids prednisone 1 to 
2 mg/kg/day PO or IV equivalent. 
- IV hydration 

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Permanently discontinue 
study drug/study 
regimen. 
 
Nervous System Disorders 
Aseptic Meningitis 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
- Symptoms may 
include headache, 
photophobia, and neck 
stiffness, nausea/ 
vomiting which may 
resemble an infectious 
meningitis. 
- Patients may be 
febrile. 
- Mental status should 
be normal 
For Any Grade 
- Consider neurology consult 
- Consider MRI brain with and without contrast 
with pituitary protocol and a lumbar puncture for 
diagnosis. 
- Exclude bacterial and viral infections. (ie HSV) 
- Consider antibiotic for bacterial coverage  until 
cultures/panel results are back 
- Consider IV acyclovir until polymerase  chain 
reactions are available 
Any Grade 
Permanently 
discontinue study 
drug/study regimen 
For Any Grade 
- Consider neurology consult 
- Consider MRI brain with and without contrast 
with pituitary protocol and a lumbar puncture 
for diagnosis. 
- Exclude bacterial and viral infections. (ie HSV) 
- Consider IV acyclovir until polymerase chain 
reactions are available 
- Consider, as necessary, discussing with Clinical 
Study Lead.( Last bullet) 
- Consider hospitalization. 
- Once infection has been ruled out promptly 
initiate empiric IV methylprednisolone 1 to 2 
mg/kg/day or equivalent. 
Encephalitis 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
− Symptoms may include 
Confusion, altered 
behaviour, headaches, 
seizures, short-term 
memory loss, depressed 
level of consciousness 
focal weakness, and 
speech abnormality. 
For Any Grade 
- Consider neurology consult 
- Consider testing including MRI of the brain 
with and without contrast, lumbar puncture, 
electroencephalogram (EEG) to evaluate for 
subclinical seizures, ESR, CRP, antineutrophil 
cytoplasmic antibody (ANCA) (if vasculitic 
process suspected), thyroid panel including TPO 
and thyroglobulin and additional autoantibodies 
to rule out paraneoplastic disorders. 
- Exclude bacterial and viral infections. (i.e. 
HSV) Consider IV acyclovir until polymerase 
chain reactions are available. 
- Add bacterial coverage 

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Grade 2 
For Grade 2 
Permanently discontinue 
study drug/study regimen 
For Grade 2 
- Consider, as necessary, discussing with the 
Clinical Study Lead. 
- Once infection has been ruled out 
methylprednisolone 1–2 mg/kg/day 
- For progressive symptoms or if oligoclonal 
bands are present consider methylprednisolone 1 
g IV daily for 3–5 days plus IVIG or 
plasmapheresis 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue 
study drug/study regimen 
For Grade 3 or 4 
- Consider, as necessary, discussing with Clinical 
Study Lead. 
-  Consider hospitalization. 
- Once infection is ruled out, start 
methylprednisolone 1 g IV daily for 3–5 days 
for progressive symptoms consider adding IVIG 
or plasmapheresis 
Demyelinating Disease 
(optic neuritis, transverse 
myelitis, acute 
demyelinating 
encephalomyelitis 
(ADEM)) 
Any Grade  
General Guidance 
- 
Permanently 
discontinue 
immunotherapy 
- 
Consider MRI of the 
spine and brain Once 
imaging is complete, 
consider lumbar 
puncture. 
- 
Consider testing to 
rule out additional 
aetiologies: B12, 
copper, HIV, rapid 
plasma reagin (RPR), 
ANA, anti- Ro/La 
antibodies, aquaporin-
4 IgG, myelin 
oligodendrocyte 
glycoprotein (MOG) 
IgG, paraneoplastic 
panel 
For Any Grade  
- Consider neurology consult 
- Inpatient care 
- Consider prompt initiation of high 
methylprednisolone pulse dosing 
- Strongly consider IVIG or plasmapheresis 
Peripheral neuropathy 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
 
For Any Grade 
- Patients should be evaluated to rule out any 
alternative etiology for neuropathy (e.g., disease 
progression, infections, metabolic syndromes or 
medications). It should be noted that the 
diagnosis of immune-mediated peripheral 
neuromotor syndromes can be particularly 
challenging in patients with underlying cancer, 
due to the multiple potential confounding effects 
of cancer (and its treatments) throughout the 

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neuraxis. Given the importance of prompt and 
accurate diagnosis, it is essential to have a low 
threshold to obtain a neurological consult. 
- Neurophysiologic diagnostic testing (e.g., 
electromyogram and nerve conduction 
investigations are routinely indicated upon 
suspicion of such conditions and may be best 
facilitated by means of a neurology consultation. 
Grade 1 
No dose modification  
For Grade 1 
- Consider discussing with the Clinical Study 
Lead, as needed. 
- Monitor symptoms for interference with ADLS, 
gait difficulties, imbalance, or autonomic 
dysfunction 
Grade 2 
Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
For Grade 2 
- Consult a neurologist. 
- Consider EMG/NCS 
- Consider discussing with the Clinical Study 
Lead, as needed. 
- Observation for additional symptoms or 
consider initiating prednisone 0.5–1 mg/kg 
orally 
- If progression, initiate methylprednisolone 2–4 
mg/kg/day and treat as GBS 
- Sensory neuropathy/neuropathic pain may be 
managed by appropriate medications (e.g., 
gabapentin or duloxetine). 
 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue 
study drug/study 
regimen. 
For Grade 3 or 4 
- Consider discussing with Clinical Study Lead, 
as needed. 
- Recommend hospitalization. 
- Monitor symptoms and consult a neurologist. 
- Treat per Guillain-Barré Syndrome 
recommendations 
Guillain-Barré Syndrome 
(GBS) 
 
General Guidance  
- Recommend hospitalization 
- Obtain neurology consult 
- Obtain MRI of spine to rule out compression 
lesion 
- Obtain lumbar puncture 
- Antibody tests for GBS variants 
- Pulmonary function tests 
- Obtain electromyography (EMG) and nerve 
conduction studies 
- Frequently monitor pulmonary function tests 
and neurologic evaluations 
- Monitor for concurrent autonomic dysfunction 

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- Initiate medication as needed for neuropathic 
pain 
Grade 2-4 
Grade 2-4 
Permanently discontinue  
Start IVIG or plasmapheresis in addition to 
methylprednisolone 1 gram daily for 5 days, 
then taper over 4 weeks. 
Myasthenia gravis 
 
General Guidance 
- Obtain neurology consult 
- Recommend hospitalization 
- Obtain pulmonary function tests 
- Obtain labs: ESR, CRP, creatine phosphokinase 
(CPK), aldolase and anti-striational antibodies 
- Consider cardiac exam, ECG, troponin, 
transthoracic echocardiogram for possible 
concomitant myocarditis 
- Obtain electromyography (EMG) and nerve 
conduction studies 
- Consider MRI of brain/spine to rule out CNS 
involvement by disease 
- Avoid medications that might exacerbate MG 
(e.g.beta blockers, some antibiotics, IV 
magnesium 
Grade 2 
Permanently discontinue 
- Consider pyridostigmine 30mg three times daily 
and gradually increase based on symptoms (max 
dose 120mg four times daily) 
- Consider starting low dose prednisone 20mg 
daily and increase every 3-5 days. (Target dose 
1mg/kg/day. Max dose 100mg daily) 
Grade 3-4  
Permanently discontinue 
- Start methylprednisolone 1-2mg/kg/day. Taper 
steroids based on symptom improvement 
- Start plasmapheresis or IVIG 
- Consider rituximab if refractory to 
plasmapheresis or IVIG 
- Frequent PFT assessments 
- Daily neurologic evaluations 
Myocarditis 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance 
Discontinue drug 
permanently if biopsy 
proven immune-mediated 
myocarditis. 
For Any Grade 
- Initial work-up should include clinical 
evaluation, B type natriuretic peptide (BNP), 
cardiac enzymes, electrocardiogram (ECG), 
echocardiogram (ECHO), monitoring of 
oxygenation via pulse oximetry (resting and 
exertion), and additional laboratory work-up as 
indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion 
abnormalities when needed. 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, or infections)  

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- The prompt diagnosis of immune-mediated 
myocarditis is important, particularly in patients 
with baseline cardiopulmonary disease and 
reduced cardiac function. 
- Consider discussing with the Clinical Study 
Lead, as needed. 
- Monitor patients for signs and symptoms of 
myocarditis (new onset or worsening chest pain, 
arrhythmia, shortness of breath, peripheral 
edema). As some symptoms can overlap with 
lung toxicities, simultaneously evaluate for and 
rule out pulmonary toxicity as well as other 
causes (e.g., pulmonary embolism, congestive 
heart failure, malignant pericardial effusion). 
Consult a cardiologist early, to promptly assess 
whether and when to complete a cardiac biopsy, 
including any other diagnostic procedures. 
- as indicated. Spiral CT or cardiac MRI can 
complement ECHO to assess wall motion 
abnormalities when needed. 
Grade 2, 3 or 4 
If Grade 2-4 permanently 
discontinue study 
drug/study regimen 
For Grade 2-4 
- Monitor symptoms daily, hospitalize. 
- Consider cardiology consultation and prompt 
start of high-dose/pulse corticosteroid therapy 
- Supportive care (e.g., oxygen). 
- If no improvement consider additional 
immunosuppressive therapy such as TNF 
inhibitors (e.g., infliximab), IVIG or 
plasmapheresis or other therapies depending on 
the clinical condition of the patient, based on the 
discretion of the treating specialist consultant r 
or relevant practice guidelines. Caution: It is 
important to rule out sepsis and refer to 
infliximab label for general guidance before 
using infliximab. Infliximab is 
contraindicated for patients who have heart 
failure. 
Myositis/ Polymyositis 
Any Grade 
(Refer to NCI 
CTCAE 
applicable version 
in study protocol 
for defining the 
CTCAE 
grade/severity) 
General Guidance  
For Any Grade 
- Patients should be thoroughly evaluated to rule 
out any alternative etiology (e.g., disease 
progression, other medications, or infections). 
- Monitor patients for signs and symptoms of 
poly/myositis. Typically, muscle weakness/pain 
occurs in proximal muscles including upper 
arms, thighs, shoulders, hips, neck and back, 
and; also difficulty breathing and/or trouble 
swallowing can occur and progress rapidly. 
Increased general feelings of tiredness and 

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fatigue may occur, and there can be new-onset 
falling, difficulty getting up from a fall, and 
trouble climbing stairs, standing up from a 
seated position, and/or reaching up. 
- If poly/myositis is suspected, a Neurology 
consultation should be obtained early, with 
prompt guidance on diagnostic procedures. 
Myocarditis may co-occur with poly/myositis; 
refer to guidance under Myocarditis. Given 
breathing complications, refer to guidance under 
Pneumonitis/ILD. Given possibility of an 
existent (but previously unknown) autoimmune 
disorder, consider Rheumatology consultation. 
- Consider, as necessary, discussing with the 
Clinical Study Lead. 
- Consider that patients may present with or 
progress to rhabdomyolysis. Treat signs and 
symptoms as per institutional protocol or 
local clinical practice. 
- Initial work-up should include clinical 
evaluation, creatine kinase, aldolase, lactate 
dehydrogenase (LDH), blood urea nitrogen 
(BUN)/creatinine, erythrocyte sedimentation 
rate or C-reactive protein (CRP) level, urine 
myoglobin, and additional laboratory work-up 
as indicated, including a number of possible 
rheumatological/antibody tests (i.e., consider 
whether a rheumatologist consultation is 
indicated and could guide need for rheumatoid 
factor, antinuclear antibody, anti-smooth 
muscle, antisynthetase [such as anti-Jo-1], 
and/or signal recognition particle antibodies). 
Confirmatory testing may include 
electromyography, nerve conduction studies, 
MRI of the muscles, and/or a muscle biopsy. 
Consider Barium swallow for evaluation of 
dysphagia or dysphonia. 
Grade 1 
No dose modification 
For Grade 1 
- Monitor and closely follow up in 2 to 4 days for 
clinical symptoms and initiate evaluation as 
clinically indicated. 
- Consider Neurology consult 
- Consider, as necessary, discussing with the 
Clinical Study Lead. 
Grade 2 
- Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
- Permanently 
discontinue study 
For Grade 2 
- Monitor symptoms daily and consider 
hospitalization. 

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drug/study regimen if 
it does not resolve to 
Grade ≤1 within 30 
days or if there are 
signs of respiratory 
insufficiency. 
- Consider Rheumatology or Neurology consult, 
and initiate evaluation. 
- Consider, as necessary, discussing with the 
Clinical Study Lead. 
- If clinical course is rapidly progressive 
(particularly if difficulty breathing and/or 
trouble swallowing), promptly start IV 
methylprednisolone 2 to 4 mg/kg/day systemic 
steroids along with receiving input from 
Neurology consultant 
- If clinical course is not rapidly progressive, start 
systemic steroids (e.g., prednisone 1 to 2 
mg/kg/day PO or IV equivalent); if no 
improvement within 2 to 3 days, continue 
additional work up and start treatment with IV 
methylprednisolone 2 to 4 mg/kg/day 
- If after start of IV methylprednisolone at 2 to 4 
mg/kg/day there is no improvement within 3 
days, consider additional immunosuppressive 
therapy such as TNF inhibitors (e.g., 
infliximab), IVIG or plasmapheresis, or other 
therapies based on the discretion of the treating 
specialist consultant or relevant practice 
guideline Caution: It is important to rule out 
sepsis and refer to infliximab label for 
general guidance before using infliximab. 
 
Grade 3 
For Grade 3 
- Hold study drug/study 
regimen dose until 
resolution to Grade ≤1. 
- Permanently 
discontinue study 
drug/study regimen if 
Grade 3 imAE does 
not resolve to Grade 
≤1 within 30 days or if 
there are signs of 
respiratory 
insufficiency. 
For Grade 3 
- Monitor symptoms closely; recommend 
hospitalization. 
- Consider Rheumatology and/or Neurology 
consult 
- Consider discussing with the Clinical Study 
Lead, as needed. 
- Promptly start IV methylprednisolone 2 to4 
mg/kg/day systemic steroids along with 
receiving input from Neurology consultant If 
after start of IV methylprednisolone at 2 to 4 
mg/kg/day there is no improvement within 2 to 
3 days, consider starting another 
immunosuppressive therapy such as a TNF 
inhibitor (e.g., infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider or relevant 
practice guidelines). Caution: It is important 
to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab. 
- Consider whether patient may require IV IG, 
plasmapheresis. 

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Grade 4 
For Grade 4 
Permanently discontinue 
study drug/study regimen. 
Grade 4 
- Monitor symptoms closely; recommend 
hospitalization. 
- Consider Rheumatology and/or Neurology 
consult 
- Consider discussing with the Clinical Study 
Lead, as needed. 
- Promptly start IV methylprednisolone 2 to 4 
mg/kg/day systemic steroids along with 
receiving input from Neurology consultant. 
- If after start of IV methylprednisolone at 2 to 4 
mg/kg/day there is no improvement within 2 to 
3 days, consider starting another 
immunosuppressive therapy such as a TNF 
inhibitor (e.g., infliximab at 5 mg/kg IV, may be 
repeated at 2 and 6 weeks after initial dose at the 
discretion of the treating provider or relevant 
practice guidelines). Caution: It is important 
to rule out sepsis and refer to infliximab label 
for general guidance before using infliximab. 
 
 
 
 
 

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Other – Immune-mediated Reactions 
Severity Grade of the Event (Refer to NCI 
CTCAE applicable version in study protocol 
for defining the CTCAE grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: It is possible that events with an inflammatory or immune 
mediated mechanism could occur in nearly all organs, some of 
them are not noted specifically in these guidelines (e.g. immune 
thrombocytopenia, haemolytic anaemia, uveitis, vasculitis). 
- 
Patients should be thoroughly evaluated to rule out any 
alternative etiology (e.g., disease progression, other 
medications, or infections). 
- 
The Clinical Study Lead may be contacted for immune-
mediated reactions not listed in the “specific immune-
mediated reactions” section 
- 
Consultation with relevant specialist Treat accordingly, as 
per institutional standard. 
Grade 1 
No dose modification 
Monitor as clinically indicated 
Grade 2 
- 
Hold study drug/study regimen until resolution to ≤Grade 1 
or baseline. 
- 
If toxicity worsens, then treat as Grade 3 or Grade 4. 
- 
Study drug/study regimen can be resumed once event 
stabilizes to Grade ≤1 after completion of steroid taper. 
- 
Consider whether study drug/study regimen should be 
permanently discontinued in Grade 2 events with high 
likelihood for morbidity and/or mortality when they do not 
rapidly improve to Grade <1 upon treatment with systemic 
steroids and following full taper 
For Grade 2, 3 or 4 
Treat accordingly, as per institutional standard, appropriate 
clinical practice guidelines, and society guidelines. (See below). 
Grade 3 
Hold study drug/study regimen 
Grade 4 
Permanently discontinue study drug/study regimen 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Clinical Study Lead.” 
 
 

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Infusion-Related Reactions 
Severity Grade of the Event (Refer to NCI 
CTCAE applicable version in study protocol 
for defining the CTCAE grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
General Guidance  
- 
For Any Grade  
- 
Manage per institutional standard at the discretion of 
investigator. 
- 
Monitor patients for signs and symptoms of infusion-
related reactions (e.g., fever and/or shaking chills, 
flushing and/or itching, alterations in heart rate and 
blood pressure, dyspnea or chest discomfort, or skin 
rashes) and anaphylaxis (e.g., generalized urticaria, 
angioedema, wheezing, hypotension, or tachycardia). 
Grade 1 or 2 
For Grade 1 
- 
The infusion rate of study drug/study regimen may be 
decreased by 50% or temporarily interrupted until resolution 
of the event. 
 
For Grade 2 
- 
The infusion rate of study drug/study regimen may be 
decreased 50% or temporarily interrupted until resolution of 
the event. 
- 
Subsequent infusions may be given at 50% of the initial 
infusion rate. 
For Grade 1 or 2 
- 
Acetaminophen and/or antihistamines may be 
administered per institutional standard at the 
discretion of the investigator. 
- 
Consider premedication per institutional standard or 
study protocol prior to subsequent doses. 
- 
Consider steroids for patients who have previously 
experienced infusion reaction; use of steroid 
premedication may be permitted in these situations 
Grade 3 or 4 
For Grade 3 or 4 
Permanently discontinue study drug/study regimen. 
For Grade 3 or 4 
- Manage severe infusion-related reactions per institutional 
standard, appropriate clinical practice guidelines, and society 
guidelines. 
 
 
 

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Non-Immune-Mediated Reactions 
Severity Grade of the Event (Refer to NCI 
CTCAE applicable version in study protocol 
for defining the CTCAE grade/severity) 
Dose Modifications 
Toxicity Management 
Any Grade 
Note: Dose modifications are not required for AEs not deemed to 
be related to study treatment (i.e., events due to underlying 
disease) or for laboratory abnormalities not deemed to be 
clinically significant. 
Treat accordingly, as per institutional standard. 
Grade 1  
No dose modifications. 
Treat accordingly, as per institutional standard 
Grade 2 -4 
Hold study drug/study regimen until resolution to ≤Grade 1 or 
baseline. 
Treat accordingly, as per institutional standard 
Grade 4 
Discontinue study drug/study regimen (Note: For Grade 4 labs, 
decision to discontinue should be based on accompanying 
clinical signs/symptoms, the Investigator’s clinical judgment, 
and consultation with the Sponsor.). 
Treat accordingly, as per institutional standard 
Note: As applicable, for early phase studies, the following sentence may be added: “Any event greater than or equal to Grade 2, please discuss with Clinical 
Study Lead.” 
 
 
 

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APPENDIX 2  
ECOG Performance Status Scale 
Grade 
Description 
0 
Normal activity. Fully active, able to carry on all pre-disease 
performance without restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous 
activity, but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light housework, office work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but 
unable to carry out any work activities. Up and about more than 50% 
of waking hours. 
3 
In bed >50% of the time. Capable of only limited self-care, confined 
to bed or chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self-care. 
Totally confined to bed or chair. 
5 
Dead. 
Oken MM, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin 
Oncol 1982;5:649-55.