Clinical trial NCT02591615
Conditions: Non-Small Cell Lung Cancer
Sponsor: Alliance Foundation Trials, LLC.
Start date: 2016-03-01; Completion date: 2020-07-04
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This is a multicenter randomized phase II to determine if the administration of standard platinum-based chemotherapy before MK-3475 in with Chemotherapy naive stage IV Non-small Cell Lung Cancer (NSCLC) will improve the overall response rate (ORR) compared to MK-3475 administered before chemotherapy. Patients will be given Pembrolizumab as maintenance up to 2 years: Carboplatin and paclitaxel or pemetrexed every 3 weeks x 4 cycles followed by pembrolizumab every 3 weeks for up to 2 years. Pembrolizumab every 3 weeks x 4 cycles followed by carboplatin and paclitaxel or pemetrexed every 3 weeks x 4 cycles followed by pembrolizumab every 3 weeks for up to 2 years.

Detailed description:
While a genotype-directed strategy has been established as effective in treatment selection for patients with advanced NSCLC, only a minority of patients at this time will have a readily identifiable actionable molecular target. Furthermore, genotype-directed therapy has not been validated for patients with squamous cell carcinoma of the lung. Therefore, the majority of patients with advanced NSCLC will continue to rely on standard platinum-based doublet chemotherapy. Given the plateau in effectiveness of this approach, novel treatment strategies are clearly warranted.

Arms: arm 1: For Squamous Carcinoma Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Paclitaxel 200 mg/m2 IV day 1 every 21-days for up to 4 cycles

OR

For Non-squamous Carcinoma Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Pemetrexed 500 mg/m2 IV day 1 every 21-days for up to 4 cycles arm 2: MK-3475 200 mg/m2 IV every 21-days for up to 4 cycles

Patients with CR, PR, or SD by irRC will then be treated with:

For Squamous Carcinoma:

Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Paclitaxel 200 mg/m2 IV day 1 every 21-days for up to 4 cycles

OR

For Non-squamous Carcinoma

Carboplatin AUC = 6 IV day 1 every 21-days for up to 4 cycles Pemetrexed 500 mg/m2 IV day 1 every 21-days for up to 4 cycles
Interventions: intervention 1: MK-3475 intervention 2: Carboplatin intervention 3: Paclitaxel intervention 4: Pemetrexed
Intervention descriptions: intervention 1: Dose frequency of Q3W, Day 1 of each cycle intervention 2: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy) intervention 3: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy) intervention 4: Dose frequency of Q3W, Day 1 of each cycle (standard Chemotherapy)

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
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A L LI A N C E F O U N D A TI O N T RI A L S ( A F T)  
 
P R O T O C O L N U M B E R  
A F T –  0 9   
 
R a n d o mize d P h ase II T ri al E v al u ati n g t he O pti m al Se q ue nci n g of P D -1 I n hi biti o n wit h 
Pe m b r oliz u m a b ( M K -3 4 7 5 ) a n d St a n d ar d Pl ati n u m -b ase d C he m ot her a p y i n P atie nts wit h 
C he m ot her a p y n ai ve st a ge I V N o n-s m all Cell L u n g C a ncer 
 
Pr ot oc ol V ersi o n: # 5 . 0 
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I nvesti g ati o n al A ge nt : Pe m br oliz u m a b ( M K-3 4 7 5)  
I N D S p o ns or: Alli a nce F o u n d ati o n Tri als, L L C  
I N D #: 1 2 6 4 8 9  
I nvesti g ati o n al A ge nt  S u p plier : Merck  
 
Cli nic al Tri als. g o v I de ntifier: N C T  0 2 5 9 1 6 1 5  
 
St u d y C h air  
T h o mas He nsi n g, M. D.  
N ort h S h ore U ni versit y Healt h  S yste m  
U ni versit y of C hica g o  
 
E va nst o n, I L 6 0 2 0 1  
 
 
 
 
  
 
S p o ns or Pri nci pal I n v esti gat or  
M o nica M. Berta g n olli, M D  
Allia nce F o u n dati o n Trials  
 
B ost o n, M A 0 2 1 1 5  
 
 
 
 
 
 
 
 
 
 


 
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St u d y Res o urces  
 
A d verse E ve nt Re p orti n g  
vi a Me di d at a R a ve  i Me di d at a P o rt al/ Ar g us S afet y M a n a ge me nt 
accessi ble via t he A F T we bsite, htt ps://allia ncef o u n dati o ntrials. or g/  
I R T –  R a n d o miz ati o n S yste m  
accessi ble via t he A F T we bsite, htt ps://allia ncef o u n dati o ntrials. or g/  
Site Z o ne  
htt ps://sitez o ne. m y wi n gs pa n.c o m/sitez o ne/trials  
accessi ble via t he A F T we bsite, htt ps://allia ncef o u n dati o ntrials. or g/  
F or Site Z o ne H el p: t
 
Bi O M S A F T Res o urce Site  
htt ps://c b mia p ps. w ustl.e d u/c o nfl ue nce/ x/ Ta E T A O  
 
 
Pr ot oc ol C o nt acts  
 
Alli a nce F o u n d ati o n Tri als Pr oject M a n a ger  
 
 
 
 
 
 
Alli a nce F o u n d ati o n Tri als Bi ore p osit or y at 
W as hi n gt o n U ni versit y  
c/ o Site ma n Ca ncer Ce nter Tiss ue Pr oc ure me nt 
C ore  
4 2 5 S. E ucli d A ve n ue  
BJ CI H B uil di n g, R o o m 5 1 2 0  
St. L o uis, M O 6 3 1 1 0 -1 0 0 5  
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T his d oc u me nt c o ntai ns c o nfi d e ntial i nf or mati o n of Allia nce F o u n dati o n Trials, L L C. T he i nf or mati o n i n t his d oc u me nt ca n n ot 
be use d f or a n y p ur p ose ot her  t ha n t h e e val u ati o n or c o n d uct of t h e cli nical i n vesti gati o n wit h o ut t h e pri or writte n c o nse nt of 
Allia nce F o u n dati o n Trials, L L C.  


 
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1.  S Y N O P SI S  
1. 1.  S T U D Y  S U M M A R Y  
 
A b bre viate d Title  
O pti mal Se q ue nci n g of Pe m br oliz u ma b  (M K -3 4 7 5 ) a n d 
Sta n dar d Plati n u m -base d C he m ot hera p y i n First -Li ne 
N S C L C  
St u d y  P has e  
Ra n d o mize d p hase II  
Cli nical I n dic ati o n  
T he treat me nt of p atie nt s wit h c he m ot hera p y n ai ve  n o n -
s mall cell l u n g ca ncer ( N S C L C).  
St u d y  T y pe  
I nter ve nti o nal 
T y pe of c o ntr ol  
Acti ve c o ntr ol wit h o ut place b o.  
R o ute of a d mi nistrati o n  
I ntr a ve n o us 
St u d y  Bli n di n g  
U n bli n de d O pe n -la bel 
Treat me nt Gr o u ps  
Car b o plati n a n d paclita xel or pe metre x e d e ver y 3 wee ks x 4 
c ycles f oll o we d b y p e m br oliz u ma b ( M K -3 4 7 5 ) e v er y 3 
wee ks f or u p t o 2 4 m o nt hs .  
 
Pe m br oliz u ma b ( M K -3 4 7 5 ) e ver y 3 wee ks x 4 c ycles 
f oll o we d b y car b o plati n a n d paclita xel or pe metre x e d e ver y 
3 wee ks x 4 c ycles f oll o we d b y  pe m br oliz u ma b ( M K -3 4 7 5)  
e ver y 3 wee ks f or u p t o 2 4 m o nt hs .  
 
Treat me nt wit h pe m br oli z u ma b  ( M K-3 4 7 5)  ma y c o nti n ue 
f or u p t o 2 4 m o nt hs, per i n vesti gat or discreti o n. Treat me nt, 
visit assess me nts a n d t u m or assess me nt s hall c o nti n ue o n 
a p pr o xi matel y t he sa me s c he d ule as pri or c ycl es a n d ma y b e 
a dj uste d t o i nstit uti o nal sta n dar d of care f or p e m br oliz u ma b 
( M K-3 4 7 5)  i n N S C L C.  
  
N u m ber of st u d y patie nt s 
A p pr o xi matel y 9 0 p atie nt s will be e nr olle d at a n a ntici pate d 
3 0 sites.  
Esti mate d d urati o n of 
st u d y 
T he s p o ns or esti mates t h at t he st u d y will re q uir e 
a p pr o xi matel y 3 6 m o nt hs fr o m t he ti me of t he first patie nt  
si g ns t he i nf or me d c o nse nt u ntil t he last patie nt ’s last visit.  
D urati o n of Partici pati o n  
Eac h patie nt  will partici p ate i n t he st u d y fr o m t he ti me t he 
patie nt  si g ns t he I nf or me d C o nse nt F or m (I C F) t hr o u g h 
t he fi nal pr ot oc ol-s pecifi e d c o ntact. Eli gi ble p atie nt s will 
recei v e assi g ne d tr eat me nt o n da y 1 of eac h 3-wee k 
d osi n g c ycl e. Patie nt s wit h c o m plete res p o nse ( C R) , 


 
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partial res p o nse ( P R) or sta ble disease ( S D) , per R E CI S T 
1. 1 [ 1], after treat me nt wit h 4 c ycl es of car b o plati n 
c o m bi ne d wit h paclita xel or pe metre x e d will c o nti n ue 
treat me nt wit h pe m br oliz u ma b ( M K -3 4 7 5 ) u ntil 2 4 
m o nt hs  of t hera p y ha ve  b ee n a d mi nistere d, d o c u m e nte d 
disease pr o gressi o n, u nacce pta ble a d verse e ve nt(s), 
i nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of 
treat me nt, i n vesti gat or’s decisi o n t o wit h dra w t he patie nt , 
patie nt  wit h dra ws c o nse nt, pre g n a nc y of t he patie nt , n o n-
c o m plia nce wit h st u d y treat me nt or pr o ce d ure 
re q uire me nts, or a d mi nistrati ve reas o ns. After t h e e n d of 
treat me nt, eac h patie nt  will be f oll o we d f or a mi ni m u m 
of 3 0 da ys f or a d verse e v e nt m o nit ori n g (seri o us a d verse 
e ve nts will be c ollecte d f or u p t o 9 0 da ys after t he e n d of 
treat me nt). 
Patie nt s will ha ve p ost-treat me nt f oll o w u p f or dis ease 
stat us, i ncl u di n g i nitiati n g a n o n-st u d y ca n cer treat me nt a n d 
e x perie nci n g dis ease pr o gressi o n, u ntil deat h, wit h dra wi n g 
c o nse nt or bec o mi n g l ost t o f oll o w -u p.  
 
 
 
 
 
 




 
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Patie nts w h o pr o gress w hile recei vi n g C b A U C 6 + P A C 2 0 0 m g/ m 2 or P E M 5 0 0 m g/ m 2 ma y 
c o nti n ue recei vi n g treat m e nt wit h  pe m br oliz u ma b  (M K -3 4 7 5 ). 
 
Treat me nt wit h pe m br oli z u ma b  ( M K-3 4 7 5)  ma y  c o nti n ue f or u p t o 2 4 m o nt hs  after t he i nitial 
assi g ne d s eq ue n ci n g c he m o/ pe m br oliz u ma b ( M K -3 4 7 5) treat me nt  or u ntil disease pr o gressi o n 
o n pe m br oliz u ma b ( M K -3 4 7 5 ) or a n u nacce pta ble a d verse e ve nt.  
 
Patie nts will be f oll o we d f or at least 3 0  m o nt hs p ost -ra n d o mizati o n or u ntil deat h, w hic he v er 
c o mes first.  
 
Ple as e r efer t o t he f ull pr ot oc ol t e xt f or a c o m pl ete descri pti o n of t he eli gi bilit y criteri a a n d 
tre at me nt pl a n. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2.  T A B L E O F C O N T E N T S  
2.  
T A B L E O F C O N T E N T S  ................................................................................................................ 7  
3.  
B A C K G R O U N D  ............................................................................................................................ 1 0  
3. 1.  P har mace utical a n d T hera pe utic bac k gr o u n d  ............................................................................... 1 0  
3. 1. 1.  
I ntr o d ucti o n ...................................................................................................................... 1 0  
3. 1. 2.  
P D -1 P at h w ay –  P h ar m ace utic al a n d T her a pe utic B ack gr o u n d  ...................................... 1 1  
3. 1. 3.  
I m m u ne C heck p oi nt I n hi biti o n a n d L u n g C a ncer ............................................................. 1 2  
3. 2.  St u d y Desi g n  ................................................................................................................................ 1 3  
4.  
R A TI O N A L E  ................................................................................................................................. 1 4  
4. 1.  Rati o nale f or t he Trial a n d Selecte d Patie nt P o p ulati o n  ............................................................... 1 4  
4. 1. 1.  
R ati o n ale f or D ose Selecti o n/ Re gi me n/ M o dific ati o n  ........................................................ 1 6  
5.  
R A TI O N A L E F O R E N D P OI N T S  ............................................................................................... 1 6  
5. 1.  Efficac y e n d p oi nts  ........................................................................................................................ 1 6  
5. 1. 1.  
Pri m ary  ............................................................................................................................. 1 6  
5. 1. 2.  
Sec o n d ary .......................................................................................................................... 1 7  
5. 1. 3.  
M olec ul ar a n d Ge n o mic C orrel ates of Tre at me nt Res p o nse a n d O utc o me  ..................... 1 7  
6.  
O B J E C TI V E S  ................................................................................................................................ 1 7  
6. 1.  Pri mar y O bjecti ve ......................................................................................................................... 1 7  
6. 2.  S ec o n dar y O bj ecti ves  ................................................................................................................... 1 7  
6. 3.  C orrelati ve O bjecti ves  .................................................................................................................. 1 8  
6. 4.  F ut ure Bi o me dical Researc h  ........................................................................................................ 1 8  
7.  
P A TI E N T S E L E C TI O N  ............................................................................................................... 1 8  
7. 1.  i ncl usi o n Criteria .......................................................................................................................... 1 8  
7. 2.  E xcl usi o n Criteria  ......................................................................................................................... 2 0  
8.  
P A TI E N T E N R O L L M E N T  .......................................................................................................... 2 2  
8. 1.  S ite e nr oll me nt Re q uire me nts ...................................................................................................... 2 2  
8. 2.  Patie nt e nr oll me nt Re q uire me nts  ................................................................................................. 2 2  
8. 3.  Patie nt scree ni n g, e nr oll me nt/ Ra n d o mizati o n Pr oce d ures  ........................................................... 2 2  
8. 4.  stratificati o n fact ors a n d treat me nt assi g n me nts ........................................................................... 2 3  
9.  
S C H E D U L E O F A S S E S S M E N T S  ............................................................................................... 2 4  
1 0.  
T R E A T M E N T P L A N  .................................................................................................................... 3 0  
1 0. 1.  Trial Treat me nts  ........................................................................................................................... 3 0  
1 0. 2.  D ose Selecti o n a n d Pre parati o n  .................................................................................................... 3 1  
1 0. 2. 1.  
Ti mi n g of D ose A d mi nistr ati o n  ......................................................................................... 3 1  
1 0. 2. 2.  
Pe m br oliz u m a b ( M K -3 4 7 5)  .............................................................................................. 3 2  
1 0. 2. 3.  
C ar b o pl ati n  ....................................................................................................................... 3 2  
1 0. 2. 4.  
P aclit axel  .......................................................................................................................... 3 2  
1 0. 2. 5.  
Pe metrexe d ........................................................................................................................ 3 3  
1 1.  
D A T A A N D S P E CI M E N S U B MI S SI O N, T RI A L P R O C E D U R E S  ......................................... 3 3  
1 1. 1.  Data C ollecti o n a n d S u b missi o n  .................................................................................................. 3 3  
1 2.  
BI O S P E CI M E N C O L L E C TI O N, S HI P PI N G A N D P R O C E S SI N G  ....................................... 3 3  
1 2. 1.  Bi os peci me n C ollecti o n Sc he ma  .................................................................................................. 3 4  
1 2. 1. 1.  
Bi os peci me n L o g gi n g a n d Tr acki n g ( A F T Bi o M S)  ........................................................... 3 4  
1 2. 1. 2.  
Bi os peci me n S hi p pi n g  ....................................................................................................... 3 5  
1 2. 1. 3.  
Bi os peci me n c ollecti o n  ..................................................................................................... 3 6  


 
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Scree ni n g/ E nr oll me nt  ......................................................................................................................... 3 6  
1 2. 1. 4.  
S u bse q ue nt Cycles  ............................................................................................................. 3 6  
1 2 . 1. 5. 
Bi os peci me n Pr ocessi n g  ................................................................................................... 3 7  
1 2. 2.  T u m or i ma gi n g a n d ce ntral re vie w  ............................................................................................... 3 7  
1 2. 2. 1.  
T u m or i m a gi n g sc he d ule  ................................................................................................... 3 7  
1 2. 2. 2.  
I m a gi n g c ore l a b Ce ntr al Revie w ..................................................................................... 3 7  
1 3.  
D O S E A N D T R E A T M E N T M O DI FI C A TI O N S, C O N C O M I T A N T M E DI C A TI O N S, 
S U P P O R TI V E C A R E  .............................................................................................................................. 3 9  
1 3. 1.  D ose M o dificati o n  ........................................................................................................................ 3 9  
1 3. 1. 1.  
C he m ot her a py  ................................................................................................................... 3 9  
1 3. 2.  Pe m br oliz u ma b ( M K -3 4 7 5)  ......................................................................................................... 4 1  
1 3. 3.  C o nc o mita nt me dicati o ns/ vacci nati o ns (all o we d & Pr o hi bite d)  .................................................. 4 3  
1 3. 3. 1.  
Acce pt a ble c o nc o mit a nt me dic ati o ns  ................................................................................ 4 3  
1 3. 3. 2.  
Pr o hi bite d c o nc o mit a nt me dic ati o ns  ................................................................................ 4 3  
1 3. 4.  Resc ue me dicati o ns a n d S u p p orti ve Care  .................................................................................... 4 4  
1 3. 4. 1.  
S u p p ortive C are G ui deli nes f or Pe m br oliz u m a b ( M K -3 4 7 5)  ........................................... 4 4  
1 3. 4. 2.  
S u p p ortive c are g ui deli nes f or P ne u m o nitis  ..................................................................... 4 7  
1 3. 4. 3.  
S u p p ortive c are g ui deli nes f or eve nts of Cli nic al i nterest/i m m u ne -rel ate d a dverse eve nts 
(ir A Es) 
4 7  
1 3. 5.  Ot her c o nsi derati o ns  ..................................................................................................................... 4 8  
1 3. 5. 1.  
C o ntr ace pti o n  ................................................................................................................... 4 8  
1 3. 5. 2.  
Use i n pre g n a ncy  .............................................................................................................. 4 9  
1 3. 5 . 3. 
Use i n N ursi n g W o me n  ..................................................................................................... 4 9  
1 4.  
M E A S U R E M E N T O F E F F E C T  .................................................................................................. 4 9  
1 4. 1.  Sc he d ule of E val uati o ns:  .............................................................................................................. 4 9  
1 4. 2.  Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T) 1. 1 Criteria f or       E val uati n g 
Res p o nse i n S oli d T u m ors  ...................................................................................................................... 5 0  
1 4. 2. 1.  
Defi niti o ns of Me as ur a ble a n d N o n -Me as ur a ble Dise ase  ................................................ 5 0  
1 4. 2. 2.  
G ui deli nes f or Ev al u ati o n of Me as ur a ble Dise ase  ........................................................... 5 1  
1 4. 2. 3.  
Res p o nse Criteri a  ............................................................................................................. 5 2  
1 4. 3.  I m m u ne relate d res p o nse criteria.................................................................................................. 5 5  
1 5.  
E N D O F T R E A T M E N T/I N T E R V E N TI O N  ............................................................................... 5 6  
1 5. 1.  D urati o n of treat me nt  ................................................................................................................... 5 6  
1 5. 1. 1.  
C R, P R, or S D  ................................................................................................................... 5 6  
1 5. 1. 2.  
Dise ase Pr o gressi o n  ......................................................................................................... 5 6  
1 5. 1. 3.  
Disc o nti n u ati o n of st u dy a ge nt  ......................................................................................... 5 6  
1 5. 2.  Patie nt Wit h dra wal/ Disc o nti n uati o n Criteria  ............................................................................... 5 6  
1 5. 2. 1.  
P atie nt Wit h dr a w al  ........................................................................................................... 5 6  
1 5 . 3. Defi niti o ns a n d F oll o w -u p Re q uire me nts  .................................................................................... 5 7  
1 5. 4.  F oll o w -u p f or I neli gi ble Patie nts  .................................................................................................. 5 8  
1 5. 5.  F oll o w -u p f or Patie nts Ne ver Recei vi n g Pr ot oc ol I nter ve nti o n  ................................................... 5 8  
1 6.  
A D V E R S E E V E N T S  ..................................................................................................................... 5 8  
1 6. 1.  R o uti ne A d verse E ve nt Re p orti n g  ................................................................................................ 5 9  
1 6. 2.  E x pe dite d A d verse E ve nt Re p orti n g  ............................................................................................ 5 9  
1 6. 2. 1.  
Seri o us A dverse Eve nt ( S A E)  ............................................................................................ 6 0  
1 6. 2. 2.  
Eve nts of Cli nic al I nterest a n d I m m u ne Rel ate d A dverse Eve nts  ..................................... 6 1  
1 6. 2. 3.  
Defi niti o n of a n Over d ose f or t his Pr ot oc ol a n d Re p orti n g of Over d ose t o A F T  ............. 6 2  
1 6. 2. 4.  
Re p orti n g of Pre g n a ncy a n d L act ati o n  ............................................................................. 6 2  
1 6. 3.  E val uati n g a d verse e ve nts  ............................................................................................................ 6 2  


 
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1 7.  
D R U G I N F O R M A TI O N  ............................................................................................................... 6 7  
1 7. 1.  I n vesti gati o nal Pr o d uct ................................................................................................................. 6 7  
1 7. 2.  pac ka gi n g a n d la beli n g i nf or mati o n  ............................................................................................. 6 7  
1 7. 3.  cli nical s u p plies discl os ure  ........................................................................................................... 6 7  
1 7. 4.  st ora ge a n d ha n dli n g re q uire me nts ............................................................................................... 6 7  
1 7. 5.  ret ur ns a n d rec o nciliati o n ............................................................................................................. 6 8  
1 8.  
S T A TI S TI C A L C O N SI D E R A TI O N S  ......................................................................................... 6 8  
1 8. 1.  Sa m ple Size J ustificati o n  .............................................................................................................. 6 8  
1 8. 2.  Accr ual a n d F oll o w U p  ................................................................................................................ 6 9  
1 8. 3.  A d verse E ve nts M o nit ori n g  .......................................................................................................... 6 9  
1 8. 4.  Statistical A nal ysis Pla n  ............................................................................................................... 6 9  
1 9.  
G E N E R A L R E G U L A T O R Y A N D  O T H E R C O N SI D E R A TI O N S .......................................... 7 0  
1 9. 1.  C o m plia nce wit h Trial E nr oll me nt a n d Res ults P osti n g Re q uire me nts  ....................................... 7 0  
1 9. 2.  Re g ulat or y a n d et hical c o m plia nce  .............................................................................................. 7 1  
1 9. 3.  I nf or me d C o nse nt ......................................................................................................................... 7 1  
1 9. 4.  Res p o nsi bilities of t he I n vesti gat or/I R B/I E C/ R E B  ...................................................................... 7 1  
1 9. 5.  Fi na ncial Discl os ure  ..................................................................................................................... 7 2  
1 9. 6.  Pr ot oc ol De viati o ns  ...................................................................................................................... 7 2  
1 9. 7.  Pr ot oc ol A me n d me nts  .................................................................................................................. 7 2  
1 9. 8.  Rete nti o n of Rec or ds  .................................................................................................................... 7 2  
1 9. 9.  Data C o nfi de ntialit y  ..................................................................................................................... 7 3  
1 9 . 1 0. Data base Ma na ge me nt a n d Q ualit y C o ntr ol  ................................................................................. 7 3  
1 9. 1 1.  Site M o nit ori n g ............................................................................................................................. 7 4  
1 9. 1 2.  Data a n d Safet y M o nit ori n g B oar d ( D S M B)  ................................................................................ 7 4  
1 9. 1 3.  Re g ulat or y Re p orti n g  ................................................................................................................... 7 4  
1 9. 1 4.  A u dits a n d I ns pecti o ns  ................................................................................................................. 7 4  
1 9. 1 5.  Cli nical Criteria f or Earl y Trial T er mi nati o n  ............................................................................... 7 5  
1 9. 1 6.  P u blicati o n o f St u d y Pr ot oc ol a n d Res ults ................................................................................... 7 5  
2 0.  
LI S T O F R E F E R E N C E S  .............................................................................................................. 7 6  
2 1.  
A P P E N DI C E S  ................................................................................................................................ 8 0  
2 1. 1.  A P P E N DI X  I: Ec o g Perf or ma nce Stat us ..................................................................................... 8 0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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3. 1.  P H A R M A C E U TI C A L A N D T H E R A P E U TI C B A C K G R O U N D  
3. 1. 1.  
I ntr o d ucti o n 
 
L u n g ca ncer c o nti n ues t o be t he m ost c o m m o n ca use of ca n cer -rel ate d m ortalit y i n t he U nite d 
States. I n 2 0 1 4, a p pr o xi matel y 2 2 4, 0 0 0 p atie nts were e x pecte d t o be dia g n ose d wit h l u n g ca ncer 
a n d 1 6 0, 0 0 0 patie nts were e x pecte d t o die fr o m t his disease. [2 ] M ost patie nts will be dia g n ose d 
wit h n o n -s mall cell hist ol o g y t hat is re gi o n all y a d v a nce d or has s prea d t o dista nt metastatic sites. 
I n p atie nts wit h sta ge I V n o n-s mall cell l u n g ca ncer ( N S C L C) w h o ha v e g o o d perf or ma nce stat us 
( E C O G le vel 0 or 1), treat me nt wit h a “ ne wer” or t hir d-ge nerati o n plati n u m -base d d o u blet 
(cis plati n or car b o plati n c o m bi ne d wit h paclita xel, d oceta xel, ge mcita bi ne, pe metre x e d or 
vi n orel bi ne) is m ost c o m m o nl y rec o m me n de d. [ 3] I n t he Easter n C o o perati ve O nc ol o g y Gr o u p 
( E C O G) 1 5 9 4 trial, f o ur plati n u m-base d d o u blets were c o m pare d. N o ne were s u peri or i n ter ms 
of acti vit y or s ur v i val wit h a n o verall res p o nse rate ( O R R) f or t he 1 1 5 5 eli gi ble patie nts of 1 9 % 
a n d 1- a n d 2-year s ur vi val rates of 3 1 % a n d 1 0 %, res pecti vel y. [ 4] W hile t here are differe n ces i n 
t o xicit y, t he res ults of E C O G 1 5 9 4 are c o nsiste nt wit h t he res ults of ot her ra n d o mize d trials t hat 
ha ve re p orte d t he relati ve e q ui vale nce of t hir d -ge n erati o n plati n u m -base d d o u blets i n t he 
ma na ge me nt of p atie nts wit h a d va nce d N S C L C.   
 
I n a dditi o n t o perf or ma n ce stat us a n d t o xicit y, t u m or hist ol o g y a n d m olec ular pr ofili n g h a ve 
bee n esta blis he d as fact ors t hat ca n hel p g ui de re gi me n selecti o n i n t his setti n g. I n t he la n d m ar k 
E C O G 4 5 9 9 trial, t he re gi me n of be vaciz u ma b c o m bi ne d wit h car b o plati n  a n d paclita xel was 
f o u n d t o be s u peri or i n ter ms of res p o nse rate, me dia n a n d o ne-year s ur vi val rate c o m p are d t o 
car b o plati n a n d p aclita x el al o ne i n a hi g hl y sel ecte d patie nt p o p ulati o n base d o n perf or ma nce 
stat us, t u m or hist ol o g y, as well as lac k of C N S metastatic disease, blee di n g or t hr o m b otic 
e ve nts. [ 5] I n t his trial, patie nts wit h s q ua m o us cell carci n o ma were e x cl u de d base d o n a p h ase II 
trial t hat re p orte d a hi g h er rate of si g nifica nt he m o pt ysis i n patie nts wit h s q ua m o us hist ol o g y.[ 6] 
I n a n o n-i nferi orit y, p h as e III tri al, o verall s ur vi val i n 1 7 2 5 patie nts wit h pre vi o usl y u ntreate d 
N S C L C was f o u n d t o be n o n -i nferi or after treatme nt wit h cis plati n a n d pe metre x e d c o m pare d t o 
cis plati n c o m bi ne d wit h ge m cita bi ne ( me dia n s ur vi val 1 0. 3 m o nt hs vers us 1 0. 3 m o nt hs; hazar d 
rati o ( H R), 0. 9 4; 9 5 % CI, 0. 8 4 –  1. 0 5 %). [ 7] H o we ver, i n a pla n ne d s u b gr o u p a nal ys is, cis plati n 
a n d pe metre x e d was f o u n d t o be s u peri or i n patie nts wit h n o n -s q ua m o us N S C L C ( n = 1 0 0 0; H R 
0. 8 1; 9 5 % CI, 0. 7 –  0. 9 4; p = 0. 0 0 5). I n c o ntrast, p atie nts wit h s q ua m o us cell hist ol o g y di d better 
wit h cis plati n a n d ge m cita bi ne ( n = 4 7 3; 1 0. 8 m o nt hs  vers us 9. 4 m o nt hs, res pecti vel y, p = 0. 0 5). 
T he hist ol o g y effect of p e metre x e d has als o be e n re p orte d i n r etr os pecti ve a nal ysis of a sec o n d 
li ne trial c o m pari n g pe m etre x e d t o d oceta xel, as well as a p has e III trial e val uati n g s witc h 
mai nte na nce p e metre x e d  after 4 c ycles of first -li ne plati n u m-base d d o u blet c he m ot hera p y. [ 8]  
 
M olec ular pr ofili n g has als o bee n esta blis he d as a strate g y t o select first -li n e c he m ot hera p y i n 
patie nts wit h a d va nce d N S C L C. T h e pres e nce of acti vati n g s o matic m utati o ns i n t he ge n e 
e nc o di n g t he e pi der mal gr o wt h fac t or rece pt or ( E G F R) has b ee n ass o ciate d wit h s u peri or acti vit y 
a n d s ur vi val o utc o mes after first -li ne treat me nt wit h a n E G F R t yr osi ne ki nase i n hi bit or ( T KI) 
c o m pare d t o sta n d ar d plati n u m -base d d o u blet c he m ot hera p y. I n t he la n d m ar k Iressa Pa n -Asi a 
St u d y (I P A S S) 1 2 1 7 cli nicall y sel ecte d patie nts were ra n d o mize d t o treat me nt wit h gefiti ni b 
c o m pare d t o c ar b o plati n a n d paclita x el. [ 9] I n t he 2 6 1 patie nts wit h c o nfir me d E G F R m utati o n, 


 
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gefiti ni b was ass ociate d wit h si g nifica nt i m pr o ve me nt i n res p o nse rat e ( 7 1 % vers us 4 7 %, 
res pecti vel y) a n d pr o gressi o n free s ur vi v al ( P F S; H R, 0. 4 8; 9 5 % CI, 0. 3 6 –  0. 6 4) c o m pare d t o 
car b o plati n a n d p aclita x el. F o ur a d diti o nal ra n d o mize d trials ha ve c o nfir me d i m pr o ve me nt i n 
res p o nse a n d P F S i n patie nts wit h E G F R m utati o ns after treat me nt wit h a n E G F R T KI c o m pare d 
t o plati n u m-base d d o u blet c he m ot hera p y i n b ot h E ast Asia n a n d E ur o p ea n p atie nt 
p o p ulati o ns. [ 1 0-1 3]  I n a rece nt a nal ysis of t w o o p e n-la bel p has e III trials ( L U X-L u n g 3 a n d 
L U X -L u n g 6), t he 2 n d ge nerati o n E G F R T KI, afati ni b, was ass ociate d wit h s u peri or P F S a n d 
o verall s ur vi v al ( O S) w h e n c o m pare d t o cis plati n -base d c he m ot hera p y i n p atie nts wit h 
“c o m m o n” ( del eti o n 1 9 or L 8 5 8 R) E G F R m utati o ns. [ 1 4] I n t he U nite d Stat es t here are n o w t w o 
E G F R T KIs ( erl oti ni b a n d afati ni b) t hat are a p pr o ve d b y t h e F D A f or t he first -li ne treat me nt of 
patie nts wit h sta ge I V E G F R -m utate d N S C L C. I n a d diti o n, base d o n  cli nical trials i n m olec ularl y 
selecte d patie nts, t he F D A has als o rece ntl y a p pr o ve d t w o a na plastic l y m p h o ma ki nase ( A L K) 
i n hi bit ors (criz oti ni b a n d ceriti ni b) f or t he tr eat me nt of patie nts wit h a d va n ce d N S C L C a n d 
d oc u me nte d A L K f usi o ns. [ 1 5, 1 6]    
 
3. 1. 2.  
P D -1 P at h w a y  –  P h ar m ace utic al a n d T her a pe utic B ac k gr o u n d  
 
T he i m p orta nce of i ntact i m m u ne s ur veilla nce i n c o ntr olli n g o ut gr o wt h of n e o plastic 
tra nsf or mati o n has bee n k n o w n f or deca des.[ 1 7] Acc u m ulati n g e vi de nce s h o ws a c orrelati o n 
bet wee n t u m or -i nfiltrati n g l y m p h oc ytes ( TI Ls) i n ca ncer tiss ue a n d fa v ora ble pr o g n osis i n 
vari o us mali g n a ncies. [ 1 8-2 2]  I n partic ular, t he prese nce of C D 8 + T-cells a n d t he rati o of C D 8 + 
effect or T-cells / F o x P 3 + re g ulat or y T -cells seems t o c orrelat e wit h i m pr o ve d pr o g n osis a n d 
l o n g-ter m s ur vi val i n ma n y s oli d t u m ors. I n N S C L C, rece nt st u dies ha v e s h o w n t hat t u m or 
i nfiltrati o n wit h C D 4 + a n d/ or C D 8 + T cells is ass o ciate d wit h better o v erall pr o g n osis i n patie nts 
wit h earl y sta ge dise ase. [ 2 3-2 5]   
 
T he P D -1 rece pt or -li ga n d i nteracti o n is a maj or p at h wa y hijac k e d b y t u m ors t o s u p press i m m u ne 
c o ntr ol.  T he n or mal f u n cti o n of P D -1, e x presse d o n t he cell s urface of acti vate d T -cells u n der 
healt h y c o n diti o ns, is t o d o w n -m o d ulate u n wa nte d or e x cessi ve i m m u ne res p o nses, i ncl u di n g 
a ut oi m m u ne reacti o ns.  P D -1 (e n c o de d b y t he ge n e P dc d 1) is a n I g s u perfa mil y m e m ber relate d 
t o C D 2 8 a n d C T L A-4, w hic h has bee n s h o w n t o n e gati vel y re g ulat e a nti ge n rece pt or si g n ali n g 
u p o n e n ga ge me nt of its li ga n ds ( P D -L 1 a n d/ or P D -L 2). [ 2 6, 2 7]  T he str uct ure of m uri ne P D -1 
has bee n res ol ve d. [ 2 8] P D -1 a n d fa mil y me m bers are t y pe I tra ns me m bra n e gl yc o pr otei ns 
c o ntai ni n g a n I g Varia ble -t y pe ( V-t y pe) d o mai n res p o nsi ble f or li ga n d bi n di n g a n d a c yt o plas mic 
tail w hic h is res p o nsi ble f or t he bi n di n g of si g n ali n g m olec ul es.  T he c yt o plas mic tail of P D-1 
c o ntai ns 2 t yr osi ne -base d si g nali n g m otifs, a n i m m u n orece pt or t yr osi n e -b ase d i n hi biti o n m otif 
(I TI M) a n d a n i m m u n orece pt or t yr osi ne-b ase d s witc h m otif (I T S M).  F oll o wi n g T -cell 
sti m ulati o n, P D-1 recr uits t he t yr osi ne p h os p h atas es S H P -1 a n d S H P -2 t o t he I T S M m otif wit hi n 
its c yt o plas mic tail, lea di n g t o t he de p h os p h or yl ati o n of effect or m olec ules s uc h as C D 3ζ, P K C θ 
a n d Z A P 7 0 w hic h are i n v ol ve d i n t he C D 3 T -cell si g nali n g cas ca d e. [ 24, 2 6, 2 9, 3 0]   T he 
mec ha nis m b y w hic h P D -1 d o w n m o d ulates T -cell res p o nses is si milar t o, b ut disti nct fr o m t hat 
of C T L A -4 as b ot h m olec ules re g ulat e a n o verla p pi n g set of si g nali n g pr ot ei ns. [ 2 4, 3 1]  P D -1 
was s h o w n t o be e x press e d o n acti vate d l y m p h oc yt es i ncl u di n g peri p heral C D 4 + a n d C D 8 + T -
cells, B-cells, T re gs a n d Nat ural  Killer cells. [ 3 2, 3 3]  E x pressi o n has als o bee n s h o w n d uri n g 
t h y mic de v el o p me nt o n C D 4-C D 8 - ( d o u ble ne gati ve) T-cells as well as s u bsets of macr o p ha ges 
a n d de n dritic cells. [ 3 4] T he li ga n ds f or P D -1 ( P D -L 1 a n d P D -L 2) are c o nstit uti vel y e x presse d or 


 
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ca n be i n d uc e d i n a variet y of cell t y p es, i ncl u di n g n o n -he mat o p oietic tiss ues as well as i n  
vari o us t u m ors. [ 3 4-3 7]  B ot h li ga n ds are t y pe I tr a ns me m bra ne rece pt ors c o ntai ni n g b ot h I g V - 
a n d I g C -li ke d o mai ns i n t he e xtracell ular re gi o n a n d c o ntai n s h ort c yt o plas mic re gi o ns wit h n o 
k n o w n si g nali n g m otifs.  Bi n di n g of eit her P D -1 li ga n d t o P D -1 i n hi bits T -cell acti vati o n 
tri g gere d t hr o u g h t he T-cell rece pt or.  P D -L 1 is e x presse d at l o w le v els o n vari o us n o n -
he mat o p oietic tiss ues, m ost n ota bl y o n vasc ul ar e n d ot heli u m, w hereas P D -L 2 pr ot ei n is o nl y 
detecta bl y e x presse d o n a nti ge n -pres e nti n g cells f o u n d i n l y m p h oi d tiss ue or c hr o nic 
i nfla m mat or y e n vir o n me nts.  P D-L 2 is t h o u g ht t o c o ntr ol i m m u ne T -cell acti vati o n i n l y m p h oi d 
or ga ns, w hereas P D -L 1 s er ves t o da m pe n u n warra nte d T -cell f u ncti o n i n peri p heral tiss ues. [ 3 7] 
Alt h o u g h healt h y or ga ns e x press little (if a n y) P D -L 1, a v ariet y of ca n cers were d e m o nstrate d t o 
e x press a b u n da nt le vels of t his T -cell i n hi bit or.  P D -1 has b ee n s u g geste d t o re g ulate t u m or -
s pecific T-cell e x pa nsi o n i n patie nts wit h mela n o ma ( M E L). [ 3 8] T his s u g gests t hat t he P D -1/ P D -
L 1 pat h w a y pla ys a critic al r ole i n t u m or i m m u ne e vasi o n a n d s h o ul d be c o nsi dere d as a n 
attracti ve tar get f or t hera pe utic i nter ve nti o n.  
 
P D -L 1 is e x presse d i n a p pr o xi matel y 5 0 % of N S C L C, i ncl u di n g b ot h a de n o carci n o ma a n d 
s q ua m o us cell carci n o ma, a n d is ass ociate d wit h p o or pr o g n osis.[ 3 9-4 1]  T he e x pressi o n of t he 
P D -L 1 li ga n d i n t u m ors ca n be b ot h i n nate, t hr o u g h c o nstit uti ve o nc o ge ni c si g nali n g, or i n d uce d 
i n res p o nse t o i nfla m mat or y si g nals ge nerate d b y t he a ntit u m or i m m u ne res p o nse.[ 4 0] I n 
a d diti o n, s o me c he m ot hera p y a ge nts, i ncl u di n g paclita xel, ha ve bee n s h o w n t o i ncrease P D -L 1 
e x pressi o n i n t u m ors. [ 4 0, 4 2]   
 
Pe m br oliz u ma b ( M K -3 4 7 5)  is a p ote nt a n d hi g hl y selecti ve h u ma nize d m o n ocl o nal a nti b o d y 
( m A b) of t he I g G 4/ ka p pa is ot y pe desi g ne d t o directl y bl oc k t he i nteracti o n bet wee n P D-1 a n d its 
li ga n ds, P D-L 1 a n d P D -L 2.  K e ytr u da T M  (pe m br oliz u ma b ( M K -3 4 7 5) ) has rece ntl y bee n 
a p pr o ve d i n t he U nite d State d f or t he treat me nt of patie nts wit h u nresecta bl e or metastatic 
mela n o ma a n d diseas e pr o gressi o n f oll o wi n g i pil u m u ma b a n d, if B R A F V 6 0 0 m utati o n p ositi ve, 
a B R A F i n hi bit or.  
 
3. 1. 3.  
I m m u ne C he ck p oi nt I n hi biti o n a n d L u n g C a ncer  
 
I n cli nical trials, m o n ocl o nal a nti b o dies tar geti n g P D-1 a n d P D -L 1 ha v e bee n ass ociate d wit h 
res p o nses i n a p pr o xi matel y 2 0 % of patie nts, ma n y of w hic h are d ura ble.[ 4 3-4 7]  Hi g her res p o nse 
rates ha v e bee n re p ort e d i n patie nts wit h P D-L 1 -p ositi ve t u m ors ( b y i m m u n o hist oc he mistr y) 
c o m pare d t o P D -L 1 -ne gat i ve t u m ors.[ 4 4, 4 5, 4 8] H o we ver, res p o nses after treat me nt wit h P D -
1/ P D -L 1 i n hi biti o n i n patie nts wit h P D -L 1 -n e gati v e t u m ors ha ve bee n descri be d. [ 4 6]  
 
I n a m ulti-ce nter p h ase I B trial, 3 8 patie nts wit h pre vi o usl y tr eate d a d va nce d N S C L C were 
e nr olle d i nt o a n e x pa n de d c o h ort a n d treate d wit h 1 0 m g/ k g of pe m br oliz u ma b ( M K -3 4 7 5 ) e ver y 
2 1 da ys u ntil disease  pr o gressi o n. [ 4 5] T he m ost c o m m o n dr u g -relate d a d v erse e v e nts i ncl u de d 
ras h ( 2 1 %), pr urit us ( 1 8 %), fati g ue ( 1 6 %), diarr h ea ( 1 3 %) a n d art hral gia ( 1 1 %). M ost dr u g-
relate d A E’s were l ow gra de ( gra de 1 or 2). O ne p atie nt de vel o pe d gra de 2 p ne u m o nitis a n d o ne 
patie nt de vel o pe d gra de 3 p ul m o nar y e de ma. T h e O R R b y ir R C assesse d b y i n vesti gat ors as well 
as R E CI S T 1. 1 criteria b y ce ntral r e vie w was 2 4 % a n d 2 1 %, res pecti vel y. T he me dia n 
pr o gre ssi o n free s ur vi val ( P F S) of res p o n d ers was n ot reac h e d at 6 2 wee ks. [ 4 5] I n a f oll o w u p 
re p ort t hat i ncl u de d 1 9 4 e val ua ble p atie nts wit h pre vi o usl y tr eate d N S C L C, t he O R R was 1 8 % 


 
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a nd 2 0 % b y ir R C a n d R E CI S T 1. 1, res p ecti vel y. [ 4 6] I n P D-L 1 -p ositi ve pati e nts ( n = 1 5 9, 
defi ne d as ≥ 1 % t u m or cells p ositi ve b y I H C), t he O R R was 1 9 % b y ir R C a n d 2 3 % b y R E CI S T 
1. 1 c o m pare d t o 1 3 % a n d 9 % i n patie nts wit h P D -L 1 -ne gati ve t u m ors ( n = 3 5). B y ir R C, t he 
me dia n P F S f or patie nts wit h P D -L 1 -p ositi ve vers us P D -L 1 -n e gati ve t u m ors was t he sa me ( 1 6 
wee ks, r a n ge 1 0 –  1 8 ( P D -L 1 -p ositi ve) a n d 9 -2 8 wee ks ( P D -L 1 -ne gati ve), res pecti vel y). [ 4 6]  
 
I n a c o h ort of 4 5 treat me nt-naï ve patie nts wit h P D -L 1 -p ositi ve, E G F R - a n d A L K-ne gati ve 
a d va nce d N S C L C, t he O R R b y ir R C a n d R E CI S T 1. 1 after treat me nt wi t h pe m br oliz u ma b ( M K -
3 4 7 5)  ( d ose 2 or 1 0 m g/ k g q 2-3 wee ks) was 4 7 % (ra n ge 3 2 -6 2 %) a n d 2 6 % (ra n ge 1 4 -4 2 %), 
res pectf ull y, wit h diseas e c o ntr ol rates of 7 8 % (ir R C) a n d 6 4 % ( R E CI S T 1. 1).[ 4 7] T he me dia n 
P F S was 3 7 wee ks b y ir R C a n d 2 7 wee ks b y R E CI S T a n d 9 0 % of res p o n ders b y ir R C a n d 1 0 0 % 
of res p o n ders b y R E CI S T re mai ne d i n r es p o nse ( me dia n n ot reac he d) at t he ti me of t he re p ort. 
8 0 % of patie nts e x perie n ce a n A E, m ost of w hic h were gra de I -II, i ncl u di n g fati g u e ( 2 2 %), 
pr uritis ( 1 3 %), h y p ot h yr oi dis m ( 9 %), der matitis ( 7 %), diarr h ea ( 7 %), d ys p nea ( 7 %) a n d ras h 
( 7 %). O n e patie nt disc o nti n ue d t hera p y after e x perie nci n g gra d e 3 p ne u m o nitis a n d 1 patie nt 
disc o nti n ue d treat me nt after e x perie nci n g gra de 2 ac ute ki d ne y i nj ur y.  
3. 2.  S T U D Y  D E SI G N  
T his is a m ultice nter ra n d o mize d p hase II st u d y t o deter mi ne if t he a d mi nistrati o n of sta n dar d 
plati n u m -base d c h e m ot hera p y b ef ore pe m br oliz u ma b ( M K -3 4 7 5)  i n patie nts wit h sta ge I V n o n -
s mall cell l u n g ca n cer ( N S C L C) w h o h a ve n ot pre vi o usl y b ee n tre ate d wit h che m ot her a p y 
(c he m ot her a p y n ai ve ) will i m pr o ve t he o verall res p o nse rate (O R R) c o m pare d t o pe m br oliz u ma b 
( M K-3 4 7 5) a d mi nistere d bef ore c h e m ot hera p y. F or t he  pri mar y e n d p oi nt, O R R will be meas ure d 
usi n g t he Res p o nse E val uati o n Criteria i n S oli d T u m ors ( R E CI S T versi o n 1. 1). [ 1] Ni net y ( 9 0 ) 
eli gi ble patie nts will be ra n d o mize d a n d a “ pic ki n g t he wi n ner” d esi g n will be utilize d t o select t he 
m ost pr o misi n g se q ue nce of a d mi nistrati o n of pe m br oliz u ma b ( M K -3 4 7 5) a n d sta n dar d plati n u m -
base d c h e m ot hera p y f or f urt her i n vesti gati o n. Patie nts will be ra n d o mize d i n a 1: 1 rati o t o recei v e 
sta n dar d hist ol o g y-ali g ne d plati n u m -base d c he m ot hera p y (car b o plati n c o m bi ne d wit h pe metre x e d 
or paclita x el) f o r 4 c ycl es f oll o we d b y pe m br oliz u ma b ( M K -3 4 7 5) 2 0 0 m g e ver y 3 wee ks f or 4 
c ycles or p e m br oliz u ma b ( M K -3 4 7 5) f or 4 c ycles f oll o we d b y sta n dar d plati n u m-base d 
c he m ot hera p y f or 4 c ycl es. Patie nts o n b ot h treat me nt ar ms wit h c o ntr olle d disease  ( C R, P R or 
S D)  after c ycle 8 will c o nti n ue t o recei ve p e m br oliz u ma b ( M K -3 4 7 5) f or u p t o 2 4 m o nt hs . 
Patie nts will be e val uate d e ver y 6 wee ks ( 4 2 ± 7 da ys) wit h ra di o gra p hic i ma gi n g t o assess 
res p o nse t o tr eat me nt. I n vesti gat ors will ma ke all treat me nt-bas e d decisi o ns usi n g  t he I m m u n e-
R elate d Res p o nse Criteria (ir R C) w hile o n pe m br oliz u ma b ( M K -3 4 7 5)  t hera p y. Patie nts o n b ot h 
treat me nt ar ms wit h c o ntr olle d disease ( C R, P R or S D) after t heir assi g ne d tr eat me nt will c o nti n ue 
pe m br oliz u ma b  ( M K-3 4 7 5)  e ver y 3 wee ks u ntil 2 4 m o nt hs  of t hera p y h a ve  bee n a d mi nistere d, 
d oc u me nte d dise ase pr o gressi o n, u nacce pta bl e a d verse e ve nt(s), i nterc urre nt ill ness t hat pre ve nts 
f urt her a d mi nistrati o n of treat me nt, i n vesti gat or’s decisi o n t o wit h dra w t he patie nt, patie nt 
wit h dra ws c o ns e nt, pre g na nc y  of t he patie nt, n o n -c o m plia nce wit h st u d y treat me nt or pr oce d ure 
re q uire me nts or a d mi nistrati ve reas o ns. Patie nts recei vi n g pe m br oliz u ma b ( M K-3 4 7 5)  al o ne after 
c ycle 8 will be e v al uate d wit h ra di o gra p hic i ma gi n g e v er y 9 wee ks ( 6 3 ± 7 da ys). After t he e n d of 
treat me nt, eac h patie nt will be f oll o we d f or a mi ni m u m of 3 0 d a ys f or a d verse e v e nt m o nit ori n g. 
Seri o us a d vers e e v e nts will be c ollecte d f or u p t o 9 0 da ys aft er t he e n d of treat me nt  o r i nitiati o n 
of a ne w a nti ne o plastic t hera p y, 
w hic he v er c o mes first a n d 
w het her or n ot relate d t o 
pe m br oliz u ma b  ( M K-3 4 7 5) . Patie nts will ha ve p ost-treat me nt f oll o w-u p f or disease stat us, 


 
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i ncl u di n g i nitiati n g a n o n-st u d y ca ncer treat me nt a n d e x perie nci n g dise ase pr o gressi o n, u ntil deat h, 
wit h dra wi n g c o nse nt or bec o mi n g l ost t o f oll o w -u p. Treat me nt -relate d t o xicities will be res ol ve d 
bef ore p artici pa nts e nt er t he cli nical f oll o w -u p p h ase.  
T he pri mar y e n d p oi nt of t he st u d y is O R R b y R E CI S T 1. 1. Sec o n dar y e n d p oi nts i ncl u de O R R b y 
ir R C, pr o gressi o n free s ur vi val ( P F S) b y  ir R C a n d b y R E CI S T 1. 1, o verall s ur vi val ( O S) a n d s afet y 
as assesse d b y a variet y of para met ers of a d verse e ve nts ( A Es). A E s will be m o nit ore d t hr o u g h o ut 
t he st u d y a n d gra d e d i n se verit y acc or di n g t o t he g ui d eli nes o utli ne d i n t he N CI C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E) versi o n 4. Pre -s pecifi e d ad verse e ve nts of 
cli nical i nterest i ncl u de: 1) Gra d e ≥ 2 diarr hea, 2) Gra de ≥ 2 c olitis, 3) Gra de ≥ 2 p ne u m o nitis, 4) 
Gra de ≥ 3 h y p o - or h y pert h yr oi dis m.  
Partici pati o n i n t his st u d y will be de pe n de nt o n s u p pl yi n g t u m or tiss ue fr o m a pre vi o usl y c ollecte d 
o r ne wl y o btai n e d f or m ali n -fi x e d s peci me n fr o m l ocati o ns n ot ra diate d pri or t o bi o ps y. T h e 
s peci me n will be e v al uate d at a ce ntr al la b orat or y facilit y f or e x pressi o n of P D -L 1 b y 
i m m u n o hist oc he mistr y (I H C) i n a pr os pecti ve ma n or. O nl y patie nts wit h a de q uate tiss ue t o 
esta blis h P D -L 1 stat us (str o n gl y p ositi ve ( ≥ 5 0 % stai ni n g), wea kl y p ositi v e ( 1 -4 9 % stai ni n g) or 
ne gati ve ( 0 % stai ni n g)) will be eli gi ble f or ra n d o mizati o n i n t his st u d y.  
T he c h oice of t he 2 0 0 m g Q 3 W as a n a p pr o priate d ose f or t he s witc h t o fi x e d  d osi n g is base d o n 
si m ulati o ns perf or me d usi n g t he p o p ulati o n P K m o del of pe m br oliz u ma b ( M K-3 4 7 5) s h o wi n g t hat 
t he fi x e d d ose of 2 0 0 m g e ver y 3 w ee ks will pr o vi de e x p os ures t hat 1) are o pti mall y c o nsiste nt 
wit h t h ose o btai ne d wit h t he 2 m g/ k g d ose e ver y 3  wee ks, 2) will mai ntai n i n di vi d ual patie nt 
e x p os ures i n t he e x p os ure ra n ge esta blis he d i n mela n o ma as ass ociate d wit h ma xi mal efficac y 
res p o nse a n d 3) will mai ntai n i n di vi d ual patie nts e x p os ure i n t he e x p os ure ra n ge esta blis he d i n 
mela n o ma t hat are well t olerate d a n d s afe.  
A fi x e d d ose re gi me n will si m plif y t he d osi n g re gi me n t o be m ore c o n v e ni e nt f or p h ysicia ns a n d 
t o re d uce p ote ntial f or d osi n g err ors.  A fi x e d d osi n g sc h e me will als o re d uce c o m ple xit y i n t he 
l o gistical c hai n at treat m e nt facilities a n d re d uce wasta ge. 
4.  R A TI O N A L E  
4. 1.  R A TI O N A L E F O R T H E T RI A L A N D S E L E C T E D P A TI E N T P O P U L A TI O N   
W hile a ge n ot y pe -directe d strate g y has bee n esta blis he d as effecti ve i n treat me nt selecti o n f or 
patie nts wit h a d va nce d N S C L C, o nl y a mi n orit y of patie nts at t his ti me will ha ve a rea dil y 
i de ntifia ble acti o na ble m olec ular tar get. F urt her m ore, ge n ot y pe-direc t e d t hera p y has n ot b ee n 
vali date d f or patie nts wit h s q ua m o us cell carci n o ma of t he l u n g. T heref ore, t he maj orit y of 
patie nts wit h a d va nce d N S C L C will c o nti n ue t o r el y o n sta n dar d plati n u m -base d d o u blet 
c he m ot hera p y. Gi ve n t he platea u i n effecti ve n ess of t his a p pr oac h, n o v el treat me nt strate gies are 
clearl y w arra nte d.  
 
I n hi biti o n of t he P D-1/ P D -L 1 pat h wa y h as bee n i de ntifie d as a p ote ntial t h era pe utic t ar get i n 
patie nts wit h a d va nce d n o n -s mall cell l u n g ca ncer ( N S C L C).[ 4 0, 4 3, 4 9] T he pr o g n ostic 
si g nifica n ce of P D-L 1 e x pressi o n i n N S C L C s u g gests t hat t his pat h wa y ma y pla y a n i m p orta nt 
r ole i n i m m u ne esca p e a n d t u m or pr o gressi o n. [ 3 9] T he re p ort e d cli nical acti vit y of P D -1 a n d 


 
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P D -L 1 i n hi bit ors i n t he treat me nt of patie nts wit h a d va nce d N S C L C s u p p orts c o nti n ue d 
i n vesti gati o n of t his t hera pe utic strate g y.  
 
I n a n eff ort t o i m pr o ve t h e a nti-t u m or i m m u ne res p o nse, t here has bee n rece nt i nterest i n 
c o m bi ni n g i m m u ne c hec k p oi nt i n hi bit ors wit h c yt ot o xic c he m ot hera p y. [ 4 0] I n a d diti o n t o 
i ncreasi n g e x pressi o n of P D-L 1 o n t u m or cells, c o n ve nti o nal c he m ot hera p y has bee n s h o w n t o 
be ca p a ble of m o d ulati n g t he i m m u ne s yste m a n d sti m ulati n g t u m or -s pecifi c i m m u ne res p o nse, 
raisi n g t he p ossi bilit y t hat c o m bi ni n g c he m ot hera p y wit h i m m u ne c hec k p oi nt i nhi bit ors ma y 
e n ha nce efficac y. [ 4 0] I n partic ular, tr eat me nt wit h paclita xel has bee n ass o ciate d wit h se veral 
i m m u n o m o d ulat or y effects, i ncl u di n g e n ha n ce d T-cell acti vati o n t hr o u g h u p -re g ulati o n of maj or 
hist oc o m pati bilit y c o m pl e x -1 e x pressi o n a n d de n dritic cell m o d ulati o n [ 5 0, 5 1], as well as 
affecti n g re g ulat or y T -cells. [ 5 2]  
 
A rece nt p hase I trial c o nfir me d t he feasi bilit y of c o m bi ni n g a P D-1 i n hi bit or ( ni v ol u ma b) wit h 
plati n u m -base d d o u blets (cis plati n/ ge m cita bi ne, cis plati n/ pe metre x e d, a n d 
car b o plati n/ paclita x el). I n 5 6 treat me nt -naï v e patie nts wit h sta ge III B/I V N S C L C a n d E C O G P S 
0 -1, t he O R R after treat me nt w it h c he m ot hera p y pl us t he P D-1 i n hi bit or ra n ge d b et wee n 3 3 –  
4 7 % wit h a 1 -year O S rat e of 5 0 -8 7 %. [ 5 3] T he safet y pr ofile reflecte d a d diti ve t o xicities b ut n o 
u n us ual safet y si g nals were see n a n d t here were n o treat me nt -relate d deat hs. Acr oss all treat me nt 
arms, treat me nt -relate d p ne u m o nitis occ urre d i n 7 patie nts ( 1 3 %), i ncl u di n g gra de 3/ 4 
p ne u m o nitis i n 4 patie nts ( 7 %). T he m ost fre q ue nt A Es wit h p ote ntial i m m u n ol o gic eti ol o g y 
i ncl u de d s ki n ( 3 4 % a n y gra de/ 5 % gra de 3/ 4), gastr oi ntesti nal ( 2 3 % a n y gra de a n d 4 % gra de 3/ 4), 
i nf usi o n reacti o n ( 2 3 % a n y gra de, 2 % gra d e 3/ 4), re nal ( 1 4 % a n y gra de, 5 % gra de 3/ 4), a n d 
p ul m o nar y ( 1 3 % a n y gra de, 7 % gra d e 3/ 4).  
 
T he ti mi n g of a d mi nistrati o n of c he m ot hera p y a n d c hec k p oi nt i n hi biti o n ma y b e i m p orta nt a n d 
f urt her i n vesti gati o n is w arra nt e d t o defi ne t he o pti mal sc he d uli n g strat e g y. W hile e n ha nce d 
effic ac y ma y o cc ur t hr o u g h i ncreas e i n t u m or -s pecific i m m u nit y, c o n ve nti o nal c yt ot o xic 
c he m ot hera p y ca n als o decrease t he i m m u ne cell p o p ulati o n a n d miti gate t he res p o nse t o 
i m m u n othera p y. [ 4 0] H o we ver, i n a precli nical m o del of ge mcita bi ne a d mi nistere d wit h a 
c yt ot o xic T-l y m p h o c yt e-ass ociate d pr ote i n 4 ( C T L A-4) i n hi bit or, c o nc o mita nt sc he d uli n g 
a p peare d t o be t he m ost effecti ve str ate g y. [ 5 4] I n c o ntrast, a ra n d o mize d trial e val uati n g t h e 
c o m bi nati o n of t he C T L A -4 c hec k p oi nt i n hi bit or i pili m u ma b wit h car b o plati n a n d paclita xel i n 
patie nts wit h sta ge I V c h e m ot hera p y -n aï ve N S C L C s h o we d t hat p hase d a d mi nistrati o n of 
i pili m u ma b wit h c he m ot hera p y (2 d os es of place b o pl us car b o plati n a n d paclita xel f oll o we d b y 4 
c ycles of i pili m u ma b a n d car b o plati n a n d p aclita xel) res ulte d i n i m pr o ve d ir P F S c o m pare d t o 
c he m ot hera p y al o ne ( H R, 0. 7 2; p = 0. 0 5), w hereas c o nc urre nt sc he d uli n g di d n ot ( H R, 0. 8 1, p = 
0. 1 3) .[ 5 5] C ortic oster oi ds f or paclita x el pre me dicati o n were all o we d. T he o verall rat es of gra d e 
3/ 4 i m m u ne -relate d A Es were 15 %, 2 0 %, a n d 6 % f or p hase d i pili m u ma b, c o nc urre nt i pili m u ma b 
a n d c o ntr ol, res p ecti vel y. [ 5 5]  
 
P D -L 1 e x pressi o n b y I H C is a pr o misi n g pre dicti ve bi o mar ker f or P D -1 a n d P D -L 1 i n hi bit ors. 
H o we ver, t here are at least 3 disti nct P D -L 1 a nti b o dies t hat are b ei n g d e vel o pe d as c o m pa ni o n 
dia g n ostics wit h var yi n g perf or ma n ce c haracteristics a n d t hres h ol ds f or p ositi vit y. I m p orta ntl y, 
res p o nses t o P D-1 a n d  P D -L 1 i n hi bit ors wit h pr ol o n ge d dis ease c o ntr ol ha ve bee n re p orte d i n 
patie nts wit h P D -L 1 -n e gati ve t u m ors. [ 4 0, 4 6] T heref ore, c o nti n ue d i n vesti gati o n will be nee de d 


 
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t o defi ne t he o pti mal patie nt p o p ulati o n t hat w o ul d be nefit fr o m treat me nt wit h i m m u ne 
c hec k p oi nt i n hi bit ors a n d e nr oll me nt of m olec ularl y u nselecte d patie nts r e m ai ns j ustifie d.  
 
4. 1. 1.  
R ati o n ale f or D ose Selecti o n/ Re gi me n/ M o dific ati o n  
 
A n o pe n -la bel P has e I tri al ( Pr ot oc ol 0 0 1) is bei n g c o n d ucte d t o e v al uate t h e safet y a n d cli nical 
acti vit y of si n gle a ge nt p e m br oliz u ma b  ( M K-3 4 7 5) .  T he d ose escalati o n p orti o n of t his trial 
e val uate d t hr ee d ose le vels, 1 m g/ k g, 3 m g/ k g, a n d 1 0 m g/ k g, a d mi nistere d e ver y 2 wee ks 
( Q 2 W) i n patie nts wit h a d va nce d s oli d t u m ors.  All t hree d ose le vels w ere well t olerate d a n d n o 
d ose -li miti n g t o xicities were o bser ve d.  T his first i n h u ma n st u d y of p e m br oliz u ma b ( M K -3 4 7 5)  
s h o we d e vi de n ce of tar get e n ga ge me nt a n d o bj ecti ve e vi de nce of t u m or size re d ucti o n at all d ose 
le vels ( 1 m g/ k g, 3 m g/ k g a n d 1 0 m g/ k g Q 2 W).  N o M T D has bee n i d e ntifie d t o date.  1 0. 0 
m g/ k g Q 2 W, t he hi g h est d ose teste d i n P N 0 0 1, will be t he d ose a n d sc h e d ule utilize d i n C o h orts 
A, B, C a n d D of t his pr ot oc ol t o test f or i nitial t u m or acti vit y.  Rece nt dat a fr o m ot her cli nical 
st u dies wit hi n t he pe m br oliz u ma b  ( M K-3 4 7 5) pr o gra m has s h o w n t hat a  l o wer d ose of 
pe m br oliz u ma b ( M K -3 4 7 5)  a n d a less fre q u e nt sc he d ule ma y be s ufficie nt f or tar get e n ga ge m e nt 
a n d cli nical acti vit y.  
 
P K data a nal ysis of pe m br oliz u ma b ( M K -3 4 7 5)  a d mi nistere d Q 2 W a n d Q 3 W s h o we d sl o w 
s yste mic cl eara nce, li mite d v ol u me of distri b uti o n, a n d a l o n g half-life (refer t o I B).  
P har mac o d y na mic d ata (I L -2 rel ease assa y) s u g geste d t hat peri p heral tar get e n ga ge me nt is 
d ura ble ( > 2 1 da ys).  T his earl y P K a n d p h ar mac o d y n a mic d ata pr o vi des s cie ntific rati o nale f or 
testi n g a Q 2 W a n d Q 3 W d osi ng sc he d ul e.   
 
A p o p ulati o n p har mac o ki netic a nal ysis has bee n p erf or me d usi n g s er u m c o nce ntrati o n ti me data 
fr o m 4 7 6 patie nts. Wit hi n t he res ulti n g p o p ulati o n P K m o del, cleara n ce a n d v ol u me para meters 
of pe m br oliz u ma b ( M K -3 4 7 5)  were f o u n d t o be de pe n de nt o n b o d y wei g ht. T he relati o ns hi p 
bet wee n cleara nce a n d b o d y w ei g ht, wit h a n all o metric e x p o ne nt of 0. 5 9, is wit hi n t he ra n ge 
o bser ve d f or ot her a nti b o dies a n d w o ul d s u p p ort b ot h b o d y wei g ht n or mali ze d d osi n g or a fi x e d 
d ose acr oss all b o d y w ei g hts.  P e m br oliz u ma b ( M K-3 4 7 5)  has b ee n f o u n d t o ha ve a wi d e 
t hera pe utic ra n ge b ase d o n t he mela n o ma i n dicati o n.  T he differe nces i n e x p os ure f or a 2 0 0 m g 
fi x e d d ose re gi me n relati ve t o a 2 m g/ k g Q 3 W b o d y wei g ht b ase d re gi me n are a ntici p ate d t o 
re mai n well wit hi n t he esta blis he d e x p os ure mar gi ns of 0. 5 –  5. 0 f or pe m br oliz u ma b ( M K -3 4 7 5)  
i n t he mela n o ma i n dicati o n. T he e x p os ure mar gi ns are bas e d o n t he n oti o n of si milar efficac y 
a n d safet y i n mela n o m a at 1 0 m g/ k g Q 3 W vs. t he pr o p ose d d ose re gi me n of 2 m g/ k g Q 3 W (i.e. 
5 -f old hi g h er d ose a n d e x p os ure). T he p o p ul ati o n P K e val uati o n re veale d t hat t here was n o 
si g nifica nt i m pa ct of t u m or b ur de n o n e x p os ure. I n a d diti o n, e x p os ure was si milar bet wee n t he 
N S C L C a n d mela n o ma i n dicati o ns. T heref ore, t h ere are n o a ntici pate d c h a n ges i n e x p os ure 
bet wee n differe nt i n dicati o n setti n gs.  
5.  R A TI O N A L E F O R E N D P OI N T S  
5. 1.  E F FI C A C Y E N D P OI N T S  
5. 1. 1.  
Pri m ar y  
 
T his ra n d o mize d p hase II trial will utilize a selecti o n (“ pic k t he wi n ner”) desi g n. T w o differe nt 
i n vesti gati o nal sc h e d ules of P D-1 i n hi bit or a d mi nistrati o n wit h sta n dar d plati n u m -base d d o u blet 


 
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c he m ot hera p y will be e v al uate d. I n t his desi g n, O R R re mai ns a n acce pta bl e scie ntific e n d p oi nt t o 
i de ntif y t he b est ar m f or f urt her e v al uati o n. O R R a n d d urati o n of res p o nse will be assesse d b y 
b ot h ir R C, as well as b y  R E CI S T 1. 1. [ 1] F or t he pri mar y e n d p oi nt, t he treat me nt re gi me n wit h 
t he best O R R per R E CI S T 1. 1 will be selecte d f or f urt her i n vesti gati o n. ir R C was de vel o pe d 
fr o m m o difie d W H O crit eria t o better ca pt ur e u ni q ue res p o nses t o i m m u ne c hec k p oi nt i n hi bit ors, 
i ncl u di n g re gressi o n of i n de x lesi o ns i n t he face of ne w lesi o ns a n d i nitial pr o gressi o n f oll o we d 
b y t u m or sta biliz ati o n or re gressi o n. [ 5 5-5 7]   
 
5. 1. 2.  
Sec o n d ar y  
P F S will be assesse d b y ir R C a n d R E CI S T 1. 1 as deter mi ne d b y t he i n vesti gat ors. P F S a n d O S 
differe n ces will be e val u ate d as a n e x pl orat or y a n al ysis. T he tr eat me nt -relate d a d verse e ve nts of 
pe m br oliz u ma b ( M K -3 4 7 5)  a n d plati n u m -base d c he m ot hera p y will be s u m marize d b y a d v erse 
e ve nt t y p e a n d gra de f or eac h tr eat me nt ar m. All mai n a nal ys es will be e v al uate d base d o n P D-
L 1 e x pressi o n stat us, i ncl u di n g ne gati ve ( 0 % t u m or cells p ositi ve), l o w e x pressi o n ( 1 -4 9 % t u m or 
cells p ositi ve) a n d hi g h  e x pressi o n ( 5 0 -1 0 0 % t u m or cells p ositi ve).  
 
5. 1. 3.  
M olec ul ar a n d Ge n o mi c C orrel ates of Tre at me nt Res p o nse a n d 
O utc o me  
 
T u m or tiss ue, peri p heral le u k oc yt es, a n d bl o o d plas ma s peci me ns at bas eli ne a n d d uri n g t hera p y 
will be c ollecte d as p art of t his st u d y.  I n a d diti o n t o a nal ysis of P D -L 1 e x pressi o n b y I H C, 
c ollecte d tiss ue bi os peci me ns will be f urt her use d t o perf or m ge n o mic, e pi ge n o mic, ge ne 
e x pressi o n, a n d/ or pr ote o mic a nal ys es t o i de ntif y ca n di date bi o mar kers of tr eat me nt res p o nse 
a n d o utc o me.  Serial, peri p heral bl o o d plas ma bi os peci me ns will be use d t o e val uate n u cleic 
aci d, pr ote o mic, a n d/ or meta b olic bi o mar kers of res p o nse a n d o ut c o me.  All c ollecte d 
bi os peci me ns will be st ore d i n t he Allia nce F o u n d ati o n Bi ore p osit or y ( A F B), u ntil bi os peci me n 
accr ual a n d  cli nic al f oll o w u p is s ufficie ntl y c o m plete t o all o w f or t he d esi g n a n d e x ec uti o n of 
s pecific c orrel ati ve a nal yses. 
 
6.  O B J E C TI V E S  
6. 1.  P RI M A R Y O B J E C TI V E  
1.  T o c o m pare t h e O R R per R E CI S T 1. 1 of pe m br oli z u ma b ( M K -3 4 7 5 ) i n patie nts wit h 
che m ot hera p y n ai ve  a d v a nce d N S C L C after treat me nt wit h first -li ne car b o plati n-
base d c he m ot hera p y t o p atie nts treate d wit h pe m br oliz u ma b ( M K -3 4 7 5)  pri or t o first -
li ne c he m ot hera p y. 
6. 2.  S E C O N D A R Y O B J E C TI V E S  
1.  T o c o m pare t h e pr o gressi o n -free s ur vi val ( P F S) per R E CI S T 1. 1 i n pre vi o usl y 
c he m ot hera p y n ai ve wit h a d va nce d N S C L C treate d wit h first li ne car b o plati n -base d 
c he m ot hera p y f oll o we d b y pe m br oliz u ma b ( M K -3 4 7 5) t o patie nts treate d wit h 
pe m br oliz u ma b ( M K -3 4 7 5) pri or t o first -li ne car b o plati n-base d c h e m ot hera p y.  
2.  T o c haracteriz e t he a d verse e ve nts rel ate d t o pe m br oliz u ma b ( M K -3 4 7 5) b y 
fre q ue n c y, t y pe a n d gra d e i n patie nts wit h c he m ot hera p y nai v e a d va n ce d N S C L C 
base d o n t he se q u e nce of a d mi nistrati o n wit h first -li ne c he m ot hera p y.  


 
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3.  T o e val uate t he O R R per ir R C of pe m br oliz u ma b ( M K -3 4 7 5)  a d mi nistere d pri or t o or 
after treat me nt wit h first -li ne car b o plati n-b ase d c h e m ot hera p y i n patie nts wit h  
c he m ot hera p y n ai ve  N S C L C.  
4.  T o e val uate t he P F S per ir R C of c he m ot hera p y n ai ve  patie nts wit h a d va nce d N S C L C 
w h o are tr eate d wit h pe m br oliz u ma b ( M K -3 4 7 5)  a d mi nistere d pri or t o or after first -
li ne car b o plati n-b ase d c h e m ot hera p y.  
5.  T o e val uate t he res p o nse d urati o n of pe m br oliz u ma b ( M K -3 4 7 5)  b ase d o n s c he d ule 
of a d mi nistrati o n wit h sta n dar d plati n u m -bas e d c he m ot hera p y i n patie nts wit h 
c he m ot hera p y n ai ve  a d v a nce d N S C L C.  
6.  T o e val uate t he o v erall s ur vi val ( O S) of patie nts wit h  c he m ot hera p y n ai ve  a d va nce d 
N S C L C w h o recei ve d p e m br oliz u ma b ( M K -3 4 7 5)  a d mi nistere d pri or t o or after 
treat me nt wit h first li ne car b o plati n-base d c he m ot hera p y.  
6. 3.  C O R R E L A TI V E O B J E C TI V E S  
1.  T o  e val uate O R R per R E CI S T 1. 1 a n d p er ir R C, P F S per R E CI S T 1. 1 a n d per ir R C, 
a n d O S after treat me nt wit h pe m br oliz u ma b ( M K -3 4 7 5) base d o n P D -L 1 e x pressi o n.  
2.  T o e val uate t he ass ociati o n bet wee n s m o ki n g stat us ( ne ver, pre vi o us, or c urre nt 
s m o kers) a n d cli nic al o utc o mes, i ncl u di n g O R R, P F S a n d O S.  
 
6. 4.  F U T U R E B I O M E DI C A L R E S E A R C H  
All c ollecte d bi os peci me ns will be st ore d i n t he Allia nce F o u n d ati o n Bi ore p osit or y ( A F B), a 
C A P -accre dite d bi ore p osit or y at W as hi n gt o n U ni versit y i n St. L o uis, u ntil bi os peci me n accr ual 
a n d cli nical f oll o w -u p is s ufficie ntl y c o m plete t o all o w f or t he desi g n a n d e x ec uti o n of s pecific 
c orrel ati ve a nal yses usi n g ‘stat e -of -t h e-art’ a n al ytical platf or ms t hat will be a vaila ble at t hat 
ti me.  
S uc h bi o mar ker researc h will a d dress e mer ge nt q u esti o ns n ot descri be d else w here i n t his 
pr ot oc ol a n d will o nl y be c o n d ucte d o n s peci me ns fr o m a p pr o pri atel y c o ns e nte d patie nts. T he 
o bjecti ve of c ollecti n g s p eci me ns f or f ut ure bi o me dical researc h is t o e x pl ore a n d i de ntif y 
bi o mar kers t hat i nf or m t he scie ntific u n d ersta n di n g of disease a n d/ or t heir t hera pe utic tr eat me nts 
i n t he c o nte xt of t his trial. Pr o p osals f or f ut ure c orrelati ve researc h will u n d er g o ri g or o us 
scie ntific, pr o gra m matic, a n d statistical re vie w b y A F T, a n d bi os peci me ns will o nl y b e rel ease d 
t o t h ose i n vesti gat ors w h o ha ve o btai ne d a p pr o pri ate re g ulat or y a p pr o val a n d de m o nstrate 
a de q uate f u n di n g t o s u ccessf ul c o m plete pr o p ose d researc h ai ms. A F T will e ns ure t hat all 
c ollecte d s peci me ns are use d o nl y f or a p pr o ve d researc h pr ot oc ols.  
A n o n y mize d ( de -i dentifie d) data ge nerate d fr o m bi os peci me ns use d f or f ut ure c orrelati ve 
researc h, i ncl u di n g s o matic a n d c o nstit uti o nal ( ger mli ne) ge n o mic data, m a y b e s hare d wit h 
ot her researc hers or d e p osite d i n a p u blicl y accessi ble or c o ntr olle d -access data re p osit ories.  
C orrelati ve st u d y res ults a n d data will ne ver be ret ur ne d t o i n di vi d ual patie nts.  
7.  P A TI E N T S E L E C TI O N  
F or q uesti o ns re gar di n g eli gi bilit y criteri a, c o ntact t he St u d y PI. Please n ote t hat t he St u d y PI 
ma y n ot gra nt wai vers t o eli gi bilit y re q uire me nts.  
7. 1.  I N C L USI O N C RI T E RI A  
I n or der t o be eli gi ble f or partici pati o n i n t his trial, t he patie nt  m ust:  


 
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1.  Be  1 8 years of a ge o n da y of si g ni n g i nf or me d c o nse nt.  
2.  Ha ve a life e x pecta nc y of at least 3 m o nt hs.  
3.  Ha ve a hist ol o gicall y or c yt ol o gicall y c o nfir me d dia g n osis of sta ge I V ( M 1a or M 1 b 
acc or di n g t o AJ C C Sta gi n g Ma n u al, 7 t h e diti o n) n o n -s mall cell l u n g ca ncer ( N S C L C).   
4.  Ha ve a p erf or ma nce stat us of 0 or 1 o n t he E C O G Perf or ma nce Scale.  
5.  Ha ve me as ura bl e diseas e base d o n R E CI S T 1. 1.  T he tar get lesi o n(s) s h o ul d als o ha v e 
bi -di me nsi o nal meas ura bilit y f or ir R C e val uati o n o n st u d y.  
6.  Ha ve pr o vi de d tiss ue fr o m a n arc hi val tiss ue sa m ple or ne wl y o btai ne d c ore or 
e x cisi o nal bi o ps y of a t u m or lesi o n , t hat is a d e q uate t o esta blis h P D-L 1 e x pressi o n 
stat us. Ne wly -o bt ai ne d is defi ne d  as a s peci me n o bt ai ne d u p t o 6 weeks ( 4 2 d ays) pri or 
p atie nt e nr oll me nt.  
7.  I n patie nts  wit h n o n -s q ua m o us n o n-s mall cell l u n g ca n cer, I n v esti gat ors m ust be a ble 
t o pr o d uce s o urce d oc u me ntati o n of t he E G F R m utati o n stat us or A L K tra nsl ocati o n 
stat us.  
i. If a patie nt is k n o w n t o ha ve o ne m olec ular alterati o n ( E G F R m utati o n 
or A L K tr a nsl ocati o n), t he n testi n g f or t he ot h er alterati o n is n ot 
re q uire d.  
ii. If a patie nt is k n o w n t o ha ve a m utati o n i n K R A S, t he n testi n g f or a n 
E G F R m utati o n or A L K tra nsl ocati o n will n ot be re q uire d.  
8.  De m o nstrate a d e q uate or ga n f u ncti o n as defi ne d i n Ta ble 1 .  
Ta ble 1 .  A de q u ate Or ga n F u ncti o n La b orat or y Val ue s 
 
S yste m  
La b orat or y Val ue  
He m at ol o gic al  
 
A bs ol ute ne utr o p hil c o u nt 
( A N C) 
≥1, 5 0 0 / mc L  
Platelets  
≥1 0 0, 0 0 0 / mc L  
He m o gl o bi n  
≥9 g/ d L or ≥5. 6 m m ol/ L  
Re n al  
 
Ser u m creati ni ne O R  
 G F R (Gl o m er ul ar Filtrati o n 
Rate)   
≤1. 5 X u p per li mit of n or mal ( U L N) O R  
 
G F R ≥6 0 m L/ mi n f or p atie nt  wit h creati ni ne 
le vels > 1. 5 X i nstit uti o nal U L N 
He p atic  
 
Ser u m t otal bilir u bi n  
≤ 1. 5 X U L N O R  


 
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Direct bilir u bi n ≤ U L N f or patie nt s wit h t otal 
bilir u bi n le vels > 1. 5 U L N  
A S T ( S G O T) a n d A L T ( S G P T)  ≤ 2. 5 X U L N  O R  
≤ 5 X U L N f or p atie nt s wit h li ver metastases 
Al b u mi n  
>  2. 5 m g/ d L  
C o a g ul ati o n  
I nter nati o nal N or m alize d Rati o 
(I N R) or Pr ot hr o m bi n Ti me 
( P T) 
 
Acti vate d Partial 
T hr o m b o plasti n Ti me (a P T T)  
≤1. 5 X U L N u nless patie nt  is recei vi n g 
a ntic oa g ula nt t hera p y  
as l o n g as P T or P T T is wit hi n t hera pe utic ra n ge 
of i nte n de d use of a ntic o a g ul a nts  
≤1. 5 X U L N u nless patie nt  is recei vi n g 
a ntic oa g ula nt t hera p y  
as l o n g as P T or P T T is wit hi n t hera pe utic ra n ge 
of i nte n de d use of a ntic o a g ul a nts  
 
 
9.  Fe male patie nt  of c hil d beari n g p ote ntial s h o ul d ha ve a ne gati ve uri ne or ser u m 
pre g na nc y wit hi n 7 2 h o urs pri or t o recei vi n g t he first d ose of st u d y m e dicati o n.  If t he 
uri ne test is p ositi ve or ca n n ot be c o nfir m e d as n e gati ve, a s er u m pre g n a n c y t est will 
be re q uir e d.   
1 0.  Fe male p atie nt s of c hil d beari n g p ote ntial m ust  be willi n g t o use 2 met h o ds of birt h 
c o ntr ol or be s ur gic all y sterile, or a bstai n fr o m h eter ose x ual acti vit y f or t h e c o urse of 
t he st u d y t hr o u g h 1 2 0 da ys after t he last d ose of st u d y m e dicati o n  (see S ecti o n 1 3 . 5).  
Patie nt s of c hil d beari n g p ote ntial are t h ose w h o h a ve n ot bee n s ur gicall y sterilize d or 
ha ve n ot bee n free fr o m me nses f or > 1 year.  
1 1.  Male patie nt s m ust  a gree t o use a n a de q uate met h o d of c o ntrace pti o n  starti n g wit h t he 
first d ose of st u d y t h era p y t hr o u g h 1 2 0 d a ys after t he last d ose of st u d y t h era p y. 
1 2.  P ati e nts wit h se nsitizi n g E G F R m ut ati o n or A L K re a rr a n ge me nt m ust h a ve 
pr o gresse d o n a n a p pr o pri ate t yr osi ne ki n ase i n hi bit or (T KI ). 
 
7. 2.  E X C L U SI O N C RI T E RI A  
T he patie nt  m ust be e x cl u de d fr o m partici p ati n g i n t he trial if t he patie nt : 
 
1.  Has recei ve d pri or treat me nt wit h c he m ot hera p y or bi ol o gic t hera p y f or sta ge I V 
N S C L C.   
2.  Is c urre ntl y partici p ati n g i n or has p artici pate d i n a st u d y of a n i n vesti gati o nal a ge nt or 
usi n g a n i n vesti gati o nal de vice wit hi n 4 wee ks of t he first d ose of treat me nt.  
3.  Has a dia g n osis of i m m u n o deficie nc y or is recei vi n g s yste mic ster oi d t hera p y or a n y 
ot her f or m of i m m u n os u p pressi ve t hera p y wit hi n 7 da ys pri or t o t h e first d ose of trial 
treat me nt.   


 
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4.  Has ha d a pri or m o n ocl o nal a nti b o d y ( m A b) wit hi n 4 wee ks pri or t o st u d y Da y 1 or 
w h o has n ot rec o vere d (i. e., ≤ Gra d e 1 or at bas eli ne) fr o m a d v erse e v e nts d u e t o a ge nts 
a d mi nistere d m ore t ha n 4 wee ks earlier.  
5.  Has ha d pri or c he m ot hera p y, tar gete d  s mall m olec ule t hera p y, or ra diati o n t hera p y 
wit hi n 2 wee ks pri or t o st u d y Da y 1 or w h o has n ot rec o vere d (i.e., ≤ Gra de 1 or at 
baseli ne) fr o m a d vers e e ve nts d ue t o a pre vi o usl y a d mi nistere d a ge nt.  
- 
N ote:  Patie nt s wit h n o n -s q ua m o us hist ol o g y ≤ Gra de 2 n e ur o pat h y are a n 
e x ce pti o n t o t his criteri o n a n d ma y q ualif y f or t h e st u d y.  
- 
N ote:  If p atie nt  recei ve d maj or s ur ger y, t he y m ust ha ve rec o vere d a de q uat el y 
fr o m t he t o xicit y a n d/ or c o m plicati o ns fr o m t he i nter ve nti o n pri or t o starti n g 
t hera p y.   
6.  Has a k n o w n a d diti o nal mali g na n c y t hat is pr o gressi n g or re q uir es acti ve treat me nt.  
E x ce pti o ns i ncl u de basal cell carci n o ma of t he s ki n, s q ua m o us cell carci n o ma of t he 
s ki n, or i n sit u cer vical c a ncer t h at has u n der g o n e p ote ntiall y c urati ve t hera p y.   
7.  Has k n o w n acti ve  ce ntr al ner v o us s yste m ( C N S) metastases a n d/ or carci n o mat o us 
me ni n gitis.  Patie nt s wit h pre vi o usl y treat e d brai n metastases ma y p artici pate pr o vi de d 
t he y are sta ble ( wit h o ut e vi de nce of pr o gressi o n b y i ma gi n g f or at least t w o wee ks pri or 
t o t he first d ose of trial tr eat me nt a n d a n y cli nical/ ne ur ol o gi c s y m pt o ms ha ve ret ur n e d 
t o baseli ne), ha ve n o e vi de nce of n e w or e nlar gi n g brai n metastases, a n d are n ot usi n g 
ster oi ds f or at least 7 da ys pri or t o trial tr eat me nt. Patie nts w o ul d n ot re q uir e f oll o w -u p 
M RI be f ore starti n g st u d y tr eat me nt.  T his e x ce pti o n d oes n ot i ncl u de carci n o mat o us 
me ni n gitis w hic h is e x cl u de d re gar dless of cli nical sta bilit y.   
8.  Has a n acti ve a ut o i m m u ne disease re q uiri n g s yste mic treat me nt wit hi n t he past 3 
m o nt hs or a d o c u me nt e d hist or y of  cli nicall y se vere a ut oi m m u ne disease, or a 
s y n dr o me t hat re q uires s yste mic ster oi ds or i m m u n os u p pressi ve a ge nts.  P atie nt s wit h 
vitili g o or res ol ve d c hil d h o o d ast h ma/at o p y w o ul d be a n e x ce pti o n t o t his r ule.  Patie nt s 
t hat re q uire i nter mitte nt use of br o nc h o dilat ors or l ocal ster oi d i njecti o ns w o ul d n ot be 
e x cl u de d fr o m t he st u d y.  Patie nt s wit h h y p ot h yr oi dis m sta ble o n h or m o ne re place m e nt 
or Sj or ge n’s s y n dr o me will n ot be e x cl u de d fr o m t he st u d y.  
9.  Has e vi de nce of i nterstitial l u n g disease , or hist or y of  (n o n -i nfecti o us) p ne u m o nitis  t hat 
re q uire d ster oi ds, or c urre nt p ne u m o nitis . 
1 0.  Has a n acti ve i nfecti o n re q uiri n g s yste mic t hera p y.  
1 1.  Has a hist or y or c urre nt e vi de nce of a n y c o n diti o n, t hera p y, or la b orat or y a b n or malit y 
t hat mi g ht c o nf o u n d t he res ults of t he trial, i nterfere wit h t he patie nt ’s partici pati o n f or 
t he f ull d urati o n of t he tri al, or is n ot i n t he best i nterest of t he p atie nt  t o partici pate, i n 
t he o pi ni o n of t he treati n g i n vesti gat or.   
1 2.  Has k n o w n ps yc hiatric or s u bsta nce a b use dis or ders t hat w o ul d i n terfere wit h 
c o o perati o n wit h t he re q uire me nts of t he trial.  


 
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1 3.  Is pre g na nt or breastfee di n g, or e x pecti n g t o c o ncei ve or fat her c hil dre n wit hi n t he 
pr ojecte d d urati o n of t he trial, starti n g wit h t he pre -scree ni n g or scree ni n g visit t hr o u g h 
1 2 0 da ys after t he  last d ose of trial treat me nt. 
1 4.  Has recei ve d pri or t hera p y wit h a n a nti -P D -1, a nti -P D -L 1, a nti -P D -L 2, a nti -C D 1 3 7, or 
a nti-C yt ot o xic T -l y m p h oc yt e-ass oci ate d a nti ge n -4 ( C T L A -4) a nti b o d y (i ncl u di n g 
i pili m u ma b or a n y ot her a nti b o d y or dr u g s pecifi call y tar geti ng T -cell c o -sti m ulati o n 
or c hec k p oi nt pat h w a ys).  
1 5.  Has a k n o w n hist or y of H u ma n I m m u n o deficie nc y Vir us ( HI V) ( HI V 1/ 2 a nti b o dies).  
1 6.  Has k n o w n acti ve He patitis B (e. g., H Bs A g reacti ve) or He p atitis C (e. g., H C V R N A 
[ q ualitati ve] is detecte d). 
1 7.  Has recei v e d a li ve v acci ne wit hi n 3 0 d a ys pri or t o t he pl a n ne d first d os e of st u d y 
t hera p y.  
N ote:  Se as o n al i nfl ue nz a v acci nes f or i njecti o n are ge ner ally i n activ ate d fl u v acci nes 
a n d are all o we d; h o wever i ntr a n as al i nfl ue nz a v acci nes (e. g., Fl u -Mist ®) are live 
atte n u ate d v acci n es, a n d are n ot all o we d.  
 
1 8.   Has a k n o w n hist or y of acti ve T B ( Bacill us T u berc ul osis)  
 
1 9.  H y p erse nsiti vit y t o pe m br oliz u ma b  ( M K-3 4 7 5)  or a n y of its e xci pie nts.  
8.  P A TI E N T E N R O L L M E N T  
8. 1.  S I T E E N R O L L M E N T R E Q UI R E M E N T S  
Re q uire me nts f or Site E nr oll me nt  
• I R B Certificati o n  
• I R B/ Re g ulat or y A p pr o v al  
S u b mit c o m plete d f or ms al o n g w it h a c o p y of y o ur I R B A p pr o val, M o del I nf or me d C o nse nt  
a n d a n y ot her re q uire d d oc u me ntati o n t o t he A F T e T M F s yste m.  
8. 2.  P A TI E N T E N R O L L M E N T R E Q UI R E M E N T S  
I nf or me d c o nse nt: T he patie nt m ust be a ware of t he ne o plastic n at ure of his/ her diseas e a n d 
willi n gl y c o nse nt after bei n g i nf or me d of t he pr oce d ure t o b e f oll o we d, t he e x peri me ntal nat ure of 
t he t hera p y, alter nati ves, p ote ntial be nefits, si de-effects, ris ks, a n d disc o mf orts.  C urre nt h u ma n 
pr otecti o n c o m mittee a p pr o val of t his pr ot oc ol a n d a c o nse nt f or m is re q uire d  pri or t o patie nt 
c o nse nt a n d e nr oll me nt . 
8. 3.  P A TI E N T  S C R E E NI N G , E N R O L L M E N T /R A N D O MI Z A TI O N P R O C E D U R E S  
Patie nt e nr oll me nt will be facilitate d usi n g t he A F T we b -base d I R T (i nteracti ve res p o ns e 
tec h n ol o g y) s yste m.   


 
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Patie nts m ust si g n i nf or me d c o nse nt a n d be scree ne d  pri or t o a n y st u d y relate d testi n g,  i ncl u di n g 
s u b missi o n of bi os peci me ns. After writte n i nf or me d c o nse nt has bee n o btai ne d, t he st u d y site will 
o btai n a u ni q ue patie nt n u m ber or u ni q ue patie nt i de ntifier w hic h will sta y t he sa me t hr o u g h o ut 
t he e ntire st u d y. Patie nts 
ma y be e nr olle d/ ra n d o mize d u p o n c o nfir mati o n fr o m t he A F T-
bi ore p osit or y t hat t u m or tiss ue f or bi o mar ker a nal ysis ha s bee n recei ve d  a n d t hat t he patie nt meets 
all eli gi bilit y re q uire m e nts f or e nr oll me nt . Patie nts scree ne d b ut n ot ra n d o mize d f or a n y reas o n 
ha ve t o be re gistere d as a Scree ni n g Fail ure i n I R T.  
 
Pri or t o accessi n g A F T I R T , site staff s h o ul d verif y t he f oll o wi n g: 
• 
All eli gi bilit y criteria ha v e bee n met wit hi n t he pr ot oc ol state d ti mefra mes.  
• 
All patie nts ha ve si g ne d a n a p pr o priat e c o ns e nt f or m a n d HI P A A a ut h orizati o n f or m (if 
a p plica ble).  
• 
T u m or tiss ue will be a vaila ble a n d ca n be se nt t o t he A F T bi ore p osit or y f or ce ntr al 
la b orat or y a n al ysis. 
 
T he  A F T I R T  s yst e m will pr o vi de t he site wit h a pri nta ble c o nfir mati o n of e nr oll me nt  a n d 
treat me nt ra n d o mizati o n i nf or mati o n. Please pri nt t his c o nfir mati o n f or y o ur rec or ds.   T he site will 
recei v e i nstr ucti o ns f or dr u g or deri n g via I R T, u p o n ra n d o mizati o n. 
8. 4.  S T R A TI FI C A TI O N F A C T O R S A N D T R E A T M E N T A S S I G N M E N T S 
Ra n d o mizati o n will be stratifie d acc or di n g t o:  
1)  S m o ki n g Hist or y:  Ne ver, Pre vi o us  or  C urre nt  
2)  Hist ol o g y: S q u a m o us vs. N o n -S q u a m o us  
T his is a n o pe n -la bel trial; t heref ore, A F T , t he i n vesti gat or a n d patie nt  will k n o w t he 
treat me nt a d mi nistere d. 


 
 
 
 
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9.  S C H E D U L E O F A S S E S S M E N T S  
Ta ble 2 .  Sc he d ule of Assess me nts  
Tri al Peri o d:  
Tre at me nt C ycles 1 
E n d of 
Tre at m
e nt  
P ost -Tre at me nt  
Treat me nt C ycle/ Title : 
 
Scree ni n g 
( Visit 0) 1  
2  
3  
4  
T o be re p eate d 
be y o n d 8 c ycles  
Disc o n  
Safet y 
F oll o w
-u p 1 9  
F oll o w 
U p 
Visits 2 0  
S ur vi val 
F oll o w -
U p 2 1  
5  
6  
7  
8  
Sc he d uli n g Wi n d o w ( Da ys) 2: -2 8 t o -1  
 ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  
At ti me 
of 
Disc o n  
3 0 da ys 
p ost 
disc o n  
E ver y 9 
wee ks 
p ost 
disc o n  
E ver y 1 2 
wee ks  
I nf or me d C o nse nt3  
X  
 
 
 
 
 
 
 
 
 
 
 
 
I n cl usi o n/ E x cl usi o n Criteria 
X  
 
 
 
 
 
 
 
 
 
 
 
 
De m o gra p hics a n d Me di cal 
Hist or y 2 3  
X  
 
 
 
 
 
 
 
 
 
 
 
 
Pri or a n d C o nc o mita nt 
Me dicati o n Re vie w
4  
X  
X  X  
X  
X  
X  
X  
X  
X  
X  
 
 
 
N S C L C Disease Details  
X  
 
 
 
 
 
 
 
 
 
 
 
 
Trial Treat me nt 
A d mi nistrati o n 2 4 
 
X  X  
X  
X  
X  
X  
X  
X  
 
 
 
 
Re vie w A d vers e E ve nts 5, 6, 2 2  
 
X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
F ull P h ysical E x a mi nati o n 1 7  
X  
 
 
 
 
 
 
 
 
X  
 
 
X  
Directe d P h ysical E x a mi nati o n 1 7  
 
X  X  
X  
X  
X  
X  
X  
X  
 
X  
X  
 
Vital Si g ns a n d Wei g ht 7  
X  
X  X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
E C O G Perf or ma n ce Stat us  
X  
X  X  
X  
X  
X  
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X  
X  
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Tri al Peri o d:  
Tre at me nt C ycles 1 
E n d of 
Tre at m
e nt  
P ost -Tre at me nt  
Treat me nt C ycle/ Title : 
 
Scree ni n g 
( Visit 0) 1  
2  
3  
4  
T o be re p eate d 
be y o n d 8 c ycles  
Disc o n  
Safet y 
F oll o w
-u p 1 9  
F oll o w 
U p 
Visits 2 0  
S ur vi val 
F oll o w -
U p 2 1  
5  
6  
7  
8  
Sc he d uli n g Wi n d o w ( Da ys) 2: -2 8 t o -1  
 ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  ± 3  
At ti me 
of 
Disc o n  
3 0 da ys 
p ost 
disc o n  
E ver y 9 
wee ks 
p ost 
disc o n  
E ver y 1 2 
wee ks  
Pre g n a nc y T est –  Uri ne or 
Ser u m 
-H C G 8, 1 0  
X  
 
 
 
 
 
 
 
 
 
 
 
 
P T/I N R a n d a P T T 9, 1 0  
X  
 
 
 
 
 
 
 
 
 
 
 
 
C B C wit h Differe ntial 1 0, 1 1  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
C o m pre he nsi ve Ser u m 
C he mistr y Pa nel 1 0, 1 1  
X  
 
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
Uri nal ysis 1 0, 1 2  
X  
 
 
 
X  
 
 
 
X  
X  
 
 
 
T 3, F T 4 a n d T S H 1 0, 1 1, 1 3  
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
 
A L K Tra nsl oc ati o n Testi n g 1 8  
X  
 
 
 
 
 
 
 
 
 
 
 
 
E G F R Tra nsl o cati o n Testi n g 1 8  
X  
 
 
 
 
 
 
 
 
 
 
 
 
C T Sca n ( T u m or I ma gi n g) 1 4, 1 5  
 
X  
 
X  
 
X  
 
X  
 
X  
X  
 
 
X  
 
Arc hi val or N e wl y O btai ne d 
Tiss ue C ollecti o n 1 6  
X  
 
 
 
 
 
 
 
 
 
 
 
 
C orrelati ve St u dies Bl o o d 
C ollecti o n 1 6 A  
X  
 
 
 
X  
 
 
 
X  
 
 
 
 


 
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1 I n ge n eral, ass ess me nts/ pr oce d ures are t o be perf or me d o n da y 1 a n d pri or t o t he first d ose of trial treat me nt f or eac h c ycle  u nless 
ot her wise s pecifie d. Treat me nt c ycles are 3 wee ks ( 2 1 -da ys) ; h o we ver t he pe m br oliz u ma b ( M K -3 4 7 5)  treat me nt c ycle i nter val ma y 
be i ncrease d d ue t o t o xicit y acc or di n g t o t he d ose m o dif icati o n g ui d eli nes pr o vi de d i n S ecti o n 1 3 . If treat me nt c ycl es are i ncrease d 
all pr oce d ures e x ce pt i ma gi n g will be c o m plete d acc or di n g t o c ycl e n u m ber a n d n ot wee ks o n treat me nt, i ma gi n g will be perf or me d 
e ver y 6 wee ks ( ± 7 da ys) fr o m t he first d ose of trial treat me nt re gar dless of a n y tr eat me nt dela ys  d uri n g t he first 8 c ycl es.  After c ycl e 
8, i m a gi n g will be perf or me d e ver y 9 wee ks  ( 6 3 ± 7 da ys).  
2 I n ge neral, t he wi n d o w f or eac h visit is ± 3 da ys u nless ot her wise s pecifie d.  
3 Writte n c o nse nt m ust be o btai ne d pri or t o perf or mi n g a n y pr ot oc ol s pecific pr oce d ure. Res ults of a test perf or me d pri or t o t he patie nt 
si g ni n g c o nse nt as part of r o uti ne cli nical ma na ge me nt are acce pta ble i n lie u of a scree ni n g test if perf or me d wit hi n t he s pe cifie d 
ti me fra me.  
4 Pri or me dicati o ns –  rec or d all me dicati o ns ta ke n wit hi n 3 0 da ys of visit 1 a n d all treat me nts for a pri or ca ncer ot her t ha n N S C L C e ve n 
if ta ke n greater t ha n 3 0 da ys pri or t o visit 1. Aft er t he Safet y F oll o w-u p Visit rec or d all me di cati o ns ta ke n f or S A Es a n d E CIs as 
defi ne d i n S ecti o n 1 3 . 4.  
5 A Es a n d la b orat or y safet y me as ure me nts will be gra de d per N CI C T C A E versi o n 4. 0. All A Es, w het her gra da ble b y C T C A E or n ot 
will als o be e val uate d f or seri o us ness.  
6 All A Es of u n k n o w n eti ol o g y ass oci ate d wit h trial treat me nt e x p os ure s h o ul d be e val uate d t o d eter mi n e if it is p ossi bl y a n E CI.  
7 Vital si g ns t o i ncl u de : te m perat ur e, p ulse, res pir at or y rate, wei g ht a n d bl o o d press ure. Hei g ht will be meas ure d at visit 1 o nl y.  
8 F or w o me n of re pr o d ucti ve p ote ntial, a uri ne pre g na nc y t est will be perf or me d wit hi n 7 2 h o urs pri or t o t he first d ose of tria l treat me nt. 
If uri ne pre g n a nc y res ults ca n n ot be c o nfir me d as n e gati ve, a ser u m pre g n a n c y test, perf or me d b y t he l ocal st u d y site la b orat or y, will 
be re q uir e d. Pre g na n c y tests (ser u m a n d/ or uri ne tests) s h o ul d be re peate d if re q uire d b y l ocal g ui deli nes.  
9 C oa g ulati o n fact ors ( P T/I N R a n d a P T T) s h o ul d be m o nit ore d cl osel y t hr o u g h o ut t h e trial f or a n y p atie nt recei vi n g a ntic oa g ula n t 
thera p y.  
1 0 La b orat or y tests f or scree ni n g are t o be perf or me d wit hi n 1 0 da ys pri or t o t he first d ose of trial treat me nt. See Ta ble 3  f or details 
re gar di n g la b orat or y tests.  
1 1 After C ycl e 1, la b sa m ples ca n be c ollecte d u p t o 4 8 h o urs pri or t o t he sc he d ule d ti me p oi nt. La b orat or y res ults m ust be k n o w n a n d 
acce pta ble pri or t o d osi n g.  
1 2 Perf or m uri nal ysis e v er y 4 c ycles .  
1 3  Re q uire d at baseli ne. Perf or m t h yr oi d testi n g e v er y o t her c ycle w hile p atie nts are recei vi n g p e m br oliz u ma b ( M K -3 4 7 5) . 


 
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1 4 T he i nitial t u m or i ma gi n g will be p erf or me d wit hi n 3 0 da ys pri or t o t he first d ose of trial treat me nt. Sca ns p erf or me d as par t of r o uti ne 
cli nical ma na ge m e nt are acce pta ble f or use as t he scree ni n g s ca n if t h e y are of dia g n ostic q ualit y a n d perf or m e d wit hi n 3 0 da ys pri or 
t o t he first d ose of trial treat me nt. O n-st u d y i m a gi n g d uri n g t he first 8 c ycles of t hera p y will be perf or me d e v er y 6 wee ks ( 4 2 ± 7 
da ys) after t he first d ose of trial trea t me nt or m ore fre q ue ntl y if cli nicall y i n dicate d. Patie nts o n b ot h  ar ms recei vi n g pe m br oliz u ma b 
( M K-3 4 7 5)  al o ne after c ycl e 8 will be i ma ge d e v er y 9 wee ks ( 6 3 ± 7 d a ys) T he ti mi n g f or i ma gi n g st u dies s h o ul d f oll o w cale n dar 
da ys a n d s h o ul d n ot be a dj uste d f or dela ys i n c ycl e starts or e xte nsi o n of pe m br oliz u ma b ( M K -3 4 7 5)  c ycle fre q ue nci es. T he sa me 
i ma gi n g tec h ni q u e s h o ul d be use d i n a patie nt t hr o u g h o ut t he trial. L o cal rea di n g (i n vesti gat or assess me nt wit h site ra di ol o gy rea di n g) 
will be use d t o deter mi ne eli gi bilit y a n d f or patie nt ma na ge me nt.  
1 5 After first d oc u me ntati o n of pr o gressi o n (if t he p atie nt is cli nicall y sta ble) or res p o ns e per R E CI S T 1. 1 re peat i ma gi n g f or c o nfir mati o n 
is re q uire d. C o nfir mat or y i ma gi n g ma y b e p erf or me d as earl y as 2 8 d a ys later; alter nati vel y, t he sca n p erf or me d at t he n e xt sc he d ule d 
ti me p oi nt ma y be use d as c o nfir mati o n.  
1 6 T u m or tiss ue f or bi o mar ker a nal ysis fr o m a n arc hi val tiss ue sa m ple or ne wl y o btai ne d f or mali n fi x e d t u m or tiss ue fr o m a rece n t 
bi o ps y of a t u m or lesi o n n ot pre vi o usl y ra di ate d (re q uire d f or P D -L 1 det er mi nati o n) m ust be pr o vi de d a n d recei ve d b y t h e A F T -
Bi ore p osit or y bef ore ra n d o mizati o n.  
1 6 A C orrelati ve bl o o d sa m ples will be c ollecte d per Secti o n 1 2. 1. 3 . At baseli ne,  w h ole bl o o d sa m ple i n E D T A t u be a n d Strec k B C T t u be. 
At C 4 a n d C 8, Strec k B C T t u be o nl y. Bl o o d v ol u mes, pr ocessi n g, st ora ge a n d s hi p pi n g are des cri be d i n secti o n 1 2. 1. 2 . 
1 7 Perf or m a f ull p h ysic al e x a mi nat i o n at t he scree ni n g visit, e n d of treat me nt, a n d e ver y 1 2 w ee ks d uri n g s ur vi val f oll o w u p.   Ot her wise, 
perf or m a direct e d p h ysi cal e x a mi nati o n t he da y of t he st u d y tr eat me nt visit.  
1 8 Site m ust be a ble t o pr o vi de d oc u me ntati o n of t he patie nt’s t u m or E G F R m utati o n a n d A L K tra nsl ocati o n stat us.  
1 9 T he ma n dat or y Safet y F oll o w -u p Visit s h o ul d be c o n d ucte d a p pr o xi matel y 3 0 da ys after t he last d ose of trial treat me nt or bef ore t he 
i nitiati o n of a ne w a nti ne o plastic treat me nt, w hic h e ver c o m es first. Patie nts wit h a n A E of gra de > 1 will be f urt her f oll o we d u ntil 
t he res ol uti o n of t he A E t o Gra de 0-1 or u ntil be gi n ni n g of a ne w a nti ne o plastic t hera p y, w hi c he ver occ urs first.  
2 0 Patie nts w h o disc o nti n ue trial treat me nt f or a reas o n ot her t ha n dis ease pr o gressi o n  will m o ve i nt o t he Cli nical F oll o w -u p P hase a n d 
s h o ul d be assesse d e ver y 9 wee ks ( 6 3 ± 7 da ys) b y ra di ol o gic i ma gi n g t o m o nit or disease stat us.  Treat me nt -relate d t o xicities will be 
res ol ve d b ef ore tra nsiti o ni n g t o cli nical f oll o w-u p.  F oll o w -u p visit 1 s h o ul d be sc he d ul e d 9  wee ks  aft er t he last d ose of trial tr eat me nt. 
F oll o w -u p visit 2 s h o ul d occ ur 9 wee ks after F oll o w -u p visit 1.  After F oll o w -u p visit 2, patie nts o nl y nee d t o be assesse d e ver y 9 
wee ks ( 6 3 ± 7 da ys) b y ra di ol o gic i ma gi n g t o m o nit or disease  stat us, de vel o p me nt of dr u g relat e d S A Es a n d E CIs/ir A Es, a n d i nitiati o n 
of a ne w a nti ne o plastic t hera p y. U nless ot her wise n ote d i n t he fl o w c hart, e ver y eff ort s h o ul d be ma de t o c ollect patie nt i nf or mati o n 
u ntil t he start of ne w a nti ne o plastic t hera p y, di sease pr o gressi o n, or d eat h, w hic he ver c o mes first.  
2 1 O nce a patie nt e x perie nces diseas e pr o gressi o n or starts a ne w a nti ne o pl astic t hera p y, t he p atie nt m o ves i nt o t he S ur vi val F o ll o w-u p 
P hase a n d s h o ul d be c o ntacte d b y tel e p h o ne e ver y 3 m o nt hs t o assess  f or s ur vi val stat us, de vel o p me nt of dr u g rel ate d S A Es a n d 
E CIs/ir A Es a n d t he start  of ne w a nti ne o plastic t h era p y if a p plica ble.  


 
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2 2 Rec or d all A Es occ urri n g wit hi n 3 0 da ys after t he last d os e of trial tr eat me nt or u ntil i nitiati o n of a ne w a nti ne o plasti c t hera p y, 
w hic he ver c o mes first. Re p ort all S A Es (relate d a n d u nrelate d t o trial tr eat me nt), E CIs /ir A Es occ urri n g wit hi n 9 0 da ys of t h e last 
d ose of trial treat me nt or  t he i nitiati o n of a ne w a nti ne o plastic t hera p y, w hic he ver c o m es first a n d w het her or n ot rel ate d t o 
pe m br oliz u ma b  ( M K-3 4 7 5) . After t his ti me, re p ort o nl y S A Es a n d E CIs /ir A Es t hat are c o nsi dere d relate d t o trial treat me nt.  
2 3 T he st u d y staff will c o m plete a me dical hist or y re vie w wit h t he p atie nt.  T his will i ncl u de d oc u me ntati o n of N S C L C Dise ase Details.  
2 4 Pe m br oliz u ma b a d mi nistere d be y o n d 1 2 m o nt hs ma y b e gi v e n per i nstit uti o nal sta n dar d f or N S C L C. Treat me nt, visit assess me nts 
a n d t u m or assess me nts s hall c o nti n ue o n a p pr o xi matel y t he sa me sc h e d ul e as pri or c ycles. Data ca pt ure d be y o n d 1 2 m o nt hs will be 
li mite d t o S A Es, disease stat us a n d o verall s ur vi val.  
 
 
 


 
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Ta ble 3. La b orat or y Tests  
 
He m at ol o g y  
C he mistr y  
Uri n al ysis  
Ot her  
He mat ocrit  
Al b u mi n  
Bl o o d  
Ser u m β -h u ma n c h ori o nic g o na d otr o pi n †  
He m o gl o bi n  
Al kali ne p h os p hatase  
Gl uc ose  
  ( β-h C G) †  
Platelet c o u nt  
Ala ni ne a mi n otra nsferase ( A L T)  
Pr otei n  
P T (I N R)  
W B C (t otal a n d differe ntial)  
As partate a mi n otra nsferase ( A S T)  
S pecific gra vit y  
a P T T  
Re d Bl o o d Cell C o u nt  
 
Micr osc o pic e xa m (If a b n or m al)  
T otal t hrii o d ot h yr o ni ne ( T 3)  
A bs ol ute Ne utr o p hil C o u nt  
Car b o n Di o xi de ‡  
res ults are n ote d 
Free t yr o xi ne ( T 4)  
 
  ( C O2 or bi oc ar b o n ate)  
Uri ne pre g na nc y test †  
T h yr oi d sti m ulati n g h or m o ne ( T S H)  
 
Uric Aci d  
 
 
 
Calci u m  
 
 
 
C hl ori de  
 
 
 
Gl uc ose  
 
  
 
 
 
  
 
P otassi u m   
 
  
 
S o di u m  
 
  
 
 
 
  
 
T otal Bilir u bi n  
 
  
 
Direct Bilir u bi n (If t ot al bilir u bi n is 
elev ate d a b ove t he u p per li mit of 
n or m al)  
 
 
 
T otal pr otei n  
 
 
 
Bl o o d Urea Nitr o ge n  
 
 
† P erf or m o n w o me n of c hil d beari n g p ote ntial o nl y. If uri ne pre g na nc y res ults ca n n ot be c o nfir me d as ne gati ve, a ser u m pre g na nc y test will be re q uire d.   
‡ If c o nsi dere d sta n dar d of care i n y o ur re gi o n.  
 
La b orat or y tests f or scree ni n g or e ntr y i nt o t he Sec o n d C o urse P hase s h o ul d be perf or me d wit hi n 1 0 da ys pri or t o t he first d os e of 
treat me nt.  After C ycle 1, pre-d ose la b orat or y pr oce d ures ca n be c o n d ucte d u p t o 7 2 h o urs pri or t o d osi n g.  Res ults m ust be re vie we d 
b y t he i n vesti gat or or q ua lifie d desi g n ee a n d f o u n d t o be acce pta ble pri or t o eac h d ose of trial treat me nt


 
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1 0.  T R E A T M E N T P L A N  
1 0. 1.  
T RI A L T R E A T M E N T S  
T he treat me nt t o be us e d i n t his trial is o utli ne d bel o w i n Ta ble 4.  
Ta ble 4. Trial Tr eat me nt  
Dr u g  
D ose/ P ote nc
y  
D ose 
Fre q ue nc y  
R o ute of 
A d mi nistr ati o
n  
Re gi me n/ Tre at me n
t Peri o d 
Use  
Pe m br oliz u m a b 
( M K-3 4 7 5)  
2 0 0 m g  
Q 3 W  
I V i nf usi o n 
Da y 1 of eac h c ycle  
E x peri me ntal  
C ar b o pl ati n  
A U C 6  
Q 3 W  
I V i nf usi o n 
Da y 1 of eac h c ycle  
Sta n dar d 
c he m ot hera p
y  
P aclit a xel  
2 0 0 m g/ m 2  
Q 3 W  
I V i nf usi o n 
Da y 1 of eac h c ycle  
Sta n dar d 
c he m ot hera p
y  
Pe metre xe d  
5 0 0 m g/ m 2  
Q 3 W  
I V i nf usi o n 
Da y 1 of eac h c ycle  
Sta n dar d 
c he m ot hera p
y  
T he pe m br oliz u ma b ( M K -3 4 7 5)  d osi n g i nter val ma y be i ncr ease d d ue t o t o xicit y.  
 
Trial treat me nt s h o ul d b e gi n o n t he da y of ra n d o mizati o n or as cl ose as p ossi ble t o t he date o n 
w hic h treat me nt is all ocate d/assi g ne d.  
 
Ar m A  
 
F or S q u a m o us C arci n o m a  
 
C ar b o pl ati n A U C = 6 I V da y 1 e ver y 2 1 -da ys f or u p t o 4 c ycles.  
 
P aclit a xel 2 0 0 m g/ m 2 I V da y 1 e ver y 2 1-da ys f or u p t o 4 c ycl es  
 
Or  
 
F or N o n -s q u a m o us C arci n o m a  
 
C ar b o pl ati n  A U C = 6 I V da y 1 e ver y 2 1 -da ys f or u p t o 4 c ycles  
 
Pe metre x e d  5 0 0 m g/ m 2 I V da y 1 e ver y 2 1-da ys f or u p t o 4 c ycles.  
 
Patie nts wit h pr o gressi ve disease ( P D) b y R E CI S T 1. 1 after c ycl e 2 or c ycle 4 will be all o we d 
t o tra nsiti o n t o pe m br oliz u ma b ( M K -3 4 7 5)  2 0 0 m g I V e ver y 2 1 -da ys f or u p t o 2 4 m o nt hs .  
 


 
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Patie nts wit h c o m plete res p o nse ( C R), partial res p o nse ( P R) or sta ble diseas e ( S D) b y R E CI S T 
1. 1 criteria after c ycle 4 will be treate d wit h pe m br oliz u ma b ( M K -3 4 7 5)  2 0 0 m g I V e ver y 2 1 -
d a ys f or u p t o 2 4 m o nt hs . 
 
 
A R M B  
 
Pe m b r oliz u m a b ( M K -3 4 7 5)  2 0 0 m g I V e ver y 2 1 -da ys f or u p t o 4 c ycles  
 
Patie nts wit h C R, P R or S D b y ir R C will t he n be treate d wit h:  
 
F or S q u a m o us C arci n o m a  
 
C ar b o pl ati n A U C = 6 I V da y 1 e ver y 2 1 -da ys f or u p t o 4 c ycles.  
 
P aclit a xel 2 0 0 m g/ m 2 I V da y 1 e ver y 2 1-da ys f or u p t o 4 c ycl es  
 
Or  
 
F or N o n -s q u a m o us C arci n o m a 
 
C ar b o pl ati n  A U C = 6 I V da y 1 e ver y 2 1 -da ys f or u p t o 4 c ycles  
 
Pe metre x e d  5 0 0 m g/ m 2 I V da y 1 e ver y 2 1-da ys f or u p t o 4 c ycles.  
 
Patie nts wit h P D b y R E CI S T 1. 1 after c ycle 6 or c ycl e 8 will be all o we d t o tra nsiti o n bac k t o 
pe m br oliz u ma b ( M K -3 4 7 5)  2 0 0 m g I V e ver y 2 1 -da ys f or u p t o 2 4 m o nt hs , at t he i n v esti gat or’s 
discreti o n.  
 
Patie nts wit h c o m plete res p o nse ( C R), partial res p o nse ( P R) or sta ble diseas e ( S D) b y R E CI S T 
1. 1 criteria after c ycl e 8 will t he n be treat e d wit h pe m br oliz u ma b ( M K -3 4 7 5)  2 0 0 m g I V e ver y 
2 1 -da ys f or u p t o 2 4 m o nt hs .  
 
 
1 0. 2.  
D O S E S E L E C TI O N A N D P R E P A R A TI O N  
T he rat i o nale f or sel ecti o n of d oses t o be use d i n t his trial is pr o vi de d i n –  Bac k gr o u n d a n d 
Rati o nale.   
 
T he s pecific i nstr ucti o ns f or pe m br oliz u ma b ( M K -3 4 7 5)  d ose cal c ulati o n, rec o nstit uti o n, 
pre parati o n of t he i nf usi o n fl ui d, a n d a d mi nistrati o n are i ncl u de d i n t he P har mac y Ma n u al.  
 
Car b o plati n, pe metre x e d a n d paclita xel will be pre pare d a n d a d mi nistere d as per t he a p pr o ve d 
pr o d uct la bel.  
 
1 0. 2. 1.  
Ti mi n g of D ose A d mi nistr ati o n  


 
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Trial treat me nt s h o ul d be a d mi nistere d o n Da y 1 of eac h c ycle after all pr oce d ures/assess m e nts 
ha ve bee n c o m plete d as detaile d o n t he Sc he d ule of Assess me nts ( Secti o n 9 ).  Trial treat me nt 
ma y b e a d mi nistere d u p t o 3 da ys b ef ore or after t he sc he d ule d Da y 1 of eac h c ycle d u e t o 
a d mi nistrati ve reas o ns.  
 
All trial treat me nts will be a d mi nistere d o n a n o ut patie nt basis.  
 
1 0. 2. 2.  
P e m b r oliz u m a b ( M K -3 4 7 5)  
 
P e m br oliz u ma b ( M K -3 4 7 5)  will be a d mi nistere d as a n a p pr o xi matel y  3 0 mi n ute I V i nf usi o n  
per i nstit uti o nal sta n dar d  (treat me nt c ycle i nter vals ma y be i ncreas e d d ue to t o xicit y). Sites 
s h o ul d ma ke e ver y eff ort t o tar get i nf usi o n ti mi n g t o be as cl ose t o 3 0 mi n utes as p ossi ble.   
T he s pecific g ui d a nce  f or pe m br oliz u ma b ( M K -3 4 7 5)  d ose calc ulati o n, rec o nstit uti o n, 
pre parati o n of t he i nf usi o n fl ui d, a n d a d mi nistrati o n are i ncl u de d i n t he P har mac y Ma n u al. 
 
1 0. 2. 3.  
C ar b o pl ati n  
 
C alc ul ati o n of C ar b o pl ati n D ose  
Car b o plati n D ose will be base d o n t he Cal vert F or m ula  
Car b o plati n d ose ( m g) = A U C of 6  x ( G F R + 2 5)  
G F R is esti mate d usi n g t he C oc kr oft -Ga ult f or m ula f or creati ni ne cl eara nce:  
( 1 4 0-patie nt’s a ge) x ( patie nt’s wei g ht i n kil o gra ms)  
 
7 2 x patie nt’s ser u m creati ni ne  
* F or fe males, m ulti pl y t h e res ult b y 0. 8 5  
 
Act ual  b o d y wei g ht , n ot i deal b o d y wei g ht will be use d. T his val ue will s u bstit ute f or G F R i n 
t he Cal vert f or m ula a b o v e.  
 
Use  t he ser u m Cr val ue re p orte d b y t he la b orat or y; d o n ot a p pl y a n y c orrecti o n fact ors t o t he 
re p orte d v al ue.  
 
T he ma xi m u m Cr Cl t hat ca n b e use d i n t his calc ulati o n f or b ot h w o me n a n d me n is 1 2 5 
m L/ mi n.  
 
I n t he case of l o w creati ni ne val ues res ulti n g i n hi gh Cr Cl val ues t hat see m t o o veresti mate 
re nal f u n cti o n, a 2 4-h o ur uri ne c ollecti o n f or deter mi nati o n of Cr Cl is rec o m me n de d.  
 
 
1 0. 2. 4.  
P aclit a xel  
 
F or all c o urses w here paclita x el is t o be a d mi nistere d, it is rec o m me n de d t hat a pre parati ve 
re gi me n be e m pl o ye d o n e h o ur pri or t o t he treat me nt re gi me n o n t hat da y t o re d u ce t he ris k 
ass ociate d wit h h y p erse nsiti vit y reacti o n. T his re gi me n s h o ul d i ncl u de a  sta n dar d d ose of 


 
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de x a met has o ne (eit her I V or P O), a n a nti hista mi ne H 1 ( di p he n h y dra mi ne 2 5 –  5 0 m g I V or 
orall y, or e q ui vale nt of alter nate H 1 bl o c ker), a n d a sta n dar d d os e of a nti -hista mi ne H 2 (s uc h 
as ci meti di ne, ra niti di ne, or fa m oti di ne).  T he s pecific  re gi me n use d ma y be per i nstit uti o nal 
sta n dar d. 
Paclita x el will be i nf use d o ver 3 h o urs. D ue t o ris k of i m me diate h y p erse nsiti vit y reacti o n, 
paclita x el s h o ul d be i nf use d pri or t o car b o plati n. Car b o plati n will be a d mi nistere d as a 3 0 
mi n ute i nf usi o n f oll o wi n g paclita x el a d mi nistrati o n.  
1 0. 2. 5.  
P e metre x e d  
 
Pe met re x e d pre me dicati o ns ma y b e use d as p er i nstit uti o nal sta n dar d. T he f oll o wi n g g ui deli nes 
ma y b e c o nsi dere d.  
 F olic aci d: Start a l o w -d ose oral f olic aci d pre parati o n or m ulti vita mi n wit h f olic aci d at 
least 1 wee k bef ore t he first pe metre x e d d ose a n d c o nti nue f or 2 1 da ys aft er t he last d os e 
of pe metre x e d.  
 Vita mi n B 1 2: vita mi n B 1 2 1 0 0 0 mc g I M i njecti o n. A vita mi n B 1 2 i njecti o n m ust be 
a d mi nistere d at least 1 wee k bef ore t he i nitial pe metre x e d d ose a n d re peate d e ver y 3 c ycl es 
w hile o n pe metre x e d.  
 De x a met has o ne: De x a met has o ne ( 4 m g orall y or e q ui vale nt) s h o ul d be a d mi nistere d BI D 
dail y t he da y bef ore, d a y of, a n d t he d a y after eac h d ose of p e metre x e d f or a t otal of 6 
d oses/c ycle.  
1 1.  D A T A A N D S P E CI M E N S U B MI S SI O N , T RI A L P R O C E D U R E S  
1 1. 1.  
 D A T A C O L L E C TI O N A N D S U B MI S SI O N  
D ata c ollecti o n f or t his st u d y will be d o ne t hr o u g h t h e 
Me di data Ra ve cli nical dat a 
ma na ge me nt s yst e m. Access t o t he trial i n Ra ve is gra nte d t hr o u g h t he i Me di data a p plicati o n 
t o all pers o ns wit h t he a p pr o priate r oles assi g n e d i n A F T C T M S S yste m.   
1 2.  B I O S P E CIM E N  C O L L E C TI O N , S HI P PI N G A N D P R O C E S SI N G   
T u m or tiss ue fr o m an arc hi val sa m ple or ne wl y o btai ne d f or mali n fi x e d bi o ps y of a t u m or 
lesi o n n ot pre vi o usl y irra diate d m ust  be c ollecte d f or i nte grate d c orrelati ve P D -L 1 bi o mar ker 
a nal ysis.  A fi ne nee dle as pirate or c yt ol o gic s peci me n will n ot be acce pte d. Nee dle or 
e x cisi o nal bi o psies, or resecte d tiss ue is re q uir e d.  N o s yste mic a nti ne o plastic t hera p y ma y be 
a d mi nistere d be t wee n t his bi o ps y a n d i nitiati n g st u d y me dicati o n. O nl y p atie nts wit h a n 
a de q uate tiss ue bi o ps y s u b missi o n are eli gi ble f or e nr oll me nt.  
 T he A F T Bi or e p osit or y at Was hi n gt o n U ni versit y is t he ce ntral la b orat or y t o recei v e 
t hese sa m ples. 
 
 
 
 
 




 
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Bi os peci me n S hi p pi n g  
Bi os peci me n s hi p pi n g kits will be a vaila ble f or c ollecti n g a n d s hi p pi n g bi os peci me ns at 
baseli ne a n d C 4 a n d C 8  collecti o n ti me p oi nts. Bi os peci me n c ollecti o n a n d s hi p pi n g kits ma y 
be or dere d t hr o u g h t he A F T. Bi o M S s yst e m.  A kit f or eac h ti me p oi nt m ust be re q ueste d 
i n de pe n de ntl y.   Kits will be s hi p pe d t o sites wit hi n 1 0 w or ki n g d a ys of re q uest.  Si nce t he 
s hi p pi n g kits c o ntai n s pecializ e d c o m p o ne nts nee de d f or tiss ue a n d bl o o d c ollecti o n, please 
ma ke certai n a kit h as b ee n or dere d at least 1 0 d a ys pri or t o  patie nt re gistrati o n.  Als o, n ot e 
t hat si nce s o me kit c o m p o ne nt e x pire, kits s h o ul d n ot be or dere d m ore t h a n 9 0 da ys pri or t o a n 
a ntici pate d c ollecti o n.  N o m ore t ha n t hree s hi p pi n g kits will be se nt per re q uest.  
 
Alt h o u g h bi os peci me ns ma y b e s hi p pe d  i n batc hes , n ote t hat: 
1.  Sli des of t he bi o ps y l esi o n f or P D -L 1 bi o mar ker a nal ysis M U S T  be recei ve d bef ore 
t he patie nt ca n be re gistere d t o t he t hera pe utic trial. 
2.  W h ole bl o o d c ollecte d i n E D T A t u bes m ust be s hi p pe d wit hi n 2 4 h o urs of c ollecti o n.  
3.  W h ole bl o o d c oll ecte d i n B C T t u bes m ust be s hi p pe d wit hi n 7 2 h o urs of c ollecti o n.  
 
All s u b mitte d bi os peci me ns m ust be p h ysicall y la bele d wit h t he A F T patie nt n u m ber, patie nt’s 
i nitials a n d date of s peci me n c ollecte d.  A c o p y of t he S hi p me nt Pac ki n g Sli p pr o d uce d b y 
Bi o M S m ust be pri nte d a n d place d i n t he s hi p me nt wit h t he s peci me ns.  A pri nte d, de -i de ntifie d 
c o p y of t he i nstit uti o nal s ur gic al pat h ol o g y re p ort c orres p o n di n g t o t he tiss ue / sli des t hat are 
bei n g s u b mitte d s h o ul d als o be i ncl u de d wit h t he s hi p me nt.  Please be s ure t o use a met h o d of 
s hi p pi n g t hat is sec ure a n d tracea bl e.  S hi p s peci me ns o n M o n da y t hr o u g h T h urs da y o nl y . 
S hi p pi n g b y o v er ni g ht ser vice t o ass ur e recei pt is re q uire d. D o n ot s hi p s peci me ns o n Fri da ys 
or Sat ur da ys.  All s peci m e ns s h o ul d be se nt t o t h e f oll o wi n g a d dress:  
 
A F T Bi ore p osit or y at Was hi n gt o n U ni versit y  
c/ o Site ma n Ca ncer Ce nt er Tiss ue Pr oc ure me nt C ore  
4 2 5 S. E ucli d A ve.  
BJ CI H B uil di n g,  R o o m 5 1 2 0  
St. L o uis, M O 6 3 1 1 0 -1 0 0 5  
 
 
 
A d diti o nal Res o urce I nf or mati o n:  
 
Bi o M S. A F T Res o urce Site: 
 
 
Bi o M S. A F T Us er ma n ual: 
 
 
 
 
 
 
 


 
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1 2. 1. 3.  
Bi os peci me n c ollecti o n  
 
Scree ni n g/ E nr oll me nt  
T he f oll o wi n g bi os peci me ns will be c ollecte d at scree ni n g:  
 
A.  M A N D A T O R Y - Sli des f or P D -L 1 st ai ni n g.  Fi ve ( 5), f o ur micr o n, u nstai ne d t u m or tiss ue 
secti o ns fr o m a f or mali n fi x e d / paraffi n e m be d de d tiss ue bl oc k c o ntai ni n g t u m or lesi o n s h o ul d 
be c ut a n d m o u nte d o nt o c har ge d sli des.  Sli des s h o ul d be la bele d wit h t he patie nt st u d y I D, 
i nstit uti o nal s ur gical pat h ol o g y n u m ber, a n d seri al c ut n u m ber, i.e. 1-5.   Pl ease n ote s p ecific 
i nstr ucti o ns f or sli des t o be c ut f or P D-L 1 stai ni n g.  Please use t he sli des i n cl u de d wit h t he kit 
a n d f oll o w t he i nstr ucti o ns pr o vi de d f o r c utti n g a n d pac ka gi n g t hese sli des f or s hi p me nt.  
 
B .  Sli des f or c orrel ati ve ge n o mic st u dies .  If tiss ue is a vaila ble, a n a d diti o nal set of fi ve 
u nstai ne d, ei g ht micr o n t u m or tiss ue secti o ns fr o m t he sa me f or mali n fi x e d / paraffi n 
e m be d de d tiss ue bl oc k use d f or P D -L 1 stai ni n g s h o ul d be c ut a n d m o u nte d o nt o plai n  sli des.  
T hese sli des ca n be c ut s eriall y after t he ma n dat or y sli des ( A).  Sli des s h o ul d be la bele d wit h 
t he patie nt st u d y I D, i nstit uti o nal s ur gical p at h ol o g y n u m ber, a n d serial c ut n u m ber.  
 
If a n i nstit uti o n is u na ble or u n willi n g t o c ut t u m or sli des as o utli ne d a b o ve a n d it is per missi ble 
b y t he i nstit uti o n’s s ur gic al pat h ol o g y de p art me nt, a si n gle re prese ntati ve  t u m or bl oc k ma y b e 
s u b mitte d i nstea d of sli des.  T he t u m or bl oc k will be c ut at t he A F T Bi ore p osit or y f or 
c orrel ati ve scie nce st u dies a n d ret ur ne d t o t he i nstit uti o n at t he c o ncl usi o n of t he st u d y.   
 
C .  Ori gi n al t u m or tiss ue f or c orrel ati ve ge n o mic st u dies .    If s u b mitti n g tiss ue fr o m a 
rece ntl y rec urre nt or pr o gressi ve lesi o n, a n d an  a d diti o nal  t u m or tiss ue bl oc k fr o m t he pri mar y 
s ur gic al resecti o n is als o a vaila ble, a re prese ntati v e t u m or tiss ue bl o c k or  fi ve u nstai ne d, ei g ht 
micr o n t u m or tiss ue secti o ns m o u nte d o nt o plai n  sli des s h o ul d be s u b mitte d as well. Sli des 
s h o ul d be la bele d wit h t he patie nt st u d y I D, i nstit uti o nal s ur gical pat h ol o g y n u m ber, a n d serial 
c ut n u m ber.  
 
D.  W h ole bl o o d i n E D T A t u be.   C ollect 7 cc of w h ole bl o o d b y sta n dar d ve n o us p hle b ot o m y 
i nt o t he E D T A t u be pr o vi de d.  T u be s h o ul d be la bele d wit h patie nt st u d y n um ber, patie nt 
i nitials, a n d date / ti me of c ollecti o n.  After c ollecti o n i n vert t he t u be 1 0 ti mes t o e ns ure 
a de q uate mi xi n g a n d a ntic oa g ulati o n.  St ore t u be at r o o m te m perat ure u ntil rea d y f or s hi p me nt.  
 
E.  W h ole bl o o d i n B C T  ( Strec k) t u be.  C ollect 8  cc of w h ole bl o o d b y sta n dar d v e n o us 
p hle b ot o m y i nt o eac h of t he t w o  B C T ( Strec k) t u be pr o vi de d  ( 8cc per t u b e).  T u b e s h o ul d b e 
la bele d wit h patie nt st u d y n u m ber, p atie nt i nitials, a n d d ate / ti me of c ollecti o n.  After 
c ollecti o n i n vert t he t u b e s 1 0 ti mes t o e ns ure a de q uate mi xi n g a n d preser vati o n.  St ore t u be s 
at r o o m te m perat ur e u ntil rea d y f or s hi p me nt.  
 
1 2. 1. 4.  
S u bse q ue nt C yc les 
A.  W h ole bl o o d i n B C T ( Strec k) t u be t o be c ollecte d at C ycle 4 a n d C ycle 8 as per T a ble 
2.   C ollect 8 cc of w h ole bl o o d b y sta n d ar d ve n o us p hle b ot o m y i nt o eac h of t he t w o B C T 
( Strec k) t u bes pr o vi d e d ( 8cc p er t u b e).  T u be s h o ul d be la bele d wit h patie nt st u d y n u m ber, 
patie nt i nitials, a n d date / ti me of c ollecti o n.  After c ollecti o n i n vert t he t u bes 1 0 ti mes t o 


 
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e ns ure a de q u ate mi xi n g a n d preser vati o n.  St ore t u bes at r o o m te m perat ure u ntil rea d y f or 
s hi p me nt. 
 
1 2. 1. 5.  
Bi os peci me n Pr o cessi n g  
U p o n recei pt at t he A F T Bi ore p osit or y, bi os peci m e ns will be pr ocess e d as f oll o ws:  
 
A.  M A N D A T O R Y  - Sli des f or P D -L 1 st ai ni n g. O ne of 5 sli des s u b mitte d ( Sli de # 3) wi ll be 
stai ne d b y H/ E a n d re vi e we d b y a q u alifie d pat h ol o gist f or perce nta ge t u m or cell ularit y, 
perce nt a ge t otal cell ularit y, p erce nta ge n ecr osis, a n d perce nta ge l y m p h o c ytic i n vasi o n. If t he 
s u b mitte d s peci me n is dee me d i na de q uate, t he site ma y B E R E Q U E S T E D  t o res u b mit a ne w 
bi o ps y s p eci me n.  Sli des fr o m eac h patie nt will be batc he d s hi p pe d fr o m t he A F T bi ore p osit or y 
t o Q ual Te x La b orat ories f or P D-L 1 stai ni n g a n d ce ntral re vi e w. After stai ni n g a n d ce ntral 
re vie w, sli des will be ret ur ne d t o t he A F T bi ore p ositor y, a n d st ore d a n d i ma ge d f or f ut ure use.  
B.  A d diti o n al tiss ue sli des fr o m bi o ps y lesi o n a n d/ or i niti al t u m or di a g n osis.   All tiss ue 
recei v e d f or sec o n d ar y c orrelati ve ge n o mic st u dies will be re vi e we d f or t u m or tiss ue 
cell ularit y.  W here n ecessar y, area s of hi g h t u m or cell ularit y will be macr o dissecte d t o e nric h 
f or t u m or cells.  Tiss ue secti o ns or macr o dissect e d t u m or sli des will be use d f or D N A a n d 
R N A is olati o n a n d st ore d f or sec o n d ar y ge n o mic c orrelati ve st u dies.  
 
C. W h ole bl o o d i n E D T A t u be.   F oll o w i n g A F T Bi ore p osit or y S O Ps, w h ole bl o o d w hite cells 
(“ b uff y c o at”) will be is olate d a n d use d t o e xtract c o nstit uti o nal ( w hite bl o o d cell) ge n o mic 
D N A, w hic h will be st or e d f or sec o n dar y ge n o mic st u dies.  
 
D.  W h ole bl o o d i n cell st a biliz ati o n ( Strec k) t u be.   F oll o wi n g A F T Bi ore p osit or y S O Ps, 
plas ma will be is olate d fr o m all B C T t u bes b y hi g h s pee d ce ntrif u gati o n.  Res ulti n g plas ma 
sa m ples will be ali q u ote d a n d fr oze n i n 4. 5 ml ali q u ots, a n d s u bse q ue ntl y us e d f or cf D N A 
is olati o n a n d ge n o mic st u dies. 
 
1 2. 2.  
T U M O R I M A GI N G A N D C E N T R A L R E VI E W  
1 2. 2. 1.  
T u m or i m a gi n g sc he d ule  
 
T he i nitial t u m or i ma gi n g will be perf or me d wit hi n 3 0 da ys pri or t o t he first d ose of trial 
treat me nt. Sca ns perf or m e d as part of r o uti ne cli ni cal ma na ge me nt are acce pta ble f or use as 
t he scree ni n g s ca n if the y are of di a g n ostic q ualit y a n d perf or me d wit hi n 3 0 da ys pri or t o t he 
first d ose of trial treat me nt. O n-st u d y i ma gi n g d uri n g t he first 8 c yclers of t hera p y will be 
perf or me d e ver y 6 wee ks ( 4 2 ± 7 da ys) after t he first d ose of trial treat me nt or m ore 
fre que ntl y if cli nic all y i n dicate d. Patie nts  o n all 2 ar ms recei vi n g p e m br oliz u ma b ( M K -3 4 7 5)  
al o ne after c ycl e 8 will be i ma ge d e v er y 9 wee ks ( 6 3 ± 7 da ys) T he ti mi n g f or i ma gi n g 
st u dies s h o ul d f oll o w cale n dar da ys a n d s h o ul d n ot be a dj uste d f or del a ys i n c ycle starts or 
e xte nsi o n of pe m br oliz u ma b ( M K -3 4 7 5)  c ycle fre q ue ncies. T he sa me i ma gi n g tec h ni q u e 
s h o ul d be use d i n a patie nt  t hr o u g h o ut t he trial. L ocal rea di n g (i n vesti gat or assess me nt wit h 
site ra di ol o g y rea di n g) will be use d t o deter mi ne eli gi bilit y a n d f or patie nt  ma na ge me nt.  
 
1 2. 2. 2.  
I m a gi n g c ore l a b Ce ntr al Re vie w  
 


 
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Sca ns will be s u b mitte d t o t he I m a gi n g C ore La b (I C L) at O hi o State U ni versit y f or ce ntr al 
re view wit hi n 3 da ys of i ma gi n g ac q uisiti o n.  
 
T he c o m plete C T sca ns will be s u b mitte d t o t he I ma gi n g C ore La b o rat or y i n di gital DI C O M 
f or mat; B M P files, J P G files, or h ar d c o pies (fil ms) are n ot ac ce pt a ble.  
 
T he e ntire i ma gi n g data i n DI C O M f or mat m ust be s u b mitte d t o t he I C L wit hi n n o m ore t ha n 
3 0 b usi ness d a ys o nce t he i ma ge ac q uisiti o n is c o m plete d at site.  
 
De -i de ntif y t he patie nt data usi n g i nstit uti o nal pr oce d ures t o r e m o ve patie nt na me a n d 
me dical rec or d n u m ber w hile preser vi n g t he p ati e nt I D n u m ber  a n d pr ot oc ol n u m ber of 
t he A F T trial. T h e de-i d e ntifie d di gital i ma ges ma y be b ur ne d t o a C D or tra nsferre d t o a P C 
bas e d s yste m f or f urt her electr o nic d ata tra nsfer p ur p oses.  
 
Data ca n be el ectr o nicall y tra nsferre d t o t he I m a gi n g C ore La b b y 1) We b Tr a nsfer; 2 ) F T P 
tr a nsf er: 
1.  We b Tr a nsf er:  
A n y P Cs wit h i nter net access a n d we b br o wser (e. g., I nt er net E x pl orer, M o zilla Firef o x) ca n 
be use d t o tra nsfer DI C O M i ma ges a n d ot her re q uire d files t o t he I C L t hr o u g h we bsite 
u pl oa d.i ma gi n gc orela b. c o m. T he sta n dar d 
We b Tra nsfer i nf or m ati o n 
will be pr o vi de d 
se parat el y t hr o u g h t he s p ecific trial e-mail, per t h e re q uest b y p artici pati n g si tes bef ore t heir 
first data s u b missi o n. 
 
2.  F T P Tr a nsf er:  
A n y F T P s oft w are ca n b e use d t o i nitiate access t o t he sec ure F T P Ser ver of t he I C L. T he 
sta n dar d F T P access i nf or mati o n will be pr o vi de d se parat el y t hr o u g h t he s p ecific tri al e -mail, 
per t he re q uest b y partici pati n g sites bef ore t heir first data s u b missi o n.  
Se n d a n e -mail n otificati o n t o i nf or m t he I ma gi n g C ore La b at t he s pecifi c trial e mail of t he 
data s u b missi o n o nce t he d at a tr a nsfer is c o m plete d . 
 
3.  S hi p me nt/ M ail ( n ot preferre d b ut acce pte d):  
If t he a b o ve el ectr o nic data tra nsfers ca n n ot be ac hie ve d, t he de -i de ntifie d i ma ges i n DI C O M 
f or mat ca n b e b ur ne d t o a C D, la bele d wit h i nf o of patie nt I D, st u d y dat e, b aseli ne/f oll o w-u ps 
o n t he C D c o ver, a n d maile d t o t he I C L at:  
I ma gi n g C ore La b 
De part me nt of  Ra di ol o g y  
T he O hi o State U ni versit y Me dical Ce nter  
 
 
 
 
 
 
 


 
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A n y q uesti o ns or pr o ble ms a b o ut t he d at a tr a nsfer t o t he I m a gi n g C ore L a b, e m ail t he 
I C L at t he s pecific tri al e m ail A F T 0 9 @I m a gi n g C ore L a b.c o m, or c all t he I C L I T gr o u p 
at 
 f or hel p.  
1 3.  D O S E A N D T R E A T M E N T M
O DI FI C A TI O N S , C O N C O MI T A N T  M
E DI C A TI O N S , S U P P O R TI V E 
C A R E  
1 3. 1.  
D O S E M
O DI FI C A TI O N  
1 3. 1. 1.  
C he m ot her a p y  
 
Ge ner al g ui deli nes  
If m ore t ha n o n e of t he d ose m o dificati o ns a p pli es, use t h e m ost stri n ge nt (i.e., t he greatest 
d ose re d ucti o n).  
T he d ose le vels o utli ne d i n t he ta ble bel o w are use d f or d ose m o dificati o ns. If d os e re d u cti o n 
bel o w le vel -2 is re q uire d, disc o nti n ue t he dr u g ca usi n g t he t o xicit y a n d c o nti n ue t he ot her dr u g 
(s). If b ot h dr u gs re q uir e disc o nti n uati o n d ue t o t o xicit y, pat ie nts ma y b e all o we d t o tra nsiti o n 
t o or ret ur n t o treat me nt wit h pe m br oliz u ma b u p o n disc ussi o n wit h st u d y c hair/ A F T .  
Ta ble 5. D ose m o dificati o n g ui deli nes f or dr u g -relate d a d verse e v e nts (c he m ot hera p y).  
D ose Le vel  
Pe metre x e d  
Car b o plati n  
Paclita xel  
0  
5 0 0 m g/ m 2  
1 0 0 %  
2 0 0 m g/ m 2  
-1  
3 7 5 m g/ m 2  
7 5 %  
1 5 0 m g/ m 2  
-2  
2 5 0 m g/ m 2  
5 0 %  
1 0 0 m g/ m 2  
 
He m at ol o gic T o xicit y  
 
F or A N C < 1 5 0 0 or platelets < 1 0 0, 0 0 0 o n da y 1, dela y treat me nt wit h car b o plati n a n d 
pe metre x e d or paclita x el u ntil A N C ≥ 1 5 0 0 a n d platelets ≥ 1 0 0, 0 0 0, t he n res u me at t he 
pre vi o us d oses. If treat m e nt is dela ye d f or ≥ 3 wee ks, disc o nti n ue pr ot oc ol t hera p y.  
F or platelets < 2 5, 0 0 0, decreas e car b o plati n a n d pe metre x e d or paclita xel b y o ne d ose le vel 
f or all s u bse q ue nt d oses.  
F or fe brile ne utr o p e nia o cc urri n g at a n y ti me d uri n g a c ycle, decreas e car b o plati n a n d 
pe metre x e d or paclita x el b y o ne d os e le vel f or al l s u bse q ue nt d oses.  
F or a s ec o n d e pis o d e of t hr o m b oc yt o p e nia < 2 5, 0 0 0 or fe brile n e utr o pe nia, decrease 
car b o plati n a n d p e metre x e d or paclita xel b y o n e d ose le vel f or all s u bse q ue nt d oses.  
G astr oi ntesti n al T o xicit y  
 
 M uc ositis  
 
F or gra d e 3 or 4 m uc ositis des pite pr o p h yl actic vita mi n s u p ple me ntati o n, dela y car b o plati n 
a n d pe metre x e d u ntil t o xicit y res ol ves t o ≤ gra d e 2. W he n m uc ositis res ol ves t o ≤ gra d e 2, 


 
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res u me car b o pl ati n at t he pre vi o us d os e a n d pe m etre x e d wit h o ne l e vel d os e re d ucti o n f or all 
s u bse q uent c ycles. If treat me nt is dela ye d ≥ 3 wee ks, disc o nti n ue pr ot oc ol t hera p y.  
 
 
Di arr he a  
 
See S ecti o n 1 3 . 4 f or s u p p orti ve c are g ui deli nes if t he p atie nt is als o recei vi n g c o nc urre nt 
pe m br oliz u m a b ( M K -3 4 7 5) .  F or gr a d e 3 or 4 di arr hea des pite a nti diarr heal me dicati o n a n d 
pr o p h yla ctic vita mi n s u p ple me ntati o n, dela y car b o plati n a n d pe m etre x e d or paclita xel. O nce 
diarr hea res ol v es t o ≤ gra de 2, res u me t hera p y wit h car b o plati n at t h e pre vi o us d ose a n d o n e 
d ose le vel re d u cti o n of pe metre x e d or paclita xel f or all s u bse q ue nt c ycl es. If treat me nt is 
dela ye d f or ≥ 3 wee ks, disc o nti n ue all pr ot oc ol t hera p y.  
 
Ne p hr ot o xicit y  
 
If creati ni ne cleara nce is < 4 5 ml/ mi n, dela y car b o plati n a n d pe metre x e d. W he n Cr Cl i m pr o ves 
t o ≥ 4 5 ml/ mi n, res u me car b o plati n a n d pe metre x e d at t he pre vi o us d oses. If treat me nt is 
dela ye d/i nterr u pte d f or ≥ 3 wee ks, disc o nti n ue treat me nt wit h c he m ot hera p y .  
 
S ki n T o xicit y  
 
See S ecti o n Secti o n 1 3. 4  f or s u p p orti ve c are g ui deli nes if t he p atie nt is als o recei vi n g 
c o nc urre nt pe m br oliz u m a b ( M K -3 4 7 5) .  
 
Gr a de 3: H ol d car b o plati n a n d pe metre x e d or paclita xel u ntil t o xicit y i m pr o ves t o ≤ gra de 1, 
t he n res u me car b o plati n at t he pre vi o us d ose le vel a n d pe metre x e d or paclita xel wit h o ne d ose 
le vel re d ucti o n. If c he m ot hera p y is hel d f or s ki n t o xicit y f or > 3 wee ks, disco nti n ue pr ot oc ol 
t hera p y.  
 
P ul m o n ar y T o xicit y  
 
See Secti o n 1 3. 4  f or s u p p orti ve c are g ui deli nes if t he p atie nt is als o recei vi n g c o nc urre nt 
pe m br oliz u m a b ( M K -3 4 7 5) . 
 
If a patie nt is recei vi n g c he m ot hera p y al o ne (ar m A or ar m B): Pe metre x e d a n d paclita xel ma y 
rarel y ca use p ul m o nar y t o xicit y c haract erize d b y d ys p nea a n d i nterstitial p ne u m o nitis. T he 
p ne u m o nitis will us uall y res p o n d t o ster oi ds. Ot her ca us es of d ys p nea s h o ul d be e x cl u de d (i.e. 
a ne mia, car di ac, C O P D e x acer bati o n, etc) bef ore c o ncl u di n g t hat p ul m o nar y t o xicit y is 
c he m ot hera p y relate d.  
 
F or gra d e 2 p ul m o nar y t o xicit y d ue t o paclita xel or pe metre x e d, h ol d pr ot oc ol treat me nt. 
Patie nts ma y be retr eate d wit h a t w o le vel d ose re d ucti o n i n pe metre x e d or paclit a x el o n t he 
ne xt a n d all s u bse q ue nt c ycles at t he p h ysici a n’s discreti o n if p ul m o nar y s y m pt o ms i m pr o ve 
t o gra d e 0-1 wit hi n 3 wee ks.  
 
F or gra de 3 or 4 p ul m o nar y t o xicit y, disc o nti n ue c he m ot hera p y.  
 


 
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H y perse nsiti vit y Re acti o ns  
 
See Secti o n 1 3. 4  f or s u p p orti ve c are g ui deli nes if t he p atie nt is als o recei vi n g c o nc urre nt 
pe m br oliz u m a b ( M K -3 4 7 5) . 
 
F or gra d e 3 aller gic or a na p h yl a xis reacti o ns t h o u g ht t o be d ue t o car b o plati n or paclita xel, 
disc o nti n ue treat me nt wit h c he m ot hera p y.  
 
Ot her N o n -He m at ol o gi c  
 
Gr a de 3 t o xicit y ( n ot descri be d a b o ve). Dela y all dr u gs u ntil t o xicit y i m pr o ves t o ≤ gra d e 2, 
t he n res u me treat me nt wit h o ne d ose le vel re d ucti o n f or eac h a ge nt. If tr eat me nt is dela ye d f or 
> 3 wee ks, disc o nti n ue c he m ot hera p y.  
 
Gr a de 4 t o xicit y ( n ot descri be d a b o v e). Disc o nti n ue all c he m ot hera py.  
1 3. 2.  
P E M B R O LI Z U M A B (M K -3 4 7 5 ) 
A d verse e ve nts ( b ot h n o n -seri o us a n d seri o us) ass ociate d wit h pe m br oliz u ma b ( M K-3 4 7 5)  
e x p os ure ma y re prese nt a n i m m u n ol o gic eti ol o g y.  T hese a d v erse e ve nts ma y occ ur s h ortl y 
after t he first d ose or se v eral m o nt hs after t he last d ose of treat me nt. Pe m br oliz u ma b ( M K-
3 4 7 5) m ust be wit h hel d f or dr u g -relate d t o xicities a n d se vere or life-t hreate ni n g A Es as p er 
Ta bles 6 a n d 7 bel o w. See Secti o n 1 3 . 4 f or s u p p orti ve care g ui d eli nes, i ncl u di n g use of 
c ortic oster oi ds.  
 
Pe m br oliz u ma b ( M K -3 4 7 5)  will be wit h hel d f or dr u g -relat e d Gra de 4 he mat ol o gic t o xicities, 
n o n -he mat ol o gi cal t o xicit y ≥ Gra de 3 i ncl u di n g la b orat or y a b n or malities, a n d se vere or life -
t hreate ni n g A Es as p er Ta bles 6 a n d 7 bel o w.  
Ta ble 6 . D ose m o dificati o n g ui deli nes f or dr u g -relate d he mat ol o gic a d verse e ve nts 
(pe m br oliz u ma b ( M K -3 4 7 5) ). 
T o xicit y  
Gr a de  
H ol d 
Tre at me nt 
( Y/ N) 
Ti mi n g f or 
rest arti n g 
tre at me nt 
D ose/ Sc he d ule 
f or rest arti n g 
tre at me nt 
Disc o nti n ue 
P atie nt  ( after 
c o ns ult ati o n 
wit h S p o ns or)  
He mat ol o gical 
T o xicit y  
 
1, 2  
N o  
N/ A  
N/ A  
N/ A  
3 *  
* E xcl u di n g 
Gra d e 3 
ne utr o pe nia, 
a ne mia, a n d 
t hr o m b oc yt o pe nia 
Yes  
T o xicit y 
res ol ves t o 
Gra de 0 -1 or 
baseli ne  
Ma y i ncrease 
t he d osi n g 
i nter val b y 1 
wee k  
T o xicit y d oes 
n ot res ol ve 
wit hi n 1 2 
wee ks of last 
i nf usi o n 
Per m a ne nt 
disc o nti n u ati o n 
s h o ul d be 
c o nsi dere d f or 
a ny severe or 
life-t hre ate ni n g 
eve nt 
4  
Yes  
T o xicit y 
res ol ves t o 
Gra de 0 -1 or 
baseli ne  
Ma y i ncrease 
t he d osi n g 
i nter val b y 1 
wee k  
 
 


 
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Ta ble 7 . D ose m o dificati o n g ui deli nes f or dr u g -relate d a d verse e v e nts 
 
T o xicit y  
H ol d 
Tre at me n
t F or 
Gr a de  
Ti mi n g f or Rest arti n g Tre at me nt  
Disc o nti n ue S u bject  
Di arr he a/ C oliti
s 
2 -3  
 
T o xicit y res ol ves t o Gr a de 0 -1.  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose  
or i n a bilit y t o re d uce c ortic oster oi d t o 1 0 m g or less of 
pre d nis o ne or e q ui v ale nt pe r d a y wit hi n 1 2 w ee ks.  
4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
A S T, A L T, or 
I ncre ase d 
Bilir u bi n  
2  
T o xicit y res ol ves t o Gr a de 0 -1  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose.  
3 -4  
Per m a ne ntl y disc o nti n ue  
(see e xce pti o n bel o w)1  
Per m a ne ntl y disc o nti n ue  
T y pe 1 
di a betes 
mellit us (if ne w 
o nset) or 
H y per gl yce mi a  
T 1 D M or  
3 -4  
H ol d pe m br oliz u m a b ( M K -3 4 7 5)  
f or ne w o nset T y pe 1 di a betes 
mellit us or Gr a de 3 -4 
h y per gl yce mi a ass oci ate d wit h 
e vi de nce of bet a cell f ail ure.  
 
Res u me pe m br oliz u m a b ( M K -3 4 7 5)  w he n p atie nts are 
cli nic all y a n d met a b ol ic all y st a ble. 
H y p o p h ysitis  
2 -3  
T o xicit y res ol ves t o Gr a de 0 -1  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose  
or i n a bilit y t o re d uce c ortic oster oi d t o 1 0 m g or less of 
pre d nis o ne or e q ui v ale nt pe r d a y wit hi n 1 2 w ee ks.  
4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
H y pert h yr oi dis
m  
3  
T o xicit y res ol ves t o Gr a de 0 -1  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose  
or i n a bilit y t o re d uce c ortic oster oi d t o 1 0 m g or less of 
pre d nis o ne or e q ui v ale nt pe r d a y wit hi n 1 2 w ee ks.  
4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
H y p ot h yr oi dis
m  
2 -4  
T her a p y wit h pe m br oliz u m a b 
( M K-3 4 7 5)  c a n be c o nti n ue d 
w hile tre at me nt f or t he t h yr oi d 
dis or der is i nstit ute d  
T her a p y wit h pe m br oliz u m a b ( M K -3 4 7 5)  c a n be 
c o nti n ue d w hile tre at me nt f or t he t h yr oi d dis or der is 
i nstit ute d. 
I nf usi o n 
Re a cti o n  
3 -4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
P ne u m o nitis  
2  
T o xicit y res ol ves t o Gr a de 0 -1  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose 
or i n a bilit y t o re d uce c ortic oster oi d t o 1 0 m g or less of 
pre d nis o ne or e q ui v ale nt pe r d a y wit hi n 1 2 w ee ks.  
3 -4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
Re n al F ail ure 
or Ne p hritis  
2  
T o xicit y res ol ves t o Gr a de 0 -1  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose 
or i n a bilit y t o re d uce c ortic oster oi d t o 1 0 m g or less of 
pre d nis o ne or e q ui v ale nt pe r d a y wit hi n 1 2 w ee ks.  
3 -4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
All Ot her 
Dr u g -Rel ate d 
T o xicit y 2 
3  or 
Se vere  
T o xicit y res ol ves t o Gr a de 0 -1  
T o xicit y d oes n ot res ol ve wit hi n 1 2 w ee ks of l ast d ose 
or i n a bilit y t o re d uce c ortic oster oi d t o 1 0 m g or less of 
pre d nis o ne or e q ui v ale nt pe r d a y wit hi n 1 2 w ee ks.  
4  
Per m a ne ntl y disc o nti n ue  
Per m a ne ntl y disc o nti n ue  
N ote: Per m a ne ntl y disc o nti n ue f or a n y se v ere or Gr a de 3 dr u g -rel ate d A E t h at rec urs or a n y life -t hre ate ni n g e v e nt. 
1 F or p atie nts wit h li ver met ast asis w h o be gi n tre at me nt wit h Gr a de 2 A S T or A L T, if A S T or A L T i ncre ases b y g re ater 
t h a n or e q u al t o 5 0 % rel ati ve t o b aseli ne a n d l asts f or at le ast 1 w ee k t he n p atie nts s h o ul d be disc o nti n ue d. 
2 P atie nts wit h i nt oler a ble o r persiste nt Gr a de 2 dr u g -rel ate d A E m a y h ol d st u d y me dic ati o n at p h ysici a n discreti o n.  
Per m a ne ntl y disc o nti n ue st u d y dr u g f or persiste nt Gr a de 2 a d verse re acti o ns f or w hic h tre at me nt wit h st u d y dr u g h as 
bee n hel d, t h at d o n ot rec o ver t o Gr a de 0 -1 wit hi n 1 2 w ee ks of t he l ast d ose.   


 
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I n case t o xicit y d oes n ot res ol ve t o Gra de 0-1 wit hi n 1 2 wee ks after last i nf usi o n, trial treat me nt 
s h o ul d be disc o nti n ue d after c o ns ultati o n wit h t he St u d y PI .  Wit h i n vesti gat or a n d St u d y PI 
a gree m e nt, patie nts  wit h a la b orat or y a d verse e ve nt still at Gr a d e 2 aft er 1 2 wee ks ma y 
c o nti n ue treat me nt i n t he trial o nl y if as y m pt o mati c a n d c o ntr olle d.  
 
Patie nts  w h o e x perie nce a rec urre nce of t he s a me se vere or life -t hreat e ni n g e ve nt at t he s a me 
gra de or greater wit h re -c halle n ge of pe m br oliz u ma b ( M K -3 4 7 5)  s h o ul d b e disc o nti n ue d fr o m 
trial treat me nt. 
 
D osi n g i nterr u pti o ns are per mitte d i n t he case of me dical / s ur gical e ve nts or l o gistical 
reas o ns  n ot rel ate d t o st u d y t hera p y (e. g., electi ve s ur ger y, u nrelate d me dical e ve nts, patie nt 
vacati o n, a n d/ or h oli d a ys). S u bjects s h o ul d be place d bac k o n st u d y t hera p y wit hi n 3 wee ks 
of t he sc he d ule d i nterr u pti o n, u nless ot her wise disc usse d wit h t he St u d y C h air . T he reas o n 
f or i nterr u pti o n s h o ul d be d oc u me nte d i n t he p atie nt's st u d y rec or d. 
 
1 3. 3.  
C O N C O MI T A N T M E DI C A TI O N S /V A C CI N A TI O N S (A L L O W E D &  P R O HI BI T E D ) 
Me dicati o ns or vacci nati o ns s pecificall y pr o hi bite d i n t he e x cl usi o n criteria are n ot all o we d 
d uri n g t he o n g oi n g trial.  If t here is a cli nical i n di cati o n f or o ne of t hese or ot her me dicati o ns 
or vacci nati o ns s pecificall y pr o hi bite d d uri n g t he trial, disc o nti n uati o n fr o m trial t hera p y or 
vacci nati o n ma y be re q uire d.  T he i n vesti gat or s h o ul d disc uss a n y q uesti o ns re gar di n g t his 
wit h t he St u d y C h air .  T he fi nal d ecisi o n o n a n y s u p p orti ve t hera p y or vacci nati o n rests wit h 
t he i n vesti gat or a n d/ or t he patie nt’s  pri mar y p h ysicia n. F or patie nts recei vi n g sta n dar d 
c he m ot hera p y re gi me ns, sites ma y f oll o w l ocal i n vesti gat or discreti o n f or t he a d mi nistrati o n 
of pre -m e dicati o ns.  H o we ver, t h e decisi o n t o c o nti n ue t he patie nt  o n trial t h era p y or 
vacci nati o n s c he d ule re q uires t he m ut ual a gree me nt of t he I n v esti gat or, t h e S p o ns or, a n d t h e 
patie nt .  
 
1 3. 3. 1.  
Acce pt a ble c o nc o mit a nt me dic ati o ns  
 
All treat me nts t hat t he i n vesti gat or c o nsi d ers necessar y f or a patie nt ’s welfare ma y be 
a d mi nistere d at t he  discreti o n of t he i n vesti gat or i n kee pi n g wit h t he c o m m u nit y sta n dar ds of 
me dical care.  All c o nc o mita nt me dicati o n will be rec or de d o n t he case re p ort f or m ( C R F) 
i ncl u di n g all prescri pti o n, o ver-t he-c o u nter ( O T C), her bal s u p ple me nts, a n d I V me dicati o ns 
an d fl ui ds.  If c h a n ges occ ur d uri n g t he trial peri o d, d oc u me ntati o n of dr u g d osa ge, fre q u e nc y, 
r o ute, a n d date m a y als o be i ncl u de d o n t he C R F. 
All c o nc o mita nt me dicati o ns recei ve d wit hi n 2 8 da ys bef ore t he first d ose of trial treat me nt 
a n d 3 0 d a ys after t he l ast d ose of trial tr eat me nt s h o ul d be rec or de d.  C o nc o mita nt me dicati o ns 
a d mi nistere d after 3 0 da ys aft er t he last d ose of trial treat me nt s h o ul d be rec or de d f or S A Es 
a n d E CIs.  
1 3. 3. 2.  
Pr o hi bite d c o nc o mit a nt me dic ati o ns  
 
Patie nt s are pr o hi bite d fr o m recei vi n g t he f oll o wi n g t hera pi es d uri n g t he Scree ni n g a n d 
Treat me nt P hase of t his trial:  


 
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 A nti -ca ncer s yste mic c h e m ot hera p y or bi ol o gical t hera p y  
 I m m u n ot hera p y n ot s pecifie d i n t his pr ot oc ol 
 C he m ot hera p y n ot s pecifie d i n t his pr ot oc ol  
 I n v esti gati o nal a ge nts ot her tha n pe m br oliz u ma b ( M K -3 4 7 5)  
 Ra diati o n t hera p y   
o  N ote:  Ra diati o n t hera p y t o a s y m pt o matic s olitar y lesi o n or t o t he brai n ma y be 
all o we d after c o ns ultati o n wit h S p o ns or.   
 Li ve vacci nes wit hi n 3 0 da ys pri or t o t he first d ose of trial treat me nt a n d w hile 
par tici pati n g i n t he trial.  E x a m ples of li ve vacci n es i ncl u de, b ut are n ot li mite d t o, 
t he f oll o wi n g: m easles, m u m ps, r u bella, c hic ke n p o x, yell o w fe v er, ra bies, B C G, a n d 
t y p h oi d ( oral) vacci ne. S eas o nal i nfl ue nza vacci n es f or i njecti o n are ge n erall y kille d 
vir us vacci nes a n d are all o we d; h o we ver i ntra n asal i nfl ue nza vacci nes (e. g. Fl u -
Mist ®) are li ve atte n uat e d vacci nes, a n d are n ot  all o we d.  
 Gl uc oc ortic oi ds f or a n y p ur p ose ot her t ha n t o m o d ulate s y m pt o ms fr o m a n e ve nt of 
cli nical i nterest of s us pecte d i m m u n ol o gi c eti ol o g y or  as a s u p p orti ve care 
me dicati o n if t he patie nt is recei vi n g c o nc urre nt c he m ot hera p y (ar m C). I n h ale d 
c ortic oster oi ds are all o w e d.  T he use of p h ysi ol o gic d oses of c ortic oster oi ds ma y be 
a p pr o ve d after c o ns ultati o n wit h t he S p o ns or.  
Patie nts  w h o, i n t he assess me nt b y t he i n vesti gat or, re q uire t he use of a n y of t he 
af ore m e nti o ne d treat me nts f or cli nical ma na ge me nt s h o ul d be re m o ve d fr o m t he trial.  
Patie nts  ma y recei ve ot h er me dicati o ns t hat t he i n vesti gat or dee ms t o b e me dicall y 
neces sar y. 
T he E x cl usi o n Criteria descri bes ot her me dicati o ns w hic h are pr o hi bite d i n t his trial.  
T here are n o pr o hi bite d t hera pies d uri n g t he P ost -Treat me nt F oll o w -u p P hase.  
1 3. 4.  
R E S C U E M E DI C A TI O N S A N D  S U P P O R TI V E C A R E  
1 3. 4. 1.  
S u p p orti ve C are G ui deli nes  f or Pe m br oliz u m a b 
( MK -3 4 7 5)  
 
Patie nts  s h o ul d recei ve a p pr o priate s u p p orti ve care meas ures as dee me d necessar y b y t he 
treati n g i n v esti gat or i ncl u di n g b ut n ot li mite d t o t he ite ms o utli ne d bel o w: 
 Diarr hea: Patie nts  s h o ul d be caref ull y m o nit ore d f or si g ns a n d s y m pt o ms of 
e nter oc olitis (s uc h as diarr hea, a b d o mi nal pai n, bl o o d or m uc us i n st o ol, wit h or 
wit h o ut fe ver) a n d of b o wel perf orati o n (s uc h as perit o neal si g ns a n d ile us).  I n 
s y m pt o matic patie nts , i nfecti o us eti ol o gies s h o ul d be r ule d o ut, a n d if s y m pt o ms 
are persiste nt a n d/ or se v ere, e n d osc o pi c e val u ati o n s h o ul d be c o nsi dere d.  
o  I n p atie nts  wit h se vere e nter oc olitis ( Gra de 3), pe m br oliz u ma b ( M K -
3 4 7 5)  will be per ma n e ntl y disc o nti n ue d a n d treat me nt wit h s yste mic 
c ortic oster oi ds s h o ul d b e i nitiate d at a d ose of 1 t o 2 m g/ k g/ da y of 


 
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pre d nis o ne or e q ui v ale nt.  W he n s y m pt o ms i m pr o ve t o Gra de 1 or less, 
c ortic oster oi d ta per s h o ul d be starte d a n d c o nti n ue d o ver at least 1 m o nt h.  
o  I n p atie nts  wit h m o derat e e nter o c olitis ( Gra de 2), pe m br oliz u ma b ( M K -
3 4 7 5)  s h o ul d be wit h hel d a n d a nti-diarr heal treat m e nt s h o ul d be starte d.  If 
s y m pt o ms are p ersiste nt f or m ore t ha n o n e wee k, s yste mic c ortic oster oi ds 
s h o ul d be i nitiate d (e. g., 0. 5 m g/ k g/ da y of pre d nis o ne or e q ui vale nt).  W he n 
s y m pt o ms i m pr o ve t o Gra de 1 or less, c ortic oster oi d ta per s h o ul d be starte d 
a n d c o nti n ue d o ver at least 1 m o nt h.   
o  All patie nts  w h o e x perie nce diarr hea s h o ul d be a d vise d t o dri n k li beral 
q ua ntities of cle ar fl ui ds.  If s ufficie nt oral fl ui d i nt a ke is n ot f easi ble, fl ui d 
a n d electr ol ytes s h o ul d b e s u bstit ute d via I V i nf usi o n.  
 Na usea/ v o miti n g: N a usea a n d v o miti n g s h o ul d be treate d a g gressi vel y, a n d 
c o nsi derati o n s h o ul d be gi ve n i n s u bse q ue nt c ycl es t o t he a d mi nistrati o n of 
pr o p h yla ctic a ntie metic t hera p y acc or di n g t o sta n dar d i nstit uti o nal practice.  
Patie nts  s h o ul d be str o n gl y e n c o ura ge d t o mai ntai n li beral oral fl ui d i nta ke.  
 A nti -i nfecti ves: Patie nts  wit h a d oc u me nte d i nfecti o us c o m plicati o n s h o ul d recei v e 
oral or I V a nti bi otics or ot her a nti -i nf ecti ve a ge nts as c o nsi dere d a p pr o priat e b y t h e 
treati n g i n v esti gat or f or a gi ve n i nfecti o us c o n diti o n, acc or di n g t o sta n dar d 
i nstit uti o nal practice. 
 I m m u ne-relat e d a d verse e ve nts: Please see Secti o n 1 3. 4. 3  bel o w re gar di n g 
dia g n osis a n d ma n a ge m e nt of a d verse e x perie n ces of a p ote ntial i m m u n ol o gic 
eti ol o g y.   
 Ma na ge me nt of I nf usi o n Reacti o ns:  Ac ute i nf usi o n reacti o ns ( w hic h ca n i ncl u de 
c yt o ki ne rele ase s y n dr o me, a n gi oe de ma, or a n a p h yl a xis) are differe nt fr o m  
aller gic/ h y pers e nsiti ve reacti o ns, alt h o u g h s o me of t he ma nifestati o ns are c o m m o n 
t o b ot h A Es.  Si g ns a n d s y m pt o ms us uall y de v el o p d uri n g or s h ortl y aft er dr u g 
i nf usi o n a n d ge n erall y res ol ve c o m pletel y wit hi n 2 4 h o urs of c o m pleti o n of 
i nf usi o n. 
Si g ns/s y m pt o ms 
ma y i ncl u de: 
Aller gi c reacti o n/ h y perse nsiti vit y 
(i ncl u di n g dr u g fe v er); Art hral gia (j oi nt pai n); Br o nc h os pas m; C o u g h; Dizzi ness; 
D ys p n ea (s h ort ness of breat h); Fati g ue (ast h e nia, let har g y, malaise); Hea dac h e; 
H y p erte nsi o n; H y p ote nsi o n; 
M yal gia ( m uscle  pai n); Na usea; Pr uritis/itc hi n g; 
Ras h/ des q ua mati o n; Ri g ors/c hills; S weati n g ( dia p h oresis); Tac h ycar dia; T u m or 
pai n ( o nset or e x acer bati o n of t u m or pai n d ue t o treat me nt); Urticaria ( hi ves, welts, 
w heals); V o miti n g.  
Ta ble 8  bel o w  s h o ws tr eat me nt g ui deli nes f or p atie nts  w h o e x perie nce a n i nf usi o n reacti o n 
ass ociate d wit h a d mi nistrati o n of pe m br oliz u ma b ( M K -3 4 7 5) . 
 
 
 
 


 
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Ta ble 8 .  I nf usi o n Reacti o n Treat me nt G ui deli nes 
N CI C T C A E Gr a de  
Tre at me nt  
Pre me dic ati o n at s u bs e q ue nt 
d osi n g  
Gra de 1  
Mil d reacti o n; i nf usi o n 
i nterr u pti o n n ot i n dicate d; 
i nter ve nti o n n ot i n dicate d 
 
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t h e patie nt  is 
dee me d me dicall y sta ble i n t h e o pi ni o n of 
t h e i n vesti gat or. 
 
N o ne  
Gra de 2  
Re q uires i nf usi o n i nterr u pti o n b ut 
res p o n ds pr o m ptl y t o 
s y m pt o matic treat me nt (e. g., 
a nti hista mi n es, N S AI D S, 
narc otics, I V fl ui ds); pr o p h ylactic 
me dicati o ns i n dicate d f or < = 2 4 
hrs  
 
St o p I nf usi o n a n d m o nit or s y m pt o ms.  
A d diti o nal a p pr o priate me dical t hera p y 
ma y i n cl u de b ut is n ot li mite d t o:  
I V fl ui ds 
A nti hista mi n es  
N S AI D S  
Ac eta mi n o p he n  
Narc otics  
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t h e patie nt  is 
dee me d me dicall y sta ble i n t h e o pi ni o n of 
t h e i n vesti gat or. 
If s y m pt o ms res ol ve wit hi n o ne h o ur of 
st o p pi n g dr u g i nf usi o n, t he i nf usi o n ma y be 
restarte d at 5 0 % of t h e ori gi n al i nf usi o n rate 
(e. g. fr o m 1 0 0 m L/ hr t o 5 0 m L/ hr).  
Ot her wise d osi n g will be hel d u ntil 
s y m pt o ms res ol ve a n d t h e patie nt  s h o ul d be 
pre me dicate d f or t h e ne xt sc he d ule d d ose.  
P atie nts  w h o de vel o p Gr a de 2 t o xicit y 
des pite a de q u ate pr e me dic ati o n s h o ul d 
be per m a ne ntl y disc o nti n ue d fr o m 
f urt her tri al tre at ment a d mi nist r ati o n.  
 
P atie nt  ma y be pre me dicate d 
1. 5 h ( ± 3 0 mi n utes) pri or t o 
i nf usi o n of pe m br oliz u ma b 
( M K-3 4 7 5)  wit h:  
 
Di p he n h y dra mi n e 5 0 m g p o ( or 
e q ui vale nt d ose  of 
a nti hista mi n e).  
 
Ac eta mi n o p he n 5 0 0 -1 0 0 0 m g 
p o ( or e q ui vale nt d ose of 
a nti p yretic).  
Gra des 3 or 4  
Gra de 3:  
Pr ol o n ge d (i.e., n ot ra pi dl y 
res p o nsi ve t o s y m pt o matic 
me dicati o n a n d/ or brief 
i nterr u pti o n of i nf usi o n); 
rec urre nce of s y m pt o ms f oll o wi n g 
i nitial i m pr o ve me nt; 
h os pitalizati o n i n dicate d f or ot her 
cli nical se q uelae (e. g., re nal 
i m pair me nt, p ul m o nar y i nfiltrates) 
 
Gra de 4:  
Life -t hreate ni n g; press or or 
ve ntilat or y s u p p ort i n dicate d  
 
St o p I nf usi o n.  
A d diti o nal a p pr o priate me dical t hera p y ma y 
i n cl ude b ut is n ot li mite d t o:  
I V fl ui ds 
A nti hista mi n es  
N S AI D S  
Ac eta mi n o p he n  
Narc otics  
O x y ge n  
Press ors  
C ortic oster oi ds  
E pi n e p hri ne  
 
I ncrease m o nit ori n g of vital si g ns as 
me dicall y i n dicate d u ntil t h e patie nt  is 
dee me d me dicall y sta ble i n t h e o pi ni o n of 
t h e i n vesti gat or. 
H os pitalizati o n ma y be i n dicate d.  
P atie nt  is per m a ne ntl y disc o nti n ue d fr o m 
f urt her tri al tre at me nt a d mi nist r ati o n. 
 
N o s u bse q ue nt d osi n g  
A p pr o priate res uscitati o n e q ui p me nt s h o ul d be a vaila ble i n t h e r o o m a n d a p h ysicia n rea dil y a vaila ble d uri n g t h e 
peri o d of dr u g a d mi nistrati o n.  
F or F urt her i nf or mati o n, please refer t o t h e C o m m o n Ter mi n ol o g y Criteria f or A d verse E ve nts v 4. 0 ( C T C A E) at 
htt p://cte p .ca ncer. g o v 


 
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1 3. 4. 2.  
S u p p orti ve c are g ui deli nes f or P ne u m o nitis  
 
Patie nts wit h s y m pt o mati c p ne u m o nitis s h o ul d i m me diatel y st o p recei vi n g pe m br oliz u ma b 
( M K-3 4 7 5)  a n d h a ve a n e val uati o n.  T he e v al uati o n ma y i ncl u d e br o nc h os c o p y a n d 
p ul m o nar y f u ncti o n tests t o r ule o ut ot her ca us es s uc h as i nfecti o n.  If t he p atie nt is 
deter mi ne d t o ha ve st u d y dr u g ass ociate d p ne u m o nitis, t he s u g geste d treat me nt pla n is 
detaile d i n Ta ble 9 . 
Ta ble 9 . Rec o m me n d e d A p pr oac h t o H a n dli n g P ne u m o nitis  
St u d y dr u g ass oci ate d 
p ne u m o nitis  
Wit h h ol d/ Disc o nti n ue 
pe m br oliz u m a b ( M K -
3 4 7 5) ?  
S u p p orti ve C are  
Gra d e 1 (as y m pt o matic)  
N o acti o n  
I nter ve nti o n n ot i n dicate d 
Gra d e 2  
Wit h h ol d pe m br oliz u ma b 
( M K-3 4 7 5) , ma y ret ur n t o 
treat me nt if i m pr o ves t o 
Gra d e 1 or res ol ves wit hi n 
1 2 wee ks  
S yste mic c ortic oster oi ds are i n dicate d.  T a per 
if necessar y. 
Gra d e 3 a n d Gra d e 4  
Disc o nti n ue 
pe m br oliz u ma b ( M K -3 4 7 5)  
S yste mic c ortic oster oi ds are i n dicate d. T he use 
of i nfli xi ma b ma y be i n dicate d as a p pr o priate.  
Refer t o t he E ve nt of Cli nical I nterest a n d 
I m m u ne-relate d A d verse E ve nt G ui da nce 
D oc u me nt f or a d diti o nal rec o m me n dati o ns.  
 
F or Gra de 2 p ne u m o nitis t hat i m pr o ves t o ≤ Gra de 1 wit hi n 1 2 wee ks, t he f oll o wi n g r ules  
s h o ul d a p pl y: 
 First e pis o de of p ne u m o nitis  
o  Ma y i ncrease d osi n g i nter val b y o ne wee k i n s u bs e q ue nt c ycl es  
 Sec o n d e pis o de of p ne u m o nitis –  per ma ne ntl y disc o nti n ue pe m br oliz u ma b ( M K -3 4 7 5)  
if u p o n rec h alle n ge patie nt de vel o ps p ne u m o nitis  Gra de 2  
1 3. 4. 3.  
S u p p orti ve c are g ui deli nes f or e ve nts of Cli nic al 
i nterest/i m m u ne-rel ate d a d verse e ve nts (I RA E S ) 
E ve nts of cli nic al i nterest of a p ote ntial i m m u n ol o gic eti ol o g y (ir E CIs) m a y be d efi ne d as a n 
a d verse e ve nt of u n k n o w n eti ol o g y, ass oci ate d wit h dr u g e x p os ure a n d is c o ns iste nt wit h a n 
i m m u ne p he n o me n o n.  ir A Es ma y be pre dicte d base d o n t he nat ure of t he pe m br oliz u ma b 
( M K-3 4 7 5)  c o m p o u n d, its 
mec ha nis m 
of 
acti o n, 
a n d re p orte d 
e x perie nce 
wit h 
i m m u n ot hera pies t hat ha ve a si milar mec ha nis m of acti o n.  S pecial atte nti o n s h o ul d be pai d t o 
A Es t hat ma y be s u g gesti ve of p ote ntial ir A Es.  A n ir A E ca n o cc ur s h ortl y after t he first d ose 
or  se veral m o nt hs after t h e last d ose of treat me nt. 
   


 
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If a n ir A E is s us pecte d, eff orts s h o ul d be ma de t o r ule o ut ne o plastic, i nfecti o us, meta b olic, 
t o xi n or ot her eti ol o gic ca uses pri or t o la beli n g a n a d verse e ve nt as a n ir A E.  Patie nts  w h o 
de vel o p a Gra de  2 or hi g her ir A E s h o ul d be disc usse d i m me diatel y wit h t h e St u d y PI .  
  
Rec o m me n dati o ns t o ma na gi n g ir A Es n ot det aile d else w here i n t he pr ot oc ol are det aile d i n 
Ta ble 9 . 
Ta ble 1 0 .  Ge n eral A p pr oac h t o Ha n dli n g ir A Es  
ir A E 
Wit h h ol d/ Disc o nti n ue 
pe m br oliz u m a b ( M K-
3 4 7 5) ?  
S u p p orti ve C are  
Gra d e 1  
N o acti o n  
Pr o vi de s y m pt o matic treat me nt  
Gra d e 2  
Ma y 
wit h h ol d 
pe m br oliz u ma b ( M K -3 4 7 5)  
C o nsi der s yste mic c ortic oster oi ds i n a d diti o n t o 
a p pr o priate s y m pt o matic treat me nt  
Gra d e 3 a n d Gra d e 4  
Wit h h ol d 
pe m br oliz u ma b 
( M K-3 4 7 5)  
Disc o nti n ue if u na ble t o 
re d uce c ortic oster oi d d ose 
t o 
< 
1 0 
m g 
per 
da y 
pre d nis o ne  
e q ui vale nt 
wit hi n 1 2 wee ks of t o xicit y  
S yste mic 
c ortic oster oi ds 
are i n dicate d i n 
a d diti o n t o a p pr o priate s y m pt o matic treat me nt.  
Ma y utilize 1 t o 2 
m g/ k g pre d nis o ne  or 
e q ui vale nt per da y.  
Ster oi d ta per s h o ul d 
be c o nsi dere d 
o nce 
s y m pt o ms i m pr o ve t o Gra de 1 or less a n d 
ta pere d o ver at least 4 wee ks. 
 
1 3. 5.  
O T H E R C O N SI D E R A TI O N S  
1 3. 5. 1.  
C o ntr ace pti o n  
 
Pe m br oliz u ma b ( M K -3 4 7 5 ) ma y ha v e a d verse effects o n a fet us i n uter o.  F urt her m ore, it is 
n ot k n o w n if pe m br oliz u ma b ( M K -3 4 7 5)  has  tr a nsie nt a d verse effects o n t he c o m p ositi o n of 
s per m.  N o n -pre g na nt, n o n -breast -fee di n g w o me n ma y b e e nr olle d if t he y are willi n g t o use 2 
met h o ds of birt h c o ntr ol or are c o nsi dere d hi g hl y u nli kel y t o c o n cei ve.  Hi g hl y u nli kel y t o 
c o ncei ve is defi ne d as 1) s ur gic all y sterilize d, or 2) p ost me n o pa usal (a w o ma n w h o is ≥4 5 
years of a ge a n d has n ot ha d 
me nses f or greater t ha n 1 year 
will be c o nsi dere d 
p os t me n o pa usal), or 3) n ot heter ose x uall y acti ve f or t he d urati o n of t he st u d y.  T he t w o birt h 
c o ntr ol met h o ds ca n be eit her t w o barrier met h o ds or a barrier met h o d pl us a h or m o nal met h o d 
t o pre ve nt pre g n a nc y. patie nt  s h o ul d start usi n g birt h c o ntr ol fr o m st ud y Visit 1 t hr o u g h o ut t he 
st u d y peri o d u p t o 1 2 0 da ys after t he last d ose of st u d y t hera p y.  
 
T he f oll o wi n g are c o nsi dere d a d e q uate b arri er met h o ds of c o ntrace pti o n: dia p hra g m, c o n d o m 
( b y t he p art ner), c o p per i ntra uteri ne d e vice, s p o n ge, or s per mici de.  A ppr o priate h or m o n al 
c o ntrace pti ves will i ncl u de a n y re gistere d a n d mar kete d c o ntrace pti ve a ge nt t hat c o ntai ns a n 
estr o ge n a n d/ or a pr o gestati o nal a ge nt (i ncl u di n g oral, s u bc uta ne o us, i ntra uteri ne, or 
i ntra m usc ular a ge nts). 
 
Patie nts  s h o ul d be i nf or me d t hat ta ki n g t he st u d y m e dicati o n ma y i n v ol ve u n k n o w n ris ks t o 
t he fet us ( u n b or n ba b y) if pre g n a nc y were t o occ ur d uri n g t he st u d y.  I n or der t o partici pate i n 


 
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t he st u d y, t he y m ust a d here t o t he c o ntr ace pti o n re q uire me nt ( descri be d a b o ve) f or t he d urati o n 
of t he  st u d y a n d d uri n g t h e f oll ow -u p peri o d defi ne d i n S ecti o n 1 5. 2. 4 -Re p orti n g of Pre g na n c y 
a n d Lactati o n t o A F T .  If t here is a n y q u esti o n t hat a patie nt  will n ot relia bl y c o m pl y wit h t he 
re q uire me nts f or c o ntr ace pti o n, t hat patie nt  s h o ul d n ot be e ntere d i nt o t he st u d y. 
 
1 3. 5. 2.  
Use i n pre g n a nc y  
 
If a patie nt  i na d v erte ntl y bec o mes pre g na nt w hile o n treat me nt wit h pe m br oliz u ma b ( M K -
3 4 7 5) , t he patie nt  will i m me diatel y b e re m o ve d fr o m t he st u d y.  T h e site will c o ntact t he p atie nt  
at least m o nt h l y a n d d oc u me nt t he patie nt’s  stat us u ntil t he pre g na nc y has bee n c o m plete d or 
ter mi nate d.  T he o utc o m e of t he pre g na n c y will be re p orte d t o t he A F T  wit h o ut dela y a n d 
wit hi n 2 4 h o urs if t he o utc o me is a seri o us a d verse e x perie nce (e. g., deat h, a b orti o n, c o n ge nital 
a n o mal y, or ot her disa bli n g or life -t hr eate ni n g c o m plicati o n t o t he m ot her or ne w b or n).  T he 
st u d y i n vesti gat or will ma ke e ver y eff ort t o o bt ai n per missi o n t o f oll o w t he o utc o me of t h e 
pre g na nc y a n d re p ort t h e c o n diti o n of t he fet us or ne w b or n t o A F T .   If a male p atie nt  
i m pre g n ates his fe male p art ner t he st u d y p ers o n nel at t he site m ust be i nf or me d i m me diatel y 
a n d t he pre g na n c y re p orte d t o A F T  a n d f oll o we d as descri be d a b o v e . A F T will re p ort 
pre g na nc y o ut c o mes t o Merc k.  
1 3. 5. 3.  
Use i n N ursi n g W o me n  
 
It is u n k n o w n w het her p e m br oliz u ma b ( M K -3 4 7 5)  is e x crete d i n h u ma n mil k.  Si nce ma n y 
dr u gs are e x crete d i n h u ma n mil k, a n d beca use of t he p ote ntial f or seri o us a d verse reacti o ns i n 
t he n ursi n g i nf a nt, s u bjects w h o are breast-fee di n g are n ot eli gi ble f or e nr oll me nt. 
1 4.  M
E A S U R E M E N T O F E F F E C T  
R E CI S T versi o n 1. 1 will be use d f or assess me nt of t u m or res p o nse f or assess me nt of t he 
pri mar y e n d p oi nt. I m m u ne relate d res p o nse criteria will be utilize d t o ma ke patie nt 
ma na ge me nt decisi o ns d uri n g t he tri al.  
1 4. 1.  
S C H E D U L E O F E V A L U A TI O N S : 
T he i nitial t u m or i ma gi n g will be perf or me d wit hi n 3 0 da ys pri or t o t he first d ose of trial 
treat me nt. Sca ns perf or m e d as part of r o uti ne cli nical ma na ge me nt are acce pta ble f or use as 
t he scree ni n g sca n if t he y are of dia g n ostic q ualit y a n d perf or m e d wit hi n 3 0 da ys pri or t o t he 
first d ose of trial treat me nt. O n st u d y i ma gi n g f or t he first 8 c ycl es o n all 2 ar ms will be 
perf or me d e ver y 6 wee ks ( 4 2 ± 7 da ys) after t he first d ose of trial treat me nt or m ore fre q u e ntl y 
if cli nicall y i n dicate d. C T timi n g s h o ul d f oll o w cale n dar da ys a n d s h o ul d n ot be a dj uste d f or 
dela ys i n c ycl e starts or e xte nsi o n of pe m br oliz u ma b ( M K -3 4 7 5)  c ycl e fre q ue ncies. O n st u d y 
i ma gi n g w hile patie nts are recei vi n g pe m br oliz u ma b ( M K -3 4 7 5)  al o ne after c ycl e 8 will be 
perf or me d e v er y 9 wee ks ( 6 3 ± 7 da ys).  
After t he first d oc u m e ntati o n of res p o nse per ir R C, c o nfir mat or y sca ns m a y b e perf or me d as 
earl y as 2 8 d a ys later; alter nati vel y, t he sca n perf or me d at t he ne xt sc he d ul e d ti me p oi nt (e. g. 
e ver y 4 2 ± 7 da ys) ma y b e use d as c o nfir mati o n f or res p o nse. After t he first d oc u me ntati o n of 
pr o gressi o n (if t he patie nt is cli nicall y st a ble) per ir R C, c o nfir mat or y sca ns will be perf or me d 
bet wee n 4 a n d 6 wee ks fr o m t he n.  


 
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After t he first d oc u me nt ati o n of pr o gressi o n w hil e recei vi n g p e m br oliz u ma b ( M K -3 4 7 5)  
al o ne it is at t he discreti o n of t he i n vesti gat or t o kee p a cli nicall y sta ble patie nt o n trial 
treat me nt or t o st o p trial treat me nt u ntil re peat i ma gi n g perf or me d 4-6 wee ks later c o nfir ms 
pr o gressi o n. Cli nical sta bilit y is defi ne d as:  
 A bse nce of s y m pt o ms a n d si g ns i n dicati n g cli nicall y si g nifi ca nt pr o gressi o n of disease 
(i ncl u di n g w orse ni n g la b orat or y val ues).  
 N O decli ne i n E C O G p erf or ma nce stat us.  
 A bse nce of ra pi d pr o gressi o n of disease or pr o gressi ve t u m or at critical a n at o mical sit es 
(e. g. c or d c o m pressi o n) re q uiri n g ur ge nt alter n ati ve me dical i nter v e nti o n.  
Patie nts t hat are d ee me d cli nicall y u nst a ble are n ot re q uire d t o h a ve re peat i ma gi n g f or 
c o nfir mati o n. If pr o gressi o n is c o nfir me d, t h e n t h e patie nt will be disc o nti n ue d fr o m tr ial 
treat me nt. If pr o gressi o n is n ot c o nfir me d, t he n t he patie nt s h o ul d res u m e/c o nti n ue trial 
treat me nt a n d ha v e t heir ne xt sca n acc or di n g t o t he e v er y 6-wee k ( 4 2 ± 7 da ys) sc h e d ule 
fr o m t he first d ose of st u d y treat me nt. W he n feasi ble, patie nts s h o ul d n ot be disc o nti n ue d 
u ntil pr o gressi o n is c o nfir me d.  
I ma gi n g d uri n g t he f oll o w-u p peri o d is t o b e re p eate d e ver y 9 wee ks ( 6 3 ± 7 da ys) f or 
patie nts w h o disc o nti n ue trial treat me nt f or reas o ns ot her t ha n disease pr o gressi o n u ntil t he 
patie nt e x perie nces c o nfir me d disease pr o gressi o n or starts a ne w a nti ne o pl astic t hera p y.  
Trial eli gi bilit y will be acc or di n g t o R E CI S T 1. 1 criteria; h o we ver dise ase res p o nse o n trial 
will be assesse d usi n g ir R C b y i n v esti gat ors.  
T he sa me i ma gi n g tec h ni q ue s h o ul d be use d i n a pat ie nt t hr o u g h o ut t he trial.  
1 4. 2.  
R E S P O N S E E V A L U A TI O N 
C RI T E RI A I N 
S O LI D 
T U M O R S 
( R E CI S T) 1. 1  
C RI T E RI A F O R       E V A L U A TI N G R E S P O N S E I N S O LI D T U M O R S  
R E CI S T versi o n 1. 1 * will be use d i n t his st u d y f or assess me nt of t u m or res p o nse.  
 
* As p u blis he d i n t he E ur o pea n J o ur nal of Ca ncer:  
 
 
E. A. Eise n ha uer, P. T herasse, J. B o gaerts, L. H. Sc h wartz, D. Sar ge nt, R. F or d, J. 
Da nce y, S. Ar b uc k, S. G w yt her, M. M o o ne y, L. R u bi nstei n, L. S ha n k ar, L. D o d d, R. 
Ka pla n, D. Lac o m be, J. Ver weij. Ne w res p o nse e val uati o n criteria i n s oli d  t u m ors: 
Re vise d R E CI S T g ui deli ne ( versi o n 1. 1). E ur J Ca ncer. 2 0 0 9 J a n; 4 5( 2): 2 2 8 -4 7.  
 
 
1 4. 2. 1.  
Defi niti o ns of Me as ur a ble a n d N o n -Me as ur a ble 
Dise ase  
 
Me as ur a ble Dise ase  
A n o n -n o dal lesi o n is c o nsi dere d meas ura ble if its l o n gest dia meter ca n be acc uratel y 
meas ure d as 2. 0 c m wit h c hest x -ra y, or as ≥1. 0 c m wit h C T sca n,   


 
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A s u perficial n o n -n o d al lesi o n is meas ura ble if its l o n gest dia meter is ≥ 1. 0 c m i n dia meter 
as assesse d usi n g cali pers (e. g. s ki n n o d ules) or i ma gi n g.  I n t he case of s ki n lesi o ns, 
d oc u me ntati o n b y c ol or p h ot o gra p h y, i ncl u di n g a r uler t o esti mate t he siz e of t he lesi o n, 
is rec o m me n de d. 
A mali g na nt l y m p h n o de is c o nsi dere d meas ura ble if its s h ort a xis is > 1. 5 c m w he n 
assesse d b y C T sca n ( C T sca n slice t hic k ness rec o m me n de d t o be n o greater t ha n 5 m m).   
N o n -Me as ur a ble Dise as e  
All ot her lesi o ns ( or sites of diseas e) are c o nsi dere d n o n -meas ura ble dise ase, i ncl u di n g 
pat h ol o gic al n o des (t h ose wit h a s h ort a xis ≥ 1. 0 t o < 1. 5 c m).  B o ne l esi o ns, 
le pt o me ni n geal 
diseas e, 
ascites, 
ple ural/ p ericar dial 
eff usi o ns, 
l y m p h a n gitis 
c utis/ p ul m o nis, i nfla m mat or y breast diseas e, a n d a b d o mi nal masses ( n ot f oll o we d b y C T), 
are c o nsi d ere d as n o n -me as ura ble as well.  
N ote: ‘ C ystic lesi o ns’ t h o u g ht t o re pres e nt c ystic metastases ca n be c o nsi dere d as 
meas ura ble l esi o ns, if t he y 
meet t he d efi niti o n of 
meas ura bilit y des cri be d a b o v e. 
H o we ver, if n o n -c ystic lesi o ns are pres e nt i n t he sa me patie nt, t hese are preferre d f or 
selecti o n as t ar get l esi o ns.  I n a d diti o n, l y m p h n o des t hat ha v e a s h ort a xis < 1. 0 c m are 
c o nsi dere d n o n -pat h ol o gi cal (i.e., n or m al) a n d s h o ul d n ot be rec or de d or f oll o we d.  
1 4. 2. 2.  
G ui deli nes f or E v al u ati o n of Me as ur a ble Dise ase  
Me as ure me nt Met h o ds:   
• 
All meas ure me nts s h o ul d be  rec or de d i n metric n ot ati o n (i.e., deci mal fracti o ns 
of ce nti meters) usi n g a r uler or cali pers.  
• 
T he sa me met h o d of assess me nt a n d t he sa me tec h ni q ue m ust be use d t o 
c haracteriz e eac h i de ntifi e d a n d re p orte d l esi o n at baseli ne a n d d uri n g f oll o w -
u p. F or p atie nts ha vi n g o nl y lesi o ns meas uri n g at least 1 c m t o less t ha n 2 c m 
m ust use C T i ma gi n g f or b ot h pre - a n d p ost -tr eat me nt t u m or assess me nts.   
• 
I ma gi n g-base d e val u ati o n is preferre d t o e val u ati o n b y cli nical e x a mi nati o n 
w he n b ot h met h o ds ha ve bee n use d a t t he sa me e val uati o n t o assess t he 
a ntit u m or effect of a tr eat me nt.   
Acce pt a ble M o d alities  f or Me as ur a ble Dise as e: 
 C o n ve nti o nal C T: T his g ui deli ne has defi ne d meas ura bilit y of lesi o ns o n C T sca n base d o n 
t he ass u m pti o n t hat C T slice t hic k ness be at least  2. 5 m m b ut n o great er t ha n 5 m m.  
 
 Me as ure me nt at F oll o w -u p E v al u ati o n:    
• 
A s u bse q ue nt sca n m ust be o btai ne d n ot less t h a n 4  wee ks f oll o wi n g i nitial 
d oc u me ntati o n of a n o bjecti ve stat us of eit her c o m plete res p o nse ( C R) or partial 
res p o nse ( P R). 
• 
I n t h e case of sta ble dise ase ( S D), f oll o w -u p meas ure me nts m ust ha ve met t he 
S D criteria at least o nce after st u d y e ntr y at a mi ni m u m i nter val of n ot less t h a n 
6 wee ks . 
• 
T he c yt ol o gic al c o nfir m ati o n of t he ne o plastic ori gi n of a n y eff usi o n t hat 
a p pears or w orse ns d uri n g treat me nt w he n t he meas ura ble t u m or has met 


 
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criteria f or res p o nse or sta ble disease is ma n dat or y t o differe ntiate bet w ee n 
res p o nse or sta ble diseas e (a n eff usi o n ma y b e a si de effect of t he treat m e nt) 
a n d pr o gressi ve dis ease.  
• 
C yt ol o gic a n d hist ol o gic tec h ni q ues ca n be use d t o differe ntiate bet wee n P R 
a n d C R i n rare cases (e. g., resi d u al lesi o ns i n t u m or t y pes s uc h as ger m cell 
t u m ors, w here k n o w n resi d ual be ni g n t u m ors ca n re mai n.) 
 
Me as ure me nt of Tre at me nt/I nter ve nti o n Effect  
 
T ar get Lesi o ns & T ar g et L y m p h N o des  
• 
Meas ura ble lesi o ns u p t o a ma xi m u m of 5 lesi o ns re pres e ntati ve of all i n v ol ve d 
or ga ns, s h o ul d be i de ntifie d as “ Tar get Lesi o ns” a n d rec or de d a n d meas ure d at 
baseli ne.  T hese lesi o ns ca n be n o n -n o dal or n o dal w here n o m or e t ha n 2 l esi o ns 
are fr o m t he sa me or ga n a n d n o m ore t ha n 2 mali g n a nt n o dal lesi o ns are selecte d.  
N ote:  If fe wer t ha n 5 tar get lesi o ns a n d tar get l y m p h n o des are i de ntifie d (as 
t here ofte n will be), t here is n o reas o n t o p erf or m a d diti o nal st udies be y o n d 
t h ose s pecifie d i n t he pr ot oc ol t o disc o ver ne w lesi o ns.   
• 
Tar get lesi o ns a n d tar get l y m p h n o des s h o ul d b e selecte d o n t he basis of t heir 
siz e, be re pres e ntati ve of all i n v ol ve d sites of disease, b ut i n a d diti o n s h o ul d be 
t h ose t hat le n d t he msel ves t o re pr o d uci ble re peat e d meas ure me nts.  It ma y be 
t he case t hat, o n occasi o n, t he lar gest lesi o n ( or mali g na nt l y m p h n o d e) d oes 
n ot le n d itself t o re pr o d uci ble meas ure me nts i n w hic h circ u msta n ce t he ne xt 
lar gest lesi o n ( or mali g n a nt l y m p h n o d e) w hich ca n be m eas ure d re pr o d uci bl y 
s h o ul d be selecte d.   
• 
B aseli ne S u m of Di me nsi o ns ( B S D):   A s u m of t he l o n gest dia meter f or all 
tar get lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des will 
be calc ulat e d a n d re p orte d as t he baseli ne s u m of di me nsi o ns ( B S D).  T he B S D 
will be use d as refere n ce t o f urt her c haracterize a n y o bjecti ve t u m or res p o nse 
i n t he meas ura ble di me nsi o n of t he disease.   
• 
P ost -B aseli ne S u m of t he Di me nsi o ns ( P B S D):   A s u m of t he l o n gest dia meter 
f or all tar get lesi o ns pl us t he s u m of t he s h ort a xis of all t he tar get l y m p h n o des 
will be calc ulate d a n d re p orte d as t he p ost -baseli ne s u m of di me nsi o ns ( P B S D).  
If t he ra di ol o gist is a ble t o pr o vi de a n act ual meas ure f or t he tar get lesi o n ( or 
tar get l y m p h n o de), t h at s h o ul d be rec or de d, e ve n if it is bel o w 0. 5 c m.  If t he 
tar get lesi o n ( or tar get l y m p h n o de) is belie v e d t o be pres e nt a n d is fai ntl y s ee n 
b ut t o o s mall t o meas ure, a defa ult val ue of 0. 5 c m s h o ul d be assi g ne d.  If it is 
t he o pi ni o n of t he ra di ol o gist t hat t he tar get lesi o n or tar get l y m p h n o de has 
li kel y disa p peare d, t h e meas ure m e nt s h o ul d be rec or de d as 0 c m. 
• 
T he mi ni m u m s u m of t he di me nsi o ns ( M S D) is t he mi ni m u m of t he B S D a n d 
t he P B S D. 
 
N o n -T ar get Lesi o ns & N o n -T ar get L y m p h N o des  
N o n -meas ur a ble sites of diseas e are classifie d as n o n - tar get lesi o ns or n o n-tar get l y m p h 
n o des a n d s h o ul d als o be rec or de d at  bas eli ne.  T hese lesi o ns a n d l y m p h n o des s h o ul d 
be f oll o we d . 
1 4. 2. 3.  
Res p o nse Criteri a  


 
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All tar get lesi o ns a n d tar get l y m p h n o des f oll o we d b y C T m ust be meas ure d o n re -
e val uati o n at e v al uati o n ti mes s pecifie d i n Secti o n 1 4. 2. 1  & 1 4. 2. 2 .  S p ecificall y, a 
c ha n ge i n o bjecti ve stat us t o eit her a P R or C R ca n n ot be d o ne wit h o ut re -meas uri n g 
tar get lesi o ns a n d tar get l y m p h n o des.  
 
N ote: N o n -tar get lesi o ns a n d n o n-tar get l y m p h n o des s h o ul d be e val uate d at 
eac h ass ess me nt, es peci all y i n t he case of first res p o nse or c o nfir mati o n of 
res p o nse.  I n selecte d circ u msta n ces, cert ai n n o n-tar get or ga ns 
ma y b e 
e val uate d less fre q ue ntl y.  F or e x a m ple, b o ne sca ns ma y nee d t o be re peate d 
o nl y w he n c o m plet e res p o nse is i de ntifie d i n tar get disease or w he n pr o gressi o n 
i n b o ne is s us pecte d. 
 
 E v al u ati o n of T ar get Lesi o ns  
• 
C o m plete R es p o nse ( C R):  All of t he f oll o wi n g m ust be tr ue: 
a. Disa p peara nce of all tar get lesi o ns.  
b.  Eac h tar get l y m p h n o de m ust ha ve re d ucti o n i n s h ort a xis t o < 1. 0 c m.  
• 
P arti al Res p o nse ( P R): At least a 3 0 % d ecrease i n P B S D (s u m of t h e 
l o n gest dia m eter f or all tar get lesi o ns pl us t he s u m of t he s h ort a xis of all t he 
tar get l y m p h n o d es at c urre nt e val uati o n) ta ki n g as refere nce t he B S D. 
• 
Pr o g ressi o n ( P D):  At least o ne of t he f oll o wi n g m ust be tr ue:  
a. At least o ne ne w mali g n a nt lesi o n, w hic h als o i n cl u des a n y l y m p h 
n o de t hat was n o r mal at baseli ne ( < 1. 0 c m s h ort a xis) a n d i ncreas e d 
t o ≥ 1. 0 c m s h ort a xis d uri n g f oll o w-u p.  
b.  At least a 2 0 % i ncrease i n P B S D (s u m of t he l o n gest dia meter f or all 
tar get lesi o ns pl us t h e s u m of t he s h ort a xis of all t he tar get l y m p h 
n o des at c urre nt e v al uati o n) ta ki n g as refere nce t he M S D . I n a d diti o n, 
t he P B S D m ust als o de m o nstrate a n a bs ol ute i ncrease of at least 0. 5 
c m fr o m t he M S D.  
• 
St a ble Dise ase ( S D):  Neit her s uffi cie nt s hri n ka ge t o q ualif y f or P R, n or 
s ufficie nt i ncrease t o q ualif y f or P D t a ki ng as refere nce t h e M S D.  
 
 
E v al u ati o n of N o n -T ar get Lesi o ns & N o n -t ar g et L y m p h N o des 
• 
C o m plete R es p o nse ( C R):  
All of t he f oll o wi n g m ust be tr ue:  
a. Disa p peara nce of all n o n -tar get lesi o ns.  
b.  Eac h n o n -t ar get l y m p h n o de m ust ha ve a re d ucti o n i n s h ort a xis t o 
< 1. 0 c m  
• 
N o n -C R/ N o n -P D:  Persiste nce of o ne or m ore n o n -tar get l esi o ns or n o n-
tar get l y m p h n o d es. 
• 
Pr o g ressi o n ( P D): At least o ne of t he f oll o wi n g m ust be tr ue:  
a. At least o ne ne w mali g n a nt lesi o n, w hic h als o i n cl u des a n y l y m p h 
n o de t hat was n or mal at  baseli ne ( < 1. 0 c m s h ort a xis) a n d i ncreas e d 
t o ≥ 1. 0 c m s h ort a xis d uri n g f oll o w-u p.   




 
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1 4. 3.  
IM M U N E R E L A T E D R E S P O N S E C RI T E RI A  
F or all patie nts w h o e x perie nce diseas e pr o gressi o n o n st u d y, t h e date n ote d of dise ase 
pr o gressi o n is t he ti me of t he s ca n w here it is ori gi nall y d etecte d, a n d n ot t he f oll o wi n g d ate 
of t he c o nfir mat or y sca n.  
Defi niti o ns of me as ur a ble a n d n o n -me as ur a ble dise ase.  
Me as ur a ble dise ase: 
N e o plastic masses t hat ca n be precisel y meas ure d i n 2 i n -pla ne 
per pe n dic ular dia meters. B ot h its l o n gest dia meter a n d its l o n gest per pe n dic ular m ust be 
greater t ha n or e q u al t o 1 0 m m or 2 ti mes t he a xial sli de t hic k ness if a xial slice t hic k ness is 
greater t ha n 5 m m. L y m p h n o des m ust ha ve a s h ort -a xis li ne-le n gt h of ≥ 1 5 m m. Mali g na nt 
l y m p h n o des m ust be me as ura ble i n 2 per pe n dic ul ar dia meters. B ot h its l o n gest dia m eter a n d 
its l o n gest per pe n dic ular m ust be greater t ha n or e q ual t o 1 5 m m. T he q ua ntitati ve e n d p oi nt 
will be defi ne d as t he pr o d uct of t he l o n gest dia meter wit h its l o n gest per p e n dic ular.  
N o n -me as ur a ble dise ase: 
N o n -m eas ura ble lesi o ns are t h os e t hat are n ot s uita ble f or 
q ua ntitati ve assess me nt o ver ti me. T hese i ncl u d e:  
 Ne o plastic masses w hic h are t o o s mall t o meas ure, beca use t heir l o n gest u ni nterr u pte d 
dia meter or l o n gest per pe n dic ular are less t ha n 1 0 m m.  
 Ne o plastic masses w h os e b o u n daries ca n n ot b e disti n g uis he d. T his i ncl u des masses t hat 
ca n n ot be de marcate d fr o m s urr o u n di n g tiss ue beca use of i na de q uate c o ntr ast, masses wit h 
o verl y c o m ple x m or p h ol o g y, or t h ose wit h hi g hl y heter o ge n e o us tiss ue c o m p ositi o n.  
 Ot her t y p es of lesi o ns t hat are c o nfi d e ntl y felt t o be re pres e nt ne o plastic tiss ue, b ut diffic ult 
t o q ua ntif y i n a re pr o d uci ble ma n ner. T h ese i ncl u de b o ne metastases, le pt o me ni n geal 
metastases, mali g na nt as cites, ple ural/ pericar dial eff usi o ns, i nfla m mat or y  breast disease, 
l y m p ha n gitic diseas e, c ystic lesi o ns, ill-defi ne d a b d o mi nal masses, etc.  
F or ir R C, o nl y t ar g et l esi o ns selecte d at b aseli ne a n d me as ur a ble ne w lesi o ns are t a ke n 
i nt o acc o u nt.  
At t he bas eli ne t u m or assess me nt, t he s u m of t he pr o d ucts of t he t w o lar gest p er pe n dic ular 
dia meters ( S P D) of all i n de x lesi o ns (fi ve lesi o ns per or ga n, u p t o 1 0 visceral lesi o ns a n d fi ve 
c uta ne o us i n de x lesi o ns) is calc ulate d.  
At eac h s u bse q ue nt t u m or assess me nt, t he S P D of t he i n de x lesi o ns a n d of ne w, meas ura bl e 
lesi o ns ( ≥ x 5 m m; u p t o 5 ne w lesi o ns per or ga n: 5 ne w c uta ne o us lesi o ns a n d 1 0 visceral 
lesi o ns) are a d de d t o get h er t o pr o vi de t he t otal ti me-p oi nt t u m or b ur de n.  
O ver all res p o nse usi n g ir R C:  
 C o m plete 
Res p o nse (i r C R):  C o m plete disa p peara n ce of all t u m or  lesi o ns 
( w het her me as ura bl e or n ot, a n d n o ne w lesi o ns). C R m ust b e c o nfir me d b y 
re peat e d c o ns ec uti ve assess me nts ma de n o less t ha n 4 wee ks fr o m t he d ate first 
d oc u me nte d.  


 
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 P arti al Res p o nse (ir P R):  Decreas e i n S P D of 5 0 % or greater b y a c o ns ec uti ve 
assessme nt at least 4 wee ks after first d o c u me ntati o n.  
 St a ble Dise ase (ir S D):  Fail ure t o meet criteria f or ir C R or ir P R, i n a bse nce of ir P D.  
 Pr o g ressi ve Dise ase (i r P D):  at least 2 5 % i ncrease i n S P D rel ati ve t o na dir 
( mi ni m u m rec or de d t u m or b ur de n). C o nfir m ati on b y a re peat, c o ns ec uti ve 
assess me nt n o less t ha n 4 wee ks fr o m t he data first d oc u me nte d.  
Please n ote ot her ke y differe nces bet w ee n ir R C a n d t he ori gi nal W H O criteria:  
 Ne w meas ura ble lesi o ns will be i nc or p orate d i nt o t he S P D.  
 Ne w n o n meas ura ble lesi o ns  d o n ot defi ne pr o gressi o n b ut precl u de ir C R.  
 N o n -i n de x lesi o ns c o ntri b ute t o defi ni n g ir C R (c o m plete disa p peara nce re q uire d).  
Ir R C f or t he c urre nt pr ot oc ol is a d o pte d fr o m t he f oll o wi n g refere nce:  
W olc h o k, J D, H o os, A, O’ Da y S, et al., G ui deli nes f or t he E val uati o n of I m m u ne T h era p y 
Acti vit y i n S oli d T u m ors: I m m u ne -Rel ate d Res p o nse Criteria. Cli nical Ca ncer Researc h, 2 0 0 9 
Dec 1; 1 5 ( 2 3): 7 4 1 2 -2 0. E p u b 2 0 0 9 N o v 2 4.  
1 5.  E N D O F T R E A T M E N T /I N T E R V E N TI O N 
1 5. 1.  
D U R A TI O N O F T R E A T M E N T  
1 5. 1. 1.  
C R, P R, or S D  
 
Patie nts w h o are i n C R, P R or S D will c o nti n ue o n t hera p y per t he st u d y cale n dar.  After 
treat me nt is disc o nti n ue d, patie nts will be f oll o we d per t he st u d y cal e n dar. 
 
1 5. 1. 2.  
Dise ase Pr o g ressi o n  
 
Re m o ve fr o m pr ot oc ol t h era p y a n y p atie nt wit h disease pr o gressi o n  b y ir R C w hile recei vi n g 
pe m br oliz u ma b ( M K -3 4 7 5)  d oc u me nt details, i ncl u di n g t u m or meas ure me nts, o n data f or ms.  
After diseas e pr o gressi o n, patie nts s h o ul d be f oll o we d f or s ur vi v al per t he st u d y cale n dar 
(Secti o n 9 ). 
 
1 5. 1. 3.  
Disc o nti n u ati o n of st u d y a ge nt  
If t he p atie nt disc o nti n ues pe m br oliz u ma b  ( M K-3 4 7 5)  patie nts s h o ul d be f oll o we d f or s ur vi val 
per t he st u d y cal e n dar ( Secti o n 9 ). 
1 5. 2.  
P A TI E N T W
I T H D R A W A L/ DI S C O N TI N U A TI O N C RI T E RI A  
1 5. 2. 1.  
P at i e nt Wit h dr a w al 
 
Patie nts ma y wit h dra w c o nse nt at a n y ti me f or a n y reas o n or be dr o p pe d fr o m t he tri al at t h e 
discreti o n of t h e i n vesti gat or s h o ul d a n y u nt o war d effect o cc ur.  I n a d diti o n, a p atie nt ma y b e 


 
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wit h dra w n b y t he i n vesti gat or or t he S p o ns or if e nr oll me nt i nt o t he trial is i na p pr o priate, t he 
trial pla n is vi olate d, or f or a d mi nistrati ve a n d/ or ot her safet y reas o ns. If, at a n y ti me t he 
c o nstrai nts of t his pr ot oc ol are detri me ntal t o t he patie nt's healt h a n d/ or t he patie nt n o l o n ger 
wis hes t o c o nti n ue pr ot oc ol t hera p y, pr ot o c ol t hera p y s h all be disc o nti n ue d.  
 
A patie nt m ust be disc o nti n ue d fr o m t he trial f or a n y of t he f oll o wi n g reas o ns:  
 
 T he patie nt or le gal re prese ntati ve (s uc h as a pare nt or le gal g uar di a n) wit h dra ws 
c o nse nt.  
 C o nfir me d ra di o gra p h i c disease pr o gressi o n b y ir R C w hile recei vi n g pe m br oliz u ma b 
( M K-3 4 7 5)  
N ote : A patie nt ma y b e gra nte d a n e x ce pti o n t o c o nti n ue o n treat m e nt wit h 
c o nfir me d ra di o gra p hic pr o gressi o n if cli nicall y st a ble or cli nicall y i m pr o ve d.  
 
 U nacce pta ble a d vers e e x perie nces  (see S ecti o n 1 5 ) 
 I nterc urre nt ill ness t hat pre ve nts f urt h er a d mi nistrati o n of treat me nt 
 I n v esti gat or’s decisi o n t o wit h dra w t he patie nt 
 T he patie nt has a c o nfir m e d p ositi ve ser u m pre g n a nc y t est  
 N o nc o m plia nce w it h trial treat me nt or pr o ce d ure re q uire me nts 
 T he patie nt is l ost t o f oll o w -u p  
 C o m plete d 2 4  m o nt hs of treat me nt wit h pe m br oliz u ma b ( M K -3 4 7 5)  
 N ote: 2 4  m o nt hs of st u dy me dic ati o n is c alc ul at e d fr o m t he e n d of 8 
cycles of se q ue nci n g c he m o/ pe m br oliz u m a b ( M K -3 4 7 5)  
 A d mi nistrati ve reas o ns  
T he E n d of Treat me nt a n d F oll o w -u p visit pr oce d ures are liste d i n Secti o n 9 . After t he e n d of 
treat me nt, eac h patie nt will be f oll o we d f or 3 0 da ys f or a d v erse e v e nt m o nit ori n g (seri o us 
a d verse e v e nts will be c ollecte d f or 9 0 da ys after t he e n d of treat me nt ). Patie nts w h o 
disc o nti n ue f or reas o ns ot her t ha n pr o gressi ve dis ease will ha ve p ost -treat me nt f oll o w-u p f or 
disease stat us u ntil disease pr o gressi o n, i nitiati n g a n o n -st u d y ca ncer treat me nt, wit h dra wi n g 
c o nse nt or b ec o mi n g l ost t o f oll o w -u p.  Treat me nt -relate d t o xicities will be res ol ve d bef ore 
partici pa nts e nter t he cli nical f oll o w -u p p hase.  After d oc u me nte d dise as e pr o gressi o n eac h 
patie nt will be f oll o we d b y tele p h o ne f or o verall  s ur vi val u ntil deat h, wit h dra wal of c o nse nt, 
or t he e n d of t he st u d y, w hic he ver occ urs first.  
1 5. 3.  
D E FI NI TI O N S A N D F O L L O W -U P R E Q UI R E M E N T S  
Defi niti o n of i neli gi ble p atie nts : A st u d y partici p a nt w h o is re gistere d t o t he trial b ut d oes n ot 
meet all of t he eli gi bi lit y criteria is dee me d t o be i n eli gi ble. Patie nts w h o are dee me d i neli gi ble 


 
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ma y c o nti n ue pr ot oc ol tr eat me nt, pr o vi de d t he treati n g p h ysicia n, st u d y c h air, a n d e x ec uti ve 
officer a gree t here are n o safet y c o ncer ns if t he patie nt were t o c o nti n ue pr ot oc ol tr eat me nt. 
N otificati o n of t he l ocal I R B ma y be necessar y per l ocal I R B p olicies.  
Defi niti o n of cli nical f oll o w -u p : T he f oll o w-u p peri o d w here t he st u d y partici pa nt is n o l o n ger 
recei vi n g tr eat me nt, b ut is still f oll o wi n g t he st u d y cale n dar f or tests, e x a ms, a n d c orrelati ve 
e n d p oi nts (e. g., s peci me n c ollecti o n, q ualit y of life, disease assess me nts as re q uire d b y t h e 
st u d y).  
Defi niti o n of s ur vi val o nl y f oll o w -u p : T he f oll o w-u p peri o d w here t he st u d y p artici pa nt is 
m o nit ore d f or l o n g -t er m e n d p oi nts, is n o l o n ger recei vi n g st u d y treat me nt, a n d is n ot re q uire d 
t o f oll o w t he st u d y cal e n dar f or tests, e x a ms, a n d c orrelati ve e n d p oi nts (e. g. s p eci me n 
c ollecti o n, q ualit y of life, disease assess me nts as re q uire d b y t h e st u d y). I n t his f oll o w -u p 
peri o d, t here is a sc he d ule i n w hic h case re p ort f or ms s h o ul d be s u b mitte d, b ut t he p h ysicia n 
visits are base d o n t he sta n dar d of care.  
 
1 5. 4.  
F O L L O W -U P F O R IN E LI GI B L E P A TI E N T S  
St u d y partici pa nts w h o are re gistere d t o t he trial a n d recei ve a n y pr ot oc ol treat me nt b ut dee me d 
i neli gi ble m ust f oll o w t he sc he d ule of assess me nts detaile d i n Secti o n 9 . 
1 5. 5.  
F O L L O W -U P F O R P A TI E N T S N E V E R R E C EI VI N G P R O T O C O L IN T E R V E N TI O N  
St u d y partici pa nts w h o are e nr olle d i nt o  t he trial b ut w h o ne ver g o o n t o recei ve st u d y 
i nter ve nti o n m ust still c o m plete f oll o w-u p re q uir e me nts as s pecifie d b el o w.  
Scree ni n g , o n-st u d y, e n d p oi nt (e. g., rela pse or pr o gressi o n), a n d s ur vi v al data s u b missi o n 
re q uire d. 
1 6.  A D V E R S E E V E N T S  
A n a d vers e e ve nt ( A E) is defi ne d as a n y u nt o war d me dical occ urre n ce i n a patie nt or cli nical 
i n vesti gati o n s u bject a d mi nistere d a p har m ace utical pr o d uct a n d w hic h d oes n ot necessaril y 
ha ve t o ha ve a ca usal rel ati o ns hi p wit h t his treat me nt. A n a d verse e v e nt ca n t heref ore be a n y 
u nfa v ora bl e a n d u ni nte n d e d si g n (i n cl u di n g a n a b n or mal la b orat or y fi n di n g, f or e x a m ple), 
s y m pt o m, or disease t e m p orall y ass ociate d wit h t he use of a m e dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure, w het her or n ot c o nsi dere d rel ate d t o t he me dici nal pr o d uct or pr ot oc ol -
s pecifie d pr oce d ure.  A n y w orse ni n g (i.e., a n y cli nicall y si g nifica nt a d verse c ha n ge i n 
fre q ue n c y a n d/ or i nte nsit y) of a pree xisti n g c o n diti o n t hat is te m p orall y ass ociate d wit h t he 
use of pe m br oliz u ma b  ( M K-3 4 7 5)  is als o a n a d v erse e v e nt. 
 
C ha n ges res ulti n g fr o m n or mal gr o wt h  a n d de v el o p me nt t hat d o n ot var y si g nifica ntl y i n 
fre q ue n c y or se v erit y fr o m e x pecte d le vels are n ot t o be c o nsi dere d a d verse e ve nts.  
E x a m ples of t his ma y i n cl u de, b ut are n ot li mite d t o o nset of me nses or me n o pa use occ urri n g 
at a p h ysi ol o gic all y a p pr o pr iate ti me. 
 
A d verse e ve nts ma y occ ur d uri n g t h e c o urse of t h e use of pe m br oliz u ma b ( M K-3 4 7 5) d uri n g 
t his st u d y or wit hi n t he f oll o w-u p peri o d s pecifi e d b y t he pr ot oc ol, or pres cri be d i n cli nical 
practice, fr o m o ver d ose ( w het her acci de nt al or i nte nti o nal), fr o m a b us e a n d fr o m wit h dra wal. 
 


 
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Pr o gressi o n of t he ca ncer u n der st u d y is n ot c o nsi dere d a n a d verse e v e nt u nless it is 
c o nsi dere d t o be dr u g rel ate d b y t he i n vesti gat or.  
 
T he pr o m pt re p orti n g of a d verse e v e nts is t he res p o nsi bilit y of eac h i n vesti gat or e n g a ge d i n 
cli nical researc h, as re q uire d b y Fe deral Re g ulati o ns. A d verse e ve nts m ust be descri b e d a n d 
gra de d usi n g t he ter mi n ol o g y a n d gra di n g cate g ori es defi ne d i n t he N CI’s C o m m o n 
Ter mi n ol o g y Criteria f or A d verse E ve nts ( C T C A E), Versi o n 4. 0. T he C T C A E is a vaila ble at 
cte p.ca n cer. g o v/ pr ot oc ol De vel o p me nt/electr o nic _ a p plicati o ns/ctc. ht m. Attri b uti o n t o pr ot oc ol 
treat me nt f or eac h a d v erse e ve nt m ust be deter mi ne d b y t he i n vesti gat or a n d re p orte d o n t he 
re q uire d f or ms, usi n g t he c o des pr o vi de d. 
1 6. 1.  
R O U TI N E A D V E R S E E V E N T R E P O R TI N G  
A d verse e ve nt data c ollecti o n a n d re p orti n g, w hic h are re q uire d as part of e ver y cli nical trial 
are d o ne t o e ns ure t he s afet y of patie nts e nr olle d i n t he st u dies as well as t h ose w h o will 
e nr oll i n f ut ure st u dies usi n g si milar a ge nts.  A Es wi ll be rec or de d as part of me dical hist or y 
d uri n g Scree ni n g.   A n y ne w A Es or i ncreas e of a d oc u me nte d A E fr o m scree ni n g/ hist or y 
will be rec or de d fr o m t he ti me of t he first st u d y rel ate d pr oce d ure t hr o u g h 3 0 da ys f oll o wi n g 
cessati o n of treat me nt. A d verse e v e nts are re p orte d  i n a r o uti ne ma n ner at sc he d ule d ti mes 
acc or di n g t o t he st u d y cale n dar i n Secti o n 9 . All ad verse e v e nts are e ntere d i nt o t he e C R F i n 
Ra ve.  
 
A d verse e ve nts will n ot be c ollecte d f or p atie nts d uri n g t he pre -scree ni n g p eri o d (f or 
deter mi nati o n of arc hi v al tiss ue stat us) as l o n g as t hat patie nt has n ot u n der g o ne a n y pr ot oc ol -
s pecifie d pr oce d ure or i nter ve nti o n.  If t h e patie nt re q uir es a bl o o d dra w, fres h t u m or bi o ps y 
etc., t he p atie nt is first re q ui re d t o pr o vi de c o nse nt t o t he mai n st u d y a n d A Es will be ca pt ure d 
acc or di n g t o g ui deli nes f or sta n dar d A E re p orti n g.  
 
1 6. 2.  
E X P E DI T E D A D V E R S E E V E N T R E P O R TI N G  
I n v esti gat ors are re q uir e d b y Fe deral Re g ulati o ns t o re p ort seri o us a d verse e ve nts as defi ne d 
i n t he ta ble bel o w. I n vesti gat ors are re q uire d t o n otif y t he A F T a n d t h eir I nstit uti o nal Re vie w 
B oar d if a patie nt has a re p orta ble seri o us a d verse e ve nt. T he descri pti o ns a n d gr a di n g 
sc ales f o u n d i n t he N CI C o m m o n Ter mi n ol o g y Criteri a f or A d verse E v e nts ( C T C A E) 
ver si o n 4 will be utilize d f or A E re p orti n g.  T he C T C A E is i de ntifie d a n d l ocate d o n t he 
C T E P we bsite at: cte p.ca ncer. g o v/ pr ot oc ol D e vel o p me nt/electr o nic _ a p plicati o ns/ctc. ht m. All 
a p pr o priate treat me nt areas s h o ul d ha ve access t o a c o p y of t he C T C A E.   S A Es/I A Rs m ust 
be e ntere d i nt o t he e C R F a n d i nt o t he N o vella Ar g us Safet y M a na ge me nt S yste m, as 
a p plica ble wit hi n 2 4 h o urs of lear ni n g of t he e ve nt.    T hese will be e ntere d i nt o t he Ar g us 
s yste m wit hi n 2 4 h o urs of lear ni n g of t he e ve nt.  T his will all o w t he safet y m o nit or a n d 
m o nit or t o re vie w t he i nf or mati o n a n d assess t he s afet y of t he p atie nt.  
 
N ote:  All de at hs o n st u d y re q uire b ot h r o uti ne re p orti n g a n d re p orti n g vi a t he Ar g us 
S afet y Re p orti n g S yste m , re g ar dless of c a us alit y.  Attri b uti o n t o tre at ment or ot her c a use 
s h o ul d be pr o vi de d. 
 




 
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1 6. 2. 2.  
E ve nts of Cli nic al I nterest a n d I m m u ne Rel ate d 
A d verse E ve nts  
Selecte d n o n -seri o us a n d seri o us a d verse e v e nts are als o k n o w n as ( E CI) a n d/ or I m m u ne 
Relate d A d verse E v e nts (ir A Es) a n d m ust be rec or de d as s u c h o n t h e A d verse E ve nt case re p ort 
f or ms/ w or ks heets a n d re p orte d wit hi n 2 4 h o urs wit hi n A R G U S  Safet y Re p orti n g S yste m .  
E CIs/ir A Es a n d all S A Es, t hat occ ur i n a n y patie nt fr o m t he dat e of first st u d y relate d pr oce d ure 
t hr o u g h 9 0 da ys f oll o wi n g cess ati o n of treat me nt, or t he i nitiati o n of a ne w a ntica ncer t hera p y, 
w hic he ver is earlier, w h et her or n ot relat e d t o t he pe m br oliz u ma b ( M K -3 4 7 5) , m ust be re p orte d 
wit hi n A R G U S  Safet y Re p orti n g S yste m wit hi n 2 4 h o urs a n d A F T will  re p ort t o Merc k Gl o bal 
Safet y wit hi n 2 w or ki n g da ys.  
 
E CIs/ir A Es f or t his trial i ncl u de:  
 
1.  A n o ver d os e of pe m br oliz u ma b ( M K -3 4 7 5) , as defi ne d i n Secti o n 1 6 . 2. 3. Defi niti o n of a n 
O ver d ose f or T his Pr ot oc ol a n d Re p or ti n g of O ver d ose t o A F T, t hat is n ot ass ociate d wit h 
cli nical s y m pt o ms or a b n or mal la b orat or y res ults.  
 
2.  A n ele vate d A S T or A L T la b v al ue t hat is greater t ha n or e q ual t o 3 X t he u p per li mit of 
n or mal a n d a n ele vat e d t otal bilir u bi n la b val u e t hat is gr eater t ha n or e q u al t o 2 X t he u p p er 
li mit of n or mal a n d, at t h e sa me ti me, a n al kali ne p h os p hatase la b val ue t h at is less t ha n 2 X t he 
u p per li mit of n or mal, as deter mi ne d b y wa y of pr ot oc ol -s pecifie d la b orat or y t esti n g or 
u nsc he d ule d la b orat or y t esti n g. *  
 
* N ote:   T hese criteria are base d u p o n a vaila ble re g ul at or y g ui da nce d oc u me nts. T he p ur p ose 
of t he criteria is t o s pecif y a t hres h ol d of a b n or mal he patic tests t hat ma y re q uire a n a d diti o nal 
e val uati o n f or a n u n derl yi n g eti ol o g y.   
 
3.  I n t he e ve nt a p atie nt de vel o ps a n y of t he f oll o wi n g A Es, a d etaile d narrati ve of t he e ve nt 
s h o ul d be re p orte d as a n E CI/ir A E wit hi n A R G U S  Safet y R e p orti n g S yste m wit hi n 2 4 h o urs 
a n d A F T will re p ort t o Merc k Gl o bal Safet y wit hi n 2 w or ki n g d a ys of t he e ve nt:  
 
a.  Gra d e ≥ 3 dia rr h ea 
b.  Gra de ≥  3 c olitis  
c.  Gra d e ≥ 2 p ne u m o nitis  
d.  Gra de ≥ 3 h y p o - or h y pert h yr oi dis m  
 
Sec ti o n 1 3. 4. 3 a b o ve pr o vi des g ui da nce re gar di n g i de ntificati o n, e val uati o n a n d ma na ge m e nt 
of E CIs a n d ir A Es.  A d diti o nal E CIs are i de ntifie d i n t his secti o n a n d als o nee d t o be re p orte d 
wit hi n t he A R G U S  Safet y Re p orti n g S yste m wit hi n 2 4 h o urs a n d A F T will re p ort t o M erc k 
Gl o bal Safet y wit hi n 2 w or ki n g da ys of t he e v e nt.   
 


 
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Patie nts s h o ul d be assesse d f or p ossi ble E CIs pri or t o eac h d ose.  La b res ults s h o ul d be 
e val uate d a n d patie nts s h o ul d be as ke d f or si g ns a n d s y m pt o ms s u g gesti ve of a n i m m u ne -
relate d e v e nt.   
 
Patie nts w h o de vel o p a n E CI t h o u g ht t o be i m m u ne -rel ate d s h o ul d ha ve a d diti o nal testi n g t o 
r ule o ut ot her eti ol o gic ca uses.  If la b res ults or s y m pt o ms i n dicate a p ossi ble i m m u ne-relate d 
E CI, t h e n a d diti o nal testi n g s h o ul d b e perf or m e d t o r ule o ut ot her eti ol o gic ca use s.  If n o ot her 
ca use is f o u n d, t he n it is ass u me d t o be i m m u ne -relate d.  
 
1 6. 2. 3.  
Defi niti o n of a n O ver d ose f or t his Pr ot oc ol a n d 
Re p orti n g of O ver d ose t o A F T  
F or p ur p os es of t his trial, a n o ver d ose will be defi ne d as a n y d os e e x cee di n g t he prescri be d 
d ose f or pe m br oliz u ma b ( M K -3 4 7 5) b y 2 0 % o v er t he prescri b e d d ose. N o s pecific i nf or mati o n 
is a vaila ble o n t he tr eat me nt of o ver d ose of pe m br oliz u ma b ( M K -3 4 7 5) . I n t he e v e nt of 
o ver d ose, p e m br oliz u ma b ( M K -3 4 7 5)  s h o ul d be disc o nti n ue d a n d t he patie nt s h o ul d be 
o bser ve d cl osel y f or si g ns of t o xicit y.  A p pr o priat e s u p p orti ve treat me nt s h o ul d be pr o vi de d if 
cli nicall y i n dicat e d.  
 
If a n a d vers e e v e nt(s) is ass ociate d wit h (“res ults fr o m”) t he o ver d ose of a pe m br oliz u ma b 
( M K-3 4 7 5) , t he a d vers e e ve nt(s) is re p orte d as a seri o us a d verse e v e nt, e ve n if n o ot her 
seri o us ness criteria are m et. 
 
If a d ose of pe m br oliz u ma b ( M K-3 4 7 5)  meeti n g t he pr ot oc ol defi niti o n of o ver d ose is ta k e n 
wit h o ut a n y ass ociate d cli nical s y m pt o ms or a b n or mal la b orat or y res ults, t he o ver d ose is 
re p orte d as a n o n-seri o us E ve nt of Cli nical I nt erest ( E CI), usi n g t he ter mi n ol o g y “acci de ntal 
or i nte nti o nal o ver d ose wit h o ut a d verse effect.”  
 
1 6. 2. 4.  
Re p orti n g of Pre g n a nc y a n d L act ati o n  
Alt h o u g h pre g na nc y a n d lactati o n are n ot c o nsi dere d a d verse e v e nts, it is t he res p o nsi bilit y of 
i n vesti gat ors or t heir desi g nees t o re p ort a n y pre g n a nc y or lactati o n i n a pati e nt (s p o nta ne o usl y 
re p orte d t o t he m), i ncl u di n g t h e pre g na nc y of a mal e patie nt’s fe male part ner t hat occ urs d uri n g 
t he trial or wit hi n 1 2 0 da ys of c o m pleti n g t he trial c o m pleti n g t he tri al, or 3 0 da ys f oll o wi n g 
cessati o n of treat me nt if t he patie nt i nitiates ne w a ntica ncer t hera p y, w hic h e ver is earlier.  All 
patie nt s a n d fe mal e part ners of male p atie nts w h o bec o me pre g na nt m ust be f oll o we d t o t he 
c o m pleti o n/ter mi nati o n of t he pre g n a nc y.  Pre g na nc y o utc o mes of s p o nta ne o us a b orti o n, 
misse d a b orti o n, be ni g n h y d ati dif or m m ole, bli g hte d o v u m, fetal d eat h, i ntra uteri ne d ea t h, 
miscarria ge a n d still birt h m ust be re p orte d as seri o us e ve nts (I m p orta nt M e dical E ve nts).  If 
t he pre g na n c y c o nti n ues t o ter m, t he o utc o me ( healt h of i nfa nt) m ust als o be re p ort e d. 
1 6. 3.  
E V A L U A TI N G A D V E R S E E V E N T S  
A n i n vesti gat or w h o is a q ualifie d p h ysici a n will e val uate all a d verse e ve nts acc or di n g t o t he 
N CI C o m m o n Ter mi n ol o g y f or A d verse E ve nts ( C T C A E), versi o n 4. 0. A n y a d v erse e v e nt 
w hic h c ha n ges C T C A E gra de o ver t he c o urse of a gi ve n e pis o de will ha ve eac h c ha n ge of 
gra de rec or de d o n t he a d verse e v e nt ca s e re p ort f or ms/ w or ks heets. 
 


 
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Ta ble 1 3 bel o w f or a d diti o nal g ui da nce.


 
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Ta ble 1 3 . E val uati n g A d verse E ve nts  
 
A n i n vesti gat or w h o is a q ualifie d p h ysi cia n will e val uate all a d verse e v e nts.  
 
V 4. 0 
C T C A E 
Gr a di n g  
Gr a de 1  
Mil d; as y m pt o matic or mi d s y m pt o ms; cli nical or dia g n ostic o bser vati o ns o nl y; i nter ve nti o n n ot i n dicate d.  
 
Gr a de 2  
M o derate; mi ni mal, l ocal or n o ni n vasi ve i nter ve nti o n i n dicate d; li miti n g a ge -a p pr o priate i nstr u me ntal A D L. 
 
Gr a de 3  
Se vere or me dicall y si g nifica nt b ut n ot i m me diatel y life -t hreate ni n g; h os pitalizati o n or pr ol o n gati o n or 
h os pitalizati o n i n dicate d; disa bli n g; li miti n g self -care A D L.  
 
Gr a de 4  
Life t hreate ni n g c o nse q ue nces; ur ge nt i nter ve nti o n i n dicate d. 
 
Gr a de 5  
Deat h relate d t o A E  
Seri o us ness  
A seri o us a d verse e ve nt is a n y a d verse e ve nt occ urri n g at a n y d ose or d uri n g a n y use of Pe m br oliz u ma b  ( M K-3 4 7 5) t hat: 
 
† Res ults i n deat h; or  
 
†Is life t hreate ni n g; or places t he s u bject, i n t he vie w of t he i n vesti gat or, at i m me diate ris k of deat h fr o m t he e ve nt as it 
occ urre d ( N ote: T his d oes n ot i ncl u de a n a d verse e ve nt t hat, ha d it occ urre d i n a m ore se vere f or m, mi g ht ha ve ca use d deat h.) ; 
or  
 
† Res ults i n a persiste nt or si g nifica nt dis a bilit y/i nca pacit y (s u bsta ntial disr u pti o n of o ne’s a bilit y t o c o n d uct n or mal life 
f u ncti o ns); or 
 
† Res ults i n or pr ol o n gs a n e xisti n g i n patie nt h os pitalizati o n ( h os pitalizati o n is defi ne d as a n i n patie nt a d missi o n, re gar dle ss of 
le n gt h of sta y, e ve n if the h os pitalizati o n is a preca uti o nar y meas ure f or c o nti n ue d o bser vati o n. ( N ote: H os pitalizati o n 
[i ncl u di n g h os pitalizati o n f or a n electi ve pr oce d ure] f or a pree xisti n g c o n diti o n w hic h has n ot w orse ne d d oes n ot c o nstit ute a 
seri o us a d verse e ve nt.); or 
 
†Is  a c o n ge nital a n o mal y/ birt h defect (i n offs pri n g of s u bj ect ta ki n g t he pr o d uct re gar dless of ti me t o dia g n osis); or  
 
Is a ne w ca ncer; (t hat is n ot a c o n diti o n of t he st u d y) or 
 
Is a n o ver d ose ( w het her acci de ntal or i nte nti o nal).  A n y a d verse e ve nt ass ociate d wit h a n o ver d ose is c o nsi dere d a seri o us 
a d verse e ve nt. A n o ver d ose t hat is n ot ass ociate d wit h a n a d verse e ve nt is c o nsi dere d a n o n -seri o us e ve nt of cli nical i nterest 
a n d m ust be re p orte d wit hi n 2 4 h o urs.  
 
Ot her i m p orta nt me dical e ve nts t hat m a y n ot res ult i n deat h, n ot be life t hreate ni n g, or n ot re q uire h os pitalizati o n ma y be 
c o nsi dere d a seri o us a d verse e ve nt w he n, base d u p o n a p pr o priate me dical j u d g me nt, t he e ve nt ma y j e o par dize t he s u bject a n d 
ma y re q uire me dical or s ur gical i nter ve nti o n t o pre ve nt o ne of t he o utc o mes liste d pre vi o usl y ( desi g nate d a b o ve b y a †).  
D ur ati o n  
Rec or d t he start a n d st o p dates of t he a d verse e ve nt. If less t ha n 1 da y, i n dicate t he a p pr o priate le n gt h of ti me a n d u nits  
Acti o n 
t a ke n  
Di d t he a d verse e ve nt ca use t he Pe m br oliz u ma b  ( M K-3 4 7 5)  t o be disc o nti n ue d? 


 
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Rel ati o ns hi p 
t o test dr u g  
Di d t he Pe m br oliz u ma b  ( M K-3 4 7 5)  ca use t he a d verse e ve nt? T he deter mi nati o n of t he li keli h o o d t hat t he Pe m br oliz u ma b 
( M K-3 4 7 5)  ca use d t he a d verse e ve nt will be pr o vi de d b y a n i n vesti gat or w h o is a q ualifie d p h ysicia n. T he i n vesti gat or’s 
si g ne d/ date d i nitials o n t he s o urce d oc u me nt or w or ks heet t hat s u p p orts t he ca usalit y n ote d o n t he A E f or m, e ns ures t hat a 
me dicall y q ualifie d assess me nt of ca usalit y was d o ne. T his i nitiale d d oc u me nt m us t be retai ne d f or t he re q uire d re g ulat or y ti me 
fra me. T he criteria bel o w are i nte n de d as refere nce g ui deli nes t o assist t he i n vesti gat or i n assessi n g t he li keli h o o d of a 
relati o ns hi p bet wee n t he test dr u g a n d t he a d verse e ve nt base d u p o n t he a vaila ble i nf or mati o n.  
T he f oll o wi n g c o m p o ne nts are t o be use d t o assess t he relati o ns hi p bet wee n t he Pe m br oliz u ma b ( M K -3 4 7 5)  a n d t he A E; t he 
greater t he c orrelati o n wit h t he c o m p o ne nts a n d t heir res pecti ve ele me nts (i n n u m b er a n d/ or i nte nsit y), t he m ore li kel y t he 
Pe m br oliz u ma b ( M K -3 4 7 5)  ca use d t he a d verse e ve nt ( A E):  
 
E x p os ure  
Is t here e vi de nce t hat t he s u bj ect was act uall y e x p ose d t o t he Pe m br oliz u ma b ( M K -3 4 7 5)  s uc h as: relia ble 
hist or y, acce pta ble c o m plia nce assess me nt ( pill c o u nt, diar y, etc.), e x pecte d p har mac ol o gic effect, or 
meas ure me nt of dr u g/ meta b olite i n b o dil y s peci me n?  
 
Ti me C o urse  Di d t he A E f oll o w i n a reas o na ble te m p oral se q ue nce fr o m a d mi nistrati o n of t he Pe m br oliz u ma b ( M K -3 4 7 5) ?  
Is t he ti me of o nset of t he A E c o m pati ble wit h a dr u g-i n d uce d effect (a p plies t o trials wit h i n vesti gati o nal 
me dici nal pr o d uct)?  
 
Li kel y 
C a use  
Is t he A E n ot reas o na bl y e x plai ne d b y a n ot her eti ol o g y s uc h as u n derl yi n g disease, ot her dr u g(s)/ vacci ne(s), or 
ot her h ost or e n vir o n me ntal fact ors  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Rel ati o ns hi p  
T he  f oll o wi n g c o m p o ne nts a re t o be use d t o assess t he rel ati o ns hi p bet w ee n t he test dr u g a n d t he A E: (c o nti n ue d)  
t o 
Pe m br oliz u m a b 
( M K-3 4 7 5)  
(c o nti n ue d)  
Dec h alle n ge  
W as t he P e m br oliz u ma b ( M K -3 4 7 5)  disc o nti n ue d or d ose/e x p os ure/fre q ue nc y re d uce d?  
If yes, di d t he A E res ol ve or i m pr o ve? 
If yes, t his is a p ositi ve dec halle n ge. If n o, t his is a ne gati ve dec halle n ge. 
( N ote: T his criteri o n is n ot a p plica ble if: ( 1) t he A E res ulte d i n deat h or per ma ne nt disa bilit y; ( 2) t he A E 
res ol ve d/i m pr o ve d des pite c o nti n uati o n of t he P e m br oliz u ma b ( M K -3 4 7 5) ; or ( 3) t he trial is a si n gle-d ose dr u g trial); or 
( 4) P e m br oliz u ma b ( M K -3 4 7 5) (s) is/are o nl y use d o ne ti me.) 
 
Rec h alle n ge  
W as t he s u bj ect re -e x p ose d t o t he P e m br oliz u ma b ( M K -3 4 7 5)  i n t his st u d y? 
If yes, di d t he A E rec ur or w orse n?  
If yes, t his is a p ositi ve rec hall e n ge. If n o, t his is a ne gati ve r ec halle n ge. 
( N ote: T his criteri o n is n ot a p plica ble if: ( 1) t he i nitial A E res ulte d i n deat h or per ma ne nt disa bilit y, or ( 2) t he trial is  a 
si n gle-d ose dr u g trial); or ( 3) P e m br oliz u ma b ( M K -3 4 7 5)  is/are use d o nl y o ne ti me). 
N O T E: I F A R E C H A L L E N G E I S P L A N N E D F O R A N A D V E R S E E V E N T W HI C H W A S S E RI O U S A N D W HI C H 
M A Y H A V E B E E N C A U S E D B Y T H E P E M B R O LI Z U M A B  ( M K-3 4 7 5) , O R I F R E E X P O S U R E T O T H E 
P E M B R O LI Z U M A B ( M K -3 4 7 5)  P O S E S A D DI TI O N A L P O T E N TI A L SI G NI FI C A N T RI S K T O T H E S U BJ E C T, 
T H E N T H E R E C H A L L E N G E M U S T B E A P P R O V E D I N A D V A N C E B Y T H E U. S. C LI NI C A L M O NI T O R A S P E R 
D O S E M O DI FI C A TI O N G UI D E LI N E S I N T H E P R O T O C O L.  
 
C o nsiste nc y 
wit h Tri al 
Tre at me nt 
Pr ofile  
Is t he cli nical/ pat h ol o gical prese ntati o n of t he A E c o nsiste nt wit h pre vi o us k n o wle d ge re gar di n g t he P e m br oliz u ma b 
( M K-3 4 7 5)  or dr u g class p har mac ol o g y or t o xic ol o g y?  
T he assess me nt of relati o ns hi p will be re p orte d o n t he case re p ort f or ms / w or ks heets b y a n i n vesti gat or w h o is a q ualifi e d p h ysicia n acc or di n g t o his/ her best 
cli nical j u d g me nt, i ncl u di n g c o nsi derati o n of t he a b o ve ele me nts.  
Rec or d o ne of t he f oll o wi n g  
Use t he f oll o wi n g sc ale of criteri a as g ui d a nce ( n ot all criteri a m ust be prese nt t o be i n dic ati ve of a 
Pe m br oliz u m a b ( M K -3 4 7 5)  rel ati o ns hi p).  
Yes, t here is a re as o n a ble 
p ossi bilit y of Pe m br oliz u m a b 
( M K-3 4 7 5)  rel ati o ns hi p.  
T here is e vi de nce of e x p os ure t o  t he P e m br oliz u ma b ( M K -3 4 7 5) .  T he te m p oral se q ue nce of t he A E o nset relati ve t o t he 
a d mi nistrati o n of t he P e m br oli z u ma b ( M K -3 4 7 5)  is reas o na ble.  T he A E is m ore li kel y e x plai ne d b y t he 
P e m br oliz u ma b ( M K -3 4 7 5)  t ha n b y a n ot her ca use. 
N o, t here is n ot a re a s o n a ble 
p ossi bilit y Pe m br oliz u m a b 
( M K-3 4 7 5)  rel ati o ns hi p  
S u bj ect di d n ot recei ve t he P e m br oliz u ma b ( M K -3 4 7 5)  O R te m p oral se q ue nce of t he A E o nset relati ve t o a d mi nistrati o n 
of t he P e m br oliz u ma b ( M K -3 4 7 5)  is n ot reas o na ble O R t her e is a n ot her o b vi o us ca use of t he A E.  ( Als o e ntere d f or a 
s u bj ect wit h o ver d ose wit h o ut a n ass ociate d A E.) 


 
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1 7.  D R U G IN F O R M A TI O N  
1 7. 1.  
IN V E S TI G A TI O N A L P R O D U C T  
T he i n vesti gat or s hall ta ke res p o nsi bilit y f or a n d s hall ta ke all ste ps t o mai ntai n a p pr o priate 
rec or ds a n d e ns ure a p pr o priate s u p pl y, st ora ge, h a n dli n g, distri b uti o n a n d usa ge of 
i n vesti gati o nal pr o d uct i n acc or da n ce wit h t he pr ot oc ol a n d a n y a p plica ble la ws a n d 
re g ulati o ns. 
Cli nical S u p plies will be pr o vi de d b y Merc k as s u m marize d i n Ta ble 1 4 . 
Ta ble 1 4 .  Pr o d uct Des c ri pti o ns 
Pr o d uct N a me & P ote n c y  
D os a ge F or m  
Pe m br oliz u ma b ( M K -3 4 7 5)  1 0 0 m g/ 
4 m L  
S ol uti o n f or I njecti o n  
 
1 7. 2.  
P A C K A GI N G A N D L A B E LI N G I N F O R M A TI O N  
Cli nical s u p plies will be affi x e d wit h a cli nical la bel i n acc or da nce wit h re g ulat or y 
re q uire me nts. 
1 7. 3.  
C LI NI C A L S U P P LI E S DI S C L O S U R E  
T his trial is o pe n -la bel; t heref ore, t he patie nt, t he trial site pers o n nel, t he S p o ns or a n d/ or 
desi g nee are n ot bli n de d t o treat me nt. Dr u g i de ntit y ( na me, str e n gt h) is i ncl u de d i n t he la bel 
te xt; ra n d o m c o de/ discl os ure e n vel o p es or lists are n ot pr o vi de d. 
1 7. 4.  
S T O R A G E A N D H A N D LI N G  R E Q UI R E M E N T S  
Cli nical s u p plies m ust be st ore d i n a s ec ure, li mite d -access l ocati o n u n der t he st ora ge 
c o n diti o ns s pecifie d o n t he la bel.   
 
Recei pt a n d dis pe nsi n g of trial me di cati o n m ust be rec or de d b y a n a ut h orize d  pers o n at t he 
trial site. 
 
Cli nical s u p plies ma y n ot be use d f or a n y p ur p ose ot her t ha n t hat state d i n t he pr ot oc ol.  


 
 
 
 
Versi o n D ate 0 9 / 1 4/ 2 0 1 7 
 
 
 
 
 
 
 
Versi o n # 5. 0  
6 8  
1 7. 5.  
R E T U R N S A N D R E C O N CI L I A TI O N  
T he i n vesti gat or is res p o nsi ble f or k ee pi n g acc urate rec or ds of t he cli nical s u p plies recei ve d fr o m 
M erc k or desi g nee, t he a m o u nt dis pe nse d t o a n d ret ur ne d b y t h e patie nts  a n d t he a m o u nt re mai ni n g 
at t he c o ncl usi o n of t he trial.  
  
U p o n  c om pleti o n  or  term i nati o n of  t he st u d y, all u n use d  a n d/ or partiall y use d i n v esti gati o nal 
pr o d uct will be destr o ye d at t he  site per i nstit uti o nal p olic y. It is t he I n vesti gator ’s res p o nsi bilit y 
t o arra n ge f or dis p osal of all e m pt y c o ntai ners, pr o vi de d t hat pr oce d ures f or pr o per dis p osal ha ve 
bee n esta blis he d acc or di n g t o a p plica ble fe d eral, state, l ocal a n d i nstit uti o nal g ui d eli nes a n d 
pr oce d ures, a n d pr o vi d e d t hat a p pr o priate rec or ds of dis p osal are k e pt.  
 
1 8.  S T A TI S TI C A L C O N SI D E R A TI O N S  
T he pri mar y o bjecti ve of t his ra n d o mize d p hase II trial is t o deter mi ne t he o verall res p o nse rate 
( O R R per R E CI S T 1. 1) i n che m ot hera p y nai v e  patie nts wit h sta ge I V N S C L C aft er t h e 
a d mi nistrati o n of sta n dar d plati n u m -base d c he m ot hera p y b ef ore pe m br oliz u ma b ( M K -3 4 7 5)  (ar m 
A) a n d a d mi nistrati o n of pe m br oliz u ma b ( M K -3 4 7 5)  a d mi nistere d b ef ore sta n dar d plati n u m -bas e d 
c he m ot hera p y (ar m B).  
 
F or o ur ulti mate g oal t o select t he m ost pr o misi n g o ne fr o m t he t w o e x peri me ntal re gi me ns t o 
i n vesti gate it f urt her i n a lar ger c o m parati ve p has e II/III trial, we will use “ pic ki n g t he wi n ner” 
desi g n. [ 5 8] I n t he “ pi c ki n g t he wi n ner” desi g n, we will select t h e treat me nt re gi me n wit h t he b est 
O R R per R E CI S T 1. 1 f or f urt her i n v esti gati o n wit h n o restricti o n o n t he mi ni mal ma g nit u de of 
o bser ve d O R R differe nces a n d t he mi ni mal n u m ber of res p o n d ers.  T he mi ni mal differe nce i n t he 
n u m bers of res p o ns es of t he t w o ar ms is 1. T o be selecte d as t he “ wi n ner”, o ne treat me nt ar m m ust 
ha ve at l east 1 m or e res p o nse t ha n t he ot her.  A t otal of 9 0 eli gi ble patie nts will be ra n d o mize d wit h 
1: 1 rati o t o t he t w o ar ms wit h stratificati o n o n s m o ki n g hist or y ( ne ver, pre vi o us or c urre nt s m o k er)  
a n d hist ol o g y (s q ua m o us vs.  n o n -s q ua m o us).  
1 8. 1.  
S A M P L E S I Z E J U S TI FI C A TI O N  
W he n pe m br oliz u ma b ( M K -3 4 7 5)  was gi v e n as si n gle a ge nt f or a d va n ce d N S C L C, t he o verall 
res p o nse rates ( O R Rs) assesse d b y t h e i m m u ne-relate d res p o nse criteria a n d b y R E CI S T 1. 1 
criteria w ere 2 4 % a n d 2 1 %, res pecti vel y. We e x pect w he n sta n d ar d c h e m ot hera p y is c o m bi ne d 
wit h pe m br oliz u ma b ( M K -3 4 7 5) , t he O R R will be at least 3 0 % f or a n u ns electe d c he m ot hera p y 
nai ve  N S C L C p o p ulati o n. F or t he p ur p ose of sa m ple siz e j ustificati o n, we ass u me t h e O R R f o r 
ar m A a n d ar m B are 4 5 % a n d 3 0 %, res pecti vel y. U n der t his ass u m pti o n t he st u d y wit h 4 5 patie nts 
treate d o n eac h ar m will c h o ose t he m ost pr o misi n g ar m wit h at least 9 1 % pr o ba bilit y bas e d o n 
t he o bser ve d O R Rs, t he l east pr o misi n g ar m wit h at m ost 6 % pr o ba bilit y a n d ma ke a n i nc o ncl usi ve 
decisi o n wit h a p pr o xi matel y 3 % pr o ba bilit y. T h e t a ble bel o w dis pla ys t h e p erf or ma n ce of t his trial 
w he n t he O R Rs of t he t w o ar ms are sli g htl y differe nt fr o m t he sce n ari o we ass u me.  T he pr o ba bilit y 
of i nc o ncl usi ve is t he pr o b a bilit y t hat t he n u m bers of res p o n ses of t w o tr eat me nts are t h e sa me. I n 
a d diti o n, wit h 4 5 patie nts o n eac h ar m, t he st u d y will pr o d uce a t w o -si de d 9 0 % c o nfi de nce i nter val 
wit h a wi dt h e q ual t o 0. 2 6 0 ( 0. 2 4 2) w he n t he o bs er ve d O R R is 0. 4 5 ( 0. 3 0). [ 5 9] 
 


 
A F T - 0 9  
Versi o n D ate 0 9/ 1 4/ 2 0 1 7  
 
Versi o n # 5. 0  
6 9  
O R R 
f or A 
O R R 
f or B 
Pr o b. 
C h o osi n g A  
Pr o b. 
C h o osi n g B  
Pr o b. 
I nc o ncl usi ve 
0. 3  
0. 3  
0. 4 5 4  
0. 4 5 4 2  
0. 0 9 1 6 1  
0. 3  
0. 2  
0. 8 3 7  
0. 1 0 9 8 7  
0. 0 5 3 1 4  
0. 4 5  
0. 3 5  
0. 8 0 7  
0. 1 3 9 7 7  
0. 0 5 3 4 6  
0. 4 5  
0. 3  
0. 9 1 5  
0. 0 5 5 5 6  
0. 0 2 9 0 4  
0. 4 5  
0. 2  
0. 9 9 4  
0. 0 0 3 3 1  
0. 0 0 3 1 4  
 
1 8. 2.  
A C C R U A L A N D F O L L O W U P  
Ass u mi n g a 5 % ca ncellati o n a n d i neli gi bilit y rate, t he st u d y will re gister a t otal of 9 5 patie nts. I n 
a si milar patie nt p o p ulati o n, C A L G B 9 7 3 0 a n d C A L G B 3 0 8 0 1 accr ue d a p pr o xi matel y 1 5 p atie nts 
per m o nt h. At a n e nr oll me nt  rate of 8 patie nts per m o nt h, t he trial will reac h its accr ual tar get i n 
a p pr o xi matel y 1 2 m o nt hs. All  ra n d o mize d patie nts will be f oll o we d f or res p o nse, pr o gressi o n free 
s ur vi val a n d o verall s ur vi val f or 3 0  m o nt hs after t h e last e nr oll me nt.  
1 8. 3.  
A D V E R S E E V E N T S M
O NI T O RI N G  
If 5 or m ore of t h e first 2 0 patie nts i n a n y of t he t w o ar ms e x perie nce gra d e 4/ 5 n o n-he m at ol o gi c 
a d verse e ve nts t hat are pr o ba bl y, p ossi bl y, or d efi nitel y rel ate d t o st u d y treat me nt, O R if t he rate 
of treat me nt -relate d deat hs wit hi n t he first 6 0 da ys e x cee ds 4 or m ore i n a n ar m a m o n g t h e first 2 0 
patie nts at a n y ti me, accr ual t o t he st u d y wil l be s us pe n de d t o all o w f or i n vesti gati o n. After 
c o nsi derati o n b y t he st u d y t ea m, a decisi o n will be ma de as t o w het her accr ual ca n be res u me d, 
p ote ntiall y wit h m o dificati o ns t o e ntr y criteria a n d/ or st u d y c o n d u ct.   
1 8. 4.  
S T A TI S TI C A L A N A L Y SI S P L A N  
All ra n d o mize d patie nts will be i ncl u de d i n t he pri mar y a nal ysis. T u m or res p o nse d ue t o pr ot oc ol 
treat me nts will be deter mi ne d b y R E CI S T 1. 1. F or eac h treat me nt ar m O R R per R E CI S T 1. 1 d ue 
t o eac h t y p e of treat me nt a ge nt will b e esti mate d a n d t he e x act 9 5 % c o nfi de nce i n ter val will be 
pr o vi de d. T he c o m bi ne d O R R d ue t o car b o plati n -base d - c he m ot hera p y a n d pe m br oliz u ma b ( M K -
3 4 7 5)  u p t o t he first 8 c ycles  will be esti mate d a n d t heir e x act 9 5 % c o nfi d e nce i nter vals will be 
gi ve n. F or e x pl orat or y p ur p ose, t he differe nce of O R R per R E CI S T 1. 1 b et w ee n P D -L 1 e x pressi o n 
le vels ( p ositi ve vs. ne gati ve) will als o be e x a mi ne d.  M ulti variate l o gistic re gressi o n will be use d 
t o e val uate t h e effects of treat me nt ar m a n d P D-L 1 le vels o n O R R w hile a dj usti n g f or ot h er ris k 
fact ors. T he res p o nse d urati o n of pe m br oliz u ma b ( M K -3 4 7 5)  as well as its 9 5 % c o nfi de nce 
i nter val will be esti mate d se paratel y f or eac h ar m. Res p o nse d urati o n is defi ne d as ti me fr o m t he 
first assess me nt of C R/ P R u ntil t he first occ urre n ce of P D, or u ntil t he date of deat h (if occ urre d 
wit hi n 1 year).  T he O R R per ir R C will be defi ne d a n d a nal yze d wit h t he s a me a p pr oac h as O R R 
per R E CI S T 1. 1.  
 
F or eac h treat me nt p h as e (ar m A: C b + Pac/ Pe m 4  c ycles, p e m br oliz u ma b ( M K -3 4 7 5)  4  c ycl es, 
pe m br oliz u ma b ( M K -3 4 7 5)  u p t o 1 year ; ar m B: p e m br oliz u ma b ( M K -3 4 7 5)  4  c ycles, 
C b + Pac/ Pe m 4  c ycles, pe m br oliz u ma b ( M K -3 4 7 5)  u p t o 1 year , t he c u m ulati ve res p o nse rate ( R R) 
base d o n R E CI S T  1. 1  a n d ir R C will be calc ul ate d as well as t h eir 9 5 % CIs. T he baseli ne 
meas ure me nt f or ir R C will be reset at t he be gi n ni n g of  eac h p e m br oliz u ma b ( M K -3 4 7 5)  p h ase , 
w hile t he baseli ne me as ure f or R E CI S T  1. 1  will n ot be reset f or eac h treat me nt p hase.  


 
A F T - 0 9  
Versi o n D ate 0 9/ 1 4/ 2 0 1 7  
 
Versi o n # 5. 0  
7 0  
 
Pr o gressi o n -free s ur vi v al ( P F S) will be defi n e d wit h disease pr o gressi o n d eter mi ne d per R E CI S T 
1. 1 criteria.  T h e me dia n  pr o gressi o n free s ur vi v al ( m P F S) a n d its 9 5 % c o nfi de nce i nter val will be 
esti mate d f or eac h ar m. L o g ra n k test will be use d t o test t he s ur vi val differe nce f or descri pti ve 
p ur p ose. T he differe n ce of P F S per R E CI S T 1. 1 bet wee n P D -L 1 e x pressi o n le vels ( p osi ti ve vs. 
ne gati ve) will als o be c haract erize d.  M ulti varia ble C o x re gressi o n will be use d t o e val uate t he 
effect of treat me nt ar ms a n d P D -L 1 e x pressi o n le vels o n P F S w hile a dj usti n g f or ot her ris k fact ors. 
Pr o gressi o n -free s ur vi val will als o be defi ne d accor di n g t o t he ir R C criteria. P F S per ir R C will be 
a nal yze d wit h t he sa me a p pr oac h of P F S per R E CI S T 1. 1. Si milar a nal yses will be c o n d ucte d f or 
o verall s ur vi val ( O S).  
 
T he a nal ysis f or P F S a n d O S will be c o n d uct e d after a b o ut 6 7 % p atie nts e x perie nce d t he 
c orres p o n di n g e ve nts. All patie nts will be f oll o we d f or b ot h e n d p oi nts f or at least 2 4 m o nt hs a n d 
it will pr o vi de s ufficie nt ti me le n gt h t o o bser ve t he re q uire d n u m bers of e v e nts.  
 
T he ass ociati o n bet w ee n P D -L 1 e x pressi o n a n d cli nical o utc o mes, i ncl u di n g O R R, P F S a n d O S 
will be e v al uate d usi n g m ulti varia ble re gressi o n m o dels wit h P D -L 1 as i n de pe n de nt v aria bl es 
w hile a dj usti n g f or treat me nt ar m a n d ot her pr o g n ostic fact ors.  
 
T he ass ociati o n bet wee n s m o ki n g stat us ( ne ver, f o r mer/li g ht, c urre nt s m o kers) a n d cli nical 
o utc o mes, i ncl u di n g O R R, P F S a n d O S will be e v al uate d i n m ulti varia bl e re gressi o n m o dels w hile 
a dj usti n g f or tr eat me nt ar m a n d ot her pr o g n ostic fact ors.  
 
T he fre q ue n cies a n d perce nta ges of treat me nt relate d a d verse e v e nts of pe m br oliz u ma b ( M K -
3 4 7 5)  a n d plati n u m -base d c he m ot hera p y will be s u m marize d b y a d verse e ve nt t y pe a n d gra d e f or 
eac h tr eat me nt ar m.  
 
T he sa m ple siz e of t his ra n d o mize d p hase II trial is deter mi ne d f or a pic k -t he-wi n ner desi g n wit h 
R E CI S T O R R as t he pri mar y e n d p oi nt. T he rec o m me n dati o n a b o ut w hic h treat me nt  ar m will  be  
i n vesti gate d i n f ut ure tri als will be deci de d base d o n a t otalit y of e vi de nce fr o m eac h treat me nt 
ar m re gar di n g of c u m ulati ve  res p o nse rat es bas e d o n R E CI S T a n d ir R C, pr o gressi o n free s ur vi val, 
o verall s ur vi val a n d treat me nt relate d a d v erse e ve nts .  
 
 
 
1 9.  G E N E R A L R E G U L A T O R Y A N D O T H E R C O N SI D E R A TI O N S  
1 9. 1.  
C O M P LI A N C E  
WI T H 
T RI A L 
E N R O L L M E N T 
A N D 
R E S U L T S 
P O S TI N G 
R E Q UI R E M E N T S  
U n der t he ter ms of t he F o o d a n d Dr u g A d mi nistrati o n M o der nizati o n Act ( F D A M A) a n d t he F o o d 
a n d Dr u g A d mi nistrati o n A me n d me nts Act ( F D A A A), t he S p o ns or of t he trial is s olel y res p o nsi ble 
f or deter mi ni n g w het her t he trial a n d its res ults are s u bject t o t he re q uir e me nts f or s u b missi o n t o 
t he Cli nical Trials Data Ba n k, htt p:// w w w.cli ni caltrials. g o v.  I nf or mati o n p oste d will all o w 
patie nts t o i de ntif y p ot e ntiall y a p pr o priate trials f or t heir disease c o n diti o ns a n d p urs ue 
partici pati o n b y calli n g a ce ntral c o ntact n u m ber f or f urt her i nf or mati o n o n a p pr o priate trial 
l ocati o ns a n d trial site c o ntact i nf or mati o n. 


 
A F T - 0 9  
Versi o n D ate 0 9/ 1 4/ 2 0 1 7  
 
Versi o n # 5. 0  
7 1  
 
1 9. 2.  
R E G U L A T O R Y A N D E T HI C A L C O M P LI A N C E  
 
 
T his st u d y will be c o n d ucte d i n c o m plia nce wit h t he st u d y pr ot oc ol, s u bse q ue nt a me n d me nt(s) a n d 
wit h t he st u d y -s pecific m a n uals/ g ui deli nes, if a p plica ble. T h ese d oc u me nts e ns ure t hat t h e I C H E 6 
g ui deli ne f or G o o d Cli nical Practice is mai ntai ne d as well as c o m plia nce wit h t he pri nci ples of t he 
Declarati o n of Helsi n ki ( W orl d Me dical Ass ociati o n), or t he la ws a n d re g ulati o ns of t he c o u ntr y 
i n w hic h t he researc h is c o n d ucte d, w hic he v er aff or d t he greater pr ot ecti o n t o t he i n di vi d ual.  
 
St u dies c o n d ucte d i n t he U nite d States or u n der a U. S. I n vesti gati o nal Ne w Dr u g (I N D) a p plicati o n 
will c o m pl y wit h U. S. F D A re g ulati o n a n d a p plica ble l ocal, state a n d fe d eral la ws.  
 
 
1 9. 3.  
IN F O R M E D C O N S E N T  
 
It is t he res p o nsi bilit y of t he I n v esti gat or, or a p ers o n desi g nat e d b y t he I n vesti gat or (if acce pta ble 
b y l ocal re g ulati o ns), t o o btai n writte n I nf or me d C o nse nt fr o m eac h p atie nt partici pati n g i n t his 
st u d y, after a de q uat e e x pla nati o n of t he ai ms, met h o ds, a ntici pate d be n efits, a n d p ote ntial hazar ds 
of t he st u d y. T his i nf or mati o n m ust be pr o vi de d t o t he patie nt pri or t o u n derta ki n g a n y st u d y -
relate d pr oce d ure w hic h is n ot part of t he r o uti ne cli nical ma na ge me nt of t he patie nt (i.e. w o ul d 
n ot be i n dicate d o utsi de t he st u d y). T he pr o p ose d I nf or me d C o nse nt F or m  a n d c o nse nti n g pr ocess  
m ust c o m pl y 
wit h t he 
G C P g ui deli ne s, re g ulat or y re q uire m e nts a n d be c o nsiste nt 
wit h 
I R B/i nstit uti o nal p olicies .  
 
 
1 9. 4.  
R E S P O N SI BI LI TI E S O F T H E IN V E S TI G A T O R /I R B/I E C/ R E B 
T he re g ulat or y re q uir e me nts f or t he I n vesti gat or ca n be f o u n d i n S u b part D of 2 1 C F R 3 1 2 ( 2 1 C F R 
3 1 2. 6 0: Ge neral Res p o nsi bilities of I n vesti gat ors) a n d i n I C H E 6 Secti o n 4.  
 
A d diti o nal re q uire me nts are als o o utli ne d i n t he State me nt of I n vesti gat or Res p o nsi bilities ( F or m 
F D A 1 5 7 2) a n d t he Site Ser vices A gree me nt.  Allia nce F o u n d ati o n Trials, L L C ( A F T) will s u p pl y 
t he pr ot oc ol a n d s u bse q u e nt a me n d me nts.  
 
T he i n vesti gat or is res p o nsi ble f or o verall st u d y c o m plia nce, e x ec uti o n, o versi g ht a n d m a na ge m e nt 
of t he st u d y at t heir s ite, a n d satellite sites if a p plica ble.  
 
As s pecifie d i n 2 1 C F R 3 1 2. 6 2(I n vesti gat or Rec or d Kee pi n g a n d Rec or d Rete nti o n) a n d I C H E 6 
Secti o ns 4. 9 a n d 8, t he I n vesti gat or is r es p o nsi ble f or e ns uri n g t hat t heir st u d y staff mai ntai ns a n d 
retai ns all st u d y relate d d oc u me ntati o n, i ncl u di n g b ut n ot li mite d t o: si g ne d I nf or me d C o nse nt 
f or ms, s o urce d oc u me nts, pr ot oc ol d oc u me nts , I nstit uti o nal Re vie w B o ar d (I R B) a p pr o vals, 
rele va nt I R B a n d S p o ns or c orres p o n de n ce, a n d ass orte d re g ul at or y d o c u me nts.  T he I n vesti gat or 


 
A F T - 0 9  
Versi o n D ate 0 9/ 1 4/ 2 0 1 7  
 
Versi o n # 5. 0  
7 2  
is res p o nsi ble f or retai ni n g a n d kee pi n g safe all patie nt relate d d oc u me ntati o n.  I n or der t o d o t his, 
t he site staff will c o m plete electr o ni c cas e re p ort f or ms (e C R Fs) i n a ti mel y ma n ner.  
1 9. 5.  
F I N A N CI A L D I S C L O S U R E 
I n v esti gat ors will pr o vi de A F T wit h a d e q uate a n d acc urate fi na n cial i nf or mati o n i n acc or da nce 
wit h l ocal re g ulati o ns a n d la ws i n or der t o all o w A F T t o s u b mit c o m plete a n d acc urate fi na ncial 
certificati o n or discl os ure state me nts t o t he a p pr o priate healt h a ut h orities. I n v esti gat ors are 
res p o nsi ble f or pr o vi di n g u p date d i nf or mati o n o n fi na ncial i nterests d uri n g t he c o urse of t he st u d y 
as well as f or 1 year after c o m pleti o n of t he st u d y.  
1 9. 6.  
P R O T O C O L D E VI A TI O N S  
T he i n vesti gat or is res p o nsi ble t o d oc u me nt a n d e x plai n a n y de viati o ns fr o m t he a p pr o ve d 
pr ot oc ol.  T he i n vesti gat or s h o ul d pr o m ptl y re p ort a n y de vi ati o ns t hat mi g ht i m pact patie nt safet y 
a n d data i nte grit y t o A F T a n d if l ocall y a p plica ble, t o t he res pecti ve I R B i n acc or da nce wit h l ocal 
I R B p olicies a n d pr o ce d ures.  
 
A de viati o n is a de p art ure fr o m t he pr ot oc ol.   If d e viati o ns are dis c o vere d b y t he m o nit or or data 
ma na ger, ot her me m ber of st u d y staff or ot her wise, t he y will be disc usse d wit h t he I n vesti gat or 
a n d st u d y staff.   A F T d o es n ot  pr o vi de wai vers f or pr ot oc ol de viati o ns.   
1 9. 7.  
P R O T O C O L A M E N D M E N T S  
 
A n y m o dificati o ns t o t he pr ot oc ol or t he I nf or me d C o nse nt F or m w hic h ma y i m pact o n t he c o n d uct 
of t he st u d y, p ote ntial be nefit of t he st u d y, or ma y affect patie nt safet y, i ncl u di n g c ha n ges of st u d y 
o bjecti ves, st u d y desi g n, patie nt p o p ulati o n, sa m ple siz es , st u d y pr oce d ures, or si g nifica nt 
a d mi nistrati ve as pects will re q uire a f or mal a me n d me nt t o t he pr ot oc ol. S uc h a me n d me nt will be 
releas e d b y A F T, a gree d b y t he i n vesti gat or(s) a n d a p pr o ve d b y rele va nt I R Bs pri or t o 
i m ple me ntati o n. A si g n e d a n d dat e d stateme nt t h at t he pr ot oc ol, a n y s u bse q ue nt rele va nt a me n de d 
d oc u me nts a n d t he I nf or me d C o nse nt F or m ha ve bee n a p pr o ve d b y rele va nt I R Bs m ust be 
pr o vi de d t o A F T bef ore t he st u d y is i nitiate d. Beca use a d mi nistrati ve pr ocessi n g of a me n d me nts 
ma y t a ke ti me w hi c h c o ul d i m pact st u d y c o n d uct, A F T m a y release o perati o nal me m os t o all o w 
s uc h c ha n ges t o t he pr ot o c ol c o n d uct t o o cc ur pri or t o t he f or mal a me n d me nt re vie w  wi t ho ut bei n g 
c o nsi dere d a pr ot oc ol d e viati o n.  T his is partic ularl y tr ue f or c ha n ges w hic h i m pact patie nt safet y. 
S uc h me m os s h o ul d be pr ocesse d p er l ocal I R B/ i nstit uti o nal sta n dar d.  
 
A d mi nistrati ve c ha n ges of t he pr ot oc ol are mi n or c orrecti o ns a n d/ or clarificati o ns t hat ha ve n o 
effect o n t he wa y t he  st u d y is t o be c o n d ucte d. T hese a d mi nistrati ve c ha n ges will be release d b y 
t he A F T, a gree d b y t he i n vesti gat or(s) a n d n otifie d t o t he I R B as per i nstit uti o nal g ui deli nes .  
 
1 9. 8.  
R E T E N TI O N O F R E C O R D S  
 
A n y rec or ds a n d d oc u me nts relati n g t o t he c o n d uct of t his st u d y a n d t he distri b uti o n of 
i n vesti gati o nal dr u g, m ust be retai n e d b y t he st u d y c hair u ntil n otificati o n b y A F T, or f or t he le n gt h 
of ti me re q uire d b y rele va nt nati o nal or l ocal healt h a ut h orities, w hic h e v er is l o n ger. After t hat 
peri o d of ti me, t he d oc u me nts ma y b e destr o ye d, s u bject t o l ocal re g ulati o ns. N o rec or ds ma y b e 


 
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dis p ose d of wit h o ut t he writte n a p pr o val of A F T. Writte n n otificati o n s h o ul d be pr o vi de d t o A F T 
pri or t o tra nsferri n g a n y rec or ds t o a n ot her part y or m o vi n g t he m t o a n ot her l ocati o n.  
 
If t he I n v esti gat or bec o mes u na ble f or a n y reas o n t o c o nti n ue t o ret ai n st u d y rec or ds f or t h e 
re q uire d peri o d (e g. retire me nt, rel ocati o n), A F T s h o ul d be pr os pecti vel y n otifie d. T he st u d y 
rec or ds m ust be tra nsferre d t o a desi g n ee acce pta ble t o A F T, s uc h as an ot h er i n vesti gat or, a n ot her 
i nstit uti o n, or t o A F T itself.  
 
1 9. 9.  
D A T A C O N FI D E N TI A LI T Y  
 
Patie nt me dical i nf or mati o n b ot h, ass ociate d wit h bi ol o gic s peci me ns, is c o nfi de ntial a n d ma y o nl y 
be discl ose d t o t hir d parties as per mitte d b y t h e I C F ( or se parate a ut h or izati o n f or use a n d 
discl os ure of pers o n al healt h i nf or mati o n) w hi c h has bee n si g ne d b y t h e p atie nt, u nless per mitte d 
or re q uire d b y la w. D ata deri ve d fr o m bi ol o gic s peci me n a nal ysis o n i n di vi d ual patie nts will n ot 
be pr o vi de d t o st u d y i n vesti gat ors u nless  a re q uest f or researc h us e is gra nt e d. T he o v erall res ults 
of a n y researc h c o n d u cte d usi n g bi ol o gic s peci me ns will be a vaila ble i n acc or da nce wit h t he 
effecti ve A F T p olic y o n st u d y data p u blicati o n.  
 
Data c ollect e d d uri n g t his st u d y ma y be use d t o s u p p ort  t he de vel o p me nt, re gistrati o n or mar keti n g 
of a n i n vesti gati o nal pr o d uct. All data c ollecte d d uri n g t he st u d y will be c o ntr olle d b y t h e S p o ns or, 
A F T. A F T will a bi de b y a ll rele v a nt data pr otecti o n la ws. Aft er a patie nt h as c o nse nte d t o ta ke p art 
i n t he stu d y, t heir me dical rec or ds a n d t he data c ollecte d d uri n g t he st u d y ma y  b e re vie we d b y 
re pres e ntati ves of t he S p o ns or t o c o nfir m t hat t he data c ollecte d are acc urate a n d f or t he p ur p os e 
of a nal yzi n g t he res ults. T hese rec or ds a n d data ma y be a d diti o nall y re vi e we d b y a u dit ors or b y 
re g ulat or y a ut h orities.  
 
 
 
 
1 9. 1 0.  
D A T A B A S E M
A N A G E M E N T A N D Q U A LI T Y C O N T R O L  
 
Ra ve E D C will be use d f or t his st u d y. T he st u d y d ata will be e ntere d  b y st u d y-site pers o n nel fr o m 
t he s o urce d o c u me nts o nt o a n e C R F i n R A V E E D C.  
e C R Fs  will be c o m plete d i n a ti mel y ma n ner. 
 
I n acc or da nce wit h fe d eral re g ulati o ns, t he I n v esti gat or is res p o nsi ble f or t he acc urac y a n d 
a ut he nticit y of all cli nical a n d la b orat or y d ata e ntere d o nt o e C R Fs .  
At st u d y c o m pleti o n, w he n t he data bas e has bee n decla re d t o be c o m plete a n d acc urate, t he 
data base will be l oc k e d.  
 
If ne w p e m br oliz u ma b  ( M K-3 4 7 5)  safet y i nf or mati o n res ults i n si g nifica nt c ha n ges i n t he 
ris k/ be nefit assess me nt, t he I nf or me d C o nse nt F or m s h o ul d be re vie we d a n d u p date d if necessar y. 
All pati e nts w h o ma y b e directl y affect e d (i ncl u di n g t h ose alr ea d y b ei n g tr eate d) s h o ul d b e 
i nf or me d of t he n e w i nf or mati o n, gi ve n a re vise d f or m a n d gi ve t h eir c o ns e nt t o c o nti n ue i n t he 
st u d y. 


 
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1 9. 1 1.  
S I T E M
O NI T O RI N G  
M o nit ori n g visits will be c o n d ucte d b y re pres e ntat i ves of t h e Allia nce F o u n d ati o n acc or di n g t o t h e 
U S C F R Title 2 1 Parts 5 0, 5 6, a n d 3 1 2 a n d I C H G ui deli nes f or G C P ( E 6).  
 
1 9. 1 2.  
D A T A A N D S A F E T Y M
O NI T O RI N G B O A R D ( D S M B) 
T he Allia nce F o u n d ati o n Trials Data Safet y M o nit ori n g B o ar d will be m o nit ori n g t his st u d y  t o 
ens ure o bjecti vit y a n d t he safet y of partici pa nts . T h e D S M B will meet t wice a year eit her at a face -
t o-face meeti n g or b y tel ec o nfere n ce. At eac h meeti n g, t he st u d y will be re vie we d f or s afet y a n d 
pr o gress t o war d c o m pleti o n. 
W he n a p pr o priate, t he D S M B will als o re vie w f or m al i nteri m 
a nal ys es of t he o utc o m e data. If n ecess ar y, t h e D S M B will rec o m me n d st u d y cl os ure or 
m o dificati o ns. A n y D S M B rec o m me n d ati o ns f or c h a n ges t o t he st u d y will be circ ulat e d t o 
i n vesti gat ors i n t he f or m of a n a d de n d u m t o t his pr ot oc ol d oc u me nt.  
T he D S M B will i ncl u d e accr ual d ata, a d v erse e ve nts, a n d res ults of i nteri m a nal yses w he n 
a vaila ble. I n deter mi ni n g w h et her t he st u d y s h o ul d be c o nti n ue d, t he D S M B will c o nsi der t h e 
res ults of eac h i nteri m a nal ysis, as d escri be d a b o ve. T he D S M B will als o c o nsi der t he e vi d e nce 
re gar di n g s afet y, i.e. a d v erse e v e nts a n d t he feasi bilit y of c o m pleti n g t he st u d y, i.e., t he accr ual 
rate. Wei g hi n g t he a d vers e e ve nts a n d t he feasi bilit y of st u d y c o m pleti o n is c o m ple x a n d t heref ore 
n o partic ular c ut -offs o f t hese meas ure me nts are pr o vi de d i n a d va nce. T he D S M B will use its 
discreti o n i n wei g hi n g t h ese meas ur e me nts.   
 
1 9. 1 3.  
R E G U L A T O R Y R E P O R TI N G  
Seri o us a d vers e e v e nts will be f or w ar de d t o F D A b y t he I N D S p o ns or , A F T, acc or di n g t o 2 1 C F R 
3 1 2. 3 2.  
 
It is t he res p o nsi bilit y of t he i n vesti gat or a n d t h e res earc h tea m t o e ns ure t hat seri o us a d v erse 
e ve nts are re p orte d acc or di n g t o t he C o de of Fe d eral Re g ulati o ns, G o o d Cli nical Practices ( G C P), 
t he pr ot oc ol g ui d eli nes, A F T’s g ui deli nes, a n d I nstit uti o nal Re vie w B oar d (I R B) p olic y.  
 
1 9. 1 4.  
A U DI T S A N D IN S P E C TI O N S  
T o e na ble e val u ati o ns a n d/ or a u dits fr o m h ealt h a ut h orities or A F T, t he I n vesti gat or a grees t o k ee p 
rec or ds, i ncl u di n g t he i d e ntit y of all p artici pati n g s u bjects (s ufficie nt i nf or mati o n t o li n k rec or ds, 
e. g., e C R Fs a n d h os pital rec or ds), all ori gi n al si g n e d i nf or me d c o nse nt f or ms, c o pies of all e C R Fs, 
safet y re p orti n g f or ms, s o urce d oc u me nts, a n d detaile d rec or ds of treat me nt dis p ositi o n, a n d 
a de q uate d o c u me ntati o n of rele v a nt c orres p o n de n ce (e. g., l etters , meeti n g mi n utes, tele p h o ne calls 
re p orts).I n t he e ve nt t hat t he i n vesti gat or or ot her site pers o n nel are n otifie d of a Healt h A ut h orit y's 
i nte nt t o i ns pect t he site(s), n otificati o n will b e se nt t o c o m plia nce @allia ncef o u n dati o ntrials. or g  
i m me diatel y u p o n a ware ness. I n v esti gat or sites will be a u dite d b y A F T u n der t he A F T site a u dit 
pr o gra m. Sites will b e a u dite d wit hi n ei g htee n ( 1 8) m o nt hs of first patie nt i n ( F PI) o n a n y A F T 


 
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s p o ns ore d st u d y. Affiliate a n d s atellite sites are s u bject t o a u dit b y A F T b ut i n m ost cases will be 
ce ntrall y a u dite d at t he mai n me m ber site.   
 
1 9. 1 5.  
C LI NI C A L C RI T E RI A F O R E A R L Y T RI A L T E R MI N A TI O N  
Earl y trial ter mi nati o n will be t he res ult of t he criteria s pecifie d b el o w:  
1.  Q ualit y or q ua ntit y of dat a rec or di n g is i nacc urate or i nc o m plete  
2.  P o or a d here n ce t o pr ot oc ol a n d re g ulat or y re q uire me nts  
3.  I n ci de nce or se verit y of a d verse dr u g reacti o n i n t his or ot her st u dies i n dicates a 
p ote ntial healt h hazar d t o s u bjects  
4.  Pla ns t o m o dif y or disc o nti n ue t he de vel o p me nt of t he st u d y dr u g  
I n t he e v e nt of Merc k decisi o n t o n o l o n ger s u p pl y st u d y dr u g, a m ple n otificati o n will be pr o vi de d 
s o t hat a p pr o priate a dj ust me nts t o s u bject treat me nt ca n be ma de.  
 
1 9. 1 6.  
P U B LI C A TI O N O F S T U D Y P R O T O C O L A N D R E S U L T S  
 
Allia nce F o u n d ati o n Trials, L L C pri oritizes t he ti mel y prese ntati o n a n d p u blicati o n of st u d y 
res ults. P u blicati o ns a n d a n y ki n d of prese ntati o ns of res ults fr o m t he st u d y s hall be i n acc or da nce 
wit h acce pte d s cie ntific practice, aca de mic sta n dar ds  a n d c ust o ms a n d m ust be a p pr o ve d i n writi n g 
b y A F T as t he s p o ns or of t his st u d y. N o i n vesti gat or ma y prese nt or p u blis h a n y p orti o n of t his 
st u d y wit h o ut writte n a p pr o val fr o m A F T.  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2 0.  L I S T O F R E F E R E N C E S  
1.  
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2.  
Sie gel, R., et al., C a ncer st atistics, 2 0 1 4.  C A Ca ncer J Cli n, 2 0 1 4. 6 4 ( 1): p. 9-2 9.  
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S oci ns ki, M. A., et al., Tre at me nt of st a ge I V n o n -s m all cell l u n g c a ncer: Di a g n osis a n d 
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cli nic al pr actice g ui deli nes.  C hest, 2 0 1 3. 1 4 3 ( 5 S u p pl): p. e 3 4 1 S-6 8 S.  
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Sc hiller, J. H., e t al., C o m p aris o n of f o ur c he m ot her a py re gi me ns f or a dv a n ce d n o n -s m all-
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J o h ns o n, D. H., et al., R a n d o mize d p h ase II tri al c o m p ari n g bev aciz u m a b pl us c ar b o pl ati n 
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a dv a nce d or met ast atic n o n -s m all-cell l u n g c a ncer.  J Cli n O nc ol, 2 0 0 4. 2 2 ( 1 1): p. 2 1 8 4-
9 1.  
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Sca gli otti, G. V., et al., P h ase III st u dy c o m p ari n g cis pl ati n pl us ge mcit a bi ne wit h cis pl ati n 
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1 0.  
Mae m o n d o, M., et al., Gefiti ni b or c he m ot her a py f or n o n -s m all-cell l u n g c a ncer wit h 
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1 1.  
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cell l u n g c a ncer h ar b o uri n g 
m ut ati o ns of t he e pi der m al gr o wt h f act or rece pt or 
( WJ T O G 3 4 0 5): a n o pe n l a bel, r a n d o mise d p h ase 3 tri al. La ncet O nc ol, 2 0 1 0. 1 1 ( 2): p. 
1 2 1 -8.  
1 2.  
Z h o u, C., et a l., Erl oti ni b vers us c he m ot her a p y as first -li ne tre at me nt f or p atie nts wit h 
a dv a nce d E G F R m ut ati o n -p ositive n o n -s m all-cell l u n g c a ncer ( O P TI M A L, C T O N G -
0 8 0 2): a m ultice ntre, o p e n -l a bel, r a n d o mise d, p h ase 3 st u dy. La ncet O nc ol, 2 0 1 1. 1 2 ( 8): 
p. 7 3 5 -4 2.  
1 3.  
R osell, R., et al., Erl oti ni b vers us st a n d ar d c he m ot her a py as first -li ne tre at me nt f or 
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1 4.  
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1 5.  
S ha w, A. T., et al., Criz oti ni b vers us c he m ot her a py i n a dv a nce d A L K -p ositive l u n g c a ncer.  
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1 6.  
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1 9.  
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2 0.  
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2 5.  
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ass oci ate d wit h a f av or a ble pr o g n osis.  A p pl I m m u n o hist oc he m M ol M or p h ol, 2 0 1 0. 1 8 ( 1): 
p. 2 4 -8.  
2 6.  
Tal ma d ge, J. E., M. D o n k or, a n d E. Sc h olar, I nfl a m m at ory cell i nfiltr ati o n of t u m ors: Jekyll 
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2 7.  
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2 8.  
Al -S hi bli, K.I., et al., Pr o g n ostic effect of e pit heli al a n d str o m al ly m p h ocyte i nfiltr ati o n i n 
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2 9.  
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3 0.  
Gal o n, J., et al., Ty pe, de nsity, a n d l oc ati o n of i m m u ne cells wit hi n h u m a n c ol orect al 
t u m ors pre dict cli nic al o utc o me. Scie nce, 2 0 0 6. 3 1 3 ( 5 7 9 5): p. 1 9 6 0-4.  
3 1.  
N o bili, C., et al., Pr ol o n ge d s urviv al of a p atie nt affecte d by p a ncr e atic a de n oc arci n o m a 
wit h m assive ly m p h ocyte a n d de n dritic cell i nfiltr ati o n after i nterle uki n -2 i m m u n ot her a py. 
Re p ort of a c ase.  T u m ori, 2 0 0 8. 9 4 ( 3): p. 4 2 6-3 0.  
3 2.  
H o di, F. S. a n d G. Dra n off, T he bi ol o gic i m p ort a nce of t u m or -i nfiltr ati n g ly m p h ocytes. J 
C uta n Pat h ol, 2 0 1 0. 3 7 S u p pl 1 : p. 4 8-5 3.  
3 3.  
Kl o or, M., Ly m p h ocyte i nfiltr ati o n a n d pr o g n osis i n c ol orect al c a ncer.  La n cet O nc ol, 
2 0 0 9. 1 0 ( 9): p. 8 4 0-1.  
3 4.  
Lee, H. E., et al., Pr o g n ostic i m plic ati o ns of ty pe a n d de nsity of t u m o ur -i nfiltr ati n g 
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3 5.  
Leffers, N., et al., Pr o g n ostic si g nific a nce of t u m or -i nfiltr ati n g T-ly m p h ocytes i n pri m ary 
a n d met ast atic lesi o ns of a dv a nce d st a ge ov ari a n c a ncer.  C a ncer I m m u n ol I m m u n ot her, 
2 0 0 9. 5 8 ( 3): p. 4 4 9 -5 9.  


 
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7 8  
3 6.  
Nis hi m ura, H., T. H o nj o, a n d N. Mi nat o, F acilit ati o n of bet a selecti o n a n d m o dific ati o n of 
p ositive selecti o n i n t he t hy m us of P D -1 -d eficie nt mice.  J E x p Me d, 2 0 0 0. 1 9 1 ( 5): p. 8 9 1-
8.  
3 7.  
Hira o ka, N., T u m or -i nfiltr ati n g ly m p h ocytes a n d he p at ocell ul ar c ar ci n o m a: m olec ul ar 
bi ol o gy.  I nt J Cli n O nc ol, 2 0 1 0. 1 5 ( 6): p. 5 4 4-5 1.  
3 8.  
Li otta, F., et al., Fre q u e ncy of re g ul at ory T cells i n peri p her al bl o o d a n d i n t u m o ur -
i nfiltr ati n g ly m p h ocytes c orrel ates wit h p o or pr o g n osis i n re n al cell c arci n o m a. BJ U I n t, 
2 0 1 1. 1 0 7 ( 9): p. 1 5 0 0-6.  
3 9.  
M u, C. Y., et al., Hi g h ex pressi o n of P D -L 1 i n l u n g c a ncer m ay c o ntri b ute t o p o or pr o g n osis 
a n d t u m or cells i m m u ne esc a pe t hr o u g h s u p pressi n g t u m or i nfiltr ati n g de n dritic cells 
m at ur ati o n.  Me d O nc ol, 2 0 1 1. 2 8 ( 3): p. 6 8 2-8.  
4 0.  
C ha m piat, S., et al., I nc or p or ati n g i m m u ne-c heck p oi nt i n hi bit ors i nt o syste mic t her a py of 
N S C L C.  J T h orac O nc ol, 2 0 1 4. 9 ( 2): p. 1 4 4-5 3.  
4 1.  
C he n, Y. B., C. Y. M u, a n d J. A. H ua n g, Cli nic al si g nific a nce of pr o gr a m me d de at h -1 
li g a n d-1 ex pressi o n i n p atie nts  wit h n o n -s m all cell l u n g c a ncer: a 5-ye ar -f oll o w-u p st u dy.  
T u m ori, 2 0 1 2. 9 8 ( 6): p. 7 5 1-5.  
4 2.  
Z ha n g, P., et al., C h e m o preve ntive a ge nts i n d uce pr o gr a m me d d e at h -1 -li g a n d 1 ( P D-L 1) 
s urf ace ex pr essi o n i n bre ast c a ncer cells a n d pr o m ote P D-L 1 -me di ate d T cell a p o pt osis.  
M ol I m m u n ol, 2 0 0 8. 4 5 ( 5): p. 1 4 7 0-6.  
4 3.  
Bra h m er, J. R., et al., S afety a n d activity of a nti -P D -L 1 a nti b o dy i n p atie nts wit h a dv a nce d 
c a ncer. N E n gl J Me d, 2 0 1 2. 3 6 6 ( 2 6): p. 2 4 5 5-6 5.  
4 4.  
S pi gel, D., et al., Cli nic al activity, s afety, a n d bi o m arke rs of M P D L 3 2 8 0 A, a n e n gi neere d 
P D -L 1 a nti b o dy i n p atie nts wit h l oc ally a dv a nce d or met astic n o n -s m all cell l u n g c a ncer. 
J Cli n O nc ol, 2 0 1 3. 3 1 ( S u p pl; a bstr 8 0 0 8). 
4 5.  
Gar o n, E., et al., A bstr act A 2 0: M K -3 4 7 5 m o n ot her a py f or previ o usly tre ate d n o n -s m all 
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A 2 0.  
4 6.  
Gar o n, E., et al., S afety a n d Cli nic al Activity of M K -3 4 7 5 i n Previ o usly Tre ate d P atie nts 
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4 7.  
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A dv a nce d N o n -s m all Cell L u n g C a ncer. J Cli n O nc ol, 2 0 1 4. 3 2: 5s ((s u p pl; a bstr 8 0 0 7)). 
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5 0.  
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5 1.  
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2 0 1 0. 1 1 : p. 1 4. 
5 2.  
Z ha n g, L., et al., Differe nti al i m p air me nt of re g ul at ory T cells r at her t h a n effect or T cells 
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7 9  
5 3.  
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5 5.  
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bli n d, m ultice nter p h ase II st u dy.  J Cli n O nc ol, 2 0 1 2. 3 0 ( 1 7): p. 2 0 4 6-5 4.  
5 6.  
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Treat O pti o ns O nc ol, 2 0 1 4.  
5 7.  
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5 8.  
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Treat Re p, 1 9 8 5. 6 9 ( 1 2): p. 1 3 7 5-8 1.  
5 9.  
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E dit or. 2 0 0 3: Ne w Y or k.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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2 1.  A P P E N DI C E S  
2 1. 1.  
A P P E N DI X  I: E C O G P E R F O R M A N C E S T A T U S  
Gra de  
Descri pti o n  
0  
N or mal acti vit y. F ull y acti ve, a ble t o carr y o n all pre -disease 
perf or ma n ce wit h o ut restricti o n.  
1  
S y m pt o ms, b ut a m b ulat or y. 
Restricte d i n p h ysicall y stre n u o us 
acti vit y, b ut a m b ulat or y a n d a ble t o carr y o ut w or k of a li g ht or 
se de ntar y n at ure (e. g., li g ht h o use w or k, office w or k). 
2  
I n be d < 5 0 % of t he ti me. A m b ulat or y a n d ca pa bl e of all self-care, b ut 
u na ble t o carr y o ut a n y w or k acti vities. U p a n d a b o ut m ore t ha n 5 0 % 
of wa ki n g h o urs.  
3  
I n be d > 5 0 % of t he ti me. Ca pa ble of o nl y li mite d self-care, c o nfi ne d 
t o be d or c hair m ore t ha n 5 0 % of wa ki n g h o urs. 
4  
1 0 0 % be dri d de n. C o m pletel y disa ble d. Ca n n ot carr y o n a n y self -care. 
T otall y c o nfi ne d t o be d or c hair.  
5  
Dea d.  
*  As p u blis he d i n A m. J. Cli n. O nc ol.:  Oke n, M. M., Creec h, R. H., T or mey, D. C., H ort o n, 
J., D avis, T. E., Mc F a d de n, E. T., C ar b o ne, P. P.: T oxicity A n d Res p o nse Criteri a Of T he 
E aster n C o o per ative O nc ol o gy Gr o u p. A m J Cli n O nc ol 5: 6 4 9 -6 5 5, 1 9 8 2. T he Easter n 
C o o perati ve O nc ol o g y Gr o u p, R o bert C o mis M. D., Gr o u p C hair.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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