Clinical trial NCT03828448
Conditions: Follicular Lymphoma Small Lymphocytic Lymphoma
Keywords: Treatment naïve
Sponsor: TG Therapeutics, Inc.
Start date: 2019-07-10; Completion date: 2022-05-31
Enrollment: 34 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a phase 2, open label study to assess umbralisib in combination with ublituximab in participants with treatment naïve Follicular Lymphoma (FL) and Small Lymphocytic Lymphoma (SLL).

Detailed description:
The study will assess the safety and efficacy of umbralisib in combination with ublituximab in participants with treatment naïve FL and SLL. Ublituximab will be administered through Cycle 12, while umbralisib will be administered through Cycle 24. After this time, participants will be followed for progression free survival (PFS).

Arms: arm 1: Participants were administered ublituximab, 900 milligrams (mg), intravenous (IV) infusion through Cycles 1-6, Cycles 9 and 12. Participants also received umbralisib, 800 mg, oral tablet, daily through Cycles 1-24. 1 Cycle = 28 days.
Interventions: intervention 1: Ublituximab intervention 2: Umbralisib
Intervention descriptions: intervention 1: \- anti-CD 20 monoclonal antibody administered via IV infusion intervention 2: \- PI3K Delta Inhibitor oral daily dose

Protocol documents:
Prot_SAP_000.pdf: 
 
 Offi ci al Titl e:  
A P h a s e II St u d y E v al u ati n g t h e S af et y a n d Effi c a c y of U m br ali si b 
( T G R-1 2 0 2) i n  C o m bi n ati o n wit h U blit u xi m a b i n P ati e nt s wit h 
Tr e at m e nt N aï v e F olli c ul ar  L y m p h o m a a n d S m all L y m p h o c yti c 
L y m p h o m a  
 N C T N u m b er:  
 
N C T 0 3 8 2 8 4 4 8  
 D o c u m e nt D at e : 
 
Pr ot o c ol V er si o n 2. 0 : 2 0 D e c e m b er 2 0 1 8  
 
 
 


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D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
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P r ot o c ol v e r si o n / D at e:    
 
V ersi o n 2. 0  / 2 0  D E C 2 0 1 8  
P r ot o c ol #:   
  
  
 
U T X -T G R -2 0 3 
TI T L E:  A P h a s e II St u d y E v al u ati n g t h e S af et y a n d Effi c a c y of U m b r ali si b ( T G R -1 2 0 2 )  i n 
C o m bi n ati o n  wit h  U blit u xi m a b  i n  P ati e nt s  wit h  T r e at m e nt  N aï v e  F olli c ul a r  
L y m p h o m a a n d S m all L y m p h o c yti c L y m p h o m a   
 
S p o n s o r:   
  
 
T G T h er a p e utics, I nc.  
  
  
  
 
2 G a ns e v o ort Str e et, 9 t h Fl o or  
  
  
  
 
N e w Y or k, N Y 1 0 0 1 4 
  
  
  
 
T el: ( 2 1 2) 5 5 4 -4 4 8 4  
 
I N D N u m b e r:   
 
1 1 4, 7 7 9   
  
 
  
  
  
 
 
 
St u d y C h ai r :     
 
, M. D., P h. D. 
  
 
 
M e di c al M o n it o r:  
 
, M D 
  
  
  
 
T el: 
 e xt. 
  
  
 
St u d y C o o r di n ati o n:    
T G T h er a p e utics, I nc.  
  
  
  
 
2 G a ns e v o ort Str e et, 9 t h Fl o or  
  
  
  
 
N e w Y or k, N Y 1 0 0 1 4 
  
  
  
 
T el: ( 2 1 2) 5 5 4 -4 4 8 4  
 
V e r si o n: 1. 0     
  
  
  
  
  
 
D at e: 2 4 M arc h  2 0 1 8  
V e r si o n:  1. 1              
  
  
  
  
  
 
D at e:  2 6 A pril 2 0 1 8  
V e r si o n : 2. 0     
  
  
  
  
  
 
D at e : 2 0 D ec e m b er 2 0 1 8  
  
 
T his d oc u me nt is a c o nfi de nti al c o m m u nic ati o n of T G T h er a p e utics, I nc. Acc e pt a nc e of t his d oc u m e nt 
c o nstit ut es a gr e e m e nt b y t h e r eci pi e nt t h at n o u n p u blis h e d i nf or m ati o n c o nt ai n e d h er ei n s h all be 
p u blis h e d or discl os e d wit h o ut pri or writt e n a p pr o v al, exc e pt t h at t his d oc u me nt m a y b e disc l os e d t o 
t h e a p pr o pri at e I nstit uti o n al R e vi e w B o ar ds / I n d e p e n d e nt Et hics C o m mitt e es u n d er t h e c o n diti o n t h at 
t h e y k e e p it c o nfi d e nti al. 
 


SPONSOR APPROVAL 
The undersigned have reviewe 
UTX-TGR-203 for issuance. 
Protocol Title: 
Protocol Number: 
Study Drugs: 
IND Number: 
Date FINAL: 
MEDICAL MONITOR, TG Therap 
the format and content of this protocol and have approved Protocol 
A Phase 
II Study Evaluating the Safety and Efficacy of 
Umbralisib (TGR-1202) in Combination with Ublituximab 
in Patients with Treatment Naive Follicular Lymphoma 
and Small Lymphocytic Lymphoma 
UTX-TGR-203 
Umbralisib (TGR-1202) and Ublituximab 
114,779 
20 December 2018 
eutics, Inc. 
  
02Jun2020 MS 
| 
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, 
jefAheronMD Marta Siman, MD 
= 
02020 
Print Name 
Signature 
Date 
STUDY CHAIR, SCRI 
Jan Flinn, MD, PhD 
こ 、Ss 
一人 
だ 
と どす た の 
  
  
  
Print Name 
Signature 
그 
Date・ 
SPONSOR CONTACTS, TG Therapeutics, "Ze LS 
一 
Peter Sportelli 
ジン 
§ 
Of Jase, 2020 
Print Name 
Signature 
『 
Date 
‘DocuSigned by: 
1 
04-Jun-; 
Hari P. Miskin, MS, MSF 
oc Pian 
Jun-2020 
Print Name 
SEEN AGRE Name: Hari Miskin 
Date 
Signing Reason: 
| approve this document 
【seam 
Time: 04-Jun-2020 110:31:21 AM EDT 
F635EABB3B2549819D91139FE1D83A9B 
UTX-TGR-203 
CONFIDENTIAL 
Dated; 20 December 2018 (Ver|2.0) 
Page 2 of 85 
 


 
 
 
 
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P R O T O C O L A C C E P T A N C E F O R M  
P r ot o c ol Titl e:  
A  P h a s e  II  St u d y  E v al u ati n g  t h e  S af et y  a n d  Effi c a c y  of   
U m b r ali si b ( T G R -1 2 0 2 ) i n C o m bi n ati o n wit h U blit u xi m a b 
i n P ati e nt s wit h T r e at m e nt N aï v e F olli c ul a r L y m p h o m a 
a n d S m all L y m p h o c yti c L y m p h o m a  
P r ot o c ol N u m b e r:  
U T X -T G R -2 0 3  
I N D N u m b er: 
1 1 4, 7 7 9  
 
D at e FI N A L:  
2 0  D ec e m b er 2 0 1 8  
 
I h a v e r e a d t h e att ac h e d pr ot oc ol a n d a gr e e t h at it c o nt ai ns all t h e n ec ess ar y d et ails f or p erf or mi n g 
U T X -T G R -2 0 3. 
I will pr o vi d e c o pi es of t h e pr ot oc ol a n d of t h e u blit u xi m a b a n d u m br alisi b  I n v esti g at or’s Br oc h ur es, 
w hic h w er e gi v e n  t o m e b y T G T h er a p e utics ( S p o ns or), t o all m e m b ers of t h e st u d y t e a m f or w h o m I 
a m r es p o nsi bl e a n d w h o p artici p at e i n t h e st u d y.  I will disc uss t his m at eri al wit h t h e m t o e ns ur e t h at 
th e y ar e f ull y i nf or m e d r e g ar di n g  u blit u xi m a b , u m br alisi b , a n d t h e co n d uct of t h e st u d y.  
O nc e t h e pr ot oc ol h as b e e n a p pr o v e d b y t h e I R B, I will n ot m o dif y t his pr ot oc ol wit h o ut o bt ai ni n g t h e 
pri or a p pr o v al of T G T h er a p e utics a n d of t h e I R B.  I will s u b mit t h e pr ot oc ol m o dific ati o ns a n d / or 
a n y i nf or m e d c o ns e nt m o dific ati o ns  t o T G T h er a p e utics a n d t h e I R B, a n d a p pr o v al will b e o bt ai n e d 
b ef or e a n y m o dific ati o ns ar e i m pl e m e nt e d.  
I u n d erst a n d t h e pr ot oc ol a n d will w or k acc or di n g t o it, t h e pri nci pl es of G o o d Cli nic al Pr actic e 
(c urr e nt I C H g ui d eli n es), a n d t h e D ecl ar ati o n of H elsi n ki ( 1 9 6 4) i ncl u di n g all a m e n d m e nts u p t o a n d 
i ncl u di n g t h e W as hi n gt o n Cl arific ati o n ( 2 0 0 2). 
 
 
 
  
 
 
Pri nt N a m e  
 Si g n at ur e  
 
D at e  
 
 


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T A B L E O F C O N T E N T S  
S T U D Y S Y N O P SI S  ................................................................................................................................... 9 
LI S T O F A B B R E VI A TI O N S A N D D E FI NI TI O N S O F T E R M S  ....................................................... 1 4  
1 I N T R O D U C TI O N  ................................................................................................................................ 1 6  
1. 1 I N D O L E N T N O N -H O D G KI N’ S L Y M P H O M A  ..................................................................................................... 1 6  
1. 2 U m br alisi b ( T G R -1 2 0 2)  .......................................................................................................................................... 1 6  
1. 2. 1 Pr e -Cli nic al E v al u ati o ns of U m br alisi b  ..................................................................................................................................................... 1 6  
1. 2. 2 Cli nic al D e v el o p m e nt of U m br alisi b  .......................................................................................................................................................... 1 8  
1. 3 U B LI T U XI M A B  ............................................................................................................................................................ 2 1  
1. 3. 1 Pr e -Cli nic al D e v el o p m e nt of U blit u xi m a b  ............................................................................................................................................... 2 1  
1. 3. 2 Cli nic al D e v el o p m e nt of U blit u xi m a b  ........................................................................................................................................................ 2 2  
1. 3. 3 R ati o n al e F or T h e P h as e 2 Tri al  ................................................................................................................................................................... 2 4  
2 O BJ E C TI V E S A N D  E N D P OI N T S  ................................................................................................... 2 6  
2. 1  S T U D Y  O BJ E C TI V E S  ................................................................................................................................................ 2 6  
P RI M A R Y  O BJ E C TI V E  ................................................................................................................................................................................................. 2 6  
K E Y S E C O N D A R Y  O BJ E C TI V E S  .............................................................................................................................................................................. 2 6  
 
2. 2 E F FI C A C Y  EN D P OI N T S  ...................................................................................................................................... 2 6  
P r o g r e s si o n -f r e e s u r vi v al ( P F S) .......................................................................................................................................................................... 2 6  
O v e r all r e s p o n s e r at e  ( O R R) ................................................................................................................................................................................. 2 6  
D u r ati o n of r e s p o n s e  ( D O R) .................................................................................................................................................................................. 2 6  
3 E LI GI BI LI T Y C RI T E RI A ................................................................................................................... 2 7  
3. 1 I ncl usi o n Crit eri a  ....................................................................................................................................................... 2 7  
3. 2 E x cl usi o n Crit eri a ...................................................................................................................................................... 2 8  
4 S T U D Y D E SI G N  .................................................................................................................................. 2 9  
4. 1 O v er vi e w of St u d y D esi g n  ...................................................................................................................................... 2 9  
4. 2 S af et y R u n -I n ............................................................................................................................................................... 2 9  
4. 3 R e gistr ati o n a n d E nr oll m e nt  ................................................................................................................................ 3 0  
4. 4 St u d y Sit es  .................................................................................................................................................................... 3 0  
4. 5 Disc o nti n u ati o n fr o m St u d y Tr e at m e nt  ........................................................................................................... 3 0  
5 S T U D Y A S S E S S M E N T S A N D T R E A T M E N T S C H E D U L E  .......................................................... 3 2  
5. 1 L a b or at or y Ass ess m e nts  ........................................................................................................................................ 3 4  
5. 1. 1 L oc al L a b or at or y Ass ess m e nts  ..................................................................................................................................................................... 3 4  
5. 1. 2 C e ntr al L a b or at or y Ass ess m e nts  ................................................................................................................................................................. 3 4  


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6 T R E A T M E N T P L A N  .......................................................................................................................... 3 6  
6. 1 Tr e at m e nt S u m m ar y  ................................................................................................................................................ 3 6  
6. 2 A g e nt A d mi nistr ati o n  .............................................................................................................................................. 3 6  
6. 2. 1 G ui d eli n es f or A d mi nistr ati o n of U m br alisi b  ........................................................................................................................................ 3 6  
6. 2. 2 G ui d eli n es f or A d mi nistr ati o n of U blit u xi m a b  ...................................................................................................................................... 3 7  
6. 2. 3 Crit eri a f or O n g oi n g Tr e at m e nt .................................................................................................................................................................... 4 0  
6. 3 D osi n g D el a ys a n d M o dific ati o ns  ........................................................................................................................ 4 0  
6. 3. 1 D os e D el a y / M o dific ati o ns: U m br alisi b  .................................................................................................................................................... 4 0  
6. 3. 2 D os e D el a y / m o dific ati o ns: U blit u xi m a b  .................................................................................................................................................. 4 2  
6. 4 Or d eri n g U blit u xi m a b a n d U m br alisi b  ............................................................................................................. 4 3  
6. 5 D ur ati o n of T h er a p y  ................................................................................................................................................. 4 3  
7 S T U D Y M E DI C A TI O N O V E R VI E W A N D S A F E T Y  ...................................................................... 4 5  
7. 1 U m br alisi b ( T G R -1 2 0 2)  .......................................................................................................................................... 4 5  
7. 2 U blit u xi m a b  ................................................................................................................................................................. 4 5  
7. 2. 1  U blit u xi m a b + U m br alisi b ( T G R -1 2 0 2) C o m bi n ati o n - C o m pr e h e nsi v e A d v ers e E v e nts a n d P ot e nti al Ris ks Lists 
( C A E P R S) ............................................................................................................................................................................................................................ 4 6  
8 M E A S U R E M E N T O F E F F E C T  .......................................................................................................... 4 8  
8. 1 M et h o d  of Ass ess m e nt  ............................................................................................................................................ 4 8  
8. 2 R es p o ns e R e vi e w  ....................................................................................................................................................... 4 9  
8. 3 A ntit u m or Eff ect  ........................................................................................................................................................ 4 9  
8. 4 D efi niti o ns of T u m or R es p o ns e a n d Pr o gr essi o n  ........................................................................................ 4 9  
8. 4. 1 C o m pl et e R es p o ns e  ............................................................................................................................................................................................ 4 9  
8. 4. 2 P arti al R es p o ns e  .................................................................................................................................................................................................. 4 9  
8. 4. 3 St a bl e Dis e as e  ....................................................................................................................................................................................................... 5 0  
8. 4. 4 Pr o gr essi o n of Dis e as e ...................................................................................................................................................................................... 5 0  
8. 5 D efi niti o ns of Dis e as e P ar a m et ers  ..................................................................................................................... 5 0  
8. 6 E v al u ati o n of B est O v er all R es p o ns e  ................................................................................................................. 5 1  
8. 6. 1 D ur ati o n of R es p o ns e  ........................................................................................................................................................................................ 5 1  
9 S T A TI S TI C A L C O N SI D E R A TI O N S  ................................................................................................. 5 2  
9. 1 S a m pl e Siz e a n d P o w er  ........................................................................................................................................... 5 2  
9. 2 G e n er al A n al ysis C o n v e nti o n ................................................................................................................................ 5 2  
9. 3 St u d y P o p ul ati o ns  ..................................................................................................................................................... 5 3  
9. 4 s u bj ect D e m o gr a p hics a n d B as eli n e C h ar act eristics  .................................................................................. 5 3  
9. 5 M e dic al Hist or y  .......................................................................................................................................................... 5 3  
9. 6 E xt e nt of E x p os ur e  .................................................................................................................................................... 5 3  
9. 7 Effic ac y A n al ys es  ....................................................................................................................................................... 5 3  


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9. 8 Missi n g V al u e H a n dli n g Pr oc e d ur es .................................................................................................................. 5 4  
9. 9 St atistic al A n al ys es  ................................................................................................................................................... 5 4  
9. 9. 1 Pri m ar y Effic ac y V ari a bl e - O R R .................................................................................................................................................................. 5 4  
9. 9. 2 S ec o n d ar y Effic ac y O utc o m es  ....................................................................................................................................................................... 5 4  
 
1 0 S A F E T Y R E P O R TI N G A N D A N A L Y SI S  ....................................................................................... 5 6  
1 0. 1 S af et y A n al ys es  ........................................................................................................................................................ 5 6  
1 0. 2 A d v ers e E v e nt C h ar act eristics  .......................................................................................................................... 5 6  
1 0. 3 D efi niti o ns of A d v ers e E v e nts  ........................................................................................................................... 5 6  
1 0. 4 A d v ers e E v e nts ( A E’s) a n d Tr e at m e nt E m er g e nt A d v ers e E v e nts ( T E A E’s)  ................................. 5 7  
1 0. 5 A d v ers e E v e nts / S eri o us A d v ers e E v e nt C a us alit y Ass ess m e nt  ........................................................ 5 7  
1 0. 5. 1 R ec or di n g of A d v ers e E v e nts  ...................................................................................................................................................................... 5 8  
1 0. 5. 2  A b n or m al L a b or at or y V al u es a n d Vit al Si g ns  ..................................................................................................................................... 5 8  
1 0. 5. 3  H a n dli n g of A d v ers e E v e nts  ........................................................................................................................................................................ 5 8  
1 0. 6 S eri o us A d v ers e E v e nts  ........................................................................................................................................ 5 9  
1 0. 6. 1  D efi niti o ns of S eri o us A d v ers e E v e nts  ................................................................................................................................................... 5 9  
1 0. 6. 2  S eri o us A d v ers e E v e nt R e p orti n g b y I n v esti g at ors  ......................................................................................................................... 6 0  
1 0. 7 S p o ns or S A E R e p orti n g R e q uir e m e nts  .......................................................................................................... 6 1  
1 0. 8 R ec or di n g of A d v ers e E v e nts a n d S eri o us A d v ers e E v e nts  ................................................................... 6 1  
1 0. 9 Di a g n osis vs. Si g ns a n d S y m pt o ms  .................................................................................................................. 6 1  
1 0. 9. 1 P ersist e nt or R ec urr e nt A d v ers e E v e nts  ............................................................................................................................................... 6 1  
1 0. 9. 2 A b n or m al L a b or at or y V al u es  ..................................................................................................................................................................... 6 2  
1 0. 9. 3 D e at hs  .................................................................................................................................................................................................................... 6 2  
1 0. 9. 4 H os pit ali z ati o n, Pr ol o n g e d H os pit ali z ati o n, or S ur g er y  ................................................................................................................ 6 2  
1 0. 9. 5 Pr e -E xisti n g M e dic al C o n diti o ns  ............................................................................................................................................................... 6 2  
1 0. 9. 6 Pr ot oc ol -D efi n e d E v e nts of S p eci al I nt er est  ........................................................................................................................................ 6 3  
1 1 C LI NI C A L D A T A C O L L E C TI O N A N D M O NI T O RI N G  .............................................................. 6 4  
1 1. 1 Sit e M o nit ori n g Pl a n  .............................................................................................................................................. 6 4  
1 1. 2 A m e n d m e nts t o t h e Pr ot oc ol  ............................................................................................................................. 6 4  
1 1. 3 C urric ul a Vit a e a n d Fi n a nci al Discl os ur es  .................................................................................................... 6 5  
1 1. 4 D at a O w n ers hi p a n d P u blic ati o n  ..................................................................................................................... 6 5  
1 2 E T HI C A L, FI N A N CI A L, A N D R E G U L A T O R Y C O N SI D E R A TI O N S  ....................................... 6 6  
1 2. 1 I R B A p pr o v al  ............................................................................................................................................................ 6 6  
1 2. 2 R e g ul at or y A p pr o v al  ............................................................................................................................................. 6 6  
1 2. 3 I ns ur a nc e a n d I n d e m nit y  .................................................................................................................................... 6 6  
1 2. 4 I nf or m e d C o ns e nt ................................................................................................................................................... 6 6  


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1 2. 5 C o nfi d e nti alit y .......................................................................................................................................................... 6 7  
1 2. 6 I n v esti g at or a n d St aff I nf or m ati o n  .................................................................................................................. 6 8  
1 2. 7 Fi n a nci al I nf or m ati o n  ........................................................................................................................................... 6 8  
1 3 R E C O R D R E T E N TI O N A N D D O C U M E N T A TI O N O F T H E S T U D Y  ...................................... 6 9  
1 3. 1 D oc u m e nt ati o n R e q uir e d t o I niti at e St u d y  .................................................................................................. 6 9  
1 3. 2 St u d y D oc u m e nt ati o n a n d St or a g e  .................................................................................................................. 6 9  
1 3. 3 D at a C oll ecti o n  ......................................................................................................................................................... 7 1  
1 3. 4 St u d y M o nit ori n g, A u diti n g, a n d I ns p ecti n g  ................................................................................................ 7 1  
1 3. 5 Q u alit y Ass ur a nc e a n d Q u alit y C o ntr ol  ......................................................................................................... 7 1  
1 3. 6 Discl os ur e a n d P u blic ati o n P olic y .................................................................................................................... 7 2  
1 4 R E F E R E N C E S  ................................................................................................................................... 7 3  
1 5  
A P P E N DI X A – E C O G P e rf o r m a n c e St at u s S c al e  .......................................................... 7 5  
1 6  
A P P E N DI X B - C o nt r a c e pti o n G ui d eli n e s a n d P r e g n a n c y  ....................................... 7 6  
1 7  
A P P E N DI X C – N e w Y o r k H e a rt A s s o ci ati o n  Cl a s sifi c ati o n s  ............................. 7 8  
1 8  
A P P E N DI X D – I nt e r n ati o n al W o r ki n g G r o up R e vi s e d R e s p o n s e C rit e ri a f o r 
M ali g n a nt L y m p h o m a ( C h e s o n et al. 2 0 0 7)  ............................................................................... 7 9  
1 9  
A P P E N DI X 
E – F olli c ul a r  L y m p h o m a  St a gi n g  a n d  F olli c ul a r  L y m p h o m a  
I nt e r n ati o n al P r o g n o sti c I n d e x ( F LI PI) ....................................................................................... 8 4  
2 0  
A p p e n di x F – H e p atitis B S e r ol o gi c T e st R e s ult s  .......................................................... 8 5  
 
 
 
 
 
 
 
 
 
 
 
 


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S U M M A R Y O F C H A N G E S  
V ersi o n 1. 1 ( D at e d 2 6 A pril 2 0 1 8) of t his Pr ot oc ol is t h e first a m e n d m e nt t o t his cli nic al tri al a n d 
c o nt ai ns t h e f oll o wi n g m o dific ati o ns:  
•  
T- c ell L y m p h oc yt e S u bs et s will b e a n al y z e d b y t h e S p o ns or d esi g n at e d c e ntr al l a b or at or y 
i nst e a d of t h e sit e’s l oc al l a b or at or y ( S ecti o n 5. 1. 2. 1) 
•  
U p d at e d g ui d a nc e f or pr o p h yl a xis tr e at m e nt wit h p n e u m oc ystis jir o v eci p n e u m o ni a ( P C P) 
a n d a nti vir al t h er a p y ( Secti o n  6. 2. 1)  
V ersi o n 2. 0  ( D at e d 20 D ec e m b er 2 0 1 8) of t his Pr ot oc ol is t h e s ec o n d a m e n d m e nt t o t his cli nic al tri al 
a n d c o nt ai ns t h e f oll o wi n g m o dific ati o ns:  
•  
T h e t er m  “ p ati e nt” w as r e pl as e d wit h “s u bj ect” t hr o u g h o ut; 
•  
A d mi nistr ati v e a n d e dit ori al c h a n g es ; 
•  
T w o s af et y r u n -i n c o h orts of 3 - 6 s u bj ects e ac h w er e a d d e d at a d os e of 6 0 0 m g a n d 8 0 0 m g 
u m br alisi b t o e v al u at e f or k e y i m m u n e m e di at e d t o xiciti es.  I n t h e a bs e ns e of u n acc e pt a bl e 
t o xicit y, e nr oll m e nt will pr oc e e d wit h all s u bj ects r ec ei vi n g 8 0 0 m g u m br alisi b. 
•  
I ncl usi o n Crit eri a 
o  S u bj ects ar e n o w r e q uir e d t o h a v e a n e e d f or s yst e mic t h er a p y pri or t o e nr oll m e nt;  
o  St at e m e nt a d d e d t o bilir u bi n n oti n g e xc e pti o n of Gil b ert’s Dis e as e a n d A ut oi m m u n e 
H e m ol ytic A n e mi a ;  
o  C alc ul at e d Cr e ati ni n e Cl e ar a nc e utilizi n g t h e M o difi e d C oc kr oft -G a ult F or m ul a a n d 
I B M;  
•  
E xcl usi o n Crit eri a  
o  T h e  e xcl usi o n  of  pri or  c a nc er  t h er a p y  w as  cl arifi e d  t o  pri or  “s yst e mic”  c a nc er  
t h er a p y; 
o  U p d at e d e xcl usi o n ar y crit eri a f or h e p atitis a n d C M V scr e e ni n g crit eri a f or cl arit y ; 
o  U p d at e d  r ef er e nc e t o n ot e a p p e n di x F n ot D ; 
o  A d d e d p ar a m et ers f or c o rtic ost er oi ds d uri n g scr e e ni n g; 
•  
Sc h e d ul e of As s ess m e nts a n d Tr e at m e nt ( S ecti o n 5. 0)  
o  U p d at e r es p o ns e ass ess m e nt crit eri a.  Cl arifi e d ass ess m e nts s h o ul d b e wit hi n 1 4  d a ys 
of D a y 1 of C ycl es 3, 6, a n d 1 2, a n d t h e n e v er y 6 m o nt hs u ntil c ycl e 2 4.  Aft er c ycl e 2 4, 
r es p o ns e ass ess m e nts s h o ul d occ ur at l e ast e v er y 1 2 m o nt hs.   
•  
Cl arifi e d pr e -m e dic ati o ns f or u blit u xi m a b t hr o u g h o ut pr ot oc ol.  
•  
U p d at e d PJ P / A nti vir al pr o p h yl a xis dr u g r ec o m m e n d ati o ns.  
•  
L a n g u a g e i n pr ot oc ol r e m o v e d r e q uir e m m e nt of s u bj ect t o disc o nti n u e pr ot oc ol t h er a p y if 
dr u g  is  h el d  gr e at er  t h a n  2 8  d a ys  f or  r ec o v er y. C urr e nt  l a n g u a u g e  st at es  t o  n otif y  T G 
T h er a p e utics if st u d y dr u g (s) ar e r e -i niti at e d aft er b ei n g h el d f or gr e at er t h a n 2 c ycl es. 
•  
D os e M o dific ati o n T a bl e  
o  A d diti o n of li v er d os e m o dific ati o ns b as e d o n gr a d e . 
o  T o r es pir at or y /i nf ecti o n a d d e d  st at e m e nt f or si n o p ul m o n ar y i nf ecti o ns cl e arl y n ot 
r el at e d t o i m m u n e-m e di at e d p n e u m o nits, T G R -1 2 0 2 ( u m br alisi b) m a y b e c o nti n u e d 
at i n v esti g at or discr eti o n.    
 
















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1  I N T R O D U C TI O N 
1. 1  I N D O L E N T N O N-H O D G KI N’ S L Y M P H O M A  
I n t h e U S, a n esti m at e d 7 2, 0 0 0 n e w c as es of N o n-H o d g ki n’s L y m p h o m a ( N H L) w er e  r e p ort e d i n 
2 0 1 5 .  De at hs , d u e t o t h e dis e as e, t ot al e d a p pr o xi m at el y 2 0, 0 0 0 , acc or d i n g t o t h e Am eric a n C a nc er 
S oci et y  ( A m eric a n C a nc er S oci et y, 2 0 1 5).  I n d ol e nt N o n-H o d g ki n’s L y m p h o m a (i N H L) m a k e s u p 
a b o ut 3 0 % of all N H L c as es i n t h e U nit e d St at es, a n d s u bt y p es i ncl u d e:  
•  
F ollic ul ar l y m p h o m a ( F L)  
•  
W al d e nstr ö m m acr o gl o b uli n e mi a ( W M)  
•  
M ar gi n al z o n e l y m p h o m a ( M Z L)  
•  
S m all c ell l y m p h oc ytic l y m p h o m a ( S L L)  
 
F ollic ul ar l y m p h o m a ( F L) a n d S m all L y m p h oc ytic L y m p h o m a ( S L L) t o g et h er r e pr es e nt  m ost  of t h e  
s u bj ects i n t h e i N H L s u bt y p e.  Tr e at m e nt f or n e wl y di a g n os e d F L a n d S L L r a n g es fr o m a w atc h-a n d -
w ait a p pr o a c h t o a m or e a g gr essi v e t h er a p y i ncl u di n g c h e m ot h er a p y b as e d c o m bi n ati o ns, us u all y 
wit h a  m o n ocl o n al a nti b o d y ( Rit u x a n + B e n d a m usti n e or ot h er c h e m o b as e d r e gi m e ns).  Alt h o u g h 
eff ecti v e, t h es e c h e m ot h er a p y - b as e d r e gi m e ns will oft e n l e a d t o r el a ps e a n d u nf a v or a bl e t o xiciti es, 
es p eci all y f or el d erl y s u bj ects. 
1. 2   UM B R A LI SI B ( T G R -1 2 0 2 ) 
U m br alisi b  is  a  hi g hl y-s p ecific  a n d  or all y  a v ail a bl e  p h os p h oi n ositi d e - 3-ki n as e  ( PI 3 K)  d elt a  ( δ) 
i n hi bit or wit h n a n o m ol ar i n hi bit or y p ot e nc y, a n d hi g h s el ecti vit y o v er t h e al p h a, b et a, a n d g a m m a 
Cl ass I is of or ms of PI 3 K.  T h e PI 3 Ks ar e a f a mil y of e n z y m es i n v ol v e d i n  v ari o us c ell ul ar f u ncti o ns, 
i ncl u di n g c ell pr olif er ati o n a n d s ur vi v al, c ell diff er e nti ati o n, i ntr ac ell ul ar tr affic ki n g a n d i m m u nit y.  
T h e  d elt a  is of or m  of  PI 3 K  is  hi g hl y  e x pr ess e d  i n  c ells  of  h e m at o p oi etic  ori gi n,  a n d  str o n gl y  
u pr e g ul at e d, a n d oft e n m ut at e d i n v ari o us h e m at ol o gic m ali g n a nci es.   
 
I n t h e P h as e I st u d y, t o-d at e, a t ot al of 8 1 s u bj ects h a v e b e e n tr e at e d wit h u m br alisi b , i ncl u di n g 2 2 
F L a n d 2 1 C L L s u bj ects.  I n all tr e at e d s u bj ects, t h e m ost c o m m o nl y-occ urri n g  ( ≥1 8 % s u bj ects) 
a d v ers e e v e nts ( A Es; all gr a d es, all c a us alit y) w er e n a us e a, di arr h e a, f ati g u e, r as h, h e a d ac h e, c o u g h 
a n d v o miti n g, t h e m aj orit y of w hic h w er e Gr a d e 1 / 2.  T h e o nl y Gr a d e ≥3 A E occ urri n g i n < 5 % of 
s u bj ects w as a n e mi a ( 9 %).   Disc o nti n u ati o n d u e t o a n a d v ers e e v e nt wit h T G R -1 2 0 2 w as r e p ort e d i n 
6 / 8 1 ( 7 %) of s u bj ects.  Of t h e 1 7 e v al u a bl e C L L s u bj ects, 1 6 ( 9 4 %) ac hi e v e d a n o d al P R of w hic h 1 0 
( 5 9 %) ac hi e v e d a P R p er H all e k 2 0 0 8 crit eri a.   Cli nic al acti vit y w as als o o bs er v e d i n F L, wit h 1 2 / 1 6 
( 7 5 %) e v al u a bl e s u bj ects e x p eri e nc i n g t u m or r e d ucti o ns, a n d a pr eli mi n ar y 3 8 % O R R ( 6 / 1 6) wit h 
a n a d diti o n al 2 s u bj ects ac hi e vi n g 4 9 % r e d ucti o ns i n t u m or b ur d e ns ( s u bj ects c o nti n ui n g t o r ec ei v e 
o n g oi n g t h er a p y).  T h e l o n g est p eri o d of tr e at m e nt o n t h e st u d y t o -d at e is 3 4 c ycl es ( o v er 2. 5 y e ars), 
a n d 2 7 % of s u bj ects h a v e r ec ei v e d m or e t h a n 1 2 c ycl es of tr e at m e nt. T h e P h as e I st u d y is cl os e d as 
u m br alisi b  is n o w i n P h as e 3 d e v el o p m e nt f or s u bj ects wit h C L L ( U NI T Y -C L L st u d y).  
 
1. 2. 1  P R E -C LI NI C A L E V A L U A TI O N S O F U M B R A LI SI B  




 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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P a g e 1 8  of 8 5  
Or al a d mi nistr ati o n of 1 5 0 m g / k g / Q D o v er a 2 5 -d a y p eri o d r es ult e d i n a si g nific a nt d el a y i n  t u m or 
gr o wt h.  
FI G U R E 3: U M B R A LI SI B  I N VI V O E F FI C A C Y  
 
1. 2. 1. 2  T O XI C O L O G Y  
T o ass ess t h e s af et y a n d t o xicit y of u m br alisi b  a 2 8 -d a y r e p e at d os e st u d y wit h a 1 4 -d a y r ec o v er y 
p eri o d w as c o n d uct e d i n C D -1 mic e a n d b e a gl e d o gs, t o e v al u at e t h e p ot e nti al r e v ersi bilit y of 
fi n di n gs a n d t o s u p p ort t h e us e i n h u m a ns.  U m br alisi b  w as a d mi nist er e d or all y i n or d er t o mi mic 
t h e pl a n n e d m o d e of cli nic al a d mi nistr ati o n.       
O nc e d ail y or al a d mi nistr ati o n of u m br alisi b  w as t ol er at e d i n mic e at fr e e b as e d os e l e v els of 5 0 a n d 
1 5 0 m g / k g / d a y.  I ncr e as es i n li v er w ei g hts, micr osc o pic fi n di n gs i n t h e li v er a n d t h e i ncr e as es i n 
s er u m c h ol est er ol, a n d f e m al e o nl y A L T, A S T, a n d G G T l e v els w er e o bs er v e d at 7 5 0 m g / k g / d a y of 
fr e e b as e (t h e hi g h est d os e t est e d) a n d w er e c o nsi d er e d a d v ers e.  T h e n o-o bs er v e d - a d v ers e-eff ect 
l e v el ( N O A E L) w as c o nsi d er e d t o b e 1 5 0 m g / k g / d a y i n mic e.  
O nc e d ail y or al a d mi nistr ati o n b y c a ps ul e of u m br alisi b  w as w ell t ol er at e d i n d o gs at l e v els of 5 0 
a n d 1 5 0 m g / k g / d a y.  T h e g astr oi nt esti n al tr act, b as e d o n cli nic al si g ns, w as t h e t ar g et or g a n s yst e m.  
B as e d o n eff ects o n b o d y w ei g ht a n d t h e i nci d e nc e a n d s e v erit y of e m esis a n d di arr h e a, t h e N O A E L 
w as c o nsi d er e d t o b e 1 5 0 m g / k g / d a y ( 1 1 4. 5 m g / k g / d a y as fr e e b as e) i n t his s p eci es.  
R ef er t o t h e U m br alisi b  I n v esti g at or’s Br oc h ur e (I B) f or d et ail e d i nf or m ati o n o n t o xic ol o g y st u dies 
c o n d uct e d t o d at e. 
1. 2. 2  C LI NI C A L D E V E L O P M E N T  O F U M B R A LI SI B  
1. 2. 2. 1  S I N G L E-A G E N T  I N  S U BJ E C T S WI T H  R E L A P S E D  O R  R E F R A C T O R Y  H E M A T O L O GI C  
M A LI G N A N CI E S  
U m br alisi b  is u n d er e v al u ati o n i n a si n gl e-a g e nt P h as e I d os e -esc al ati o n st u d y i n s u bj ects wit h 
r el a ps e d a n d r efr act or y he m at ol o gic m ali g n a nci es ( B urris et al, 2 0 1 5).  A t ot al of 8 1 s u bj ects w er e 
e nr oll e d a n d eli gi bl e f or s af et y e v al u ati o n, wit h 6 3 s u bj ects e v al u a bl e f or effic ac y.  T h e m e di a n a g e 
w as 6 5 y e ars (r a n g e 2 2 -8 5) a n d 5 3 % w er e m al e.  A m o n g all s u bj ects t h e m e di a n n um b er of pri or 
t h er a pi es w as 3 ( wit h a r a n g e of 1-1 4), wit h 8 0 % r ec ei vi n g pri or rit u xi m a b -b as e d c h e m ot h er a p y.  
Hist ol o gic al di a g n os es w er e as f oll o ws: F L ( n = 2 2), C L L ( n = 2 1), diff us e l ar g e B -c ell l y m p h o m a 
( D L B C L; n = 1 4), H o d g ki n’s l y m p h o m a ( H L; n = 9), m a ntl e c ell l y m p h o m a ( M C L; n = 6), M Z L ( n = 5), W M 
( n = 2) a n d o n e e ac h of h air y-c ell l e u k e mi a ( H C L) a n d T -c ell l y m p h o m a.  T h e m aj orit y of s u bj ects 
h a d a n E C O G of 1 a n d 4 0 / 8 1 ( 4 9 %) w er e r efr act or y t o pri or t h er a p y.     


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P a g e 1 9  of 8 5  
S u bj ect s h a v e b e e n e nr oll e d i n a 3 + 3 d os e -esc al ati o n d esi g n st arti n g at 5 0 m g Q D wit h s u bs e q u e nt 
c o h orts  e v al u ati n g d os es as  hi g h  as  1 8 0 0  m g Q D.   I n  a n  eff ort  t o  f urt h er  i m pr o v e  t h e  or al 
bi o a v ail a bilit y  of  u m br alisi b ,  t h e  p articl e  si z e  of  t h e  dr u g  pr o d uct  w as  r e d uc e d  t hr o u g h  a  
micr o ni z ati o n pr oc ess, r es ult i n g i n gr e at er a bs or pti o n w h e n t est e d i n a bi o e q ui v al e nc e cr oss o v er 
st u d y i n h e alt h y s u bj ects  .  T his micr o niz e d f or m ul ati o n w as i ntr o d uc e d i nt o d os e esc al ati o n at 2 0 0 
m g Q D a n d d os e d as hi g h as 1 2 0 0 m g Q D, wit h n o m a xi m u m t ol er at e d d os e ( M T D) r e ac h e d.  I ntr a -
s u bj ect d os e esc al ati o n r ul es h a v e all o w e d s u bj ects e nr oll e d i nt o t h e st u d y i n e arl y c o h orts t o 
i ncr e as e t h eir d os e of u m br alisi b  as s u bs e q u e nt hi g h er c o h orts h a v e cl e ar e d s af et y e v al u ati o n.  
A d os e -d e p e n d e nt r es p o ns e h as b e e n o bs er v e d wit h u m br alisi b , wit h a d os e of 8 0 0 m g or hi g h er of 
t h e i niti al f or m ul ati o n or a n y d os e of t h e micr o niz e d f or m ul ati o n pr o d uci n g si g nific a nt n o d al 
r e d ucti o ns  a m o n g  C L L  s u bj ects.   Of  t h e  1 7  e v al u a bl e  C L L  s u bj ects tr e at e d  at  or  a b o v e  t his  
t h er a p e utic t hr es h ol d, 1 6 / 1 7 ( 9 4 %) h a v e ac hi e v e d a n o d al p arti al r es p o ns e, a n d n o d al r e d ucti o ns 
s h o w a n i m pr o v e m e nt wit h ti m e o n u m br alisi b  wit h a m e di a n ti m e o n st u d y of 6 m o nt hs.  Cli nic al 
acti vit y  w as  als o  o bs er v e d  i n  F L,  wit h  1 2 / 1 6  ( 7 5 %)  e v al u a bl e  s u bj ects e x p eri e nci n g  t u m or  
r e d ucti o ns, a n d a pr eli mi n ar y 3 8 % O R R ( 6 / 1 6) wit h a n a d diti o n al 2 s u bj ects ac hi e vi n g 4 9 % 
r e d ucti o ns i n t u m or b ur d e ns (s u bj ects c o nti n ui n g t o r ec ei v e o n g oi n g t h er a p y).  
I n all tr e at e d s u bj ects ( 8 1), t h e m ost c o m m o nl y-occ urri n g ( ≥1 8 % s u bj ects) a d v ers e e v e nts ( A Es; 
all gr a d es, all c a us alit y) w er e n a us e a, di arr h e a, f ati g u e, r as h, h e a d ac h e, c o u g h a n d v o miti n g, t h e 
m aj orit y  of  w hic h  w er e  Gr a d e  1 / 2.    T h e  o nl y  Gr a d e  ≥3  A E  occ urri n g  i n  > 1 0 %  of s u bj ects w as 
n e utr o p e ni a ( 1 1 %). N o e v e nts of c olitis h a v e b e e n o bs er v e d. Disc o nti n u ati o n d u e t o a n A E w as 
r e p ort e d  i n  o nl y  6 / 8 1  ( 7 %)  of  s u bj ects.   L ess  c o m m o nl y-occ urri n g  A Es  ( 9 -1 2 %)  i ncl u d e d  
c o nsti p ati o n, d ecr e as e d a p p etit e, h y p o k al e mi a, a n e mi a, diz zi n ess, d ys p n e a, p yr e xi a, a b d o mi n al 
p ai n, art hr al gi a a n d i ns o m ni a.  
D osi n g of u m br alisi b  i niti all y occ urr e d i n t h e f asti n g st at e, b ut w as tr a nsiti o n e d mi d-st u d y t o f e d 
st at e d osi n g, wit h s u bj ects i nstr uct e d t o t a k e u m br alisi b  wit h f o o d.  All d osi n g of u m br alisi b  is n o w 
c o n d uct e d usi n g t h e micr o ni z e d f or m ul ati o n a n d i n t h e f e d st at e.   
O v er all, u m br alisi b  w as w ell t ol er at e d a n d dis pl a y e d pr o misi n g si g ns of cli nic al acti vit y at t h e 
hi g h er d osi n g c o h orts wit h 8 0 0 m g Q D s el ect e d as t h e P h as e 2 d os e i n s u bj ects wit h pr e vi o usl y 
tr e at e d C L L a n d N H L. 
1. 2. 2. 2  H E A L T H Y S U BJ E C T P H A R M A C O KI N E TI C S T U DI E S  
I n  p ar all el wit h  t h e P h as e   1 si n gl e-ar m,  d os e -esc al ati o n  st u d y i n s u bj ects wit h  r el a ps e d or  
r efr act or y  h e m at ol o gic  m ali g n a nci es;  t w o  h e alt h y  s u bj ect,  cr oss o v er,  bi o e q ui v al e nc e  
p h ar m ac o ki n etics  st u di es h a v e b e e n  c o m pl et e d. T h e  first p h ar m ac o ki n etic  st u d y w as  a P h as e  1 
dr u g- f o o d i nt er acti o n st u d y wit h a si n gl e 2 0 0 m g or al d os e of u m br alisi b  i n h e alt h y v ol u nt e ers 
f oll o w e d b y a s ec o n d si n gl e d os e P h as e   1 p h ar m ac o ki n etic  st u d y e v al u ati n g  t h e a bs or pti o n,  
distri b uti o n,  m et a b olis m  a n d  e xcr et i o n c h ar act eristics of  t w o diff er e nt  or al f or m ul ati o ns of  2 0 0  
m g  u m br alisi b  ( ori gi n al f or m ul ati o n vs. micr o niz e d f or m ul ati o n) i n h e alt h y  v ol u nt e ers.  
1. 2. 2. 2. 1  T G R -1 2 0 2 -P K 1 0 1: F O O D  E F F E C T  
St u d y T G R -1 2 0 2 -P K 1 0 1 w as  t w o -p eri o d, r a n d o miz e d, t w o -w a y cr oss o v er, dr u g -f o o d,  dr u g-
g e n d er i nt er acti o n st u d y i n 2 4 h e alt h y s u bj ects ( 1 2 m al es a n d 1 2 f e m al es) t o ass ess t h e m e a n 
pl as m a  u m br alisi b  c o nc e ntr ati o n o v er ti m e f oll o wi n g a si n gl e or al d os e of 2 0 0 m g of u m br alisi b  




 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
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P a g e 2 1  of 8 5  
f ast e d c o n diti o n c a n b e e xtr a p ol at e d t o b e e q ui v al e nt t o a n or al d os e of 2 0 0 m g of t h e ori gi n al 
f or m ul ati o n u m br alisi b  u n d er f ast e d c o n diti o ns i n t er m of e x p os ur e b as e d o n  A U C 0- i nf. 
T h e i m pr o v e d e x p os ur e s e e n wit h t h e micr o niz e d f or m ul ati o n of u m br alisi b  w as c o nfir m e d  i n 
s u bj ects i n t h e P h as e  1 d os e esc al ati o n  as  w ell. T h e  c h art b el o w  ill ustr at es t h e pr e -d os e  pl as m a 
c o nc e ntr ati o ns of u m br alisi b  o n D a y 1 of C ycl e 2 i n s u bj ects a d mi nist er e d e q ui v al e nt d os es of  
eit h er t h e i niti al f or m ul ati o n i n t h e f asti n g st at e or t h e micr o ni z e d f or m ul ati o n i n t h e f e d  st at e: 
 
1. 3  U B LI T U XI M A B  
U blit u xi m a b is a n o v el t hir d g e n er ati o n c hi m eric a nti -C D 2 0 m o n ocl o n al a nti b o d y bi o e n gi n e er e d f or 
p ot e nt acti vit y, e x hi biti n g a u ni q u e gl yc os yl ati o n pr ofil e wit h a l o w f uc os e c o nt e nt, d esi g n e d t o i n d uc e 
s u p eri or a nti b o d y-d e p e n d e nt c yt ot o xicit y ( A D C C).  U bli t u xi m a b e x hi bits c o m p etiti v e c o m pl e m e nt-
d e p e n d e nt c yt ot o xicit y ( C D C), o n p ar wit h rit u xi m a b, a n d h as als o b e e n d e m o nstr at e d t o i n d uc e 
pr o gr a m m e d c ell d e at h ( P C D) u p o n bi n di n g  t o t h e C D 2 0 a nti g e n o n B-l y m p h oc yt es.  U blit u xi m a b h as 
a u ni q u e pr ot ei n s e q u e nc e, a n d t ar g ets e pit o p es o n C D 2 0 n ot t ar g et e d b y rit u xi m a b or of at u m u m a b, 
b ot h c urr e ntl y a p pr o v e d a nti -C D 2 0 a nti b o di es ( Est e v es I T, 2 0 1 1) . 
1. 3. 1  P R E -C LI NI C A L D E V E L O P M E N T O F U B LI T U XI M A B  
1. 3. 1. 1  I N-VI V O A C TI VI T Y  
I n a n i n-vitr o ass a y usi n g B -C L L c ells fr o m s u bj ect d o n ors, u blit u xi m a b d e m o nstr at e d a n e n h a nc e d 
a bilit y t o kill C L L c ells c o m p ar e d t o rit u xi m a b.  U blit u xi m a b d e m o nstr at e d i m pr o v e d Fc γ r ec e pt or 
III A  ( Fc γ RIII A) / C D 1 6  bi n di n g  a n d  Fc γ RIII A  d e p e n d e nt  eff ect or  f u ncti o ns  c o m p ar e d  t o  rit u xi m a b.  
A d diti o n all y,  u blit u xi m a b  i n d uc e d  hi g h er  i n  vitr o  A D C C  a g ai nst  C L L  c ells,  a n d  a  hi g h er  Fc γ RIII A 
m e di at e d i nt erl e u ki n -2 (I L 2) pr o d ucti o n b y Fc γ RIII A + J ur k at c ells ( d e R o m e uf C, 2 0 0 8).  U blit u xi m a b 
d e m o nstr at e d hi g h A D C C a g ai nst b ot h s u bj ect-d eri v e d C L L c ells a n d N H L c ell li n es.  U blit u xi m a b’s 
e n g a g e m e nt t o Fc γ RIII A tri g g ers a str o n g er N K c ell c yt ot o xicit y a g ai nst C L L as c o m p ar e d t o rit u x a n 
(i n vitr o) d es pit e C D 2 0 d e nsit y, li k el y r el at e d t o t h e gl yc os yl ati o n p att er n ( d e R o m e uf C, 2 0 0 8).  
1. 3. 1. 2  I N VI V O A C TI VI T Y   
T h e a ntit u m or eff ect of u blit u xi m a b w as c o m p ar e d t o t h at of rit u xi m a b wit h c h e m ot h er a p y i n 
f ollic ul ar l y m p h o m a ( F L), a n d m a ntl e c ell l y m p h o m a ( M C L) x e n o gr aft m uri n e m o d els.  Si n gl e a g e nt 
u blit u xi m a b d e m o nstr at e d d os e -r el at e d a nti-t u m or acti vit y wit h 1 0 0 % t u m or gr o wt h i n hi biti o n i n 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 2 2  of 8 5  
t h e F L x e n o gr aft at a d os e of 1 0 0 m g / k g, a n d a s u p eri or t u m or gr o wt h d el a y ( 2 1 d a ys) c o m p ar e d to 
rit u xi m a b.  U blit u xi m a b  als o  d e m o nstr at e d  s u p eri or  a nti -t u m or  acti vit y  c o m p ar e d  t o  rit u xi m a b 
a g ai nst M C L x e n o gr afts at all d os e l e v els (Est e v es I T, 2 0 1 1) . 
1. 3. 1. 3  T O XI C O L O G Y    
I n si n gl e-d os e a n d r e p e at d os e t o xic ol o g y st u di es p erf or m e d u n d er G L P, u blit u xi m a b dis pl a y e d a 
s af et y  pr ofil e  si mil ar  t o  w h at  mi g ht  b e  e x p ect e d  f or  a nti -C D 2 0  m o n ocl o n al  a nti b o di es.  Si n gl e  
a d mi nistr ati o n of u p t o 1 0 0 m g / k g u blit u xi m a b i n c y n o m ol g us m o n k e ys w as w ell t ol er at e d, wit h n o 
l oc al irrit ati o n wit h i ntr a v e n o us a d mi nistr ati o n.  G e n ot o xicit y st u di es ( A m es t est) s h o w e d t h at 
u blit u xi m a b w as n ot m ut a g e nic.  M o n k e ys t h at r ec ei v e d a si n gl e i nj ecti o n of 0. 3 m g / k g of u blit u xi m a b 
d e v el o p e d a n a nti -u blit u xi m a b r es p o ns e, w h er e as a nti -u blit u xi m a b a nti b o di es w er e n ot d et ect e d i n 
t h e a ni m als w hic h r ec ei v e d 1 0 or 1 0 0 m g / k g (s e e U blit u xi m a b I n v esti g at or Br oc h ur e). 
1. 3. 2  C LI NI C A L D E V E L O P M E N T  O F U B LI T U XI M A B  
U blit u xi m a b h as b e e n st u di e d i n a v ari et y of s u bj ect p o p ul ati o ns, b ot h as a si n gl e a g e nt, a n d i n 
c o m bi n ati o n wit h ot h er a g e nts, wit h o v er 1 0 0 s u bj ects h a vi n g r ec ei v e d u blit u xi m a b t h er a p y t o d at e 
acr oss all st u di es.  T w o Si n gl e -A g e nt P h as e I /I b tri als h a v e b e e n c o n d uct e d wit h u blit u xi m a b tr e ati n g 
b ot h N H L a n d C L L s u bj ects, wit h a t ot al of 4 1 s u bj ects wit h r el a ps e d or r efr act or y C L L h a v i n g b e e n 
tr e at e d wit h si n gl e-a g e nt u blit u xi m a b ( T G -1 1 0 1).  F urt h er, f oll o wi n g d e m o nstr ati o n of s af et y a n d 
t ol er a bilit y i n t h es e e arl y si n gl e a g e nt st u di es, P h as e I a n d II c o m bi n ati o n st u di es w er e u n d ert a k e n 
wit h a v ari et y of a g e nts.  Gi v e n t h e n u m b er of s ubj ect s w h o h a v e r ec ei v e d u blit u xi m a b i n e arl y -p h as e 
tri als, t h e s af et y a n d si d e eff ect pr ofil e of t h e a g e nt is w ell c h ar act eri z e d.  S u m m ari es of t h e si n gl e-
a g e nt e x p eri e nc e ar e pr o vi d e d b el o w as w ell as d at a wit h us e of u blit u xi m a b i n c o m bi n ati o n wit h 
i br uti ni b. 
I n a t w o p art, first-i n h u m a n d os e esc al ati o n st u d y ( pr ot oc ol C D 2 0-0 7 0 3), s u bj ects wit h r el a ps e d or 
r efr act or y C L L  r ec ei v e d o n e w e e kl y i nf usi o n of si n gl e a g e nt u blit u xi m a b f or 4 d os es i n a 3 + 3 d os e 
esc al ati o n d esi g n t hr o u g h 5 s e q u e nti al d os e l e v els.  P art II of t h e st u d y w as a d os e -c o nfir m ati o n 
c o m p o n e nt w hic h us e d a n i niti al d os e of 1 5 0 m g f oll o w e d b y 7 d os es of 4 5 0 m g (t ot al d os e 3 3 0 0 m g) 
– t h e cli nic al s u m m ar y will f oc us o n t h e P art II p art of t h e st u d y as t h e d os e is m or e r el e v a nt t o t h e 
cli nic al a p plic ati o n us e d i n c urr e nt cli nic al st u di es.  I n P art II, 1 2 s u bj ects w er e e nr oll e d at 9 c e nt ers 
i n Fr a nc e a n d f oll o w e d f or 1 2 m o nt hs.  D e m o gr a p hic d at a f or t h e 1 2 s u bj ects e nr oll e d i n t h e st u d y 
w er e as f oll o ws.  T h e m e di a n a g e w as 6 9. 5 y e ars [ 6 2 – 7 7]; m e di a n ti m e fr o m di a g n osis t o i ncl usi o n 
w as 1 0. 4 y e ars [ 4. 0 – 2 3. 6] a n d m e di a n pri or t h er a pi es w as 3 [ 1 – 8].  S e v e n s u bj ects ( 5 8 %) r ec ei v e d at 
l e ast o n e pri or rit u xi m a b-c o nt ai ni n g r e gi m e n.  T h e m e di a n l y m p h oc yt e b o n e m arr o w i nfiltr ati o n w as 
8 5 % [ 4 0 – 9 4].  
M ost fr e q u e nt dr u g -r el at e d a d v ers e e v e nts ( A E’s) r e p ort e d w er e i nf usi o n r el at e d r e acti o ns (I R R) 
( 7 5 % of t h e s u bj ects, i ncl u di n g 3 3 % of s u bj ects wit h Gr a d e 3 I R R).  Ot h er Gr a d e 3 / 4 A E’s > 1 0 % 
i ncl u d e d: n e utr o p e ni a ( 6 7 %) a n d i ncr e as e A L T / A S T ( 1 7 %).  All A Es w er e r e v ersi bl e s p o nt a n e o usl y 
or wit h s u p p orti v e c ar e i nt er v e nti o n.  N o n e of t h e r e p ort e d a d v ers e e v e nts w er e c o nsi d er e d as a 
d os e- li miti n g  t o xicit y  acc or di n g  t h e  j u d g m e nt  of  t h e  st ud y  S af et y  C o m mitt e e.   T h er ef or e,  t h e  
m a xi m u m t ol er at e d d os e w as n ot r e ac h e d i n t his st u d y.  Si g nific a nt bl o o d l y m p h oc yt e d e pl eti o n w as 
o bs er v e d i n all s u bj ects:  m e di a n l y m p h oc yt e c o u nt at b as eli n e w as 4 6. 6 ( x 1 09 /l); aft er 1 m o nt h ( M 1) 
= 1. 5 ( ↓9 4 %); M 4 = 1. 4  ( ↓9 1 %) a n d M 6 = 2. 0 ( ↓8 9 %). N o c as es of s er u m a nti-u blit u xi m a b a nti b o di es 
w er e d et ect e d at a n y ti m e p oi nt.  


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P a g e 2 3  of 8 5  
Cli nic al r es p o ns e w as b as e d o n t h e crit eri a est a blis h e d b y t h e N ati o n al C a nc er I nstit ut e ( N CI) -
W or ki n g Gr o u p u p d at e d i n 2 0 0 8  ( H all e k M, 2 0 0 8).  All s u bj ects b ut o n e r ec ei v e d t h e pl a n n e d 8 
i nf usi o ns wit h o ut a n y d os e r e d ucti o n--o n e s u bj ect w as pr e m at ur el y wit h dr a w n d u e t o a c o nc o mit a nt 
s ec o n d ar y l e u k e mi a u nr el at e d t o u blit u xi m a b t h er a p y.  R es p o ns e w as e v al u at e d at m o nt h 4 f or  t h e 
1 1 e v al u a bl e s u bj ects, wit h a n i niti al r es p o ns e r at e of 6 4 % ( 7 / 1 1) wit h a c o nfir m e d r es p o ns e at 
m o nt h 6 i n 5 / 1 1 s u bj ects ( 4 5 %) s u bj ects ( all P Rs).  F o ur of t h e 1 1 s u bj ects ac hi e v e d st a bl e dis e as e.  
At t h e 1 y e ar f oll o w -u p, n o r es p o n d ers h a d pr o gr ess e d , d e m o nstr ati n g all c o nfir m e d r es p o ns es w er e 
d ur a bl e d es pit e n o u blit u xi m a b m ai nt e n a nc e t h er a p y.  T h e m e di a n pr o gr essi o n -fr e e s ur vi v al ( P F S) 
w as n ot r e ac h e d at t h e 1 2 m o nt h f oll o w -u p ( C a zi n B, 2 0 1 3). 
A P h as e I tri al of u blit u xi m a b ( N C T 0 1 6 4 7 9 7 1) w as s u bs e q u e ntl y u n d ert a k e n i n s u bj ects wit h B -c ell 
l y m p h o m a w h o w er e r el a ps e d or r efr act or y t o a pri or rit u xi m a b c o nt ai ni n g r e gi m e n, w hic h i ncl u d e d 
8 s u bj ects wit h C L L.  T his tri al utiliz e d a 3 + 3 d esi g n, ass essi n g d os e l e v els of 4 5 0, 6 0 0, 9 0 0, a n d 1 2 0 0 
m g.  N o D L Ts w er e o bs er v e d a m o n gst t h e 1 2 s u bj ects e nr oll e d i nt o t h e d os e -esc al ati o n c o m p o n e nt, 
a n d e x p a nsi o n c o h orts w er e s u bs e q u e ntl y u n d ert a k e n at 6 0 0, 9 0 0, a n d 1 2 0 0 m g.  S u bj ect s wit h C L L 
w er e eli gi bl e t o e nr oll i nt o t h e e x p a nsi o n c o h orts at 6 0 0 a n d 9 0 0 m g, r ec ei vi n g u blit u xi m a b o n d a ys 
1, 8 & 1 5 of C ycl es 1 & 2, wit h m o nt hl y m ai nt e / n a nc e i nf usi o ns st arti n g i n C ycl e 3, f oll o w e d b y e v er y 
3 m o nt hs st arti n g i n C ycl e 6.   
Of t h e 8 C L L s u bj ects e nr oll e d, 4 h a d i nf usi o n r el at e d r e acti o ns t h at w er e m a n a g e a bl e wit h i nf usi o n 
i nt err u pti o ns o nl y a n d all s u bj ects r ec ei v e d all sc h e d ul e d os es.  Ot h er o bs er v e d a d v ers e e v e nts 
w hic h w er e c o nsi d er e d at l e ast p ossi bl y r el at e d t o st u d y dr u g i ncl u d e d n e utr o p e ni a  Gr a d e 1 / 2 
( n = 1) a n d Gr a d e 3 / 4 ( n = 3), as w ell as t hr o m b oc yt o p e ni a Gr a d e 1 / 2 ( n = 1) a n d Gr a d e 3 / 4 ( n = 1).  Si x 
s u bj ects w er e e v al u a bl e f or effic ac y as of d at a c ut off f or A S C O 2 0 1 4, wit h 4 o ut of 6 s u bj ects 
ac hi e vi n g a p arti al r es p o ns e.  R a pi d a n d pr of o u n d circ ul ati n g l y m p h oc yt e d e pl eti o n ( > 5 0 % 
r e d ucti o n) w as n ot e d wit h m e di a n ti m e t o p eri p h er al r es p o ns e of 1 d a y ( O' C o n n or O A, 2 0 1 4) . 
 
1. 3. 2. 1  P H A R M A C O KI N E TI C S  
Aft er i nf usi o n of u blit u xi m a b ( pr e vi o usl y k n o w n as L F B -R 6 0 3) at a 1 5 0 m g d os e f ol l o w e d b y s e v e n 
w e e kl y i nj ecti o n i nf usi o ns at 4 5 0 m g, r es ults s u g g est e d n o n -li n e ar p h ar m ac o ki n etics wit h r es p ect t o 
d os e ( 4 5 0 m g vs. 1 5 0 m g) a n d ti m e ( w e e k 4 vs. w e e k 8) a n d m or e t h a n pr o p orti o n al i ncr e as e of C m a x 
a n d A U C ∞ d u e t o a cl e ar a nc e d ecr e as e.  T h e v ol u m e of distri b uti o n at st e a d y st at e w as s m all ( ~ 5 L), 
a p pr o xi m at el y e q u al t o bl o o d v ol u m e.   T h es e n o n -li n e ar p h ar m ac o ki n etics m a y b e e x pl ai n e d b y 
bi n di n g of u blit u xi m a b t o its t ar g et, wit h a l ar g e c o m p o n e nt of t ar g et -m e di at e d eli mi n ati o n aft er t h e 
first d os e t h at is d ecr e as e d aft er s u bs e q u e nt i nf usi o ns d u e t o a r e d ucti o n i n t h e a v ail a bl e t ar g et.  
H o w e v er, li mit e d d at a f or e ac h d os e l e v el c o h ort a n d c o nsi d er a bl e v ari a bilit y i n b as eli n e s u bj ect 
c h ar act eristics, p artic ul arl y i n t er ms of t u m or b ur d e n, m a k e fir m c o ncl usi o ns diffic ult. 
T h e li n e ar m e a n s er u m c o nc e ntr ati o n -ti m es pr ofil e aft er t h e first, t h e f o urt h a n d t h e ei g ht h i nf usi o n 
of u blit u xi m a b ar e pr es e nt e d i n Fi g ur e 4 .  A s u m m ar y of n o n-c o m p art m e nt al P K p ar a m et ers aft er t h e 
first, t h e f o urt h a n d t h e ei g ht h i nf usi o n of u blit u xi m a b ar e pr es e nt e d i n T a bl e 1. 
FI G U R E 4 :  LI N E A R  M E A N  S E R U M  C O N C E N T R A TI O N -TI M E S P R O FI L E  A F T E R  T H E  FI R S T,  T H E  
F O U R T H A N D T H E EI G H T  I N F U SI O N O F U B LI T U XI M A B 




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P a g e 2 5  of 8 5  
t o ass ess effic ac y a n d s af et y of u blit u xi m a b + u m br alisi b c om p ar e d t o o bi n ut uz u m a b + c hl or a m b ucil 
i n s u bj ects wit h tr e at m e nt n aï v e a n d r el a ps e d /r efr act or y C L L is c urr e ntl y o n g oi n g wit h n o o bs er v e d 
s af et y tr e n ds r e p ort e d ( D S M B S e pt e m b er 2 0 1 8 ) i n o v er 6 0 0 p ati e nts.  T o d at e, u blit u xi m a b a n d 
u m br alisi b  eit h er as si n gl e a g e nts or i n c o m bi n ati o n h a v e b e e n a d mi nist er e d t o o v er 1 0 0 0  s u bj ects 
w orl d wi d e. 
As  m ost  tri als  t o  d at e  h a v e  e v al u at e d  pr e vi o usl y tr e at e d  s u bj ects,  t his  tri al  will  n o w  e v al u at e 
u m br alisi b + u blit u xi m a b i n tr e at m e nt n aï v e F L a n d S L L s u bj ects.


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P a g e 2 6  of 8 5  
2  O BJ E C TI V E S A N D  E N D P OI N T S  
 
2. 1  S T U D Y  O BJ E C TI V E S  
 
 
P RI M A R Y  O BJ E C TI V E  
•  
T o ass ess t h e o v er all r es p o ns e r at e ( O R R) i n s u bj ects wit h tr e at m e nt n aï v e f ollic ul ar 
l y m p h o m a ( F L) a n d s m all l y m p h oc ytic l y m p h o m a ( S L L) tr e at e d wit h u m br alisi b i n 
c o m bi n ati o n wit h u blit u xi m a b.  
 
K E Y S E C O N D A R Y  O BJ E C TI V E S  
•  
T o e v al u at e t h e s af et y of u m br alisi b i n c o m bi n ati o n wit h ublit u xi m a b.  
 
•  
T o ass ess t h e d ur ati o n of r es p o ns e ( D O R), C o m pl et e R es p o ns e ( C R) a n d pr o gr essi o n -fr e e 
s ur vi v al ( P F S) i n s u bj ects wit h tr e at m e nt n aï v e f ollic ul ar l y m p h o m a a n d s m all l y m p h oc ytic 
l ym p h o m a tr e at e d wit h u m br alisi b + u blit u xi m a b.  
 
 
 
 
 
2. 2  E F FI C A C Y E N D P OI N T S  
 
 
P r o g r e s si o n -f r e e s u r vi v al ( P F S) 
P F S  is d efi n e d  as  t h e i nt er v al fr o m C ycl e  1 / D a y   1 t o t h e e arli er  of  t h e first d oc u m e nt ati o n  of  
d efi niti v e dis e as e  pr o gr essi o n  or  d e at h  fr o m a n y  c a us e. D efi niti v e  dis e as e   pr o gr essi o n 
acc or di n g t o t h e R e vis e d R es p o ns e Crit eri a f or M ali g n a nt L y m p h o m a ( C h es o n et al. 2 0 0 7).  
 
O v e r all r e s p o n s e r at e  ( O R R) 
O R R is d efi n e d as s u m of C R a n d P R  r at es  
 
C o m pl et e R e s p o n s e ( C R) R at e  
C R r at e is d efi n e d as t h e pr o p orti o n of s u bj ects w h o ac hi e v e a C R.  
 
D u r ati o n of r e s p o n s e  ( D O R) 
D O R  is d efi n e d  as  t h e i nt er v al fr o m t h e first d oc u m e nt ati o n  of  C R  or  P R  t o t h e e arli er  of  t h e 
first d oc u m e nt ati o n of d efi niti v e dis e as e pr o gr essi o n or d e at h fr o m a n y c a us e. 
 


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3  E LI GI BI LI T Y C RI T E RI A  
S u bj ects  m ust  m e et   all of  t h e f oll o wi n g i ncl usi o n crit eri a a n d  n o n e  of  t h e e xcl usi o n  crit eri a t o b e 
eli gi bl e f or p artici p ati o n i n t his  st u d y. 
3. 1  I N C L U SI O N C RI T E RI A  
S u bj ect s m ust m e et all of t h e f oll o wi n g i ncl usi o n crit eri a t o b e eli gi bl e f or p artici p ati o n i n t his  st u d y: 
1.  Tr e at m e nt n aï v e, hist ol o gic all y -c o nfir m e d  di a g n osis of F ollic ul ar L y m p h o m a ( F L)  Gr a d e 1, 2, 
or 3 a, or S m all L y m p h oc ytic L y m p h o m a ( S L L).  
2.  S u bj ect s m ust h a v e m e as ur a bl e or e v al u a bl e dis e as e, a n d m ust h a v e d oc u m e nt e d e vi d e nc e 
f or r e q uiri n g tr e at m e nt ( b ul k y dis e as e ( > 5 c m), hi g h L D H, B s y m pt o ms, t hr e at e n e d or g a n 
f u ncti o n, s pl e n o m e g al y, c yt o p e ni as d u e t o l y m p h o m a, or eff usi o ns). 
3.  A d e q u at e or g a n s yst e m f u ncti o n, d efi n e d as f oll o ws:  
a.  A bs ol ut e n e utr o p hil c o u nt ( A N C) ≥ 0. 7 5 x 1 0 9 / L . N ot e:  N o gr o wt h f act ors or tr a nsf usi o ns 
ar e all o w e d t o m e et eli gi bilit y crit eri a.  
b.  Pl at el ets ≥ 5 0  x 1 0 9 / L . N ot e:  N o gr o wt h f act ors or tr a nsf usi o ns ar e all o w e d t o m e et 
eli gi b ilit y crit eri a. 
c. T ot al bilir u bi n ≤1. 5 ti m es t h e u p p er li mit of n or m al ( U L N)  wit h t h e e xc e pti o n  of Gil b ert’s 
Dis e as e a n d A ut oi m m u n e H e m ol ytic A n e mi a.    
d.  Al a ni n e a mi n otr a nsf er as e ( A L T) a n d as p art at e a mi n otr a nsf er as e ( A S T) ≤2. 5  x U L N if n o 
li v er i n v ol v e m e nt or ≤5 x t h e U L N if k n o w n li v er i n v ol v e m e nt  
e.  Cr e ati ni n e ≤ 2. 0 m g / d L O R c alc ul at e d cr e ati ni n e cl e ar a nc e ( as c alc ul at e d b y t h e m o difi e d 
C oc kcr oft -G a ult f or mul a usi n g i d e al b o d y m ass [I B M] i nst e a d of m ass)  ≥ 3 0  m L / mi n  
4.  E C O G p erf or m a nc e st at us ≤ 1.  
5.  P ati e nts m ust b e ≥1 8 y e ars of a g e.  
6.  A bilit y t o s w all o w a n d r et ai n or al m e dic ati o n  
7.  F e m al e p ati e nts w h o ar e n ot of c hil d -b e ari n g p ot e nti al , a n d f e m al e p ati e nts of c hil d -b e ari n g 
p ot e nti al w h o h a v e a n e g ati v e s er u m pr e g n a nc y t est wit hi n 7 2  h o urs pri or t o i niti al tri al 
tr e at m e nt.  F e m al e p ati e nts of c hil d-b e ari n g p ot e nti al a n d all m al e p art n ers m ust c o ns e nt t o 
us e a m e dic all y acc e pt a bl e m et h o d o f c o ntr ac e pti o n t hr o u g h o ut t h e st u d y p eri o d a n d f or 4 
m o nt hs aft er t h e l ast d os e of eit h er st u d y dr u g. 
8.  Willi n g n ess a n d a bilit y t o c o m pl y wit h tri al a n d f oll o w -u p pr oc e d ur es.  
 


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3. 2  E X C L U SI O N C RI T E RI A  
S u bj ects  w h o m e et a n y of t h e f oll o wi n g e xcl usi o n crit eri a ar e n ot t o b e  e nr oll e d t o t his  st u d y: 
1.  S u bj ect s c urr e ntl y r ec ei vi n g s yst e mic c a nc er t h er a p y or pr e vi o usl y r ec ei v e d s yst e mic c a nc er 
t h er a p y f or t h eir l y m p h o m a (i. e., c h e m ot h er a p y, i m m u n ot h er a p y, bi ol o gic t h er a p y, h or m o n al 
t h er a p y, s ur g er y, tr a ns pl a nt, a n d / or t u m or e m b oliz ati o n). 
2.  E vi d e nc e of c hr o nic acti v e H e p atitis B d efi n e d as H e p atitis B s urf ac e a nti g e n p ositi v e or 
H e p atitis B D N A p ositi v e b y P C R ( H B V, N O T  i ncl u di n g s u bj ects wit h pri or h e p atitis B 
v acci n ati o n  w h o ar e  H e p atitis B s urf ac e a nti b o d y  p ositi v e o nl y;)  or c hr o nic acti v e H e p atitis C 
i nf ecti o n ( H C V) d efi n e d as H e p atitis C R N A p ositi v e b y P C R, c yt o m e g al o vir us ( C M V ) D N A 
p ositi v e  b y P C R,  or k n o w n hist or y of HI V. If H Bc a nti b o d y , H C V a nti b o d y or C M V I g G a n d / or 
I g M a nti b o d y is p ositi v e, s u bj ects m ust b e e v al u at e d f or t h e pr es e nc e of H B V , H C V, or C M V b y 
P C R  - S e e A p p e n di x F.  
3.  S u bj ect  h as r ec ei v e d wi d e fi el d r a di ot h er a p y (i ncl u di n g t h e r a p e utic r a di ois ot o p es s uc h as 
str o nti u m 8 9) ≤ 2 8 d a ys or li mit e d fi el d r a di ati o n f or p alli ati o n ≤ 1 4 d a ys pri or t o C ycl e 
1 / D a y 1 or h as n ot r ec o v er e d fr o m si d e eff ects of s uc h t h er a p y.  
4.  Pri m ar y c e ntr al n er v o us s yst e m l y m p h o m a ( P C N S L) or k n o w n i ntr acr a ni al i n v ol v e m e nt, or 
l e pt o m e ni n g e al m et ast as es. 
5.  O n g oi n g i m m u n os u p pr essi v e t h er a p y i ncl u di n g s yst e mic c ortic ost er oi ds .  S u bj ect s ar e 
all o w e d t o us e t o pic al or i n h al e d c ortic ost er oi ds.  
a.  C ortic ost er oi d t h er a p y st art e d at l e ast 7 d a ys pri or t o C ycl e 1 / D a y 1 ( pr e d nis o n e ≤1 0 m g 
d ail y or e q ui v al e nt) is all o w e d as cli nic all y w arr a nt e d.  
6.  K n o w n hist or y of dr u g -i n d uc e d li v er i nj ur y, alc o h olic li v er dis e as e, n o n-alc o h olic 
st e at o h e p atitis, pri m ar y bili ar y cirr h osis, o n g oi n g e xtr a h e p atic o bstr ucti o n c a us e d b y st o n es, 
or cirr h osis of t h e li v er.  
7.  A n y s e v er e a n d / or u nc o ntr oll e d m e dic al c o n diti o ns or ot h er c o n diti o ns t h at c o ul d aff ect 
t h eir p artici p ati o n i n t h e st u d y s uc h as: 
a.  S y m pt o m atic, or hist or y of d oc u m e nt e d c o n g esti v e h e art f ail ur e ( N e w Y or k H e art 
Ass oci ati o n f u ncti o n al cl ass ific ati o n III-I V)[s e e A p p e n di x C- N Y H A Cl assific ati o ns]  
b.  Si g nific a nt c ar di o v asc ul ar dis e as e s uc h as u nc o ntr oll e d or s y m pt o m atic arr h yt h mi as, 
c o n g esti v e h e art f ail ur e, or m y oc ar di al i nf arcti o n wit hi n 6 m o nt hs of e nr oll m e nt.   
c. C o nc o mit a nt us e of m e dic ati o n k n o w n t o c a us e Q T pr ol o n g ati o n or t ors a d es d e p oi nt es 
s h o ul d b e us e d wit h c a uti o n a n d at i n v esti g at or discr eti o n.  
d.  P o orl y c o ntr oll e d or cli nic all y si g nific a nt at h er oscl er otic v asc ul ar dis e as e i ncl u di n g 
c er e br o v asc ul ar acci d e nt ( C V A), tr a nsi e nt isc h e mic att a c k ( TI A), a n gi o pl ast y, c ar di ac or 
v asc ul ar st e nti n g wit hi n 6 m o nt hs of e nr oll m e nt.  
8.  M ali g n a nc y  ot h er t h a n F ollicl u ar L y m p h o m a or S L L  wit hi n 3 y e ars of st u d y e nr oll m e nt 
e xc e pt f or a d e q u at el y tr e at e d b as al, s q u a m o us c ell c arci n o m a or n o n -m el a n o m at o us s ki n 
c a nc er, c arci n o m a i n sit u of t h e c er vi x, s u p erfici al bl a d d er c a nc er n ot tr e at e d wit h 
i ntr a v esic al c h e m ot h er a p y or B C G wit hi n 6 m o nt hs, l oc ali z e d pr ost at e c a nc er a n d P S A < 1. 0 
m g / d L o n 2 c o ns ec uti v e m e as ur e m e nts at l e ast 3 m o nt hs a p art wit h t h e m ost r ec e nt o n e 
b ei n g wit hi n 4 w e e ks of C ycl e 1 / D a y 1 .  
9.  W o m e n w h o ar e pr e g n a nt or l act ati n g.  


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4  S T U D Y D E SI G N  
4. 1  O V E R VI E W O F S T U D Y D E SI G N  
T his  is  a  P h as e  2,  o p e n -l a b el  st u d y  of  u m br alisi b ,  a  PI 3 K  d elt a  i n hi bit or,  a d mi nist er e d  i n 
c o m bi n ati o n wit h u blit u xi m a b, a gl yc o e n gi n e er e d a nti -C D 2 0 m A b, t o s u bj ects wit h tr e at m e nt n aï v e 
F ollic ul ar L y m p h o m a ( F L) or S m all L y m p h oc ytic L y m p h o m a ( S L L).  
D ail y d os es of or al u m br alisi b  will b e a d mi nist er e d  f or a d ur ati o n of 2 4 c ycl es ( a p pr o xi m at el y 2 4 
m o nt hs) , i n  t h e  a bs e nc e  of  dis e as e  pr o gr essi o n,  u n acc e pt a bl e  t o xicit y, or  wit h dr a w al  fr o m  
tr e at m e nt.  T w o s af et y r u n -i n c o h orts of 3 - 6 s u bj ects e ac h at a d os e of 6 0 0 m g a n d 8 0 0 m g 
u m br alisi b will first b e e nr oll e d t o e v al u at e f or k e y i m m u n e m e di at e d t o xiciti es.  I n t h e a bs e ns e of 
u n acc e pt a bl e t o xicit y, e nr oll m e nt will pr oc e e d wit h all s u bj ects r ec ei vi n g 8 0 0 m g u m br alisi b. A 
fi x e d d os e of 9 0 0 m g of u blit u xi m a b will b e a d mi nist er e d o n D a ys 1, 8, a n d 1 5 i n C ycl e 1 a n d D a y 1 
of C ycl es 2 - 6, C ycl e 9 a n d 1 2.  U blit u xi m a b will b e a d mi nist er e d t hr o u g h C ycl e 1 2 .  Tr e at m e nt c ycl es 
ar e 2 8 d a ys.  
P E T sc a ns m ust b e d o n e at scr e e ni n g, wit hi n 1 4 d a ys  pri or t o C ycl e 6 D a y 1, a n d t o c o nfir m C R (if 
a p plic a bl e).   D uri n g t h e st u d y p eri o d, all s u bj ects will b e e v al u at e d f or r es p o ns e b y C T  (if c o ntr ast 
C T is c o ntr ai n dic at e d M RI wit h a n o n -c o ntr ast C T  C h est  s h o ul d b e c o m pl et e d) wit hi n 1 4 d a ys of D a y 
1 of C ycl es 3, 6, a n d 1 2.   Aft er C ycl e 1 2 , s u bj ects s h o ul d b e e v al u at e d f or r es p o ns e b y C T  (if c o ntr ast 
C T is c o ntr ai n dic at e d M RI wit h a n o n -c o ntr ast C T s h o ul d b e c o m pl et e d) , a p pr o xi m at el y e v er y 6 
c ycl es t hr o u g h  c ycl e  2 4,  u nl ess  cli nic all y  i n dic at e d  s o o n er ( at  t h e  discr eti o n  of  t h e  tr e ati n g  
p h ysi ci a n). 
Aft er 2 4 c ycl es ( a p pr o xi m at el y 2 4 m o nt hs) of tr e at m e nt, s u bj ects will disc o nti n u e st u d y m e dic ati o n 
a n d b e f oll o w e d f or pr o gr essi o n -fr e e s ur vi v al.  S u bj ects w h o  disc o nti n u e st u d y dr u gs  will h a v e a n 
E n d of Tr e at m e nt  visit wit hi n 3 0 d a ys fr o m t h e l ast d os e of st u d y dr u g.  Aft er c ycl e 2 4, s u bj ects 
s h o ul d h a v e r es p o ns e ass ess m e nt at l e ast e v er y 1 2 m o nt hs or m or e fr e q u e ntl y as m e dic all y 
i n dic at e d.  
S u bj ects w h o disc o nti n u e fr o m st u d y tr e at m e nt (f or r e as o ns ot h er t h a n pr o g r essi v e dis e as e or 
c o m pl eti o n of t h er a p y),  will h a v e a n E n d of Tr e at m e nt  visit wit hi n 3 0 d a ys fr o m t h e l ast d os e of 
st u d y dr u g. F oll o w f or P F S as b el o w: 
•  
M o nt hs 1 -2 4 a p pr o xi m at el y e v er y 6 m o nt hs  
•  
M o nt hs 2 5 a n d b e y o n d at l e ast e v er y y e ar  
S af et y will b e e v al u at e d c o nti n u o usl y t hr o u g h o ut t h e st u d y.  
U p t o 5 0 s u bj ects ar e e x p ect e d t o b e e nr oll e d i n t his st u d y.  
4. 2  S A F E T Y R U N -I N 
A 3 + 3 a p pr o ac h will b e utili z e d t o e v al u at e s af et y d uri n g t h e s af et y r u n -i n p h as e.  T hr e e s u bj ects 
will first b e tr e at e d at 6 0 0 m g u m b r alisi b i n c o m bi n ati o n wit h u blit u xi m a b f or 1 c ycl e ( 2 8 d a ys) . 
If 1 / 3 s u bj ects e x p eri e nc e a n u n acc e pt a bl e t o xicit y ( d efi n e d b el o w), 3 a d diti o n al s u bj ects will b e 
e nr oll e d at t h e s a m e d os e l e v el. If > 1 / 6 s u bj ects at 6 0 0 m g e x p eri e nc e a n u n ac e pt a bl e t o xicit y , it 


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will b e d e e m e d t o e xc e e d t h e M T D a n d e nr oll m e nt t o t h e st u d y will st o p . If ≤1 / 6 s u bj ects 
e x p eri e nc e a n u n acc e pt a bl e t o xicit y at 6 0 0 m g , t h e n 3 s u bj ects will b e e nr oll e d t o r ec ei v e 8 0 0 m g 
u m br alisi b i n c o m bi n ati o n wit h u blit u xi m a b f or 1 c ycl e ( 2 8 d a ys) . If 1 / 3 s u bj ects e x p eri e nc e an 
u n acc e pt a bl e t o xicit y , 3 a d diti o n al s u bj ects will b e e nr oll e d at t h e s a m e d os e l e v el. If > 1 / 6 s u bj ects 
at 8 0 0 m g e x p eri e nc e a n u n ac e pt a bl e t o xicit y, it will b e d e e m e d t o e xc e e d t h e M T D a n d e nr oll m e nt 
t o t h e r e m ai n e d er of t h e st u d y will pr oc e e d at 6 0 0 m g u m br alisi b . If ≤1 / 6 s u bj ects e x p eri e nc e a n 
u n acc e pt a bl e t o xicit y at 8 0 0 m g , t h e n e nr oll m e nt will pr oc e e d f or t h e r e m ai n d er of t h e st u d y at 
8 0 0 m g u m br alisi b.  
A n u n acc e pt a bl e t o xicit y will b e d efi n e d as t h e occ ur a nc e of tr a ns a m i nitis, c olitis, p n e u m o nitis, 
or r as h d uri n g C ycl e 1 t h at is:  
•  
Gr a d e ≥3 a n d p ersists f or > 7 d a ys wit h o ut r es ol uti o n d es pit e s u p p orti v e c ar e; or  
•  
A n y gr a d e tr e at m e nt e m er g e nt t o xicit y t h at r es ults i n tr e at m e nt disc o nti n u ati o n. 
4. 3  R E GI S T R A TI O N  A N D E N R O L L M E N T  
Pr i or t o p artici p ati o n, s u bj ects m ust willi n gl y c o ns e nt t o t h e st u d y aft er b ei n g i nf or m e d of t h e 
pr oc e d ur es t o b e f oll o w e d, t h e e x p eri m e nt al n at ur e of t h e tr e at m e nt, p ot e nti al b e n efits, alt er n ati v es, 
si d e-eff ects, ris ks a n d disc o mf orts.  O nl y e li gi bl e s u bj ects will b e e nr oll e d o nt o t h e st u d y.  
I n v esti g at ors will us e a n i nt er acti v e w e b r es p o ns e s yst e m (I W R S) t o r e gist er a n d e nr oll s u bj ects t o 
st u d y U T X-T G R -2 0 3 .  U p o n e nt eri n g s u bj ect i nf or m ati o n i nt o t h e I W R S, i n v esti g at ors will r ec ei v e a 
u ni q u e s u bj ect id e ntifi er. T his c o nfir m ati o n m ust b e r ec ei v e d b y t h e sit e pri or t o dis p e nsi n g st u d y 
dr u g t o t h e p artici p a nt. F urt h er d et ails a b o ut t h e s u bj ect r e gistr ati o n pr oc ess usi n g t h e I W R S s yst e m 
will b e o utli n e d i n t h e St u d y M a n u al.  
4. 4  S T U D Y SI T E S  
U p t o 1 5 tri al  c e nt ers i n t h e U nit e d  St at es  m a y  p artici p at e  i n t his st u d y. E nr oll m e nt  is e x p ect e d t o 
b e c o m pl et e d i n a p pr o xi m at el y 1 2 -1 6  m o nt hs.  
4. 5  DI S C O N TI N U A TI O N F R O M  S T U D Y  T R E A T M E N T  
S u bj ects will b e disc o nti n u e d fr o m st u d y tr e at m e nt f or a n y of t h e f oll o wi n g  r e as o ns: 
•  
Dis e as e  pr o gr essi o n 
•  
I nt ol er a bl e t o xicit y r el at e d t o st u d y dr u g 
•  
S u bj ect r e q u ests t o wit h dr a w c o ns e nt or disc o nti n u e  tr e at m e nt 
•  
Pr e g n a nc y  
•  
I n a bilit y of t h e s u bj ect t o c o m pl y wit h st u d y r e q uir e m e nts 
•  
C o n diti o ns r e q uiri n g t h er a p e utic i nt er v e nti o n n ot p er mitt e d b y t h e  pr ot oc ol  
•  
N o n -c o m pli a nc e /l ost t o  f oll o w-u p  
•  
I n v esti g at or discr eti o n 
•  
Disc o nti n u ati o n of t h e st u d y b y t h e  S p o ns or  
•  
C o m pl eti o n of 2 4 m o nt hs of t h er a p y  
 
S u bj ects w h o disc o nti n u e fr o m st u d y tr e at m e nt (f or r e as o ns ot h er t h a n pr o gr essi v e dis e as e  or 


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c o m pl eti o n of tr e at m e nt ) s h o ul d c o nti n u e t o b e  f oll o w e d f or pr o gr essi o n-fr e e s ur vi v al ( P F S). 
F oll o w f or P F S as b el o w:  
•  
M o nt hs 1- 2 4 a p pr o xi m at el y e v er y 6 m o nt hs  
•  
M o nt hs 2 5 a n d b e y o n d at l e ast e v er y y e ar  
Aft er wit h dr a w al fr o m pr ot oc ol tr e at m e nt, s u bj ects s h o ul d b e f oll o w e d f or A Es f or 3 0 c al e n d ar 
d a ys aft er t h eir l ast d os e of eit h er st u d y dr u g. All n e w A Es occ urri n g d uri n g t his p eri o d m ust b e  
r e p ort e d a n d f oll o w e d u ntil r es ol uti o n, u nl ess, i n t h e o pi ni o n of t h e i n v esti g at or, t h es e v al u es ar e 
n ot li k el y  t o i m pr o v e b ec a us e of t h e u n d erl yi n g dis e as e. I n t his c as e t h e i n v esti g at ors m ust r ec or d 
his or  h er r e as o ni n g f or t his d ecisi o n i n t h e s u bj ect’s m e dic al r ec or ds a n d as a c o m m e nt o n t h e 
el ectr o nic  C as e R e p ort F or m  ( e C R F). 
All  s u bj ects w h o  h a v e  C T C A E  Gr a d e 3 or  4 l a b or at or y a b n or m aliti es  at  t h e ti m e of  wit h dr a w al  
s h o ul d b e f oll o w e d u ntil  t h e  l a b or at or y v al u es  h a v e   r et ur n e d t o Gr a d e   1 or  2,  u nl ess  i n t h e 
o pi ni o n  of  t h e  i n v esti g at or, it is n ot   li k el y t h at t h es e v al u es   ar e t o i m pr o v e b ec a us e  of  t h e 
u n d erl yi n g  dis e as e.  I n t his c as e, t h e i n v esti g at or m ust   r ec or d his  or  h er  r e as o ni n g f or m a ki n g  
t his d ecisi o n  i n t h e s u bj ect’s m e dic al r ec or ds a n d as a c o m m e nt o n t h e  e C R F.  




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8   C M V o nl y s h o ul d b e c h ec k e d b y P C R a p pr o xi m at el y e v er y 3 c ycl es, as p art of t h e s u bj ect’s sc h e d ul e d visit.  If s u bj ect is C M V p ositi v e, 
st o p t h er a p y a n d pr o vi d e s u p p orti v e c ar e p er i n v esti g at or discr eti o n . C M V s ur v eill a n c e s h o ul d disc o nti n u e 3 0 d a ys aft er l ast d os e of 
u m br alisi b.  
9   T h e scr e e ni n g h e m at ol o g y m ust b e d o n e ≤ 7 d a ys pri or t o i niti ati o n of tr e at m e nt.  H o w e v er, if t h es e i niti al e x a mi n ati o ns ar e o bt ai n e d 
wit hi n 7 2 h o urs of C ycl e 1 D a y 1 t h e y d o n ot h a v e t o b e r e p e at e d. C 1 ( D a y 8 & 1 5) a n d C ycl e 2 ( d a y 1), l a b or at or y ass ess m e nts h a v e a ± 
3 d a y wi n d o w, a n d a ±  7 d a ys f or all visits aft er C ycl e 2.  H e m at ol o gic al p ar a m et ers i ncl u d e t h e f oll o wi n g l a b or at or y t ests:  c o m pl et e 
bl o o d c o u nt c o nsisti n g of h m e at ocrit, h e m o g l o bi n, t ot al w hit e bl o o d c o u nt ( W B C) wit h 5-p art diff er e nti al, a n d pl at el et c o u nt.  
1 0   T h e scr e e ni n g c h e mistr y m ust b e d o n e ≤ 7 d a ys pri or t o i niti ati o n of tr e at m e nt.  H o w e v er, if t h es e i niti al e x a mi n ati o ns ar e o bt ai n e d 
wit hi n 7 2 h o urs of C ycl e 1 D a y 1 t h e y  d o n ot h a v e t o b e r e p e at e d.  C 1 ( D a y 8 & 1 5) a n d C ycl e 2 ( D a y 1) l a b or at or y ass ess m e nts h a v e a ± 
3 d a y wi n d o w, a n d ± 7 d a ys f or all visits aft er C ycl e 2.  C h e mistr y p a n el i ncl u d es t h e f oll o wi n g: ur e a or bl o o d ur e a nitr o g e n , cr e ati ni n e, 
s o di u m,  p ot assi u m,  c alci u m,  c ar b o n  di o xi d e,  m a g n esi u m,  p h os p h or o us,  gl uc os e,  al b u mi n,  t ot al  pr ot ei n,  t ot al  bilir u bi n,  al k ali n e  
p h os p h at as e, A S T, A L T, G G T, uric aci d, a n d l act at e d e h y dr o g e n as e.   
1 1   T o b e d o n e ≤ 7 d a ys pri or t o i niti al of tr e at m e nt.  H o w e v er, if t h es e i niti al  e x a mi n ati o ns ar e o bt ai n e d wit hi n 7 2 h o urs of C ycl e 1 D a y 1 
t h e y d o n ot h a v e t o b e r e p e at e d.   
1 2   F or w o m e n of c hil d -b e ari n g  p ot e nti al,  a s er u m pr e n a nc y t es et will b e p erf or m e d at b as eli n e ( wit hi n 7 2 h o urs of D a y 1 of C ycl e 1)  wit h 
a uri n e pr e g n a nc y t est D 1 of e ac h c ycl e.  
1 3   C or e n e e dl e bi o ps y o pti o n al. If c oll ect e d, s a m pl e at pr e -d os e ( wit hi n 2 8 d a ys) a n d o n e p ost d os e a n yti m e b et w e e n D a ys 1 5 &  2 8 of C ycl e 
1.  
  
   
1 5   P eri p h er al bl o o d f or l y m p h oc yt e s u bs ets will b e dr a w n o n C ycl e 1 D a y 1 ( pr e -d os e), D a y 1 of C ycl es 2 -6, 9, 1 2, 1 8 a n d 2 4 a n d at e n d of 
st u d y.   
1 6   P K s a m p l es ( pl as m a) will b e c oll ect e d acc or di n g t o t h e sc h e d ul e i n S ecti o n 5. 1. 2 ( C e ntr al L a b or at or y Ass ess m e nts).  A d diti o n al P K 
s a m pl es m a y b e c oll ect e d o utsi d e of t his sc h e d ul e u p o n t h e occ urr e nc e of t o xicit y i n or d er t o c orr el at e t o pl as m a c o nc e ntr ati o ns.  
1 7   U blit u xi m a b i nf usi o n o nl y i n C ycl e 9 & 1 2 – n o a d diti o n al u blit u xi m a b aft er C ycl e 1 2.  
1 8   R e vi e w st u d y dr u g c o m pli a nc e a n d d oc u m e nt miss e d d os es i n m e dic al r ec or d. S u bj ects  ar e r e q uir e d t o st art pr o p h yl a xis tr e at m e nt f or 
p n e u m oc ystis jir o v eci p n e u m o ni a ( P C P) as w ell as a nti vir al t h er a p y pri or t o C ycl e 1 D a y 1.  
 
 
 
 






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6  T R E A T M E N T P L A N  
6. 1  T R E A T M E N T S U M M A R Y  
Tr e at m e nt will b e a d mi nist er e d o n a n o ut p ati e nt b asis i n 4 -w e e k ( 2 8 d a y)  c ycl es. 
 
U M B R A LI SI B ( T G R -1 2 0 2 ) 
•  
6 0 0 m g (s af et y r u n-i n c o h ort) or 8 0 0 m g o nc e d ail y t hr o u g h C ycl e 2 4 ( a p pr o xi m at el y 
2 4 m o nt hs).  N o a d diti o n al u m br alisi b will b e a d mi nist er e d aft er C ycl e 2 4.  
•  
S u bj ect  di ar y will b e  utili z e d .  Miss e d d os es of u m br alisi b s h o ul d b e n ot e d b y t h e 
s u bj ect o n t h e s u bj ect di ar y.  I n a d diti o n, dr u g acc o u nt a bilit y s h o ul d b e d oc u m e nt e d 
i n t h e s u bj ects m e dic al r ec or d.  
 
U B LI T U XI M A B  
•  
9 0 0 m g U blit u xi m a b o n D a ys 1, 8, 1 5 of C ycl e 1 a n d D a y 1 of C ycl es 2 - 6, C ycl e 9 a n d 
1 2.  N o a d diti o n al u blit u xi m a b will b e a d mi nist er e d aft er  C ycl e 1 2.   
6. 2  A G E N T A D MI NI S T R A TI O N  
6. 2. 1  G UI D E LI N E S F O R A D MI N I S T R A TI O N O F U M B R A LI SI B  
•  
M et h o d of A d mi nistr ati o n: U m br alisi b  will b e a d mi nist er e d or all y o nc e d ail y wit h  f o o d. 
•  
P ot e nti al Dr u g I nt er acti o ns : N o d r u g int er acti o ns h a v e b e e n r e p ort e d t o  d at e.  
•  
Pr e -me dic ati o ns:  S u bj ect s ar e r e q uir e d t o st art pr o p h yl a xis tr e at m e nt f or p n e u m oc ystis 
jir o v eci p n e u m o ni a ( PJP) a s w ell as a nti vir al t h er a p y pri or t o C ycl e 1 D a y 1 . 
o  A nti -vir al  Pr o p h yl axis :  V altr e x 5 0 0 m g d ail y or Ac ycl o vir 4 0 0 m g BI D or e q ui v al e nt 
o  PJ P Pr o p h yl axis:   D a ps o n e 1 0 0 m g d ail y  
•  
Fi n al c h oic e of P C P a n d a nti -vir al pr o p h yl a xis t h er a p y is p er i n v esti g at or discr eti o n.  
N O T E: If P JP or a nti -vir al t h er a p y is n ot t ol er at e d, alt er n at e t o a diff er e nt P JP or a nti - vir al 
t h er a p y, disc o nti n u e, or r e d uc e d os e /sc h e d ul e as p er t h e discr eti o n of t h e i n v esti g at or.  
U m br alisi b will  b e  dis p e ns e d  at  t h e sit es b y  t h e  r es e arc h c o or di n at or or  d esi g n e e  u n d er  t h e 
dir ecti o n of  t h e PI  or  b y  a p h ar m acist  at  t h e sit e. S u bj ect s m ust  b e  pr o vi d e d dr u g i n its ori gi n al  
c o nt ai n er. S u bj ect s s h o ul d b e  i nstr uct e d t o r et ur n a n y  u n us e d  t a bl ets w h e n  t h e y  r et ur n t h e 
b ottl e  t o t h e sit e. A dr u g di ar y s h o ul d b e pr o vi d e d t o t h e s u bj ect. St u d y dr u g c o m pli a nc e s h o ul d 
b e r e vi e w e d wit h t h e s u bj ect at t h e b e gi n ni n g of e ac h n e w  tr e at m e nt c ycl e a n d as n e e d e d.  Miss e d 
d os es will b e d oc u m e nt e d i n t h e s u bj ects’ m e dic al  r ec or d. 
 
U m br alisi b  will b e s elf -a d mi nist er e d ( b y t h e s u bj ect). T a bl ets s h o ul d b e t a k e n at a p pr o xi m at el y 
t h e s a m e ti m e e ac h  d a y wit h  f o o d ( wit hi n 3 0  mi n ut es  of  a m e al).  S u bj ect s s h o ul d b e  i nstr uct e d t o 
s w all o w t h e t a bl ets w h ol e a n d s h o ul d n ot c h e w or cr us h  t h e m. 
If a d os e of  u m br alisi b  is miss e d,  it s h o ul d b e  t a k e n as  s o o n as  p ossi bl e  o n  t h e s a m e d a y.  If it is 


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miss e d f or   a p eri o d of gr e at er t h a n  1 2  h o urs,  it s h o ul d n ot  b e   r e pl ac e d. If v o miti n g  occ urs,  n o  
att e m pt  s h o ul d b e  m a d e  t o r e pl ac e t h e v o mit e d d os e.  
6. 2. 1. 1  DI S P E N SI N G O F U M B R A LI SI B  
B ef or e dis p e nsi n g, t h e sit e p h ar m acist or his / h er r e pr es e nt ati v e m ust c h ec k t h at t h e u m br alisi b  
is i n acc or d a nc e wit h t h e pr o d uct s p ecific ati o ns a n d t h e v ali dit y is wit hi n t h e r e -t est d at e.  
 
T h e p h ar m acist or his / h er r e pr es e nt ati v e s h o ul d r ec or d  all u m br alisi b  dr u g dis p e ns ati o ns i n t h e 
el ectr o nic dr u g acc o u nt a bilit y l o g. W h e n d oi n g t his, t h e c o m pl et e r ec or d s h o ul d b e l o g g e d. T his 
i ncl u d es t h e s u bj ect n u m b er, s u bj ect i niti als, d at e of dis p e ns ati o n, a n d l ot n u m b er of t h e i n di vi d u al 
b ottl e . 
T h e  e x act  d os e  a n d  t h e d at e  of  a d mi nistr ati o n  of  u m br alisi b  m ust  b e   r ec or d e d wit hi n  t h e 
e C R F  a n d t h e  s u bj ect’s m e dic al   r ec or ds. F or  t h e p ur p os e  of   dr u g acc o u nt a bilit y  a n d  d osi n g,   a 
dr u g  di ar y will  b e utili z e d.  A n y err or i n dr u g a d mi nistr ati o n s h o ul d b e r ec or d e d ( e. g., miss e d 
d os e) i n t h e e C R F . 
6. 2. 2  G UI D E LI N E S F O R A D MI N I S T R A TI O N O F U B LI T U XI M A B 
•  
M et h o d  of  A d mi nistr ati o n:  U blit u xi m a b will  b e  a d mi nist er e d as  a n  i ntr a v e n o us  i nf usi o n  
t hr o u g h a d e dic at e d li n e. 
•  
P ot e nti al Dr u g I nt er acti o ns :  N o dr u g int er acti o ns h a v e b e e n r e p ort e d t o d at e.  
•  
Pr e -m e dic ati o ns:   Ublit u xi m a b  s h o ul d  b e  st art e d  a p pr o xi m at el y  3 0  mi n ut es  aft er  t h e  
c o ncl usi o n  of  t h e  l ast  pr e-m e d ic ati o n i nf usi o n  a n d  s h o ul d  i ncl u d e  a n  a nti hist a mi n e  
( di p h e n h y dr a mi n e 5 0 m g or e q ui v al e nt), a n d a c ortic ost er oi d ( d e x a m et h as o n e 1 0 -2 0 m g or 
e q ui v al e nt). If pr e -m e dic ati o n is gi v e n or all y, t h e y s h o ul d b e gi v e n a p pr o xi m at el y 4 5 -6 0 
mi n ut es pri or t o t h e b e gi n ni n g of t h e u blit u xi m a b i nf usi o n. If s u bj ect h as a n e g ati v e r e a cti o n 
t o a pr e m e dic ati o n, c h a n g e t o a n e q ui v al e nt dr u g, d ecr e as e d os e , or disc o nti n u e if s u bj ect 
c a n n ot  t ol er at e.   A d diti o n all y,  if  s u bj ect  h as  ot h er  h e alt h  c o n diti o ns  t h at ar e  a d v ers el y 
i m p act e d b y t h e pr e m e dic ati o n  dr u g (s)  c o nsi d er c h a n gi n g dr u g / d os e , or disc o nti n ui n g if 
i n v esti g at or f e els it is i n t h e s u bj ects b est i nt er est. 
o  Us e of or al ac et a mi n o p h e n 6 5 0 m g ( or e q ui v al e nt) s h o ul d b e r estrict e d t o s u bj ects w h o 
e x p eri e nc e f e v er or p yr e xi a aft er w e e k 1 d os e, or as cli nic all y w arr a nt e d.  
o  If aft er c ycl e 6, us e of a c ortic ost er oi d is of cli nic al c o nc er n, pl e as e c o nt act s p o ns or. 
•  
H y p ers e nsiti vit y a n d I nf usi o n R e acti o n  Pr ec a uti o n s: M e dic ati o n a n d r es uscit ati o n e q ui p m e nt 
m ust b e a v ail a bl e  p er i nstit uti o n al g ui d eli n es  pri or t o u blit u xi m a b a d mi nistr ati o n f or t h e 
e m er g e nc y m a n a g e m e nt of p ot e nti al a n a p h yl actic r e acti o ns .   
•  
S u bj ect  C ar e I m plic ati o ns :   
o  U blit u xi m a b s h o ul d n ot b e a d mi nist er e d as a n I V p us h or b ol us.  
o  U blit u xi m a b m a y b e a d mi nist er e d o n a n o ut p ati e nt b asis.  
o  Dil ut e d u blit u xi m a b s h o ul d b e c h ec k e d b ef or e a d mi nistr ati o n f or cl o u di n ess, c ol or, or 
d e p osits.   U blit u xi m a b s h o ul d n ot  b e  a d mi nist er e d  if  d o es  n ot  c o nf or m  t o  t h e  


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s p ecific ati o ns. Im m e di at el y  i nf or m  t h e  M o nit or / S p o ns or  wit h  a n y  pr o d uct  q u alit y  
c o nc erns or q u esti o ns . 
o  It is r ec o m m e n d e d t h at u blit u xi m a b b e a d mi nist er e d i m m e di at el y aft er dil uti o n. 
o  N o  ot h er  tr e at m e nt  m a y  b e  c o -a d mi nist er e d  wit h  u blit u xi m a b  ( ot h er  t h a n  f or  
i m m e di at e i nt er v e nti o n f or a d v ers e e v e nt). 
o  C o nc urr e nt gl uc oc ortic oi d t h er a p y as l o n g as st art e d f or at l e ast 7 d a ys pri or t o st u d y 
e ntr y ( < 1 0 m g p er d a y of pr e d nis o n e or e q ui v al e nt) is all o w e d as cli nic all y w arr a nt e d.  
o  Si nc e i nf usi o n -r el at e d h y p ot e nsi o n m a y occ ur, a nti h y p e rt e n si v e m e di c ati o n s s h o ul d 
b e wit h h el d 1 2 -2 4  h o u r s p ri o r t o a n d t h r o u g h o ut i nf u si o n of u blit u xi m a b  at 
i n v e sti g at o r di s c r eti o n. 
o  F or s u bj ects at ris k f or t u m or l ysis s y n dr o m e i n t h e o pi ni o n of t h e tr e ati n g i n v esti g at or, 
pr o p h yl a xis wit h all o p uri n ol or p er r ec o m m e n d e d i nstit uti o n al st a n d ar ds s h o ul d b e 
c o nsi d er e d. 
 
6. 2. 2. 1  I N F U SI O N R E L A T E D R E A C TI O N S A N D I N F U SI O N R A T E G UI D A N C E - U B LI T U XI M A B  
I nf usi o n  r el at e d  r e acti o ns i ncl u di n g  s e v er e  r e acti o ns h a v e  b e e n  r e p ort e d  wit h  u blit u xi m a b  
a d mi nistr ati o n .   G ui d eli n es  ar e  pr o vi d e d  b el o w  f or  s u bj ects w h o  e x p eri e nc e  s uc h  r e acti o ns.   
S y m pt o m atic i nf usi o n r e acti o ns, d es pit e pr e m e dic ati o n, m a y b e tr e at e d at t h e discr eti o n of t h e 
tr e ati n g  p h ysici a n,  i ncl u di n g  b ut  n ot  li mit e d  t o:  or al  ac et a mi n o p h e n  6 5 0  m g  ( or  e q ui v al e nt),  
c ortic ost er oi ds, a nti hist a mi n es, o x y g e n , a n d br o nc h o dil at ors.   
T h e  f oll o wi n g  ar e  r ec o m m e n d e d  i nf usi o n  r at e  r e d ucti o n / d el a y  g ui d eli n es  f or  s u bj ects w h o 
e x p eri e nc e s e v er e I nf usi o n R el at e d R e acti o ns (I R R’s) i n w hic h tr e at m e nt s h o ul d b e i nt err u pt e d.  Fi n al 
d ecisi o n f or i nf usi o n r at e r e d ucti o n / d el a y or disc o nti n u ati o n r esi d es wit h t h e tr e ati n g i n v esti g at or. 
 
1 st o r 2 n d  I nf u si o n I nt e r r u pti o n: 
•  
H ol d i nf usi o n  a n d cl os el y m o nit or e d s u bj ect, i nstit ut e s y m pt o m atic m e dic al m a n a g e m e nt 
u ntil r es ol uti o n of I R R s y m pt o ms. 
•  
F oll o wi n g t h e j u d g m e nt of t h e I n v esti g at or, a n d pr o vi d e d t h e s u bj ect is st a bl e, t h e i nf usi o n 
m a y b e r es u m e d at n o m or e t h a n h alf t h e pr e vi o us r at e.  
•  
If t h e s u bj ect d o es n ot e x p eri e nc e a n y f urt h er I R R s y m pt o ms, i nf usi o n r at e esc al ati o n m a y 
r es u m e at t h e i ncr e m e nts a n d i nt er v als as a p pr o pri at e at t h e tr e at m e nt c ycl e d os e (s e e 
S ecti o n  6. 2. 2. 2 . 
 
3 r d I nf u si o n I nt e r r u pti o n ( s a m e d a y): 
•  
Disc o nti n u e i nf usi o n f or t h at d a y – m o nit or s u bj ect f or r es ol uti o n of all s y m pt o ms.  S u bj ect  
s h o ul d h a v e all v it al si g ns c o m pl et e d as w ell as a n y ot h er st a n d ar d of c ar e pr oc e d ur es 
c o m pl et e d as w arr a nt e d b y t h e I n v esti g at or pri or t o r el e as e of s u bj ect fr o m st u d y sit e. 
•  
A n y r e m ai ni n g dil ut e d i n v esti g ati o n al pr o d uct s h o ul d b e disc ar d e d.  
 
 
If a n i nf usi o n r el at e d r e acti o n is o bs er v e d, at a n y ti m e d uri n g  t h e u blit u xi m a b tr e at m e nt, t h e tr e ati n g 
i n v esti g at or m a y r e d uc e t h e i nf usi o n fl o w r at e at t h eir discr eti o n. 
 
 




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6. 2. 3  C RI T E RI A F O R O N G OI N G  T R E A T M E N T  
C o nti n u e tr e at m e nt as p er pr ot oc ol pr o vi d e d t h at s u bj ect h as : 
•  
N o i nt ol er a bl e t o xiciti es r el at e d t o st u d y dr u g . 
o  Tr e at m e nt m a y b e d el a y e d t o r ec o v er fr o m t o xicit y  
•  
N o cli nic al or r a di o gr a p hic e vi d e nc e of dis e as e pr o gr essi o n.  
•  
N ot wit h dr a w n fr o m t h e st u d y f or ot h er r e as o ns.  
6. 3  D O SI N G D E L A Y S A N D M O DI FI C A TI O N S  
S u bj ect s s h o ul d  b e  ass ess e d  cli nic all y  f or  t o xicit y  at  e ac h  visit  usi n g  t h e  N CI  C T C A E  v 4. 0  
(htt p: / / e vs. nci. ni h. g o v /ft p 1 / C T C A E ) gr a di n g sc al e.  D osi n g will occ ur o nl y if a s u bj ect’s cli nic al 
ass ess m e nt a n d l a b or at or y t est v al u es ar e acc e pt a bl e.   
At t h e discr eti o n of t h e I n v esti g at or, a d os e r e -esc al ati o n m a y b e p er mitt e d f or s u bj ects w h o w er e 
d os e r e d uc e d u p o n r es u mi n g u m br alisi b .  S u bj ect s t h at r e q uir e d os e r e d ucti o n f or e v e nts t h at ar e 
lif e-t hr e at e ni n g s h o ul d n ot b e r e-esc al at e d.  O n s ec o n d d os e r e d ucti o n f or t h e s a m e e v e nt c o nt act 
t h e M e dic al M o nit or pri or t o d os e r e-esc al ati n g t o disc uss m a n a g e m e nt of t h e s u bj ect.    
H oli d a ys fr o m st u d y dr u g ar e disc o ur a g e d.   H o w e v er, f or s u bj ects r e q u esti n g a dr u g h oli d a y wit h o ut 
a n a d v ers e e v e nt, a h oli d a y m a y b e p er mitt e d at t h e discr eti o n of t h e I n v esti g at or.   T h e s u bj ect m ust 
b e o n st u d y dr u g f or 3 m o nt hs t o b e eli gi bl e f or a h oli d a y fr o m st u d y dr u g > 4 w e e ks.    
A n y s u bj ect i n w h o m si mil ar t o xicit y r ec urs at t h e r e d uc e d d os e s h o ul d b e disc o nti n u e d fr o m f urt h er 
u m br alisi b  tr e at m e nt.  E xc e pti o ns t o t his disc o nti n u ati o n r ul e o n t h e b asis of o n g oi n g cli nic al b e n efit 
a n d acc e pt a bl e / mi ni m al cli nic al ris k m a y b e all o w e d f oll o wi n g a c ar ef ul ass ess m e nt a n d disc ussi o n 
of ris k v ers us b e n efit wit h t h e s u bj ect b y t h e I n v esti g at or a n d wit h a p pr o v al fr o m t h e M e dic al 
M o nit or.    
If a s u bj e ct  di s c o nti n u e s o nl y o n e st u d y d r u g, t h e s u bj e ct  m a y c o nti n u e t r e at m e nt wit h t h e 
ot h e r st u d y d r u g p e r t h e p r ot o c ol.  Pl e a s e s e e S e cti o n s 6. 3. 1 a n d 6. 3. 2 b el o w f o r s p e cifi c 
g ui d eli n e s r e g a r di n g d o s e d el a y a n d / o r m o difi c ati o n s.  C o nt a ct t h e s p o n s o r p ri o r t o 
di s c o nti n ui n g a n y  st u d y d r u g( s).  
6. 3. 1  D O S E D E L A Y / M O DI FI C A TI O N S:  U M B R A LI SI B  
S u p p orti v e c ar e s h o ul d b e c o nsi d er e d f or a n y s u bj ect w h o e x p eri e nc es Gr a d e ≥ 2 c yt o p e ni as, or Gr a d e 
≥  1  n o n -h e m at ol o gic t o xiciti es.   D el a y f or r ec o v er y fr o m t o xicit y is all o w e d f or b ot h  st u d y dr u gs 
( u blit u xi m a b  a n d / or  u m br alisi b ) f or r ec o v er y  of  h e m at ol o gic  t o xiciti es  t o  ≤Gr a d e  3  or  n o n -
h e m at ol o gic t o xiciti es t o ≤ Gr a d e 2 or t o b as eli n e l e v el.    If t h e s u bj ect wit h dr a ws c o ns e nt or h as 
d oc u m e nt e d pr o gr essi o n, a n e n d of st u d y visit s h o ul d b e c o m pl et e d.  
If a s u bj ect  disc o nti n u es o nl y o n e st u d y dr u g, t h e s u bj ect m a y c o nti n u e tr e at m e nt wit h t h e ot h er 
st u d y dr u g p er t h e pr ot oc ol. 








U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 4 4  of 8 5  
I n t h e a bs e nc e  of  tr e at m e nt  d el a ys  d u e t o a d v ers e  e v e nt(s),  u m br alisi b a n d u blit u xi m a b s h o ul d 
c o nti n u e as p er t h e tr e at m e nt pl a n  u nl ess o n e of t h e f oll o wi n g crit eri a  a p pli es:  
•  
Dis e as e pr o gr essi o n or i nt er -c urr e nt ill n ess t h at pr e v e nts f urt h er  tr e at m e nt. 
•  
S u bj ect  d eci d es t o wit h dr a w fr o m t h e st u d y, or c h a n g es i n t h e s u bj ect's c o n diti o n r e n d er 
t h e s u bj ect u n acc e pt a bl e f or f urt h er tr e at m e nt i n t h e j u d g m e nt of t h e  i n v esti g at or. 
 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 4 5  of 8 5  
7  S T U D Y M E DI C A TI O N O V E R VI E W A N D S A F E T Y  
7. 1  U M B R A LI SI B ( T G R -1 2 0 2 ) 
Cl assific ati o n:     
P h os p h ati d yli n osit ol - 3-Ki n as e ( PI 3 K) D elt a I n hi bit or  
F or m ul ati o n:    
S e e I n v esti g at or Br oc h ur e  
 
M o d e of Acti o n : 
Irr e v ersi bl y i n hi bits acti vit y of t h e Cl ass I D elt a is of or m of PI 3 K   
 
H o w S u p pli e d:    
U m br alisi b : 2 0 0 m g t a bl ets 
St or a g e:  
St or e at 2 5° C.  E xc ursi o ns p er mitt e d 1 5° C t o 3 0° C . 
St a bilit y:  
R et est d at es will b e pr o vi d e d p eri o dic all y b y S p o ns or . 
R o ut e of  
A d mi nistr ati o n : 
Or al  
P ac k a gi n g:  
U m br alisi b  is pr o vi d e d i n H D P E b ottl es e ac h c o nt ai ni n g 3 0 t a bl ets a n d a silic a 
g el c a nist er as a d esicc a nt.  
A v ail a bilit y:   
 
U m br alisi b  is a v ail a bl e fr o m T G T h er a p e utics. 
7. 2  U B LI T U XI M A B  
C h e mic al N a m e:   
Ublit u xi m a b    
Ot h er N a mes:      
T G -1 1 0 1  
Cl assific ati o n:     
R ec o m bi n a nt c hi m eric a nti -C D 2 0 m o n ocl o n al a nti b o d y     
M o d e of Acti o n : 
T ar g ets C D 2 0 a nti g e n o n B -c ells  
 
D escri pti o n:  
U blit u xi m a b  is  a  g e n etic all y  e n gi n e er e d  c hi m eric  m uri n e / h u m a n  m A b  
dir ect e d a g ai nst t h e C D 2 0 a nti g e n f o u n d o n t h e s urf ac e of B l y m p h oc yt es.  
U blit u xi m a b dis pl a ys t h e t y pic al str uct ur e of i m m u n o gl o b uli ns, c o nsisti n g of 
t w o g a m m a (γ) h e a v y c h ai ns a n d t w o k a p p a (κ ) li g ht c h ai ns li n k e d b y dis ulfi d e 
bri d g es. It is c o m p os e d of a m uri n e v ari a bl e r e gi o n ( 3 7. 2 % of t ot al a mi n o 
aci ds) f us e d o nt o h u m a n c o nst a nt r e gi o ns.  
H o w S u p pli e d:  
C o nc e ntr ati o n of 2 5 m g / m L i n 6 m L ( 1 5 0 m g) si n gl e-us e gl ass vi als.    
St or a g e:  
U blit u xi m a b m ust b e st or e d i n a s ec ur e d , li mit e d-acc ess , r efri g er at e d ar e a at 
a t e m p er at ur e r a n gi n g fr o m + 2° C / + 8° C .  U blit u xi m a b m ust n ot b e fr o z e n. 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 4 6  of 8 5  
St a bilit y:  
O nc e a vi al of u blit u xi m a b h as b e e n o p e n e d a n d / or dil ut e d it m ust b e us e d 
i m m e di at el y.  Aft er dil uti o n , u blit u xi m a b is st a bl e i n st atic c o n diti o ns f or 2 4 
h o urs at 2 5° C, a n d i n d y n a mic c o n diti o ns it is st a bl e f or 8 h o urs at 2 5° C.    
U blit u xi m a b h as a s h elf -lif e of 3 6  m o nt hs if st or e d b et w e e n + 2° C / + 8° C , 
b as e d o n st a bilit y d at a.  
R o ut e of  
A d mi nistr ati o n : 
I ntr a v e n o us 
P ac k a gi n g:   
 
U blit u xi m a b is p ac k e d i n kits . E ac h kit  c o nt ai ns:  
•  
Si x vi als c o nt ai ni n g 1 5 0 m g  s ol uti o n of u blit u xi m a b i n e ac h 
or  
•  
O n e vi al c o nt ai ni n g 1 5 0 m g s ol uti o n of u blit u xi m a b  (f or r e pl ac e m e nt 
if n e e d e d) 
 
T h e c o nt ai n er cl os ur e s yst e m f or t h e vi als c o nt ai ni n g 6 m L is a ty p e I gl ass vi al 
cl os e d b y a silic o ni z e d c hl oro b ut yl r u b b er st o p p er  s e al e d wit h a n a q u a pl astic 
a n d al u mi n u m c a p  
A v ail a bilit y:   
 
U blit u xi m a b is a v ail a bl e fr o m T G T h er a p e utics.  
7. 2. 1  U B LI T U XI M A B  +  U M B R A LI SI B  ( T G R-1 2 0 2)  C O M BI N A TI O N   - C O M P R E H E N SI V E 
A D V E R S E E V E N T S A N D P O T E N TI A L RI S K S LI S T S  ( C A E P R S) 
T h e f oll o wi n g a d v ers e e v e nts w er e o bs er v e d i n s u bj ects tr e at e d wit h t h e c o m bi n ati o n of u blit u xi m a b 
+ u m br alisi b  a n d w er e c o nsi d er e d at l e ast p ossi bl y r el at e d t o o n e or b ot h of t h e  st u d y m e dic ati o ns.  
T h e pr eli mi n ar y s af et y d at a as of M a y 1, 2 0 1 8 is pr o vi d e d f or a t ot al of 7 5 s u bj ects e x p os e d t o 
u blit u xi m a b + u m br alisi b wit h a m a xi m u m f oll o w u p of 3 + y e ars.  S e e t h e l at est u blit u xi m a b a n d 
u m br alisi b I n v esti g at or ’s  Br oc h ur es f or u p d at e d s af et y i nf or m ati o n a c o m pl et e list of all a d v ers e 
e v e nts r e p ort e d r e g ar dl ess of c a us alit y.  . 
7. 2. 1. 1  V E R Y C O M M O N ( ≥ 1 0 %) : 
Bl o o d a n d L y m p h ati c S yst e m Di s o r d e r s:  a n e mi a, n e utr o p e ni a  
G a st r oi nt e sti n al Di s o r d e r s:  di arr h e a, n a us e a, v o miti n g  
G e n e r al Di s o r d e r s a n d A d mi ni st r ati o n Sit e C o n diti o n s:  f ati g u e 
I nj u r y, P oi s o ni n g a n d P r o c e d u r al C o m pli c ati o n s: i nf usi o n r el at e d r e acti o n 
M et a b oli s m a n d N ut riti o n Di s o r d e r s:  d ecr e as e d a p p etit e  
7. 2. 1. 2  C O M M O N ( ≥ 1 % - < 1 0 %) : 
Bl o o d a n d L y m p h ati c S yst e m Di s o r d e r s: t hr o m b oc yt o p e ni a 
C a r di a c Di s o r d e r s: c ar di ac f ail ur e c o n g esti v e  
E a r a n d L a b y ri nt h Di s o r d e r s: e ar c o n g esti o n, e ar disc o mf ort  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 4 7  of 8 5  
E y e Di s o r d e r s: c o nj u ncti v al p all or, c o nj u ncti vitis, c or n e al o e d e m a, visi o n bl urr e d  
G a st r oi nt e sti n al  Di s o r d e r s:  a b d o mi n al  disc o mf ort,  a b d o mi n al  dist e nsi o n,  a b d o mi n al  p ai n,  
c o nsti p ati o n,  d ys p e psi a,  fl at ul e nc e,  g astr o o es o p h a g e al  r efl u x  dis e as e,  h a e m at oc h e zi a,  s ali v ar y  
h y p er s ecr eti o n, st o m atitis 
G e n e r al Di s o r d e r s a n d A d mi ni st r ati o n Sit e C o n diti o n s:  ast h e ni a, c hills, f ac e o e d e m a, i nf usi o n sit e 
p ai n, l oc al s w elli n g, o d e d e m a p eri p h er al, p yr e xi a, s yst e mic i nfl a m m at or y r es p o ns e s y n dr o m e  
H e p at o bili a r y Di s o r d e r s:  h y p er bilir u bi n a e mi a  
I m m u n e S y st e m Di s o r d e r s: h y p o g a m m a gl o b uli n a e mi a  
I nf e cti o n s  a n d  I nf e st ati o n s: br o nc hitis,  c ell ulitis,  cl ostri di u m  difficil e  c olitis,  e nt er oc olitis  
i nf ecti o us,  or al  c a n di di asis,  or al  h er p es,  otitis  m e di a,  p n e u m o ni a,  p n e u m o ni a  str e pt oc occ al,  
r hi n o vir us  i nf ecti o n,  s e psis,  s e psis  s y n dr o m e,  si n usitis,  s ki n  i nf ecti o n,  u p p er  r es pir at or y  t r act 
i nf ecti o n, uri n ar y tr act i nf ecti o n 
I nj u r y, P oi s o ni n g a n d P r o c e d u r al C o m pli c ati o n s: w o u n d  
I n v e sti g ati o n s: al a ni n e a mi n otr a nsf er as e i ncr e as e d, as p art at e a mi n otr a nsf er as e i ncr e as e d, bl o o d 
al k ali n e  p h os p h at as e  i ncr e as e d,  bl o o d  cr e ati ni n e  i ncr e as e d,  c o m p ut eris e d  t o m o gr a m  t h or a x  
a b n or m al, i m m u n o gl o b uli ns d ecr e as e d, w ei g ht d ecr e as e d  
M et a b oli s m  a n d  N ut riti o n  Di s o r d e r s:  d e h y dr ati o n,  f ail ur e  t o  t hri v e,  h y p er gl yc a e mi a,  
h y p er uric a e mi a, h y p o k al a e mi a, h y p o p h os p h at a e mi a  
M u s c ul o s k el et al  a n d  C o n n e cti v e  Ti s s u e  Di s o r d e r s : j oi nt  s w elli n g,  m uscl e  s p as ms,  m usc ul ar 
w e a k n ess, m y al gi a, p ai n i n e xtr e mit y  
N e r v o u s S y st e m Di s o r d e r s:  di z zi n ess, d ys g e usi a, h e a d ac h e, l et h ar g y, si n us h e a d ac h e, s o m n ol e nc e  
P s y c hi at ri c Di s o r d e r s:  a git ati o n, a n xi et y  
R e n al a n d U ri n a r y Di s o r d e r s:  mict uriti o n  ur g e nc y, r e n al f ail ur e, r e n al f ail ur e ac ut e  
R e p r o d u cti v e S y st e m a n d B r e a st Di s o r d e r s:  scr ot al c yst, s e m e n disc ol o ur ati o n 
R e s pi r at o r y, T h o r a ci c a n d M e di a sti n al Di s o r d e r s:  c h o ki n g, c o u g h, d ys p h o ni a, d ys p n e a, e pist a xis, 
h y p o xi a, or o p h ar y n g e al p ai n, p n e u m o nit is, pr o d ucti v e c o u g h, si n us c o n g esti o n 
S ki n a n d S u b c ut a n e o u s Ti s s u e Di s o r d e r s:  al o p eci a, c ol d s w e at, d er m atitis ac n eif or m, d er m atitis 
b ull o us, dr y s ki n, ecc h y m osis, pr urit us, r as h, m ac ul o -p a p ul ar, r os ac e a, urtic ari a  
V a s c ul a r Di s o r d e r s:  h y p ert e nsi o n  
 
 


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D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 4 8  of 8 5  
8  M E A S U R E M E N T O F E F F E C T  
P E T sc a ns m ust b e d o n e at scr e e ni n g, wit hi n 1 4 d a ys of C ycl e 6 D a y 1, a n d t o c o nfir m C R (if 
a p plic a bl e).  D uri n g t h e st u d y p eri o d, all s u bj ects will b e e v al u at e d f or r es p o ns e b y C T  (if c o ntr ast 
C T is c o ntr ai n dic at e d M RI wit h a n o n -c o ntr ast C T  C h est  s h o ul d b e c o m pl et e d) wit hi n 1 4 d a ys of D a y 
1 of C ycl es 3, 6, a n d 1 2 .  Aft er C ycl e 1 2, s u bj ects s h o ul d b e e v al u at e d f or r es p o ns e b y C T  (if c o ntr ast 
C T is c o ntr ai n dic at e d M RI wit h a n o n -c o ntr ast C T  C h est  s h o ul d b e c o m pl et e d) a p pr o xi m at el y e v er y 
6 c ycl es t hr o u g h c ycl e 2 4 u nl ess cli nic all y i n dic at e d s o o n er ( at t h e discr eti o n of t h e tr e ati n g 
p h ysici a n). S u bj ect s ac hi e vi n g  st a bl e  dis e as e  or  b ett er  s h o ul d  c o nti n u e  d ail y  tr e at m e nt  wit h  
u m br alisi b f or a d ur ati o n of 2 4 c ycl es ( a p pr o xi m at el y 2 4 m o nt hs).  R e s p o ns e ass ess m ets f or P F S 
aft er c ycl e 2 4 s h o ul d occ ur at l e ast e v er y 1 2 m o nt hs. All b as eli n e ass ess m e nts t o c h ar act eriz e 
dis e as e will b e p erf or m e d wit hi n 3 0 d a ys of C ycl e 1 D a y 1, pri or t o i niti ati o n of t h er a p y.  D uri n g t h e 
tr e at m e nt p eri o d, all effic ac y ass ess m e nts h a v e a + /- 1 4  d a y wi n d o w.  T h e d et er mi n ati o n of r es p o ns e 
a n d pr o gr essi o n will b e b as e d o n t h e I nt er n ati o n al W or ki n g Gr o u p (I W G) R e vis e d R es p o ns e Crit eri a 
f or M ali g n a nt L y m p h o m a ( C h es o n et al., 2 0 0 7, S e e A p p e n di x D) m o difi e d s o t h at t h e si x i n d e x  l esi o ns 
i ncl u d e b ot h n o d al a n d e xtr a n o d al l esi o ns as d escri b e d i n t h e L u g a n o cl assific ati o n ( C h es o n et al. 
2 0 1 4) r at h er t h a n c o nsi d eri n g n o d al a n d e xtr a n o d al l esi o ns s e p ar at el y.  
S u bj ects will r e m ai n o n st u d y tr e at m e nt (f or a d ur ati o n of 2 4 m o nt hs) u ntil t h e occ urr e nc e of 
d efi niti v e  dis e as e  pr o gr essi o n,  u n acc e pt a bl e  t o xicit y,  or  wit h dr a w al  fr o m  t h e  st u d y  d u e  t o  
i n v esti g at or d ecisi o n or ot h er r e as o ns. S u bj ect s w h o disc o nti n u e fr o m st u d y tr e at m e nt f or a n y 
r e as o n ot h er t h a n P D will c o nti n u e t o b e f oll o w e d f or  pr o gr essi o n , as p er t h e pr ot oc ol . 
8. 1  M E T H O D O F A S S E S S M E N T  
C T sc a n is t h e pr ef err e d m et h o d f or r a di o gr a p hic t u m or ass ess m e nt. C T wit h i o di n at e d I V c o ntr ast 
is pr ef err e d.  If i o di n at e d c o ntr ast is c o ntr ai n dic at e d, a n o n-c o ntr ast c h est C T c o u pl e d wit h a 
g a d oli ni u m- e n h a nc e d  M RI  of  t h e  a b d o m e n / p el vis  ( a n d  n ec k  as  cli n ic all y  w arr a nt e d)  is  a n  
acc e pt a bl e s u bstit ut e.  C h est x -r a y, ultr as o u n d, e n d osc o p y, l a p ar osc o p y, or t u m or m ar k ers will n ot 
b e c o nsi d er e d f or r es p o ns e ass ess m e nt.  P E T usi n g fl u or o d e o x y gl uc os e ( F D G) s h o ul d b e d o n e at 
scr e e ni n g f or all s u bj ects, a p pr o xi m at ely  1 4 d a ys of D a y 1 of C ycl e 6 a n d  t h e n t o c o nfir m a p ot e nti al 
C R f or s u bj ects wit h F D G -a vi d dis e as e.  
 
B o n e m arr o w ass ess m e nt s h o ul d b e us e d t o ass ess r es p o ns e t o t h er a p y if t h e s u bj ect w as d e e m e d 
t o h a v e dis e as e i n t h e b o n e m arr o w pri or t o i niti ati o n of pr ot oc ol t h er a p y a n d at t h e discr eti o n of 
t h e i n v esti g at or. 
 
F or r a di o gr a p hic e v al u ati o ns, t h e s a m e m et h o d of ass ess m e nt a n d t h e s a m e t ec h ni q u e ( e. g., sc a n 
t y p e, s u bj ect p ositi o n, d os e of c o ntr ast, i nj ecti o n /sc a n i nt er v al) s h o ul d b e us e d t o c h ar act eri z e e a c h 
i d e ntifi e d a n d r e p ort e d l esi o n at b as eli n e a n d d uri n g st u d y tr e at m e nt a n d f oll o w-u p. H o w e v er, if a 
s u bj ect is i m a g e d wit h o ut c o ntr ast at b as eli n e, s u bs e q u e nt ass ess m e nts s h o ul d b e p erf or m e d wit h 
c o ntr ast, u nl ess m e dic all y c o ntr ai n dic at e d.  
 
All b as eli n e ass ess m e nts t o c h ar act eriz e dis e as e will b e p erf or m e d wit hi n 3 0 d a ys of C ycl e 1 D a y 
1, pri or t o i niti ati o n of t h er a p y.    


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P a g e 4 9  of 8 5  
8. 2  R E S P O N S E R E VI E W  
T h e  r e vi e w of   r a di o gr a p hic a n d  cli nic al d at a  b y  t h e st u d y i n v esti g at ors will  b e  p erf or m e d  o n  
a n o n g oi n g  b asis.  D e -i d e ntifi e d i m a g es s h o ul d b e  a v ail a bl e  if t h e S p o ns or  r e q u ests t o c o nfir m  
a n y o bj ecti v e r es p o ns e  o bs er v e d. 
8. 3  A N TI T U M O R E F F E C T  
Ass ess m e nt of l y m p h o m a r es p o ns e ( C R, P R or S D) a n d dis e as e pr o gr essi o n will b e e v al u at e d as 
o utli n e d  i n  t h e  sc h e d ul e  of  e v e nts,  a cc or di n g  t o  t h e  R e vis e d  R es p o ns e  Crit eri a  f or  M ali g n a nt  
L y m p h o m a f or N H L s u bj ects ( C h es o n et al., 2 0 0 7).  O v er all r es p o ns e r at e, C R, P R, S D, P F S a n d D O R 
will b e c alc ul at e d as d et ail e d b el o w.  
8. 4  D E FI NI TI O N S O F T U M O R  R E S P O N S E A N D P R O G R E S SI O N  
E v al u a bl e f o r o bj e cti v e r e s p o n s e.   O nl y t h os e s u bj ects w h o h a v e h a d a pr e -tr e at m e nt b as eli n e 
effic ac y e v al u ati o n a n d at l e ast o n e p ost -tr e at m e nt effic ac y e v al u ati o n will b e c o nsi d er e d e v al u a bl e 
f or r es p o ns e.  T h es e s u bj ects will h a v e t h eir r es p o ns e cl assifi e d acc or di n g t o t h e d efi niti o ns st at e d 
b el o w.  
8. 4. 1  C O M P L E T E R E S P O N S E  
C o m pl et e r es p o ns e ( C R) is d efi n e d as t h e c o m pl et e dis a p p e ar a nc e of all e vi d e nc e of dis e as e a n d 
dis e as e -r el at e d s y m pt o ms.  T h e s pl e e n a n d / or li v er, if c o nsi d er e d e nl ar g e d b ef or e t h er a p y, o n t h e 
b asis of p h ysic al e x a m or C T sc a n, s h o ul d n ot b e p al p a bl e o n p h ysic al e x a mi n ati o n a n d s h o ul d b e 
c o nsi d er e d n or m al siz e b y i m a gi n g st u di es, a n d n o d ul es r el at e d t o l y m p h o m a s h o ul d dis a p p e ar.    
B o n e  m arr o w  i nfiltr at e  cl e ar e d  o n  r e p e at  bi o ps y,  if  i n d et er mi n at e  b y  m or p h ol o g y, 
i m m u n o hist oc h e mistr y s h o ul d b e n e g ati v e ( C h es o n et al., 2 0 0 7).   
I n s u bj ects wit h F D G -a vi d l y m p h o m a wit h a p ositi v e P E T sc a n b ef or e t h er a p y or n o pr etr e at m e nt 
P E T sc a n, a p ost -tr e at m e nt r esi d u al m ass of a n y siz e is p er mitt e d as l o n g as it is P E T n e g ati v e.  I n 
s u bj ects wit h v ari a bl y F D G -a vi d l y m p h o m as or w h er e F D G -a vi dit y is u n k n o w n, all l y m p h n o d e a n d 
n o d al  m ass es  m ust  h a v e  r e gr ess e d  o n  C T  t o  n or m al  si z e  ( ≤  1. 5  c m  i n  t h eir  gr e at est  tr a ns v ers e 
di a m et er f or n o d es > 1. 5 c m b ef or e t h er a p y).  Pr e vi o usl y i n v ol v e d n o d es t h at w er e 1. 1 t o 1. 5 c m i n 
t h e l o n g a xis a n d m or e t h a n 1. 0 c m o n t h eir s h ort a xis b ef or e tr e at m e nt m ust h a v e d ecr e as e d t o ≤ 1. 0 
c m i n t h eir s h ort a xis aft er tr e at m e nt ( C h es o n et al., 2 0 0 7).  
8. 4. 2  P A R TI A L R E S P O N S E  
P arti al r es p o ns e ( P R) is d efi n e d a s t h e r e gr essi o n of m e as ur a bl e dis e as e a n d n o n e w sit es of dis e as e.  
R e gr essi o n is d efi n e d as gr e at er t h a n or e q u al t o 5 0 % d ecr e as e i n t h e s u m of t h e pr o d ucts of t h e 
di a m et ers ( S P D) of t h e i n d e x l esi o ns , c o u pl e d wit h n o u n e q ui v oc al i ncr e as e i n si z e of ot h er l y m p h 
n o d es, li v er or s pl e e n.   N o n e w sit es of dis e as e s h o ul d b e o bs er v e d.  I n s u bj ects wit h F D G -a vi d 
l y m p h o m a wit h n o pr etr e at m e nt P E T sc a n or if t h e P E T sc a n w as p ositi v e b ef or e t h er a p y, t h e p ost-
tr e at m e nt P E T s h o ul d b e p ositi v e i n at l e ast o n e pr e vi o usl y i n v ol v e d sit e.  F or s u bj ects wit h v ari a bl y 


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P a g e 5 0  of 8 5  
F D G -a vi d l y m p h o m as or w h er e F D G -a vi dit y is u n k n o w n, if n o pr etr e at m e nt P E T sc a n is a v ail a bl e, or 
if a pr etr e at m e nt P E T sc a n w as n e g ati v e, C T crit eri a s h o ul d be us e d.  If b o n e m arr o w w as i n v ol v e d 
pri or t o t h er a p y a n d a cli nic al C R w as ac hi e v e d b ut n o b o n e m arr o w ass ess m e nt is c o m pl et e d aft er 
tr e at m e nt t h e n t h es e s u bj ects ar e c o nsi d er e d p arti al r es p o n d ers ( C h es o n et al., 2 0 0 7).  
8. 4. 3  S T A B L E DI S E A S E  
St a bl e dis e as e is d efi n e d as t h e f ail ur e t o att ai n C R / P R b ut d o es n ot f ulfill t h e crit eri a f or pr o gr essi v e 
dis e as e.  F or s u bj ects wit h F D G -a vi d l y m p h o m as, t h e P E T sc a n s h o ul d b e p ositi v e at pri or sit es of 
dis e as e a n d t h er e s h o ul d b e n o n e w ar e as of i n v ol v e m e nt.  F or t h os e wit h  dis e as e e v al u at e d b y C T 
o nl y, t h er e m ust b e n o u n e q ui v oc al c h a n g e i n t h e siz e of t h e pr e vi o us l esi o ns o n t h e p ost -tr e at m e nt 
C T sc a n ( C h es o n et al., 2 0 0 7) . 
8. 4. 4  P R O G R E S SI O N O F DI S E A S E    
A n y of t h e f oll o wi n g c o n diti o ns will c o nstit ut e r el a ps e d or pr o gr essi v e dis e as e:  
A p p e ar a nc e of a n y n e w l esi o n m or e t h a n 1. 5 c m  i n a n y a xis, e v e n if ot h er l esi o ns ar e d ecr e asi n g i n 
si z e will b e c o nsi d er e d r el a ps e d or pr o gr essi v e dis e as e.  I ncr e as e i n F D G u pt a k e i n a pr e vi o usl y 
u n aff ect e d sit e s h o ul d b e c o nfir m e d wit h ot h er m o d aliti es, a t h er a p e utic d ecisi o n s h o ul d n ot b e m a d e 
s ol el y o n t h e b asis of P E T wit h o ut hist ol o gic c o nfir m ati o n ( C h es o n et al., 2 0 0 7). 
T h er e is at l e ast a 5 0 % i ncr e as e fr o m n a dir i n o n e of t h e f oll o wi n g:  
•  
T h e S P D of i n d e x l esi o ns,  
•  
T h e gr e at est tr a ns v ers e di a m et er ( G T D) of a n y i n di vi d u al pr e vi o usl y i n v ol v e d n o d e , or  
•  
T h e G T D of a n y pr e vi o usl y i n v ol v e d n o d e pr o vi d e d t h at t h e G T D of t h at n o d e is n o w ≥ 1. 5 c m.  
L esi o ns s h o ul d b e P E T p ositi v e if o bs er v e d i n a t y pic al F D G -a vi d l y m p h o m a or t h e l esi o n w as P E T 
p ositi v e b ef or e t h er a p y u nl ess t h e l esi o n is t o o s m all t o b e d et ect e d wit h c urr e nt P E T s yst e ms ( < 1. 5 
c m i n its l o n g a xis b y C T) ( C h es o n et al., 2 0 0 7).  
8. 5  D E FI NI TI O N S O F DI S E A S E P A R A M E T E R S  
M e a s u r a bl e di s e a s e :  M e as ur a bl e l esi o ns ar e d efi n e d as t h os e t h at c a n b e acc ur at el y m e as ur e d i n at 
l e ast t w o di m e nsi o ns wit h c o n v e nti o n al t ec h ni q u es ( C T, P E T / C T, M RI, x-r a y) a n d m e et o n e of t h e 
f oll o wi n g crit eri a: n o d al l esi o n wit h a l o n g a xis > 1. 5 c m r e g ar dl ess of s h ort a xis, n o d al l esi o n wit h 
l o n g a n d s h ort a x es > 1. 0 c m, or e xtr a n o d al l esi o ns wit h l o n g a n d s h ort a x es > 1. 0 c m wit h s pir al C T 
sc a n.  All t u m or m e as ur e m e nts s h o ul d b e r ec or d e d i n c e nti m et ers .   
N o n -m e a s u r a bl e di s e a s e ( e v al u a bl e di s e a s e) :  All ot h er l esi o ns ( or sit es of dis e as e) i ncl u di n g 
s m all l esi o ns, ( < 1. 0 c m usi n g s pir al C T sc a n) ar e c o nsi d er e d n o n -m e as ur a bl e dis e as e.  B o n e l esi o ns, 
l e pt o m e ni n g e al dis e as e, ascit es, pl e ur al / p eric ar di al eff usi o ns, l y m p h a n gitis, a n d c ystic l esi o ns ar e all 
n o n -m e as ur a bl e.   


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P a g e 5 1  of 8 5  
I n d e x l e si o n s:  All m e as ur a bl e l esi o ns u p t o a m a xi m u m of 6 n o d al a n d e xtr a n o d al l esi o ns t ot al, 
r e pr es e nt ati v e of all i n v ol v e d or g a ns, s h o ul d b e i d e ntifi e d as i n d e x l e si o n s a n d r ec or d e d a n d 
m e as ur e d at b as eli n e. I n d e x l esi o ns s h o ul d b e s el ect e d o n t h e b asis of t h eir siz e (cl e arl y m e as ur a bl e 
i n t w o p er p e n dic ul ar di m e nsi o ns), a n d t h e hi g h est F D G a vi dit y ( hi g h S U V l esi o ns m a y b e pri oriti z e d 
e v e n if n ot t h e l ar g est l esi o ns, a n d t h eir s uit a bilit y f or acc ur at e r e p e at e d m e as ur e m e nts ( eit h er b y 
i m a gi n g t ec h ni q u es or cli nic all y).  A b as eli n e s u m of pr o d uct of t h e di a m et ers ( S P D) f or all i n d e x 
l esi o ns will b e c alc ul at ed a n d r e p ort e d as t h e b as eli n e S P D.  T h e b as eli n e S P D will b e us e d as 
r ef er e nc e t o f urt h er c h ar act eriz e a n y o bj ecti v e t u m or r e gr essi o n i n t h e m e as ur a bl e di m e nsi o n of t h e 
dis e as e.  
N o n -i n d e x l e si o n s:  All ot h er l esi o ns ( or sit es of dis e as e) i ncl u di n g a n y m e as ur a bl e l esi o ns o v er a n d 
a b o v e t h e 6 i n d e x l esi o ns s h o ul d b e i d e ntifi e d as n o n -i n d e x l e si o n s a n d s h o ul d als o b e r ec or d e d at 
b as eli n e.  M e as ur e m e nts of t h es e l esi o ns ar e n ot r e q uir e d, b ut t h e pr es e nc e, a bs e nc e, or i n r ar e c as es 
u n e q ui v oc al pr o gr essi o n of e ac h s h o ul d b e n ot e d t hr o u g h o ut f oll o w -u p.  
8. 6  E V A L U A TI O N O F B E S T O V E R A L L R E S P O N S E  
T h e b est o v er all r es p o ns e is t h e b est r es p o ns e r ec or d e d fr o m t h e st art of t h e tr e at m e nt u ntil dis e as e 
pr o gr essi o n /r ec urr e nc e (t a ki n g as r ef er e nc e f or pr o gr essi v e dis e as e t h e s m al l est m e as ur e m e nts 
r ec or d e d si nc e t h e tr e at m e nt st art e d).  T h e s u bj ect's b est r es p o ns e assi g n m e nt will d e p e n d o n t h e 
ac hi e v e m e nt of b ot h m e as ur e m e nt a n d c o nfir m ati o n crit eri a as p er t h e N H L est a blis h e d crit eri a us e d 
i n t his st u d y ( S e e A p p e n di x A). 
8. 6. 1  D U R A TI O N O F R E S P O N S E  
D ur ati o n of r es p o ns e is d efi n e d as t h e ti m e fr o m d oc u m e nt ati o n of a r es p o ns e t o tr e at m e nt t o t h e 
first d oc u m e nt ati o n of t u m or pr o gr essi o n or d e at h d u e t o a n y c a us e w hic h e v er c o m es first.  D ur ati o n 
of t h e r es p o ns e will b e s u m m ariz e d usi n g n (s a m pl e si z e), m e a n, st a n d ar d d e vi ati o n, m e di a n, 
mi ni m u m, a n d m a xi m u m f or t h e r es p o n d ers.  
D u r ati o n of st a bl e di s e as e : 
St a bl e dis e as e is m e as ur e d fr o m t h e st art of t h e tr e at m e nt u ntil t h e crit eri a f or pr o gr essi o n ar e m et.  
P r o g r e s si o n -F r e e S u r vi v al : 
Pr o gr essi o n fr e e s ur vi v al ( P F S) is d efi n e d as t h e ti m e fr o m st u d y e ntr y t o t h e first d oc u m e nt ati o n of 
t u m or pr o gr essi o n or d e at h d u e t o a n y c a us e w hic h e v er c o m es first.  T his v ari a bl e will b e a n al y z e d 
vi a K a pl a n -M ei er m et h o d ol o g y.  T h e m e di a n P F S will b e esti m at e d.  


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9  S T A TI S TI C A L C O N SI D E R A T I O N S 
T h e s ecti o ns of t h e St atistic al C o nsi d er ati o ns d escri b e t h e st atistic al m et h o ds t o b e us e d t o a n al y z e 
t h e effic ac y a n d s af et y. T h es e m et h o ds m a y b e r e vis e d a n d u p d at e d d u e t o r e as o ns s uc h as r e g ul at or y 
r e q uir e m e nts or n e e d f or f urt h er cl arific ati o ns. T h e fi n al a n al ysis pl a n will b e d oc u m e nt e d i n a f or m al 
st atistic al a n al ysis pl a n ( S A P) t h at m ust b e fi n ali z e d b ef or e d at a b as e l oc k. T h e S A P will i ncl u d e d et ails 
o n h o w v ari a bl es will b e d eri v e d, h o w missi n g d at a will b e h a n dl e d, a n d  h o w c e ns ori n g pr oc e d ur es 
will b e a p pli e d t o ti m e t o e v e nt r el at e d v ari a bl es as w ell as t h e d et ails o n st atistic al m et h o ds t o b e 
us e d f or s af et y a n d effic ac y a n al ys es. T h e fi n al cli nic al st u d y r e p ort will disc uss d e vi ati o ns fr o m t h e 
S A P, if a n y.  
9. 1  S A M P L E SI Z E A N D P O W E R  
 
 
 
 
 
      
9. 2  G E N E R A L A N A L Y SI S C O N V E N TI O N  
T his is a n o p e n -l a b el, P h as e 2, st u d y of t h e PI 3 K d elt a i n hi bit or u m br alisi b  i n c o m bi n ati o n wit h 
u blit u xi m a b.  T his tr i al is d esi g n e d t o e v al u at e t h e o v er all r es p o ns e r at e ( C R + P R), as w ell as d ur ati o n 
of r es p o ns e ( D O R), c o m pl et e r es p o ns e ( C R), a n d pr o gr essi o n -fr e e s ur vi v al ( P F S) i n tr e at m e nt n aï v e 
f ollic ul ar l y m p h o m a a n d s m all l y m p h oc ytic l y m p h o m a s u bj ects.  Ass ess m e nt of l y m p h o m a r es p o ns e 
( C R, P R or S D) a n d dis e as e pr o gr essi o n will b e e v al u at e d as o utli n e d i n t h e sc h e d ul e of ass ess m e nts 
(S ecti o n 5 ), acc or di n g t o t h e R e vis e d R es p o ns e Crit eri a f or M ali g n a nt L y m p h o m a ( C h es o n et al. 
2 0 0 7). S u bj ects w h o  pr o gr ess  acc or di n g  t o  t h e  c orr es p o n di n g  crit eri a  will  r ec ei v e  n o  f urt h er  
tr e at m e nt.  S u bj ects w h o r es p o n d t o t h e tr e at m e nt (i. e., C R, P R or S D) m a y r e m ai n o n tri al.  
S af et y will b e e x a mi n e d o n a n o n g oi n g b asis w hil e t h e st u d y is b ei n g c o n d uct e d.  T o xicit y will b e 
ass ess e d utili zi n g t h e N ati o n al C a nc er I nstit ut e C o m m o n T er mi n ol o g y Crit eri a f or A d v ers e E v e nts 
( N CI C T C A E) v 4. 0 ( htt p: / / e vs. nci. ni h. g o v /ft p 1 / C T C A E). 
U nl ess ot h er wis e st at e d, all a n al ys es will b e  p erf or m e d usi n g S A S V ersi o n 9. 4  or hi g h er a n d all 
h y p ot h esis t ests will b e  c o n d uct e d at a t w o -si d e d si g nific a nc e l e v el of 0. 0 5. 
I n g e n er al, s u m m ar y t a b ul ati o ns will dis pl a y t h e n u m b er of o bs er v ati o ns, m e a n, st a n d ar d d e vi ati o n, 
m e di a n, mi ni m u m, m a xi m u m, a n d a p pr o pri at e p erc e ntil es f or c o nti n u o us v ari a bl es, a n d t h e n u m b er 
a n d p erc e nt a g e b y c at e g or y f or c at e g oric al d at a. S u m m ari es will b e pr es e nt e d. T h e d at a listi n gs will 
i ncl u d e all a v ail a bl e effic ac y a n d s af et y d at a. 
 
 


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9. 3  S T U D Y  P O P U L A TI O N S  
T w o st u d y p o p ul ati o ns, i nt e nt -t o-tr e at (I T T) a n d s af et y p o p ul ati o ns, ar e pr e-d efi n e d f or t his st u d y. 
T h e I T T p o p ul ati o n will i ncl u d e all e nr oll e d s u bj ects w h o pr o vi d e s o m e effic ac y ass ess m e nts a n d t h e 
s af et y p o p ul ati o n will i ncl u d e all s u bj ects w h o t a k e at  l e ast o n e d os e of st u d y m e dic ati o n. T h e effic ac y 
a n al ys es will b e b as e d o n I T T p o p ul ati o n a n d t h e s af et y a n al ys es will b e b as e d o n t h e s af et y 
p o p ul ati o n.  
9. 4  S U BJ E C T  D E M O G R A P HI C S A N D B A S E LI N E C H A R A C T E RI S TI C S 
D e m o gr a p hics a n d b as eli n e c h ar act eristics will b e s u m m ari z e d usi n g d escri pti v e st atistics f or 
c o nti n u o us v ari a bl es, a n d fr e q u e nci es a n d p erc e nt a g es f or c at e g oric al v ari a bl es.  
9. 5  M E DI C A L HI S T O R Y  
M e dic al hist or y will b e c a pt ur e d at t h e Scr e e ni n g visit.  M e dic al hist or y will b e c o d e d usi n g M e d D R A  
a n d  will  b e  s u m m ari z e d  b y  M e d D R A  s yst e m  or g a n  cl ass  a n d  pr ef err e d  t er m  f or  t h e  S af et y  
p o p ul ati o n.  
9. 6  E X T E N T O F E X P O S U R E  
T h e  d os e  ( m g) of  st u d y dr u gs a d mi nist er e d,  t h e t ot al n u m b er  of  st u d y dr u g  d os es, a n d  t h e d ur ati o n 
of tr e at m e nt ( n u m b er of st u d y c ycl es) will b e s u m m ari z e d wit h d escri pti v e st atistics. T h e  n u m b er 
a n d  p erc e nt a g e  of  s u bj ects w h os e  d os e is m o difi e d  at  a n y  ti m e will  b e  s u m m ari z e d b y  e ac h  t y p e 
of m o dific ati o n  at a  c ycl e l e v el a n d  o v er all. T h e  pr o p orti o n  of  s u bj ects c o m pl eti n g e ac h  c ycl e of  
tr e at m e nt will b e  s u m m ari z e d. 
9. 7  E F FI C A C Y A N A L Y S E S   
T w o p o p ul ati o ns will b e us e d i n t h e effic ac y a n al ys es, I nt e nt -t o-Tr e at (I T T) a n d P er Pr ot oc ol ( P P) 
p o p ul ati o ns.  T h e I T T p o p ul ati o n will i ncl u d e all s af et y p o p ul ati o n w h o pr o vi d e effic ac y ass ess m e nt, 
a n d P P p o p ul ati o n will i ncl u d e all I T T p o p ul ati o n wit h o u t m aj or pr ot oc ol vi ol ati o ns.    
T h e effic ac y e n d p oi nts will i ncl u d e:  
•  
O v er all r es p o ns e r at e ( O R R)  
•  
C o m pl et e r es p o ns e ( C R)  
•  
D ur ati o n of R es p o ns e ( D o R)  
•  
Pr o gr essi o n -fr e e S ur vi v al ( P F S) 
T h es e v ari a bl es will b e a n al y z e d /s u m m ariz e d b as e d o n t h e I T T p o p ul ati o n as w e ll as t h e P P 
p o p ul ati o n as a p pr o pri at e.  T h e p erc e nt a g es of C R, C R + P R, a n d C R + P R + S D will b e pr es e nt e d, as will 
t h e m e di a n d ur ati o n of r es p o ns e.  T h e l o w er b o u n d of t h es e p erc e nt a g es will b e pr es e nt e d usi n g 
t h e Cl o p p er-P e ars o n E x act m et h o d t o esti m at e t h e 9 5 % c o nfi d e nc e i nt er v al.   


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 5 4  of 8 5  
A d diti o n al a n al ys es m a y als o b e p erf or m e d as a p pr o pri at e  
9. 8  MI S SI N G V A L U E H A N D LI N G P R O C E D U R E S  
I n g e n er al, ot h er t h a n f or p arti al d at es, missi n g d at a will n ot b e i m p ut e d a n d will b e tr e at e d as 
missi n g.  T h e al g orit h ms f or i m p ut ati o n of p arti al d at es m a y v ar y d e p e n di n g u p o n t h e p ar a m et er . 
9. 9  S T A TI S TI C A L A N A L Y S E S    
9. 9. 1  P RI M A R Y E F FI C A C Y V A RI A B L E  - O R R  
O v er all R es p o ns e R at e ( O R R) will b e d et er mi n e d p er  t h e R e vis e d R es p o ns e Crit eri a f or M ali g n a nt 
L y m p h o m a ( C h es o n et al. 2 0 0 7).   O v er all R es p o ns e R at e ( O R R), is d efi n e d as p erc e nt of s u bj ects 
w h o ac hi e v e C R or P R.  W e will esti m at e 9 5 % c o nfi d e nc e i nt er v als f or t h e r es p o ns e r at es. T h es e 
will b e f oll o w e d b y a d diti o n al l o gistic r e gr essi o n a n al ys es m o d el t o a dj ust f or d e m o gr a p hic a n d 
b as eli n e p ar a m et ers.  
9. 9. 2  S E C O N D A R Y E F FI C A C Y O U T C O M E S  
S ec o n d ar y effic ac y o utc o m es will  i ncl u d e: 
•  
Pr o gr essi o n -fr e e S ur vi v al ( P F S), C o m pl et e R es p o ns e ( C R)  a n d D ur ati o n of R es p o ns e  ( D O R) 
 
9. 9. 2. 1  P R O G R E S SI O N -F R E E S U R VI V A L  
Pr o gr essi o n -fr e e s ur vi v al (P F S ) is d efi n e d as t h e i nt er v al fr o m C ycl e 1 / D a y 1 t o t h e e arli er of t h e 
first d oc u m e nt ati o n of d efi niti v e dis e as e pr o gr essi o n or d e at h fr o m a n y c a us e.  P F S will b e 
pr es e nt e d usi n g t h e K a pl a n -M ei er m et h o d. M e di a n ti m e t o e v e nt a n d t h e 9 5 % c o nfi d e nc e i nt er v al o f 
t h e m e di a n ti m es will b e pr es e nt e d, if esti m a bl e. M e di a n ti m e t o e v e nt will b e t est e d a g ai nst t h e n ull 
h y p ot h esis v al u e usi n g a o n e -s a m pl e ( o n e-si d e d) l o g-r a n k t est. 
 
H y p ot h esis t esti n g f or p air wis e c o m p aris o n will b e p erf or m e d usi n g a l o g r a n k t est vi a S A S Lif et est 
pr oc e d ur es.  T h e m e di a n d ur ati o n of P F S  a n d  t h e pr o p orti o n of s u bj ects ali v e a n d pr o gr essi o n -fr e e 
at 6, 1 2, a n d 1 8 m o nt hs will b e esti m at e d usi n g t h e K a pl a n -M ei er m et h o d.  F or e ac h esti m at e, a 9 5 % 
c o nfi d e nc e i nt er v al will b e r e p ort e d. 
 
9. 9. 2. 2  C R R A T E  
C R r at e is d efi n e d as t h e p erc e nt of s u bj ects w h o ac hi e v e a C R.  C R r at e will b e a n al y z e d vi a c hi s q u ar e  
t est.  T h e 9 5 % c o nfi d e nc e i nt er v als f or t h e r es p o ns e r at es as w ell as f or t h e diff er e nc es of t h e 
c o m pl et e 
r es p o ns e r at e will b e pr es e nt e d.  A d diti o n al l o gistic a n al ys es m o d el m a y b e us e d t o ass ess t h e i m p act 
of d e m o gr a p hic a n d b as eli n e p ar a m et ers.  
 
9. 9. 2. 3  D U R A TI O N O F R E S P O N S E  
D ur ati o n of r es p o ns e ( D O R) d efi n e d as t h e i nt er v al fr o m t h e first d oc u m e nt ati o n of C R or P R t o  t h e 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 5 5  of 8 5  
e arli er of t h e first d oc u m e nt ati o n of  d efi niti v e dis e as e pr o gr essi o n or d e at h fr o m a n y c a us e.  T his 
v ari a bl e will b e s u m m ari z e d. Esti m at es of m e di a n D O R will b e m a d e usi n g K a pl a n -M ei er  m et h o ds.  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 5 6  of 8 5  
1 0  S A F E T Y R E P O R TI N G A N D  A N A L Y SI S  
1 0. 1  S A F E T Y A N A L Y S E S  
T h e s af et y p o p ul ati o n will i ncl u d e all s u bj ects w h o r ec ei v e d a n y st u d y m e dic ati o n. T h e s af et y 
e n d p oi nts will i ncl u d e:  
•  
I nci d e nc e of A Es a n d A Es c o nsi d er e d t o b e dr u g- r el at e d 
•  
I nci d e nc e of Gr a d e 3 a n d Gr a d e 4 A Es 
•  
I nci d e nc e of S A Es 
•  
L a b or at or y v al u es  
T h e s af et y e n d p oi nts will b e list e d a n d / or s u m m ari z e d.  N o i nf er e nti al st atistic al a n al ys es will b e 
p erf or m e d.  All s u bj ects w h o h a v e r ec ei v e d at l e ast o n e d os e of u blit u xi m a b a n d / or  u m br alisi b  will 
b e i ncl u d e d i n t h e s af et y p o p ul ati o n.  
T h e a n al ys es of s af et y will b e b as e d o n t h e fr e q u e nc y of a d v ers e e v e nts a n d t h eir s e v erit y f or s u bj ects 
i n e ac h p orti o n w h o r ec ei v e d at l e ast o n e d os e of st u d y tr e at m e nt. W orst t o xicit y gr ad es p er s u bj ect 
will b e t a b ul at e d f or s el ect a d v ers e e v e nts a n d l a b or at or y m e as ur e m e nts b y usi n g N CI C T C A E crit eri a 
v 4. 0.  
1 0. 2  A D V E R S E E V E N T  C H A R A C T E RI S TI C S  
C T C A E  t e r m ( A E d e s c ri pti o n)  a n d  g r a d e:  T h e  d escri pti o ns  a n d  gr a di n g sc al es f o u n d i n t h e r e vis e d 
N CI  C o m m o n  T er mi n ol o g y  Crit eri a  f or A d v ers e  E v e nts  ( C T C A E) v ersi o n  4. 0  will  b e  utili z e d  f or A E 
r e p orti n g. All a p pr o pri at e tr e at m e nt ar e as s h o ul d h a v e acc ess t o a c o p y of t h e C T C A E v ersi o n 4. 0.  A 
c o p y  of  t h e  C T C A E  v ersi o n  4. 0  c a n  b e  d o w nl o a d e d  fr o m  t h e  C T E P  w e b  
sit e 
htt p: / /ct e p.c a nc er. g o v / pr ot oc ol D e v el o p m e nt / el ectr o nic a p plic ati o ns /ctc. ht m . 
‘ E x p e ct e d n e s s’: A Es c a n b e ‘ U n e x p ect e d’ or ‘ E x p ect e d’ f or e x p e dit e d r e p orti n g p u r p os es o nl y. 
E x p ect e d  A Es  ar e  d efi n e d  as  t h os e  d escri b e d  i n  t h e  u blit u xi m a b  a n d  T G R -1 2 0 2  I n v esti g at or  
Br oc h ur es. 
1 0. 3  D E FI NI TI O N S O F A D V E R S E E V E N T S  
A n   a d v ers e e v e nt  ( A E) is a n y  u nt o w ar d  m e dic al  occ urr e nc e  i n  a s u bj ect or  cli nic al i n v esti g ati o n 
s u bj ect a d mi nist er e d  a p h ar m ac e utic al  pr o d uct.  A n  A E  d o es  n ot  n ec ess aril y  h a v e  t o h a v e  a c a us al 
r el ati o ns hi p wit h  t his tr e at m e nt. A n   a d v ers e e v e nt  ( A E) c a n  t h er ef or e b e  a n y  u nf a v or a bl e  a n d 
u ni nt e n d e d si g n (i ncl u di n g a n a b n or m al l a b or at or y fi n di n g, f or e x a m pl e), s y m pt o m, or dis e as e 
t e m p or aril y ass oci at e d  wit h  t h e us e  of  a m e dici n al  pr o d uct, w h et h er  or  n ot  c o nsi d er e d r el at e d t o t h e 
m e dici n al  pr o d uct. T his  i ncl u d es a n y  occ urr e nc e  t h at is n e w  i n o ns et  or  a g gr a v at e d  i n s e v erit y or 
fr e q u e nc y fr o m t h e b as eli n e c o n diti o n. 
I n cli nic al st u di es, a n A E c a n i ncl u d e a n u n d esir a bl e m e dic al c o n diti o n occ urri n g at a n y ti m e, 
i ncl u di n g  r u n-i n or  w as h o ut   p eri o ds, e v e n  if n o  st u d y tr e at m e nt h as  b e e n  a d mi nist er e d.  T h e  N CI 
C o m m o n   T er mi n ol o g y Crit eri a  f or A d v ers e  E v e nts  ( C T C A E) v 4. 0  is t o b e  us e d  f or t h e  gr a di n g of 


U T X -T G R -2 0 3  
 
 
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P a g e 5 7  of 8 5  
s e v erit y of s y m pt o ms a n d a b n or m al fi n di n gs. F or a d v ers e e v e nts n ot c o v er e d b y t h e  N CI -C T C A E 
V ersi o n 4. 0 gr a di n g s yst e m, t h e f oll o wi n g d efi niti o ns will b e  us e d:  
•  
G r a d e 1 : Mil d; as y m pt o m atic or mil d s y m pt o ms; cli nic al or di a g n ostic o bs er v ati o ns 
o nl y;  i nt er v e nti o n n ot i n dic at e d. 
•  
G r a d e 2: M o d er at e; mi ni m al, l oc al or n o n -i n v asi v e i nt er v e nti o n i n dic at e d. 
•  
G r a d e 3 : S e v er e or m e dic all y si g nific a nt b ut n ot i m m e di at el y lif e-
t hr e at e ni n g; h os pit ali z ati o n or pr ol o n g ati o n of h os pit aliz ati o n  i n dic at e d. 
•  
G r a d e 4 : Lif e-t hr e at e ni n g c o ns e q u e nc es; ur g e nt i nt er v e nti o n i n dic at e d. 
•  
G r a d e 5 : D e at h r el at e d t o A E.  
1 0. 4  A D V E R S E E V E N T S ( A E’ S ) A N D T R E A T M E N T E M E R G E N T A D V E R S E E V E N T S 
( T E A E’ S )  
All A Es a n d S A Es occ urri n g o n st u d y will b e list e d b y s u bj ect.  T h e fr e q u e nc y a n d p erc e nt a g es of 
s u bj ects wit h tr e at m e nt -e m er g e nt a d v ers e e v e nts ( T E A Es) will b e t a b ul at e d b y s yst e m or g a n cl ass 
( S O C) a n d pr ef err e d t er m ( P T ), w h er e tr e at m e nt-e m er g e nt is d efi n e d as a n y A E t h at:  
•  
Occ urs aft er first d osi n g of st u d y  m e dic ati o n a n d t hr o u g h t h e e n d of t h e st u d y or u p t hr o u g h 
3 0 d a ys aft er t h e l ast d os e of st u d y tr e at m e nt, or  
•  
Is c o nsi d er e d tr e at m e nt-r el at e d r e g ar dl ess of t h e st art d at e of t h e e v e nt, or  
•  
Is pr es e nt b ef or e first d osi n g of st u d y m e dic ati o n b ut w ors e ns i n int e nsit y or t h e i n v esti g at or 
s u bs e q u e ntl y c o nsi d ers tr e at m e nt -r el at e d.  
 
T E A Es t h at ar e c o nsi d er e d at l e ast p ossi bl y r el at e d t o st u d y tr e at m e nt will b e t a b ul at e d as w ell as 
d e at hs, S A Es, a n d e v e nts r es ulti n g i n tr e at m e nt disc o nti n u ati o n.  
A Es t h at occ ur aft er i nf or m e d c o ns e nt b ut b ef or e first d osi n g of st u d y m e dic ati o n will n ot b e 
s u m m ariz e d b ut will b e list e d.   
At  e ac h  l e v el  of  s u m m ari z ati o n,  a  s u bj ect will  b e  c o u nt e d  o nl y  o nc e  f or e ac h  A E,  S O C,  or  P T 
e x p eri e nc e d wit hi n t h at l e v el.  I n t h e s u m m ati o n f or A E  s e v erit y, wit hi n e ac h l e v el of A E, S O C, or P T 
e x p eri e nc e d,  t h e  o n e  wit h  t h e  hi g h est  s e v erit y  will  b e  i ncl u d e d.   I n  t h e  s u m m ati o n  f or  A E’s  
r el ati o ns hi p t o t h e st u d y dr u g, wit hi n e ac h l e v el of A E, S O C, or P T e x p eri e nc e d, t h e o n e wit h t h e 
cl os est r el ati o ns hi p t o t h e st u d y dr u g will b e i ncl u d e d.  
1 0. 5  A D V E R S E E V E N T S / S E RI O U S A D V E R S E E V E N T C A U S A LI T Y A S S E S S M E N T  
T h e I n v esti g at or m ust als o ass ess t h e r el ati o ns hi p of a n y a d v ers e e v e nt t o t h e us e of st u d y dr u gs 
( w h et h er n o n e, o n e, or b ot h), b as e d o n a v ail a bl e i nf or m ati o n, usi n g t h e f oll o wi n g g ui d eli n es:  
•  
N ot R el at e d : Cl e ar-c ut t e m p or al a n d / or m ec h a nistic r el ati o n t o a c a us e ot h er t h a n t h e st u d y 
dr u g(s).  
•  
D o u btf ul : T h er e is n o r e as o n a bl e p ossi bilit y t h at t h e e v e nt is r el at e d t o t h e stu d y dr u g(s) b ut 
a d efi nit e c a us e c a n n ot b e asc ert ai n e d.  


U T X -T G R -2 0 3  
 
 
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P a g e 5 8  of 8 5  
•  
P o s si bl e : T h er e is still a r e as o n a bl e p ossi bilit y t h at t h e c a us e of t h e e v e nt w as t h e st u d y 
dr u g(s) b ut t h er e e xists a m or e li k el y c a us e of t h e e v e nt s uc h as c o m plic ati o ns of pr o gr essi v e 
dis e as e.  
•  
P r o b a bl e : T h e m ost li k el y c a us e of t h e e v e nt is t h e st u d y dr u g(s) b ut ot h er c a us es c a n n ot b e 
c o m pl et el y e xcl u d e d. 
•  
D efi nit e: Cl e ar c ut t e m p or al a n d / or m ec h a nistic r el ati o n t o t h e st u d y dr u g(s).  All ot h er 
c a us es  h a v e  b e e n  eli mi n at e d.   E v e nts  cl assifi e d  as  d efi n it e  will  oft e n  b e  c o nfir m e d  b y  
d oc u m e nti n g  r es ol uti o n  o n  disc o nti n u ati o n  of  t h e  st u d y  dr u g  a n d  r ec urr e nc e  u p o n  
r es u m pti o n. 
1 0. 5. 1  R E C O R DI N G O F A D V E R S E  E V E N T S  
All a d v ers e e v e nts of a n y s u bj ect d uri n g t h e c o urs e of t h e st u d y will b e r e p ort e d o n t h e c as e   r e p ort 
f or m, a n d t h e i n v esti g at or will gi v e his or h er o pi ni o n as t o t h e r el ati o ns hi p of t h e a d v ers e e v e nt t o 
st u d y dr u g tr e at m e nt (i. e., w h et h er t h e e v e nt is r el at e d or u nr el at e d t o st u d y dr u gs a d mi nistr ati o n  – 
u m br alisi b  a n d / or u blit u xi m a b). If t h e a d v ers e e v e nt is  s eri o us, it s h o ul d b e r e p ort e d as s o o n as 
p ossi bl e a n d n o  gr e at er t h a n 2 4 h o urs t o t h e s p o ns or or d esi g n e e. Ot h er u nt o w ar d e v e nts occ urri n g 
i n t h e fr a m e w or k of a cli nic al  st u d y  ar e als o  t o b e   r ec or d e d as  A Es  (i. e., A Es  t h at occ ur  pri or  t o 
assi g n m e nt  of  st u d y tr e at m e nt t h at ar e r el at e d t o a pr ot oc ol-m a n d at e d i nt er v e nti o n, i ncl u di n g 
i n v asi v e pr oc e d ur es s uc h as bi o psi es, m e dic ati o n w as h o ut, or n o tr e at m e nt  r u n-i n). 
All  A Es   r e g ar dl ess of  s eri o us n ess or  r el ati o ns hi p t o u m br alisi b  a n d / or  u blit u xi m a b  tr e at m e nt 
s p a n ni n g fr o m C ycl e  1 / D a y 1 u ntil 3 0 c al e n d ar d a ys aft er disc o nti n u ati o n or c o m pl eti o n of eit h er 
pr ot oc ol -s p ecific tr e at m e nt as d efi n e d b y t h e pr ot oc ol f or t h at s u bj ect, ar e t o b e r ec or d e d o n t h e e C R F.  
1 0. 5. 2  A B N O R M A L L A B O R A T O R Y V A L U E S A N D VI T A L SI G N S  
T h e r e p orti n g of a b n or m aliti es of vit al si g ns as a d v ers e e v e nts s h o ul d b e a v oi d e d. A b n or m aliti es  of 
vit al  si g ns  s h o ul d  n ot  b e  r e p ort e d  u nl ess  a n y  crit eri o n  f or  a n  S A E  is  f ulfill e d,  t h e  vit al  si g ns 
a b n or m aliti es  c a us e t h e s u bj ect t o disc o nti n u e  st u d y tr e at m e nt, or  t h e i n v esti g at or i nsists t h at t h e 
a b n or m alit y s h o ul d b e r e p ort e d as a n A E. A b n or m al l a b or at or y r es ults s h o ul d b e n ot e d i n t h e  e C R F 
as  a n  a d v ers e  e v e nt  if t h e y  ar e ass oci at e d  wit h  a n  o v er d os e,   r e q uir e or   pr ol o n g i n p ati e nt 
h os pit ali z ati o n, or ar e ot h er wis e c o nsi d er e d cli nic all y si g nific a nt b y t h e i n v esti g at or. If a n  a b n or m al 
l a b or at or y v al u e  or  vit al  si g n is ass oci at e d  wit h  cli nic al si g ns a n d / or  s y m pt o ms, t h e si g n or  s y m pt o m 
s h o ul d b e r e p ort e d as a n A E, a n d t h e ass oci at e d l a b or at or y v al u e or vit al si g n s h o ul d b e c o nsi d er e d 
a d diti o n al i nf or m ati o n t h at m ust b e c oll ect e d i n t h e r el e v a nt e C R F. If t h e l a b a b n or m alit y is a si g n of 
a dis e as e or s y n dr o m e, o nl y t h e di a g n osis n e e ds t o b e r ec or d e d o n t h e S A E  F or m  or A E  e C R F.  
Cli nic al  L a b or at or y  R es ults  will  b e  s u m m ari z e d. S u m m ar y  st atistics f or act u al  v al u es  a n d  f or c h a n g es 
fr o m b as eli n e will b e t a b ul at e d f or l a b or at or y r es ults b y sc h e d ul e d visit. S u bj ects wit h   l a b or at or y 
v al u es o utsi d e of t h e n or m al r ef er e nc e r a n g e at a n y p ost -b as eli n e ass ess m e nt will b e  s u m m ariz e d, 
a n d gr a d e d p er N CI C T C A E V ersi o n 4. 0 w h e n a p plic a bl e. S u bj ect i nci d e nc e of a b n or m al  l a b r es ults 
will b e s u m m ari z e d b y tr e at m e nt gr o u p a n d m a xi m u m gr a d e f or e ac h a b n or m al   l a b fi n di n g. 
1 0. 5. 3  H A N D LI N G O F A D V E R S E E V E N T S  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 5 9  of 8 5  
All  a d v ers e e v e nts  r es ulti n g i n disc o nt i n u ati o n fr o m t h e st u d y s h o ul d b e  f oll o w e d u ntil  r es ol uti o n or 
st a bili z ati o n. S u bj ects  s h o ul d b e  f oll o w e d f or A Es  f or 3 0  c al e n d ar d a ys  aft er  disc o nti n u ati o n   or 
c o m pl eti o n of pr ot oc ol-s p ecific tr e at m e nt (u m br alisi b  or  u blit u xi m a b).  All n e w A Es occ urri n g d uri n g 
t his p eri o d m ust  b e  r e p ort e d a n d  f oll o w e d u ntil  r es ol uti o n u nl ess,  i n t h e o pi ni o n  of  t h e i n v esti g at or, 
t h es e v al u es ar e  n ot   li k el y t o i m pr o v e b ec a us e  of  t h e  u n d erl yi n g dis e as e.  I n t his c as e, t h e 
i n v esti g at ors m ust  r ec or d his  or  h er  r e as o ni n g f or t his d ecisi o n  i n t h e s u bj ect’s m e dic al  r ec or d a n d  as  
a c o m m e nt o n  t h e e C R F. Aft er 3 0 d a ys, o nl y A Es, S A Es, or d e at hs ass ess e d b y t h e i n v esti g at or as 
tr e at m e nt r el at e d ar e t o b e  r e p ort e d. 
1 0. 6  S E RI O U S A D V E R S E E V E N T S  
1 0. 6. 1  D E FI NI TI O N S O F S E RI O U S A D V E R S E E V E N T S  
T h e d efi niti o ns of s eri o us a d v ers e e v e nts ( S A Es) ar e gi v e n b el o w.  T h e i n v esti g at or is r es p o nsi bl e f or 
e ns uri n g t h at all st aff i n v ol v e d i n t h e st u d y ar e f a mili ar wit h t h e c o nt e nt of t his s ecti o n.  
A n S A E or r e acti o n is d efi n e d as a n y u nt o w ar d m e dic al occ urr e nc e t h at:  
•  
r es ults i n d e at h, is i m m e di at el y lif e-t hr e at e ni n g,  
•  
r e q uir es  at  l e ast  a  2 4-h o ur  i n -p ati e nt  h os pit ali z ati o n  or  pr ol o n g ati o n  of  e xisti n g  
h os pit ali z ati o n,  
•  
r es ults i n p ersist e nt or si g nific a nt dis a bilit y /i nc a p acit y, a n d / or  
•  
c a us es a c o n g e nit al a n o m a l y / birt h d ef ect. 
M e dic al a n d sci e ntific j u d g m e nt s h o ul d b e e x ercis e d i n d eci di n g w h et h er e x p e dit e d r e p orti n g is 
a p pr o pri at e i n ot h er sit u ati o ns, s uc h as i m p ort a nt m e dic al e v e nts t h at m a y n ot b e i m m e di at el y lif e -
t hr e at e ni n g or r es ult i n d e at h or h os pit ali z ati o n, b ut m a y j e o p ar diz e t h e s u bj ect or m a y r e q uir e 
i nt er v e nti o n t o pr e v e nt o n e of t h e ot h er o utc o m es list e d i n t h e pr e vi o us d efi niti o n.  T h es e s h o ul d als o 
us u all y b e c o nsi d er e d s eri o us.  E x a m pl es of s uc h e v e nts ar e i nt e nsi v e tr e at m e nt i n a n e m er g e nc y 
r o o m or at h o m e f or all er gic br o nc h os p as m; bl o o d d yscr asi as or c o n v ulsi o ns t h at d o n ot r es ult i n 
h os pit ali z ati o n; or d e v el o p m e nt of dr u g d e p e n d e nc y or dr u g a b us e.  
Pr o gr essi o n of m ali g n a nc y (i ncl u di n g f at al o utc o m es), if d oc u m e nt e d b y us e of a p pr o pri at e m et h o d 
(f or e x a m pl e, as p er C h es o n  et  al. 2 0 0 7 , s h o ul d n ot b e r e p ort e d as a s eri o us a d v ers e e v e nt.   
A s us p ect e d u n e x p ect e d s eri o us a d v ers e r e acti o n ( S U S A R ) is d efi n e d as an S A E t h at is s us p ect e d t o 
b e at l e ast p ossi bl y r el at e d t o st u d y m e dic ati o n(s) a n d is a n u n e x p ect e d  e v e nt.  S U S A R r e p orti n g is 
e nc o m p ass e d wit hi n S A E r e p orti n g g ui d eli n es as d efi n e d i n t his s ecti o n.  
Tr e at m e nt wit hi n or a d missi o n t o t h e f oll o wi n g f aciliti es is n ot c o nsi d er e d t o m e et t h e crit eri a of “i n -
p ati e nt h os pit ali z ati o n” ( alt h o u g h if a n y ot h er S A E crit eri a  ar e m et, t h e e v e nt m ust still b e tr e at e d as 
a n S A E a n d i m m e di at el y r e p ort e d):  
•  
E m er g e nc y D e p art m e nt or E m er g e nc y R o o m  
•  
O ut p ati e nt or s a m e -d a y s ur g er y u nits  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 6 0  of 8 5  
•  
O bs er v ati o n or s h ort -st a y u nit 
•  
R e h a bilit ati o n f acilit y  
•  
H os pic e or s kill e d n ursi n g f acilit y  
•  
N ursi n g h o m es, C ust o di al c ar e or R es pit e c ar e f acilit y  
•  
A d missi o n f or st u d y r el at e d tr e at m e nt  
H os pit aliz ati o n d uri n g t h e st u d y f or a pr e-pl a n n e d s ur gic al or m e dic al pr oc e d ur e ( o n e w hic h w as 
pl a n n e d pri or t o e ntr y i n t h e st u d y), d o es n ot r e q uir e r e p orti n g as a s eri o us a d v ers e e v e nt t o t h e 
S p o ns or.  
1 0. 6. 2  S E RI O U S A D V E R S E E V E N T R E P O R TI N G B Y I N V E S TI G A T O R S  
It is i m p ort a nt t o disti n g uis h  b et w e e n  “s eri o us” a n d  “s e v er e” a d v ers e e v e nts,  as  t h e t er ms ar e  n ot 
s y n o n y m o us.  S e v erit y  is a  m e as ur e  of  i nt e nsit y; h o w e v er,  a n  A E  of  s e v er e  i nt e nsit y  n e e d  n ot 
n ec ess aril y b e c o nsi d er e d s eri o us. F or e x a m pl e, n a us e a w hic h p ersists f or s e v er al h o urs m a y  b e 
c o nsi d er e d s e v er e n a us e a,  b ut  m a y  n ot  b e  c o nsi d er e d a n  S A E.  O n  t h e ot h er  h a n d,  a str o k e w hic h 
r es ults i n o nl y a li mit e d d e gr e e of dis a bilit y m a y b e c o nsi d er e d o nl y a mil d str o k e, b ut w o ul d  b e 
c o nsi d er e d a n S A E. S e v erit y a n d s eri o us n ess s h o ul d b e i n d e p e n d e ntl y ass ess e d w h e n r ec or di n g  A Es 
a n d S A Es o n t h e  e C R F.  
A d v ers e e v e nts  cl assifi e d b y  t h e tr e ati n g i n v esti g at or as  s e ri o u s  r e q uir e e x p e diti o us  h a n dli n g  a n d 
r e p orti n g t o t h e S p o ns or i n or d er t o c o m pl y wit h r e g ul at or y r e q uir e m e nts. S eri o us a d v ers e  e v e nts 
m a y occ ur at a n y ti m e aft er si g ni n g of i nf or m e d c o n ms e nt  t hr o u g h t h e 3 0-d a y f oll o w -u p p eri o d aft er 
t h e l ast st u d y tr e at m e nt. S p o ns or  or  d esi g n e e  s h o ul d b e  n otifi e d  of  all S A Es,  r e g ar dl ess of  c a us alit y, 
wit hi n  2 4  h o urs of t h e first k n o wl e d g e of t h e e v e nt b y t h e tr e ati n g p h ysici a n or r es e arc h  p ers o n n el.  
 
T o r e p o rt a n S A E, s e e t h e a p p r o p ri at e f o r m . 
All  S A Es   (r e g ar dl ess of  c a us alit y ass ess m e nt)   occ urrin g  o n  st u d y or  wit hi n  3 0  d a ys  of  l ast st u d y 
tr e at m e nt s h o ul d b e  i m m e di at el y r e p ort e d t o t h e s p o ns or as  S A Es  wit hi n  t h e C R F  a n d  f oll o w e d u ntil 
r es ol uti o n ( wit h a ut o ps y r e p ort if a p plic a bl e).  
Dis e as e  pr o gr essi o n or  d e at h  d u e t o dis e as e  pr o gr essi o n s h o ul d b e  r e p ort e d b y  t h e i n v esti g at or as  a 
s eri o us a d v ers e e v e nt  o nl y  if it is ass ess e d  t h at t h e st u d y dr u gs c a us e d or  c o ntri b ut e d t o t h e dis e as e  
pr o gr essi o n (i. e. b y a m e a ns ot h er t h a n l ac k of eff ect). U nr el at e d e v e nts of dis e as e pr o gr essi o n s h o ul d 
b e  c a pt ur e d o n t h e a p pr o pri at e e C R F.  
T h e  i n v esti g at or m ust  r e vi e w a n d  si g n off  o n  t h e S A E  d at a  o n  t h e S A E  r e p ort. T h e  S A E  s h o ul d b e  
r e p ort e d t o t h e S p o ns or ( or S p o ns or d esi g n e e) as o utli n e d i n t h e S af et y M o nit ori n g  Pl a n.  
W h e n  a n  S A E  is r e p ort e d t o t h e s p o ns or or  d esi g n e e,  t h e s a m e i nf or m ati o n s h o ul d b e  e nt er e d  o n  t h e 
e C R F wit hi n 2 4 h o urs ( 1 b usi n ess d a y). Tr a ns missi o n of t h e S A E r e p ort s h o ul d b e c o nfir m e d b y  t h e 
sit e p ers o n n el s u b mitti n g t h e  r e p ort. 
F oll o w- u p  i nf or m ati o n f or S A Es  a n d  i nf or m ati o n o n  n o n -s eri o us A Es  t h at b ec o m e  s eri o us s h o ul d als o 
b e r e p ort e d t o t h e s p o ns or or d esi g n e e as s o o n as it is a v ail a bl e; t h es e r e p orts s h o ul d b e  s u b mitt e d 
usi n g t h e a p pr o pri at e S A E  f or m. 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 6 1  of 8 5  
I n v esti g at ors m ust r e p ort S A Es a n d f oll o w-u p i nf or m ati o n t o t h eir r es p o nsi bl e I nstit uti o n a l R e vi e w 
B o ar d  (I R Bs) /I n d e p e n d e nt  Et hics  C o m mitt e e  acc or di n g  t o  t h e  p olici es  of  t h e  r es p o nsi bl e  I R B 
( R es e arc h Et hics C o m mitt e e).  
1 0. 7   S P O N S O R S A E R E P O R TI N G R E Q UI R E M E N T S  
S p o ns or is r es p o nsi bl e f or r e p orti n g r el e v a nt S A Es t o t h e c o m p et e nt a ut h orit y, ot h er a p plic a bl e 
r e g ul at or y  a ut h oriti es,  a n d  p artici p ati n g  i n v esti g at ors,  i n  acc or d a nc e  wit h  I C H g ui d eli n es,  F D A 
r e g ul ati o ns, a n d / or l oc al r e g ul at or y r e q uir e m e nts. 
S p o ns or is r es p o nsi bl e f or r e p orti n g u n e x p ect e d f at al or lif e -t hr e at e ni n g e v e nts ass oci at e d wit h th e 
us e of t h e st u d y dr u gs t o t h e r e g ul at or y a g e nci es a n d c o m p et e nt a ut h oriti es wit hi n 7 c al e n d ar d a ys 
aft er b ei n g n otifi e d of t h e e v e nt.  T h e S p o ns or will r e p ort all r el at e d b ut u n e x p ect e d S A Es i ncl u di n g 
n o n -d e at h / n o n -lif e-t hr e at e ni n g r el at e d b ut u n e x p ect ed S A Es  ( S U S A R) ass oci at e d wit h t h e us e of t h e 
st u d y m e dic ati o ns t o t h e r e g ul at or y a g e nci es a n d c o m p et e nt a ut h oriti es b y a writt e n s af et y r e p ort 
wit hi n 1 5 c al e n d ar d a ys of n otific ati o n.  F oll o wi n g t h e s u b missi o n t o t h e r e g ul at or y a g e nci es a n d 
c o m p et e nt a ut h oriti es, I n v esti g at ors a n d tri al sit es will b e n otifi e d of t h e S U S A R.  I n v esti g at ors m ust 
r e p ort S U S A R s  a n d  f oll o w-u p  i nf or m ati o n  t o  t h eir  r es p o nsi bl e  I nstit uti o n al  R e vi e w  B o ar d  
(I R Bs) /I n d e p e n d e nt Et hics C o m mitt e e acc or di n g t o t h e p olici es of t h e r es p o nsi bl e I R B ( R es e arc h 
Et hics C o m mitt e e).  
1 0. 8  R E C O R DI N G O F A D V E R S E  E V E N T S A N D S E RI O U S A D V E R S E E V E N T S  
I n v esti g at ors s h o ul d us e c orr ect m e dic al t er mi n ol o g y /c o nc e pts w h e n r ec or di n g A Es or S A Es o n t h e 
S A E R e p ort F or ms a n d A E e C R F.  A v oi d c oll o q ui alis ms a n d a b br e vi ati o ns . 
All A Es, i ncl u di n g t h os e t h at m e et S A E r e p orti n g crit eri a, s h o ul d b e r ec or d e d o n t h e A E e C R F; A Es 
t h at m e et t h e d efi niti o n of a n S A E s h o ul d a d diti o n all y b e r e p ort e d. 
1 0. 9  DI A G N O SI S V S. SI G N S A N D S Y M P T O M S  
All A Es s h o ul d b e r ec or d e d i n di vi d u all y i n t h e s u bj ect’s o w n w or ds ( v er b ati m) u nl ess, i n t h e o pi ni o n 
of t h e Pri nci p al I n v esti g at or or d esi g n at e d p h ysici a n, t h e A Es c o nstit ut e c o m p o n e nts of a r ec o g ni z e d 
c o n diti o n, dis e as e, or s y n dr o m e.  I n t h e l att er c as e, t h e c o n diti o n, dis e as e, or s y n dr o m e s h o ul d b e 
n a m e d r at h er t h a n e ac h i n di vi d u al si g n or s y m pt o m.  If a c o nst ell ati o n of si g ns a n d / or s y m pt o ms 
c a n n ot b e m e dic all y c h ar act eri z e d as a si n gl e di a g n osis or s y n dr o m e at t h e ti m e of r e p orti n g, e ac h 
i n di vi d u al e v e nt s h o ul d b e r ec or d e d as a n A E or S A E as a p pr o pri at e o n t h e r el e v a nt f or m(s) ( S A E 
R e p ort F or m a n d / or A E e C R F).  If a di a g n osis is s u bs e q u e ntl y est a blis h e d, it s h o ul d b e r e p ort e d as 
f oll o w-u p i nf or m ati o n is a v ail a bl e.  If a di a g n osis is d et er mi n e d s u bs e q u e nt t o t h e r e p orti n g of t h e 
c o nst ell ati o n of s y m pt o ms, t h e  si g ns /s y m pt o ms s h o ul d b e u p d at e d t o r efl ect t h e di a g n osis.  
1 0. 9. 1  P E R SI S T E N T O R R E C U R R E N T A D V E R S E E V E N T S  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 6 2  of 8 5  
A p ersist e nt A E is o n e t h at e xt e n ds c o nti n u o usl y, wit h o ut r es ol uti o n, b et w e e n s u bj ect e v al u ati o n ti m e 
p oi nts.  S uc h e v e nts s h o ul d o nl y b e r ec or d e d o nc e o n t h e S A E R e p ort F or m a n d / or t h e A E  eC R F.    If 
a p ersist e nt A E b ec o m es m or e s e v er e (c h a n g es fr o m a Gr a d e 1 or 2 A E t o a Gr a d e 3 or 4 A E) or l ess e ns 
i n s e v erit y (c h a n g es fr o m a Gr a d e 3 or 4 A E t o a Gr a d e 1 or 2 A E), it s h o ul d b e r ec or d e d o n a s e p ar at e 
S A E R e p o rt F or m a n d / or A E e C R F.   
A  r ec urr e nt  A E  is  o n e  t h at  occ urs  a n d  r es ol v es  b et w e e n  s u bj ect e v al u ati o n  ti m e  p oi nts,  a n d  
s u bs e q u e ntl y r ec urs.  All r ec urr e nt A Es s h o ul d b e r ec or d e d o n a n S A E R e p ort F or m a n d / or A E  eC R F 
f or e ac h r ec urr e nc e. 
1 0. 9. 2  A B N O R M A L L A B O R A T O R Y V A L U E S  
A b n or m al l a b or at or y r es ults s h o ul d b e n ot e d i n t h e e C R F as a n a d v ers e e v e nt if t h e y ar e ass oci at e d 
wit h a n o v er d os e, r e q uir e or pr ol o n g i n p ati e nt h os pit ali z ati o n, or ar e ot h er wis e c o nsi d er e d cli nic all y 
si g nific a nt b y t h e i n v esti g at or. If a n a b n or m al l a b or at or y v al u e or vit al si g n is ass oci at e d wit h cli nic al 
si g ns a n d / or s y m pt o ms, t h e si g n or s y m pt o m s h o ul d b e r e p ort e d as a n A E, a n d t h e ass oci at e d 
l a b or at or y v al u e or vit al si g n s h o ul d b e c o nsi d er e d a d diti o n al i nf or m ati o n t h at m ust b e c oll ect e d i n 
t h e r el e v a nt e C R F.  If t h e l a b or at or y a b n or m alit y is a si g n of a dis e as e or s y n dr o m e, o nl y t h e di a g n osis 
n e e ds t o b e r ec or d e d o n t h e S A E R e p ort F or m or A E e C R F.  
1 0. 9. 3  D E A T H S  
D e at hs t h at occ ur d uri n g t h e pr ot oc ol -s p ecifi e d A E r e p orti n g p eri o d t h at ar e attri b ut e d b y t h e  
i n v esti g at or s ol el y t o pr o gr essi o n of t h e s u bj ect’s dis e as e  f or u p t o 3 0 d a ys p ost t h e l ast d os e of st u d y 
dr u g will b e r ec or d e d o n t h e a p pr o pri at e st u d y e C R F a n d r e p ort e d o n t h e A d v ers e E v e nt p a g e of t h e 
e C R F, i. e. ar e e x e m pt e d fr o m e x p e dit e d r e p orti n g. All ot h er o n -st u d y d e at hs, r e g ar dl ess of attri b uti o n, 
will b e r ec or d e d o n a n S A E R e p ort F or m a n d e x p e diti o usl y r e p ort e d t o t h e S p o ns or.  
W h e n r ec or di n g a s eri o us a d v ers e e v e nt wit h a n o utc o m e of d e at h, t h e e v e nt or c o n diti o n t h at c a us e d 
or c o ntri b ut e d t o t h e f at al o utc o m e s h o ul d b e r ec or d e d as t h e si n gl e m e dic al c o nc e pt o n t h e A d v ers e 
E v e nt p a g e of t h e e C R F.  If t h e c a us e of d e at h is u n k n o w n a n d c a n n ot b e asc ert ai n e d at t h e ti m e of 
r e p orti n g, r ec or d “ D e at h N O S” o n t h e e C R F A d v ers e E v e nt p a g e.  
1 0. 9. 4  H O S PI T A LI Z A TI O N, P R O L O N G E D H O S PI T A L I Z A TI O N, O R S U R G E R Y 
A n y A E  t h at r es ults  i n  h os pit al  a d missi o n  of > 2 4 h o urs or pr ol o n g s h os pit aliz ati o n s h o ul d b e 
d oc u m e nt e d a n d r e p ort e d as a n S A E u nl ess s p ecific all y i nstr uct e d ot h er wis e i n t his pr ot oc ol.  T h er e 
ar e  s o m e  h os pit aliz ati o n sc e n ari os  t h at  d o  n ot  r e q uir e  r e p orti n g as  a n  S A E  w h e n  t h er e  is  n o 
occ urr e nc e of a n A E.   S e e s ecti o n 1 0. 6. 1 . 
1 0. 9. 5  P R E -E XI S TI N G M E DI C A L  C O N DI TI O N S  
A pr e- e xisti n g r el e v a nt m e dic al c o n diti o n is o n e t h at is pr es e nt at t h e st art of t h e st u d y.  S uc h 
c o n diti o ns s h o ul d b e r ec or d e d o n t h e st u d y’s a p pr o pri at e m e dic al hist or y e C R F.  A pr e -e xisti n g 
m e dic al c o n diti o n s h o ul d b e r ec or d e d as a n A E or S A E o nl y if t h e fr e q u e nc y, s e v erit y, or c h ar act er of 


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t h e c o n diti o n w ors e ns d uri n g t h e st u d y.  W h e n r ec or di n g s uc h e v e nts o n t h e a p pr o pri at e S A E R e p ort 
F or m a n d / or A E  eC R F, it is i m p ort a nt t o c o n v e y t h e c o nc e pt t h at t h e pr e -e xisti n g c o n diti o n h as 
c h a n g e d b y i ncl u di n g a p plic a bl e d escri pt ors.  
 
1 0. 9. 6  P R O T O C O L -D E FI N E D E V E N T S O F S P E CI A L I N T E R E S T  
T h e f oll o wi n g ar e e v e nts of s p eci al i nt er est, a n d will n e e d t o b e r e p ort e d e x p e diti o usl y:  
P r e g n a n c y, A b o rti o n, Bi rt h D ef e ct s / C o n g e nit al A n o m ali e s  
D uri n g t h e c o urs e of t h e st u d y, all f e m al e s u bj ects of c hil d b e ari n g p ot e nti al  m ust c o nt act t h e tr e ati n g 
i n v esti g at or i m m e di at el y if t h e y s us p ect t h at t h e y m a y b e pr e g n a nt ( a miss e d or l at e m e nstr u al 
p eri o d s h o ul d b e r e p ort e d t o t h e tr e ati n g i n v esti g at or).   
If a n i n v esti g at or s us p ects t h at a s u bj ect m a y b e pr e g n a nt pri or t o a d mi nistr ati o n of st u d y dr u g(s), 
t h e st u d y dr u g(s) m ust b e wit h h el d u ntil t h e r es ult of t h e pr e g n a nc y t est is c o nfir m e d.  If a pr e g n a nc y 
is c o nfir m e d, t h e s u bj ect m ust n ot r ec ei v e a n y st u d y dr u g(s), a n d m ust b e disc o nti n u e d fr o m t h e 
st u d y.   
If a n i n v esti g at or s us p ects t h at a s u bj ect m a y b e pr e g n a nt aft er t h e s u bj ect h as b e e n r ec ei vi n g st u d y 
dr u g(s), t h e st u d y dr u g(s) m ust i m m e di at el y b e wit h h el d u ntil t h e r es ult of t h e pr e g n a nc y t est is 
c o nfir m e d.  If a pr e g n a nc y is c o nfir m e d, t h e st u d y dr u g(s) m ust b e i m m e di at el y a n d p er m a n e ntl y 
st o p p e d, t h e s u bj et m ust b e disc o nti n u e d fr o m t h e st u d y, a n d t h e i n v esti g at or m ust n otif y t h e St u d y 
C h air or M e dic al M o nit or as s o o n as p ossi bl e.   
If a s u bj ect b ec o m es pr e g n a nt w hil e e nr oll e d i n t h e st u d y, a n S A E f or m s h o ul d b e c o m pl et e d a n d 
s u b mitt e d t o t h e S p o ns or.  A b orti o ns (s p o nt a n e o us, acci d e nt al, or t h er a p e utic) m ust als o b e r e p ort e d 
t o t h e S p o ns or. 
C o n g e nit al a n o m ali es / birt h d ef ects al w a y s  m e et S A E crit eri a, a n d s h o ul d t h er ef or e b e e x p e diti o us l y 
r e p ort e d as a n S A E, usi n g t h e pr e vi o usl y d escri b e d pr oc ess f or S A E r e p orti n g.  
St u d y  D r u g O v e r d o s e  
S y m pt o m atic a n d n o n -s y m pt o m atic o v er d os e m ust b e r e p ort e d i n t h e e C R F. A n y acci d e nt al or 
i nt e nti o n al  o v er d os e  wit h  t h e  st u d y  tr e at m e nt  t h at  is  s y m pt o m atic, e v e n  if  n ot  f ulfilli n g  a  
s eri o us n ess crit eri o n, is t o b e r e p ort e d t o t h e S p o ns or i m m e di at el y ( wit hi n 2 4 h o urs) usi n g t h e 
c orr es p o n di n g S A E f or m, a n d f oll o wi n g t h e s a m e pr oc ess d escri b e d f or S A Es. If a st u d y dr u g 
o v er d os e occ urs, s u bj ects s h o ul d st o p st u d y dr u g d osi n g a n d b e cli nic all y m o nit or e d as a p pr o pri at e, 
m a n a gi n g s y m pt o ms /si d e eff ects t h at m a y occ ur.  
 
S e c o n d a r y / S e c o n d  P ri m a r y M ali g n a n c y  
A n y s ec o n d ar y m ali g n a nc y  or s ec o n d m ali g n a nc y  e v e nt m ust b e r e p ort e d vi a  t h e S A E f or m  (i n 
a d diti o n t o t h e r o uti n e A E r e p orti n g m ec h a nis ms).  A n y m ali g n a nc y p ossi bl y r el at e d t o c a nc er 
tr e at m e nt s h o ul d als o b e r e p ort e d vi a t h e r o uti n e r e p orti n g m ec h a nis ms o utli n e d i n t h e pr ot oc ol. 


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1 1  C LI NI C A L D A T A C O L L E C TI O N A N D M O NI T O RI N G  
1 1. 1  SI T E M O NI T O RI N G P L A N  
A S p o ns or r e pr es e nt ati v e or d esi g n e e will h a v e m a d e a sit e visit t o e ac h i nstit uti o n wit hi n 1 2  m o nt hs 
pri or t o i niti ati n g t h e pr ot oc ol t o i ns p ect t h e dr u g st or a g e ar e a, a n d f ull y i nf or m t h e I n v esti g at or of 
his / h er  r es p o nsi biliti es  f or  st u di es  a n d  t h e  pr oc e d ur es  f or  ass uri n g  a d e q u at e  a n d  c orr ect  
d oc u m e nt ati o n.   
A st u d y i niti ati o n sit e visit , a t el ec o nf er e nc e a n d / or a  pl a n n e d i n v esti g at or m e eti n g  will b e p erf or m e d 
t o  r e vi e w  i n v esti g at or  r es p o nsi biliti es  a n d  pr ot oc ol r e q uir e m e nts.  D uri n g  t h e  i niti ati o n,  t h e  
el ectr o nic c as e r e p ort f or ms ( eC R Fs) a n d ot h er p erti n e nt st u d y m at eri als will b e r e vi e w e d wit h t h e 
i n v esti g at or’s r es e arc h st aff.  D uri n g t h e c o urs e of t h e st u d y, t h e S p o ns or will m a k e visits t o t h e sit es 
as n ec ess ar y i n or d er t o r e vi e w pr ot oc ol c o m pli a nc e, e x a mi n e e C R Fs, a n d i n di vi d u al s u bj ect m e dic al 
r ec or ds, a n d e ns ur e t h at t h e st u d y is b ei n g c o n d uct e d acc or di n g t o t h e pr ot oc ol a n d p erti n e nt 
r e g ul at or y r e q uir e m e nts.  S el ect e d e C R F e ntri es will b e v erifi e d wit h s o urc e d oc u m e nt ati o n.  T h e 
r e vi e w  of  m e dic al  r ec or ds  will  b e  d o n e  i n  a  m a n n er  t o  ass ur e  t h at  s u bj ect c o nfi d e nti alit y  is  
m ai nt ai n e d.  
Sit e m o nit ori n g s h all b e c o n d uct e d t o e ns ur e t h e h u m a n s u bj ect pr ot ecti o n, st u d y pr oc e d ur es, 
l a b or at or y, st u d y i nt er v e nti o n a d mi nistr ati o n, a n d d at a c oll ecti o n pr oc ess es ar e of hi g h q u alit y a n d 
m e e t t h e S p o ns or, G C P /I C H a n d, w h e n a p pr o pri at e, r e g ul at or y g ui d eli n es.  T h e Sit e M o nit ori n g Pl a n 
s h all d efi n e as p ects of t h e m o nit ori n g pr oc ess.  
1 1. 2  A M E N D M E N T S T O T H E P R O T O C O L  
A m e n d m e nts t o t h e pr ot oc ol s h all b e pl a n n e d, d oc u m e nt e d , a n d si g n at ur e a ut h oriz e d pri or t o 
i m pl e m e nt ati o n.   
If a n a m e n d m e nt t o t h e pr ot oc ol is r e q uir e d, t h e a m e n d m e nt will b e ori gi n at e d a n d d oc u m e nt e d b y 
t h e  S p o ns or.   All  a m e n d m e nts  r e q uir e  r e vi e w  a n d  a p pr o v al  of  t h e  S p o ns or  a n d  t h e  Pri nci p al  
I n v esti g at or s u p porti n g t h e st u d y.  T h e writt e n a m e n d m e nt m ust b e r e vi e w e d a n d a p pr o v e d b y t h e 
S p o ns or, a n d s u b mitt e d t o t h e I R B at t h e i n v esti g at or’s f acilit y f or t h e b o ar d’s a p pr o v al.  
A m e n d m e nts s p ecific all y i n v ol vi n g c h a n g e t o st u d y d esi g n, ris k t o s u bj ect, i ncr e as e t o d osi n g or 
e x p os ur e, s u bj ect n u m b er i ncr e as e, a d diti o n or r e m o v al of n e w t ests or pr oc e d ur es, s h all b e r e vi e w e d 
a n d a p pr o v e d b y t h e I R B at t h e I n v esti g at or’s f acilit y.  
T h e a m e n d m e nt will b e s u b mitt e d f or m all y t o t h e F D A or ot h er r e g ul at or y a ut h oriti es b y t h e S p o ns or 
as a p plic a bl e, a n d s p ecific all y w h e n a n i ncr e as e t o d osi n g or s u bj ect e x p os ur e a n d / or s u bj ect n u m b er 
h as b e e n pr o p os e d; or, w h e n t h e a d diti o n or r e m o v al of a n I n v esti g at or is n ec essit at e d.  
It e ms r e q uiri n g a pr ot oc ol a m e n d m e nt wit h I R B a n d Et hics C o m mitt e e  a n d / or F D A a n d C o m p et e nt 
A ut h orit y a p pr o v al m a y i ncl u d e t h e f oll o wi n g: 
•  
C h a n g e t o st u d y d esi g n  


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•  
Ris k t o s u bj ect 
•  
I ncr e as e t o d os e or s u bj ect e x p os ur e t o dr u g  
•  
S u bj ect  n u m b er i ncr e as e of m or e t h a n 2 0 %  
•  
A d diti o n or r e m o v al of t ests a n d / or pr oc e d ur es  
•  
A d diti o n /r e m o v al of a n e w I n v esti g at or  
It s h o ul d b e f urt h er n ot e d t h at, if a n a m e n d m e nt t o t h e pr ot oc ol s u bst a nti all y alt ers t h e st u d y d esi g n 
or t h e p ot e nti al ris ks t o t h e s u bj ects, t h eir c o ns e nt t o c o nti n u e p artici p ati o n i n t h e st u d y s h o ul d b e 
o bt ai n e d.  
1 1. 3  C U R RI C U L A VI T A E A N D FI N A N CI A L DI S C L O S U R E S 
All Pri nci p al I n v esti g at ors will b e r e q uir e d t o s u b mit t o t h e S p o ns or or its d esi g n e e a n u p -t o-d at e 
si g n e d c urric ul u m vit a e ( C V), c urr e nt wit hi n t w o y e ars, a c urr e nt c o p y of t h eir m e dic al lic e ns e, a n d a 
c o m pl et e d FD A f or m 1 5 7 2 a n d fi n a nci al discl os ur e st at e m e nt.  I n a d diti o n, all s u b -i n v esti g at ors will 
b e r e q uir e d t o s u b mit t o t h e S p o ns or or its d esi g n e e a n u p -t o-d at e si g n e d C V, c urr e nt wit hi n t w o 
y e ars, a c urr e nt c o p y of t h eir m e dic al lic e ns e, a n d a c o m pl et e d fi n a n ci al discl os ur e st at e m e nt.  
1 1. 4  D A T A O W N E R S HI P A N D P U B LI C A TI O N  
B y c o n d ucti n g t his st u d y, t h e I n v esti g at or affir ms t o S p o ns or t h at h e or s h e will m ai nt ai n, i n strict 
c o nfi d e nc e, i nf or m ati o n f ur nis h e d b y t h e S p o ns or i ncl u di n g d at a g e n er at e d fr o m t his st u d y a n d 
pr eli mi n ar y l a b or at or y r es ults, e xc e pt as e x e m pt e d f or r e g ul at or y p ur p os es.  
All d at a g e n er at e d d uri n g t h e c o n d uct of t his st u d y is o w n e d b y t h e S p o ns or a n d m a y n ot b e us e d b y 
t h e I n v esti g at or or affili at es wit h o ut t h e e x pr ess e d writt e n c o ns e nt of t h e S p o ns or. 
All m a n uscri pts, a bstr acts, or ot h er pr es e nt ati o n m at eri als g e n er at e d b y sit e i n v esti g at ors m ust b e 
r e vi e w e d a n d a p pr o v e d b y t h e S p o ns or pri or t o s u b missi o n.  


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1 2  E T HI C A L, FI N A N CI A L, A N D R E G U L A T O R Y C O N SI D E R A TI O N S  
T his st u d y will b e c o n d uct e d acc or di n g t o t h e st a n d ar ds of G o o d Cli nic al Pr actic e o utli n e d i n t h e I C H 
E 6 Tri p artit e G ui d eli n e a n d C F R Titl e 2 1 p art 3 1 2, a p plic a bl e g o v er n m e nt r e g ul ati o ns, i nstit uti o n al 
r es e arc h p olici es a n d pr oc e d ur es a n d a n y ot h er l oc al a p plic a bl e r e g ul at or y r e q uir e m e nt(s).  
1 2. 1  I R B A P P R O V A L 
T h e st u d y pr ot oc ol, I C F, I B, a v ail a bl e s af et y i nf or m ati o n, s u bj ect d oc u m e nts ( e. g.,  st u d y di ar y), s u bj ect 
r ecr uit m e nt pr oc e d ur es ( e. g., a d v ertis e m e nts), i nf or m ati o n a b o ut p a y m e nts (i. e., PI p a y m e nts) a n d 
c o m p e ns ati o n a v ail a bl e t o t h e s u bj ects a n d d oc u m e nt ati o n e vi d e nci n g t h e PI’s q u alific ati o ns m ust b e 
s u b mitt e d t o t h e I R B f or et hic al r e vi e w a n d a p pr o v al pri or t o t h e st u d y st art.   
T h e PI / S p o ns or a n d / or d esi g n e e will f oll o w all n ec ess ar y r e g ul ati o ns t o e ns ur e i niti al  a n d o n g oi n g, 
I R B st u d y r e vi e w. T h e PI / S p o ns or ( as a p pr o pri at e) m ust s u b mit a n d, w h er e n ec ess ar y, o bt ai n 
a p pr o v al fr o m t h e I R B f or all s u bs e q u e nt pr ot oc ol a m e n d m e nts a n d c h a n g es t o t h e i nf or m e d c o ns e nt 
d oc u m e nt.  I n v esti g at ors will b e a d vis e d b y t h e s p o ns o r or d esi g n e e w h et h er a n a m e n d m e nt is 
c o nsi d er e d s u bst a nti al  or n o n -s u bst a nti al  a n d  w h et h er  it  r e q uir es  s u b missi o n  f or  a p pr o v al  or  
n otific ati o n o nl y t o a n I R B.  
If a p plic a bl e, t h e PI will n otif y t h e I R B wit hi n 9 0 d a y s  of t h e e n d of t h e st u d y, or if t h e st u dy 
t er mi n at es e arl y, t h e PI m ust n otif y t h e I R B wit hi n 1 5 d a y s  of t h e t er mi n ati o n.  A r e as o n f or t h e e arl y 
t er mi n ati o n m ust b e pr o vi d e d ( as d efi n e d i n Dir ecti v e 2 0 0 1 / 2 0 / E C). T h e S p o ns or will eit h er pr e p ar e 
or r e vi e w all s u b missi o n d oc u m e nts pri or t o s u b miss i o n t o t h e I R B. 
1 2. 2  R E G U L A T O R Y A P P R O V A L  
As r e q uir e d b y l oc al r e g ul ati o ns, t h e S p o ns or will e ns ur e all l e g al as p ects ar e c o v er e d, a n d a p pr o v al 
of t h e a p pr o pri at e r e g ul at or y b o di es o bt ai n e d, pri or t o st u d y i niti ati o n. If r e q uir e d, t h e S p o ns or will 
als o e ns ur e t h at t h e i m pl e m e nt ati o n of s u bst a nti al a m e n d m e nt t o t h e pr ot oc ol a n d ot h er r el e v a nt 
st u d y d oc u m e nts h a p p e n o nl y aft er a p pr o v al b y t h e r el e v a nt r e g ul at or y a ut h oriti es.  
S af et y  u p d at es  f or  u blit u xi m a b  a n d / or u m br alisi b  will  b e  pr e p ar e d  b y  t h e  S p o ns or  or  its  
r e pr es e nt ati v e as r e q uir e d, f or s u b missi o n t o t h e r el e v a nt r e g ul at or y a ut h orit y.   
1 2. 3  I N S U R A N C E A N D I N D E M NI T Y 
D et ails of i ns ur a nc e a n d / or i n d e m nit y will b e c o nt ai n e d wit hi n t h e writt e n a gr e e m e nt b et w e e n t h e 
PI or sit e a n d t h e S p o ns or.  
1 2. 4  I N F O R M E D C O N S E N T 
I nf or m e d co ns e nt is a pr oc ess b y w hic h a s u bj ect v ol u nt aril y c o nfir ms his or h er willi n g n ess t o 
p artici p at e i n a p artic ul ar st u d y, aft er h a vi n g b e e n i nf or m e d of all as p ects of t h e st u d y t h at ar e 


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r el e v a nt t o t h e s u bj ect's d ecisi o n t o p artici p at e.  I nf or m e d c o ns e nt is  d oc u m e nt e d b y m e a ns of a 
writt e n, si g n e d a n d d at e d i nf or m e d c o ns e nt f or m.  
T h e I C F will b e s u b mitt e d f or a p pr o v al t o t h e I R B t h at is r es p o nsi bl e f or r e vi e w a n d a p pr o v al of t h e 
st u d y.  E ac h c o ns e nt f or m m ust i ncl u d e all of t h e r el e v a nt el e m e nts c urr e ntl y r eq uir e d b y t h e 
r es p o nsi bl e r e g ul at or y a ut h orit y, as w ell as l oc al c o u nt y a ut h orit y or st at e r e g ul ati o ns a n d n ati o n al 
r e q uir e m e nts. 
B ef or e r ecr uit m e nt a n d e nr oll m e nt i nt o t h e st u d y, e ac h pr os p ecti v e c a n di d at e will b e gi v e n a f ull 
e x pl a n ati o n of t h e st u d y.  O nc e t h e ess e nti al i nf or m ati o n h as b e e n pr o vi d e d t o t h e pr os p ecti v e 
c a n di d at e, a n d t h e i n v esti g at or is s ur e t h at t h e i n di vi d u al c a n di d at e u n d erst a n ds t h e i m plic ati o ns of 
p artici p ati n g i n t his st u d y, t h e c a n di d at e will b e as k e d t o gi v e c o ns e nt t o p artici p at e i n t h e st u d y b y 
si g ni n g a n i nf or m e d c o ns e nt f or m.  A n ot ati o n t h at writt e n i nf or m e d c o ns e nt h as b e e n o bt ai n e d will 
b e m a d e i n t h e s u bj ect’s m e dic al r ec or d.  A c o p y of t h e i nf or m e d c o ns e nt f or m, t o i ncl u d e t h e s u bj ect’s 
si g n at ur e, will b e pr o vi d e d b y t h e i n v esti g at or t o t h e s u bj ect.   
If a n a m e n d m e nt t o t h e pr ot oc ol s u bst a nti all y alt ers t h e st u d y d esi g n or t h e p ot e nti al ris ks t o t h e 
s u bj ects, t h e s u bj ect’s c o ns e nt t o c o nti n u e p artici p ati o n i n t h e st u d y m ust b e o bt ai n e d.  
1 2. 5  C O N FI D E N TI A LI T Y  
S u bj e ct  C o nfi d e nt i alit y 
C o nfi d e nti alit y of s u bj ect’s p ers o n al d at a will b e pr ot ect e d i n acc or d a nc e wit h t h e H e alt h I ns ur a nc e 
P ort a bilit y a n d  Acc o u nt a bilit y  Act  of  1 9 9 6  ( HI P A A),  a n d  n ati o n al  d at a  pr ot ecti o n  l a ws.  HI P A A 
r e g ul ati o ns r e q uir e t h at, i n or d er t o p artici p at e i n t h e st u d y, a s u bj ect m ust si g n a n a ut h ori z ati o n 
fr o m t h e st u d y t h at h e or s h e h as b e e n i nf or m e d of f oll o wi n g: 
•  
W h at pr ot ect e d h e alt h i nf or m ati o n ( P HI) will b e c oll ect e d fr o m s u bj ects i n t his st u d y; 
•  
W h o will h a v e acc ess t o t h at i nf or m ati o n a n d w h y;  
•  
W h o will us e or discl os e t h at i nf or m ati o n;  
•  
T h at h e alt h i nf or m ati o n m a y b e f urt h er discl os e d b y t h e r eci pi e nts of t h e i nf or m ati o n, a n d 
t h at if t h e i nf or m ati o n is discl os e d t h e i nf or m ati o n m a y n o l o n g er b e pr ot ect e d b y f e d er al or 
st at e pri v ac y l a ws;  
•  
T h e i n f or m ati o n c oll ect e d a b o ut t h e r es e arc h st u d y will b e k e pt s e p ar at e fr o m t h e s u bj ect’s 
m e dic al  r ec or ds,  b ut  t h e  s u bj ect will  b e  a bl e  t o  o bt ai n  t h e  r es e arc h  r ec or ds  aft er  t h e  
c o ncl usi o n of t h e st u d y; 
•  
W h et h er t h e a ut h oriz ati o n c o nt ai ns a n e x pir ati o n d at e; a n d  
•  
T h e ri g hts of a r es e arc h s u bj ect t o r e v o k e his or h er a ut h ori z ati o n.  
I n t h e e v e nt t h at a s u bj ect r e v o k es a ut h ori z ati o n t o c oll ect or us e his or h er P HI, t h e i n v esti g at or, b y 
r e g ul ati o n, r et ai ns t h e a bilit y t o us e all i nf or m ati o n c oll ect e d pri or t o t h e r e v oc ati o n of s u bj ect 
a ut h ori z ati o n.  F or s u bj ects t h at h a v e r e v o k e d a ut h ori z ati o n t o c oll ect or us e P HI, att e m pts s h o ul d b e 


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m a d e t o o bt ai n p er missi o n t o c oll ect at l e ast vit al st at us (i. e., t h at t h e s u bj ect is ali v e) at t h e e n d of 
t h eir sc h e d ul e d st u d y p eri o d. 
I n c o m pli a nc e wit h I C H G C P g ui d eli n es a n d a p plic a bl e p arts of 2 1 C F R it is a r e q uir e m e nt t h at t h e 
i n v esti g at or  a n d  i nstit uti o n  p er mit  a ut h ori z e d  r e pr es e nt ati v es  of  t h e  S p o ns or,  t h e  r e g ul at or y  
a ut h oriti es a n d t h e I R B dir ect acc ess t o r e vi e w t h e s u bj ect’s ori gi n al m e dic al r ec or ds at t h e sit e f or 
v erific ati o n of st u d y-r el at e d pr oc e d ur es a n d d at a.  
M e as ur es t o pr ot ect c o nfi d e nti alit y i ncl u d e: o nl y a u ni q u e st u d y n u m b er a n d i niti als will i d e ntif y 
s u bj ects o n t h e e C R F or ot h er d oc u m e nts s u b mitt e d t o t h e S p o ns or.  T his i nf or m ati o n, t o g et h er wit h 
t h e s u bj ect’s d at e of birt h, will b e us e d i n t h e d at a b as e f or s u bj ect i d e ntific ati o n. S u bj ect  n a m es or 
a d dr ess es will n ot b e e nt er e d i n t h e e C R F or d at a b as e. N o m at eri al b e ari n g a s u bj ect’s n a m e will b e 
k e pt o n fil e b y t h e S p o ns or. S u bj ect s will b e i nf or m e d of t h eir ri g hts wit hi n t h e I C F.  
1 2. 6  I N V E S TI G A T O R A N D S T A F F I N F O R M A TI O N 
P ers o n al d at a of t h e i n v esti g at ors a n d s u b -i n v esti g at ors m a y b e i ncl u d e d i n t h e S p o ns or d at a b as e, 
a n d s h all b e tr e at e d i n c o m pli a nc e wit h all a p plic a bl e l a ws a n d r e g ul ati o ns.  W h e n arc hi vi n g or 
pr oc essi n g p ers o n al d at a p ert ai ni n g t o t h e i n v esti g at or or s u b -i n v esti g at or, t h e S p o ns or s h all t a k e all 
a p pr o pri at e m e as ur es t o s af e g u ar d a n d pr e v e nt acc ess t o t his d at a b y a n y u n a ut h ori z e d p art y.  
1 2. 7  FI N A N CI A L I N F O R M A TI O N  
T h e fi n a nc es f or t his st u d y will b e s u bj ect t o a s e p ar at e writt e n a gr e e m e nt b et w e e n t h e S p o ns or a n d 
a p plic a bl e p arti es.  A n y I n v esti g at or fi n a nci al discl os ur es as a p plic a bl e t o 2 1 C F R P art 5 4 s h all b e 
a p pr o pri at el y pr o vi d e d.  


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1 3  R E C O R D R E T E N TI O N A N D  D O C U M E N T A TI O N O F T H E S T U D Y  
1 3. 1  D O C U M E N T A TI O N R E Q UI R E D T O I NI TI A T E S T U D Y  
B ef or e t h e st u d y m a y b e gi n, d oc u m e nt ati o n r e q uir e d b y F D A r e g ul ati o ns a n d / or l oc al r e g ul at or y 
a ut h oriti es m ust b e pr o vi d e d b y t h e I n v esti g at or.  T h e r e q uir e d d oc u m e nt a ti o n s h o ul d b e s u b mitt e d 
t o t h e S p o ns or. 
D oc u m e nts at a mi ni m u m r e q uir e d t o b e gi n t h e st u d y i ncl u d e, b ut ar e n ot li mit e d t o, t h e f oll o wi n g: 
•  
A si g n at ur e -a ut h ori z e d pr ot oc ol a n d c o ntr act;  
•  
A c o p y of t h e offici al I R B a p pr o v al of t h e st u d y a n d t h e I R B m e m b ers list;  
•  
C urr e nt C urric ul a Vit a e f or t h e pri nci p al i n v esti g at or a n d a n y ass oci at e i n v esti g at or(s) w h o 
will b e i n v ol v e d i n t h e st u d y; 
•  
I n dic ati o n of a p pr o pri at e accr e dit ati o n f or a n y l a b or at ori es t o b e us e d i n t h e st u d y a n d a c o p y 
of t h e n o r m al r a n g es f or t ests t o b e p erf or m e d b y t h at l a b or at or y;  
•  
Ori gi n al F or m F D A 1 5 7 2 ( St at e m e nt of I n v esti g at or), a p pr o pri at el y c o m pl et e d a n d si g n e d;  
•  
A c o p y of t h e I R B -a p pr o v e d c o ns e nt f or m c o nt ai ni n g p er missi o n f or a u dit b y r e pr es e nt ati v es 
of t h e S p o ns or, t h e  I R B, a n d t h e F D A;  
•  
Fi n a nci al discl os ur e f or ms f or all i n v esti g at ors list e d o n F or m F D A 1 5 7 2;  
•  
G C P C ertific at e f or st u d y tr ai ni n g; 
•  
Sit e q u alific ati o n r e p orts, w h er e a p plic a bl e;  
•  
V erific ati o n of Pri nci p al I n v esti g at or acc e pt a bilit y fr o m l oc al a n d / or n ati o n al d e b ar m e nt 
list(s). 
T h e S p o ns or / S p o ns or d esi g n e e will e ns ur e t h at all d oc u m e nt ati o n t h at is r e q uir e d t o b e i n pl ac e 
b ef or e t h e st u d y m a y st art, i n acc or d a nc e wit h I C H E 6 a n d S p o ns or S O Ps, will b e a v ail a bl e b ef or e a n y 
st u d y sit es ar e i niti at e d. 
1 3. 2  S T U D Y  D O C U M E N T A TI O N A N D S T O R A G E  
T h e PI m ust m ai nt ai n a list of a p pr o pri at el y q u alifi e d p ers o ns t o w h o m h e /s h e h as d el e g at e d st u d y 
d uti es a n d s h o ul d e ns ur e t h at all p ers o ns assisti n g i n t h e c o n d uct of t h e st u d y ar e i nf or m e d of t h eir 
o bli g ati o ns. All p ers o ns a ut h ori z e d t o m a k e e ntri es a n d / or c orr ecti o ns o n t h e e C R Fs ar e t o b e 
i ncl u d e d  o n  t his  d oc u m e nt.  All  e ntri es  i n  t h e  s u bj ect’s e C R F  ar e  t o  b e  s u p p ort e d  b y  s o urc e  
d oc u m e nt ati o n w h er e a p pr o pri at e.  
S o urc e d oc u m e nts ar e t h e ori gi n al d oc u m e nts, d at a, r ec or ds a n d c ertifi e d c o pi es of ori gi n al r ec or ds 
of cli nic al fi n di n gs, o bs er v ati o ns a n d acti viti es fr o m w hic h t h e s u bj ect’s e C R F d at a ar e o bt ai n e d. 
T h es e c a n i ncl u d e, b ut ar e n ot li mit e d t o, h os pit al r ec or ds, cli nic al a n d offic e c h arts, l a b or at or y, 
m e dic o -t ec h nic al d e p art m e nt a n d p h ar m ac y r ec or ds, di ari es, micr ofic h es, E K G tr ac es, c o pi es or 


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tr a nscri pti o ns c ertifi e d aft er v erific ati o n as b ei n g acc ur at e a n d c o m pl et e, p h ot o gr a p hic n e g ati v es, 
micr ofil m or m a g n etic m e di a, X -r a ys, a n d c orr es p o n d e nc e. 
T h e PI a n d st u d y st aff ar e r es p o nsi bl e f or m ai nt ai ni n g a c o m pr e h e nsi v e a n d c e ntr ali z e d fili n g s yst e m 
( Sit e St u d y  Fil e / S S F or I S F) of all st u d y-r el at e d ( ess e nti al) d oc u m e nt ati o n, s uit a bl e f or i ns p ecti o n at 
a n y ti m e b y r e pr es e nt ati v es fr o m t h e S p o ns or a n d / or a p plic a bl e r e g ul at or y a ut h oriti es.  T h e I S F / S S F 
m ust c o nsist of t h os e d oc u m e nts t h at i n di vi d u all y or c oll ecti v el y p er mit e v al u ati o n of t h e c o n d uct of 
t h e st u d y a n d t h e q u alit y of t h e d at a pr o d uc e d.  T h e I S F / S S F s h o ul d c o nt ai n as a mi ni m u m all r el e v a nt 
d oc u m e nts a n d c orr es p o n d e nc e as o utli n e d i n I C H G C P S ecti o n 1 3 a n d 2 1 C F R P art 3 1 2. 5 7, i ncl u di n g 
k e y d oc u m e nts s uc h as t h e I B a n d a n y a m e n d m e nts,  pr ot oc ol a n d a n y a m e n d m e nts, si g n e d I C Fs, I R B 
a p pr o v al  d oc u m e nts,  Fi n a nci al  Discl os ur e  f or ms,  s u bj ect i d e ntific ati o n  lists,  e nr oll m e nt  l o gs,  
d el e g ati o n of a ut h orit y l o g, st aff q u alific ati o n d oc u m e nts, l a b or at or y n or m al r a n g es, r ec or ds r el ati n g 
t o  t h e  st u dy dr u g  i ncl u di n g  acc o u nt a bilit y  r ec or ds.   Dr u g  acc o u nt a bilit y  r ec or ds  s h o ul d,  at  a  
mi ni m u m, c o nt ai n i nf or m ati o n r e g ar di n g r ec ei pt, s hi p m e nt, a n d dis p ositi o n.  E ac h f or m of dr u g 
acc o u nt a bilit y r ec or d, at a mi ni m u m, s h o ul d c o nt ai n PI n a m e, d at e dr u g s hi p p e d /r ec ei v e d, d at e, 
q u a ntit y a n d b atc h /c o d e, or l ot n u m b er f or i d e ntit y of e ac h s hi p m e nt.  I n a d diti o n, all ori gi n al s o urc e 
d oc u m e nts s u p p orti n g e ntri es i n t h e e C R F m ust b e m ai nt ai n e d a n d b e r e a dil y a v ail a bl e.  
T h e S p o ns or s h all m ai nt ai n a d e q u at e i n v esti g ati o n a l pr o d uct r ec or ds a n d fi n a nci al i nt er est r ec or ds 
as p er 2 1 C F R P art 5 4. 6 a n d P art 3 1 2. 5 7 f or n o l ess t h a n 2 y e ars aft er t h e l ast m ar k eti n g a p plic ati o n 
h as b e e n a p pr o v e d b y F D A; or, i n t h e e v e nt t h at t h e m ar k eti n g a p plic ati o n h as n ot b e e n a p pr o v e d b y 
F D A, f or n o l ess t h a n 2 y e ars aft er t h e l ast s hi p m e nt / d eli v er y of t h e dr u g f or i n v esti g ati o n al us e is 
disc o nti n u e d a n d F D A h as b e e n n otifi e d of t h e disc o nti n u ati o n.  
T h e I R B s h all m ai nt ai n a d e q u at e d oc u m e nt ati o n /r ec or ds of I R B acti viti es as p er 2 1 C F R P art  5 6. 1 1 5 
for at l e ast 3 y e ars aft er c o m pl eti o n of t h e r es e arc h.  
T h e I n v esti g at or s h all m ai nt ai n a d e q u at e r ec or ds of dr u g dis p ositi o n, c as e hist ori es a n d a n y ot h er 
st u d y-r el at e d r ec or ds as p er 2 1 C F R P art 3 1 2. 6 2 f or n o l ess t h a n 2 y e ars aft er t h e l ast m ar k eti n g 
a p pli c ati o n h as b e e n a p pr o v e d b y F D A; or, i n t h e e v e nt t h at t h e m ar k eti n g a p plic ati o n h as n ot b e e n 
a p pr o v e d b y F D A, f or n o l ess t h a n 2 y e ars aft er t h e l ast s hi p m e nt / d eli v er y of t h e dr u g f or 
i n v esti g ati o n al us e is disc o nti n u e d a n d F D A h as b e e n n otifi e d of t h e disc o nti n u ati o n.  
T o  e n a bl e  e v al u ati o ns  a n d / or  a u dits  fr o m  r e g ul at or y  a ut h oriti es  or  fr o m  t h e  S p o ns or  or  its  
r e pr es e nt ati v e, t h e i n v esti g at or a d diti o n all y a gr e es t o k e e p r ec or ds, i ncl u di n g t h e i d e ntit y of all 
p artici p ati n g s u bj ects (s uffici e nt i nf or m ati o n to li n k r ec or ds e. g., m e dic al r ec or ds), all ori gi n al, si g n e d 
i nf or m e d c o ns e nt f or ms, a n d c o pi es of all e C R Fs, S A E R e p orti n g f or ms, s o urc e d oc u m e nts, d et ail e d 
r ec or ds of tr e at m e nt dis p ositi o n, a n d r el at e d ess e nti al r e g ul at or y d oc u m e nts.   T h e d oc u m e nts list e d  
a b o v e m ust b e r et ai n e d b y t h e i n v esti g at or f or as l o n g as n e e d e d t o c o m pl y wit h n ati o n al a n d 
i nt er n ati o n al r e g ul ati o ns ( g e n er all y 2 y e ars aft er disc o nti n ui n g cli nic al d e v el o p m e nt or aft er t h e l ast 
m ar k eti n g a p pr o v al).   T h e S p o ns or or its r e pr es e nt ati v e will n otif y t h e i n v esti g at or(s) /i nstit uti o ns(s) 
w h e n t h e st u d y-r el at e d r ec or ds ar e n o l o n g er r e q uir e d.   
If t h e i n v esti g at or r el oc at es, r etir es, or f or a n y r e as o n wit h dr a ws fr o m t h e st u d y, eit h er t h e S p o ns or 
or its r e pr es e nt ati v e s h o ul d b e pr os p ecti v el y n oti fi e d.  T h e st u d y r ec or ds m ust b e tr a nsf err e d t o a n 
acc e pt a bl e  d esi g n e e,  s uc h  as  a n ot h er  i n v esti g at or,  a n ot h er  i nstit uti o n,  or  t o  s p o ns or.   T h e  
i n v esti g at or m ust o bt ai n t h e s p o ns or writt e n p er missi o n b ef or e dis p osi n g of a n y r ec or ds, e v e n if 


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r et e nti o n r e q uir e m e nts h a v e b e e n m et.  All st u d y fil es will b e m ai nt ai n e d b y t h e S p o ns or or its 
r e pr es e nt ati v e t hr o u g h o ut t h e st u d y, a n d will b e tr a nsf err e d t o t h e S p o ns or at t h e c o ncl usi o n of t h e 
st u d y. 
1 3. 3  D A T A C O L L E C TI O N  
T h e st u d y eC R F is t h e pri m ar y d at a c oll ecti o n i nstr u m e nt f or t h e st u d y. An el ectr o nic  c as e r e p ort 
f or m will b e utili z e d f or t h e c oll ecti o n of all d at a a n d all d at a will b e e nt er e d usi n g t h e E n glis h 
l a n g u a g e a n d s h o ul d b e k e pt c urr e nt t o e n a bl e t h e m o nit or t o r e vi e w t h e s u bj ects’ st at us t hr o u g h o ut 
t h e c o urs e of t h e st u d y. 
I n or d er t o m ai nt ai n c o nfi d e nti alit y, o nl y st u d y n u m b er, s u bj ect n u m b er, i niti als a n d d at e of birt h will 
i d e ntif y t h e s u bj ect i n t h e e C R F.  If t h e s u bj ect’s n a m e a p p e ars o n a n y ot h er d oc u m e nt ( e. g.  l a b or at or y 
r e p ort), it m ust b e o blit er at e d o n t h e c o p y of t h e d oc u m e nt t o b e s u p pli e d t o t h e i n v esti g at or sit e a n d 
r e pl ac e d i nst e a d wit h t h e s u bj ect n u m b er a n d s u bj ect’s i niti als.  T h e i n v esti g at or will m ai nt ai n a 
p ers o n al s u bj ect i d e ntific ati o n list (s u bj ect n u m b ers wit h c orr es p o n di n g s u bj ect i d e ntifi ers) t o 
e n a bl e r ec or ds t o b e i d e ntifi e d a n d v erifi e d as a ut h e ntic. S u bj ect  d at a /i nf or m ati o n will b e k e pt 
c o nfi d e nti al, a n d will b e m a n a g e d acc or di n g t o a p plic a bl e l oc al, st at e, a n d f e d er al r e g ul ati o ns.  
1 3. 4  S T U D Y  M O NI T O RI N G, A U DI TI N G, A N D I N S P E C TI N G  
T h e  i n v esti g at or will p er mit st u d y-r el at e d m o nit ori n g, q u alit y a u dits, a n d i ns p ecti o ns b y g o v er n m e nt 
r e g ul at or y a ut h oriti es, t h e S p o ns or or its r e pr es e nt ati v e(s) of all st u d y-r el at e d d oc u m e nts ( e. g., 
s o urc e d oc u m e nts, r e g ul at or y d oc u m e nts, d at a c oll ecti o n i ns tr u m e nts, c as e r e p ort f or ms).  T h e 
i n v esti g at or will e ns ur e t h e c a p a bilit y f or i ns p ecti o ns of a p plic a bl e st u d y-r el at e d f aciliti es.  T h e 
i n v esti g at or will e ns ur e t h at t h e st u d y m o nit or or a n y ot h er c o m pli a nc e or Q A r e vi e w er is gi v e n 
acc ess t o all st u d y-r el at e d d oc u m e nts a n d st u d y-r el at e d f aciliti es.   
P artici p ati o n as a n i n v esti g at or i n t his st u d y i m pli es t h e acc e pt a nc e of p ot e nti al i ns p ecti o n b y 
g o v er n m e nt r e g ul at or y a ut h oriti es  a n d  t h e s p o ns or or its r e pr es e nt ati v e(s).  
At t h e S p o ns or’s discr eti o n , S o urc e D oc u m e nt V erific ati o n ( S D V) m a y b e p erf or m e d o n all d at a it e ms 
or a p erc e nt a g e t h er e of.  
1 3. 5  Q U A LI T Y A S S U R A N C E A N D Q U A LI T Y C O N T R O L  
I n a d diti o n t o t h e Cli nic al M o nit ori n g c o m p o n e nt of t his pr ot oc ol, t h e S p o ns or’s Q u alit y Ass ur a nc e 
( Q A) d e p art m e nt s h all est a blis h a n A u diti n g Pl a n d oc u m e nt s e p ar at e fr o m t h e pr ot oc ol t o est a blis h 
t h e crit eri a b y w hic h i n d e p e n d e nt a u diti n g s h all b e c o n d ucte d d uri n g t h e c o n d uct of t h e st u d y t o 
ass ess c o m pli a nc e wit h G C P a n d a p plic a bl e r e g ul at or y r e q uir e m e nts.  D at a or d oc u m e nt ati o n a u dit e d 
s h all b e ass ess e d f or c o m pli a nc e t o t h e pr ot oc ol, acc ur ac y i n r el ati o n t o s o urc e d oc u m e nts a n d 
c o m pli a nc e t o a p plic a bl e r e g ul ati o ns. 
E ac h st u d y sit e s h all b e r e q uir e d t o h a v e St a n d ar d O p er ati n g Pr oc e d ur es ( S O P’s) t o d efi n e a n d e ns ur e 
q u alit y ass ur a nc e /c o ntr ol pr oc ess es f or st u d y c o n d uct, d at a g e n er ati o n & c oll ecti o n, r ec or di n g of 


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d at a / d oc u m e nt ati o n a n d r e p orti n g acc or di n g t o t h e pr ot oc ol, G C P a n d a n y a p plic a bl e l oc al, n ati o n al 
or i nt er n ati o n al r e g ul ati o ns.  
Acc ur at e a n d r eli a bl e d at a c oll ecti o n will b e e ns ur e d b y v erific ati o n a n d cr oss c h ec k of t h e e C R Fs 
a g ai nst t h e i n v esti g at or’s r ec or ds b y t h e st u d y m o nit or (s o urc e d oc u m e nt  v erific ati o n) a n d b y t h e 
m ai nt e n a nc e of a dr u g – dis p e nsi n g l o g b y t h e i n v esti g at or.  C oll ect e d d at a will b e e nt er e d i nt o a 
c o m p ut er d at a b as e a n d s u bj ect t o el ectr o nic a n d m a n u al q u alit y ass ur a nc e pr oc e d ur es.  
As t his is a n o p e n -l a b el st u d y, t o pr ot ect d at a i nt e grit y, t h e f oll o wi n g pr oc e d ur es will b e i m pl e m e nt e d 
t o e ns ur e all cli nic al a n d st atistic al d ecisi o ns ar e m a d e i n a tr e at m e nt bli n d e d m a n n er. T h e S p o ns or, 
e xc e pt f or Cli nic al O p er ati o ns p ers o n n el m o nit ori n g t h e st u d y a n d t h e M e dic al M o nit or, will b e 
bli n d e d t o cli nic al as p ects of t h e st u d y t h at p ert ai n t o t h e s u bj ect. T his i ncl u d es d osi n g d at a, d el a ys 
i n tr e at m e nt, etc.  I n a d diti o n, u n bli n d e d Cli nic al O p er ati o ns p ers o n n el will n ot b e i n v ol v e d i n a n y 
disc ussi o ns r e g ar di n g t h e a n al ysis of d at a aft er e nr ol l m e nt of t h e first s u bj ect i nt o t h e tri al or a n y 
pr ot oc ol a m e n d m e nt, e xc e pt t h os e r el at e d t o s af et y.  
1 3. 6  DI S C L O S U R E A N D P U B LI C A TI O N P O LI C Y  
All i nf or m ati o n pr o vi d e d r e g ar di n g t h e st u d y, as w ell as all i nf or m ati o n c oll ect e d / d oc u m e nt e d 
d uri n g t h e c o urs e of t h e st u d y, will b e r e g ar d e d as c o nfi d e nti al.  T h e S p o ns or r es er v es t h e ri g ht t o 
r el e as e lit er at ur e p u blic ati o ns b as e d o n t h e r es ults of t h e st u d y. 
A cli nic al st u d y r e p ort will b e pr e p ar e d u p o n c o m pl eti o n of t h e st u d y.  T h e S p o ns or will discl os e t h e 
st u d y r es ults, i n t h e f or m of a cli nic al st u d y r e p ort s y n o psis, t o t h e I E C a n d t h e a p plic a bl e r e g ul at or y 
a ut h oriti es wit hi n o n e y e ar of t h e e n d of t h e st u d y.  T h e f or m at of t his s y n o psis a n d t h at of t h e cli nic al 
st u d y r e p ort a n d its a d d e n d u m will c o m pl y wit h I C H E 3 g ui d eli n es f or str uct ur e a n d c o nt e nt of a 
cli nic al st u d y r e p ort. 
T h e fi n a nci al discl os ur e i nf or m ati o n will b e pr o vi d e d t o t h e S p o ns or pri or t o st u d y p artici p ati o n fr o m 
all PIs a n d S u b -I n v esti g at ors w h o ar e i n v ol v e d i n t h e st u d y a n d n a m e d o n t h e F D A 1 5 7 2 f or m.  
B y c o n d ucti n g t his st u d y, t h e I n v esti g at or affir ms t o t h e S p o ns or t h at h e or s h e will m ai nt ai n, i n strict 
c o nfi d e nc e, i nf or m ati o n f ur nis h e d b y t h e S p o ns or i ncl u di n g d at a g e n er at e d fr o m t his st u d y a n d 
pr eli mi n ar y l a b or at or y r es ults, e xc e pt as e x e m pt e d f o r r e g ul at or y p ur p os es.  
All d at a g e n er at e d d uri n g t h e c o n d uct of t his st u d y is o w n e d b y t h e S p o ns or a n d m a y n ot b e us e d b y 
t h e I n v esti g at or or affili at es wit h o ut t h e e x pr ess e d writt e n c o ns e nt of t h e S p o ns or. 
All m a n uscri pts, a bstr acts, or ot h er pr es e nt ati o n m at eri als g e n er at e d b y sit e i n v esti g at ors m ust b e 
r e vi e w e d a n d a p pr o v e d b y t h e S p o ns or pri or t o s u b missi o n.  


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1 4  R E F E R E N C E S  
 
Alt e kr us e S F, K. C. ( 2 0 1 0, N o v e m b er). S E E R C a nc er St atistics R e vi e w . R etri e v e d fr o m s e er.c a ncer. g o v: 
htt p: / /s e er.c a nc er. g o v /csr / 1 9 7 5. 2 0 0 7  
A m eric a n  C a nc er  S oci et y.  ( 2 0 1 5 ). A m eric a n  C a nc er  S oci et y.  R etri e v e d  J u n e  5,  2 0 1 5 ,  fr o m  
w w w.c a nc er. or g: 
htt p: / / w w w.c a nc er. or g / acs / gr o u ps /c o nt e nt / @r es e arc h / d oc u m e nts / w e bc o nt e nt / acs pc -
0 4 2 1 5 1. p df  
C a zi n B, L. S. ( 2 0 1 3). Fi n al r es ults of a m ultic e nt er p h as e I b si n gl e a g e nt st u d y wit h t h e n o v el a nti -
C D 2 0  m o n ocl o n al  a nti b o d y  u blit u xi m a b  ( T G -1 1 0 1)  i n  p ati e nts  wit h  r el a ps e d  c hr o nic  
l y m p h oc ytic l e u k e mi a ( C L L). E ur o p e a n H e m at ol o g y Ass oc ati o n , ( p. a bstr act P 1 1 1). St oc k h ol m. 
C h es o n, B. D., Pfist n er, B., J u w ei d, M. E., G asc o y n e, R. D., S p ec ht, L., H or ni n g, S. J., . . . Di e hl, V. ( 2 0 0 7). 
R e vis e d r es p o ns e crit eri a f or m ali g n a nt l y m p h o m a. J o ur n al of Cli nic al O nc ol o g y, 2 5( 5), 5 7 9-
5 8 6. d oi: 1 0. 1 2 0 0 /J C O. 2 0 0 6. 0 9. 2 4 0 3  
 
C h es o n, B. C., Fis h er, R.I., B arri n gt o n, S. F., C a v alli, F., Sc h w art z, L. H., Z ucc a, E., List er, T. A. ( 2 0 1 4). 
R ec o m m e n d ati o ns f or i niti al e v al u ati o n, st a gi n g, a n d r es p o ns e ass ess m e nt of H o d g ki n a n d 
N o n -h o d g ki n l y m p h o m a: T h e L u g a n o cl assific ati o n. J o ur n al of Cli nic al O nc ol o g y, 3 2, ( 1 -1 0). 
d oi: 1 0. 1 2 0 0 /J C O. 2 0 1 3. 5 4. 8 9 0 0  
 
d e R o m e uf C, D. C. -T. -B. ( 2 0 0 8). C hr o nic l y m p h oc ytic l e u k a e mi a c ells ar e eff eci e ntl y kill e d b y a n a nti -
C D 2 0  m o n ocl o n al  a nti b o d y  s el ect e d  f or  i m pr o v e d  e n g a g e m e nt  of  Fc g a m m a RIII A / C D 1 6.  
Britis h J o ur n al of H a e m at ol o g y, 6 ( 1 4 0), 6 3 5-6 4 3.  
Est e v es I T, D. C. ( 2 0 1 1). L F B -R 6 0 3 ( u blit u xi m a b), a t hir d -g e n er ati o n m o n ocl o n al a nti -C D 2 0 a nti b o d y, 
dis pl a ys a d diti v e a ntit u m or acti vit y wit h a ntil e u k e mic c h e m ot h er p e utic a g e nts i n m o us e 
x e n o gr aft m o d els. A m eric a n S oci e t y of H e m at ol o g y, a bstr act 1 6 6 0. 
G e n e nt ec h  I nc.  ( 2 0 1 3,  S e pt e m b er).  Rit u x a n  (rit u xi m a b)  Pr escri bi n g  I nf or m ati o n.  S o ut h  S a n  
Fr a ncisc o, C A.  
H all e k M, C. B. -C. ( 2 0 0 8). G ui d eli n es f or t h e di a g n osis a n d tr e at m e nt of c hr o nic l y m p h oc ytic l e u k e mi a: 
a r e p ort fr o m t h e I nt er n ati o n al Wr o ks h o p o n C hr o nic L y m p h oc ytic L e u k e mi a u p d ati n g t h e 
N ati o n al C a nc er I nstit u e - Wr o ki n g Gr o u p 1 9 9 6 G ui d eli n es. bl o o d, 1 2 ( 1 1 1), 5 4 4 6-5 4 5 6.  
Li n K, S. P. ( 2 0 0 2). R el ati o ns hi p b et w e e n p 5 3 d ysf u ncti o n, C D 3 8 e x pr essi o n a n d I g V H m ut ati n i n 
c hr o ni c l y m p hc ytic l e u k e mi a. bl o o d , 1 4 0 4. 
L u n ni n g  M, V os e J, F o wl er N, N ast o u pil L ….. O' Bri e n S. ( 2 0 1 5). U blit u xi m a b + T G R -1 2 0 2 d e m o nstr at es 
acti vit y a n d a f a v or a bl e s af et y pr ofil e i n r el a ps e d /r efr act or y B -c ell N H L a n d hi g h -ris k C L L: P h as e I 
R es ults. A S C O A n n u al M e eti n g a n d Ex p ositi o n , Orl a n d o, F L.  
 


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O' C o n n or O A, D. C. ( 2 0 1 4). A p h as e I tri al of u blit u xi m a b ( T G -1 1 0 1), a n o v el a nti -C D 2 0 m o n ocl o n al 
a nti b o d y ( M A B) i n B -c ell l y m p h o m a p ati e nts wit h pri or e x p os ur e t o rit u xi m a b. A m eric a n 
S oci et y of Cli nic al O nc ol o gy , ( p. a bstr act 8 5 2 4). C hic a g o.  
 ( 2 0 1 1). PI 3 K g a m m a e nz y m e ass a y.  S h a m e er p et, I n di a: I nc o z e n T h er a p e utics.  
 ( 2 0 1 1). A K T p h os p h or yl ati o n i n M O L T -4 c ells. J u n e St u d y R e p ort I V T -5 2 6 4 -A P M -1 0.  
S h a m e er p et, I n di a: I nc o z e n T h er a p e uticis P V T  Lt d.  
 ( 2 0 1 1). A K T p h os p h or yl ati o n i n T H P -1 c ells. St u d y R e p ort I V T -5 2 6 4 -A T P -0 8.  S h a m e er p et, 
I n di a: I nc o z e n T h er a p e uticis P V T Lt d. 
S olal -Celi g n y P, R o y P, C ol o m bat P, W hite J,  Ar mita ge J O, Arra nz -Saez R,  A u W Y, et al. F ollic ular  L y m p h o m a 
I nter nati o nal Pr o g n ostic I n de x. Bl o o d. 2 0 0 4; ( 1 0 4) 5: 1 2 5 8-6 5.  
T h er a p e utics, T. ( 2 0 1 7 ). U blit u xi m a b ( T G-1 1 0 1)  a n d T G R -1 2 0 2  I n v esti g at or's Br oc h ur e ( V ol. V ersi o n 
5 . 0). 
 
 


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1 5   A P P E N DI X A – E C O G P E R F O R M A N C E S T A T U S S C A L E  
 
 
 
E C O G P erf or m a nce St at us Sc ale  
Gr a de  
Descri pti o ns  
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 nce 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 nat 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 ble 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  
 


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1 6  A P P E N DI X B - C O N T R A C E P TI O N G UI D E L I N E S A N D P R E G N A N C Y  
 
 
W o m e n N ot of C hil d b e ari n g P ot e nti al ar e D efi n e d as  F oll o ws: 
W o m e n   ar e c o nsi d er e d p ost -m e n o p a us al  a n d  n ot  of  c hil d b e ari n g  p ot e nti al  if t h e y h a v e  h a d  
1 2 m o nt hs of n at ur al (s p o nt a n e o us) a m e n orr h e a wit h a n a p pr o pri at e cli nic al pr ofil e ( e. g.  a g e 
a p pr o pri at e,  hist or y  of  v as o m ot or  s y m pt o ms) or  si x m o nt hs  of  s p o nt a n e o us a m e n orr h e a  wit h  
s er u m F S H l e v els  > 4 0  mI U / m L  a n d  estr a di ol   < 2 0  p g / m L]  or  h a v e  h a d  s ur gic al bil at er al 
o o p h or ect o m y  ( wit h  or  wit h o ut  h yst er ect o m y)  at  l e ast  si x  w e e ks  a g o.  I n  t h e  c as e  of  
o o p h or ect o m y  al o n e,  o nl y  w h e n  t h e  r e pr o d ucti v e st at us of  t h e w o m a n  h as  b e e n  c o nfir m e d b y  
f oll o w u p  h or m o n e l e v el ass ess m e nt is s h e c o nsi d er e d n ot of c hil d b e ari n g  p ot e nti al.  
 
C o ntr ac e pti v e G ui d eli n es f or W o m e n of C hil d -B e ari n g  P ot e nti al:  
W o m e n of c hil d-b e ari n g p ot e nti al, d efi n e d as all w o m e n p h ysi ol o gic all y c a p a bl e of  b ec o mi n g 
pr e g n a nt,  m ust  us e  eff ecti v e  c o ntr ac e pti o n d uri n g  t h e st u d y a n d  f or  4 m o nt hs  aft er  t h e l a st 
d o s e of eit h e r st u d y t r e at m e nt. Eff ecti v e c o ntr ac e pti o n is d efi n e d as  eit h er:  
1.  Tr u e a bsti n e nc e:  W h e n  t his is i n li n e wit h  t h e  pr ef err e d a n d  us u al   lif est yl e of  t h e 
s u bj ect.  P eri o dic  a bsti n e nc e  ( e. g.,  c al e n d ar,  o v ul ati o n,  s y m pt ot h er m al,  p ost-o v ul ati o n 
m et h o ds)  a n d wit h dr a w al ar e n ot acc e pt a bl e m et h o ds of  c o ntr ac e pti o n. 
2.  St erili z ati o n: h a v e h a d s ur gic al bil at er al o o p h or ect o m y ( wit h or wit h o ut h yst er ect o m y)  
or t u b al li g ati o n at l e ast si x w e e ks a g o. I n c as e of o o p h or ect o m y al o n e, o nl y w h e n  t h e 
r e pr o d ucti v e st at us of  t h e w o m a n  h as  b e e n  c o nfir m e d b y  f oll o w u p  h or m o n e  l e v el 
ass ess m e nt.  
3.  M al e p art n e r st eriliz ati o n ( wit h t h e a p pr o pri at e p ost-v as ect o m y d oc u m e nt ati o n of  t h e 
a bs e nc e of s p er m i n t h e ej ac ul at e). F or f e m al e s u bj ects o n t h e st u d y, t h e v as ect o mis e d  
m al e p art n er s h o ul d b e t h e s ol e p art n er f or t h at  s u bj ect. 
4.  Or al c o ntr ac e pti o n, i nj ect e d or i m pl a nt e d h or m o n al m et h o ds.  
5.  Us e of a c o m bi n ati o n of a n y t w o of t h e f oll o wi n g  ( a + b): 
a.  Pl ac e m e nt of a n i ntr a ut eri n e d e vic e (I U D) or i ntr a ut eri n e s yst e m  (I U S). 
b.  B arri er m et h o ds of c o ntr ac e pti o n: C o n d o m or Occl usi v e c a p ( di a p hr a g m   or 
c er vic al / v a ult c a ps) wit h s p er mici d al f o a m / g el /fil m /cr e a m / v a gi n al  
s u p p osit or y. 
T h e f oll o wi n g ar e u n a c c e pt a bl e f or ms of c o ntr ac e pti o n f or w o m e n of c hil d b e ari n g p ot e nti al:  
•  
F e m al e  c o n d o m 
•  
N at ur al f a mil y pl a n ni n g (r h yt h m m et h o d) or  br e astf e e di n g  
•  
F ertilit y  a w ar e n ess  
•  
Wit h dr a w al 
•  
C er vic al  s hi el d 


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W o m e n  of  c hil d-b e ari n g  p ot e nti al  m ust  h a v e  a n e g ati v e  s er u m or  uri n e  pr e g n a nc y  t est ≤ 7 2  h o urs  
pri or t o i niti ati n g  tr e at m e nt. 
 
F ertil e M al es 
F ertil e m al es, d efi n e d as all m al es p h ysi ol o gic all y c a p a bl e of c o nc ei vi n g offs pri n g m ust us e  c o n d o m 
d uri n g tr e at m e nt a n d  f or 4 m o nt hs a ft er t h e l ast d os e of eit h er  st u d y tr e at m e nt. T h e y s h o ul d als o 
n ot f at h er a c hil d d uri n g  t his p eri o d. 
 
Pr e g n a nci es  
T o  e ns ur e  s u bj ect s af et y, e ac h  pr e g n a nc y  i n  a s u bj ect o n  st u d y tr e at m e nt m ust  b e   r e p ort e d t o 
T G T h er a p e utics  I nc. wit hi n  2 4  h o urs  of  l e ar ni n g of  its occ urr e nc e.  T h e  pr e g n a nc y  s h o ul d b e  
f oll o w e d u p f or 3 m o nt hs aft er t h e t er mi n ati o n of t h e pr e g n a nc y t o d et er mi n e o utc o m e, i ncl u di n g  
s p o nt a n e o us or v ol u nt ar y t er mi n ati o n, d et ails of t h e birt h, a n d t h e pr es e nc e or a bs e nc e of a n y birt h  
d ef ects, c o n g e nit al a b n or m aliti es, or m at er n al a n d / or n e w b or n  c o m plic ati o ns. 
Pr e g n a nc y  s h o ul d  b e  r ec or d e d  o n  a  Cli nic al  St u d y  Pr e g n a nc y  F or m  a n d  r e p ort e d  b y  t h e  
i n v esti g at or t o T G  T h er a p e utics  I nc. Pr e g n a nc y  f oll o w-u p  s h o ul d b e  r ec or d e d o n  t h e s a m e f or m 
a n d  s h o ul d i ncl u d e a n  ass ess m e nt  of  t h e p ossi bl e  r el ati o ns hi p t o t h e st u d y dr u g  a n d  r e p ort e d b y  
t h e i n v esti g at or t o T G  T h er a p e utics  I nc. A n y  S A E  e x p eri e nc e d  d uri n g  pr e g n a nc y  m ust  b e  r e p ort e d 
o n  t h e S A E  R e p ort F or m.  
Pr e g n a nc y o utc o m es m ust b e c oll ect e d f or t h e f e m al e p art n ers of a n y m al es w h o t o o k  st u d y 
tr e at m e nt i n t his st u d y. C o ns e nt t o r e p ort i nf or m ati o n r e g ar di n g t h es e pr e g n a nc y o utc o m es s h o ul d 
b e o bt ai n e d fr o m t h e  m ot h er.  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 7 8  of 8 5  
1 7  A P P E N DI X C – N E W Y O R K H E A R T A S S O CI A TI O N  
C L A S SI FI C A TI O N S  
 
 
Cl a s s  
F u n cti o n al  C a p a cit y  
O bj e cti v e  A s s e s s m e nt  
I 
P ati e nts wit h c ar di ac dis e as e b ut wit h o ut  r es ulti n g 
li mit ati o ns of p h ysic al acti vit y. Or di n ar y p h ysic al 
acti vit y d o es n ot c a us e u n d u e f ati g u e,  p al pit ati o n, 
d ys p n e a, or a n gi n al  p ai n.  
N o o bj ecti v e e vi d e nc e  of  
c ar di o v asc ul ar  dis e as e.  
II 
P ati e nts wit h c ar di ac dis e as e r es ulti n g i n  sli g ht 
li mit ati o n of p h ysic al acti vit y. T h e y ar e c o mf ort a bl e at 
r est. Or di n ar y p h ysic al acti vit y r es ults i n f ati g u e, 
p al pit ati o n, d ys p n e a, or a n gi n al  p ai n.  
O bj ecti v e e vi d e nc e  of 
mi ni m al  c ar di o v asc ul ar 
dis e as e.  
III 
P ati e nts wit h c ar di ac dis e as e r es ulti n g i n  m ar k e d 
li mit ati o n of p h ysic al acti vit y. T h e y ar e c o mf ort a bl e at 
r est. L ess t h a n or di n ar y acti vit y c a us es  f ati g u e, 
p al pit ati o n, d ys p n e a, or a n gi n al  p ai n.  
O bj ecti v e e vi d e nc e  of 
m o d er at el y s e v er e 
c ar di o v asc ul ar  dis e as e.  
I V 
P ati e nts wit h c ar di ac dis e as e r es ulti n g i n i n a bilit y  t o 
c arr y o n a n y p h ysic al acti vit y wit h o ut  disc o mf ort. 
S y m pt o ms  of  h e art  f ail ur e or  t h e a n gi n al  s y n dr o m e m a y 
b e pr es e nt e v e n at r est. If a n y p h ysic al acti vit y  is 
u n d ert a k e n, disc o mf ort is  i ncr e as e d. 
O bj ecti v e e vi d e nc e  of 
s e v er e c ar di o v asc ul ar 
dis e as e.  
S o urc e:  T h e  Crit eri a  C o m mitt e e  of  N e w  Y or k  H e art  Ass oci ati o n.  N o m e ncl at ur e  a n d  Crit eri a  f or 
Di a g n osis  of  Dis e as es  of  t h e H e art  a n d  Gr e at  V ess els.  9t h  E d.  B ost o n,  M A:  Littl e,  Br o w n  &  C o; 
1 9 9 4: 2 5 3 -2 5 6.  


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 7 9  of 8 5  
1 8  A P P E N DI X D – I N T E R N A TI O N A L W O R KI N G G R O U P R E VI S E D 
R E S P O N S E C RI T E RI A F O R M A LI G N A N T L Y M P H O M A  ( C H E S O N 
E T A L. 2 0 0 7 )  
 
C o m pl et e
 R e s p o n s e
 
( C R):  
T h e d esi g n ati o n of C R r e q uir es t h e f oll o wi n g:  
•  
C o m pl et e dis a p p e ar a nc e  of all d et ect a bl e cli nic al e vi d e nc e  
of dis e as e a n d dis e as e -r el at e d s y m pt o ms if pr es e nt b ef or e 
h er a p y.  
•  
T y pic all y F D G -a vi d l y m p h o m a: i n p ati e nts wit h n o 
pr etr e at m e nt  P E T sc a n or w h e n t h e P E T sc a n w as p ositi v e 
b ef or e t h er a p y, a  p ost -tr e at m e nt r esi d u al m ass of a n y si z e 
is p er mitt e d as l o n g as it is P E T n e g ati v e.  
•  
V ari a bl y F D G -a vi d l y m p h o m as / F D G a vi dit y u n k n o w n: i n 
p ati e nts  wit h o ut a pr etr e at m e nt P E T sc a n, or if a 
pr etr e at m e nt P E T sc a n  w as n e g ati v e, all l y m p h n o d es a n d 
n o d al m ass es m ust h a v e r e gr ess e d  o n C T t o n or m al si z e 
( ≤1. 5 c m i n t h eir gr e at est tr a ns v ers e di a m et er  f or n o d es 
> 1. 5 c m b ef or e t h er a p y). Pr e vi o usl y i n v ol v e d n o d es  t h at 
w er e 1. 1 t o 1. 5 c m i n t h eir l o n g a xis a n d m or e t h a n 1. 0
 c m 
i n t h eir s h ort a xis b ef or e tr e at m e nt m ust h a v e d ecr e as e d 
t o ≤1. 0 c m i n t heir s h ort a xis aft er tr e at m e nt.  
•  
T h e s pl e e n a n d / or li v er, if c o nsi d er e d e nl ar g e d b ef or e 
t h er a p y o n t h e b asis of a p h ysic al e x a mi n ati o n or C T sc a n, 
s h o ul d n ot  b e p al p a bl e o n p h ysic al e x a mi n ati o n a n d s h o ul d 
b e c o nsi d er e d  n or m al siz e b y i m a gi n g st u di es, a n d n o d ul es 
r el at e d t o l y m p h o m a  s h o ul d dis a p p e ar. H o w e v er, 
d et er mi n ati o n of s pl e nic i n v ol v e m e nt  is n ot al w a ys r eli a bl e 
b ec a us e a s pl e e n c o nsi d er e d n or m al i n  si z e m a y still 
c o nt ai n l y m p h o m a, w h er e as a n e nl ar g e d s pl e e n  m a y 
r efl ect v ari ati o ns i n a n at o m y, bl o o d v ol um e, t h e us e of
 
h e m at o p oi etic gr o wt h f act ors, or c a us es ot h er t h a n 
l y m p h o m a. 
•  
If t h e b o n e m arr o w w as i n v ol v e d b y l y m p h o m a b ef or e 
tr e at m e nt, t h e i nfiltr at e m ust h a v e cl e ar e d o n r e p e at b o n e 
m arr o w bi o ps y.
 T h e bi o ps y s a m pl e o n w hic h t his 
d et er mi n ati o n is m a d e m ust b e  a d e q u at e ( wit h a g o al of 
> 2 0 m m u nil at er al c or e). If t h e  s a m pl e is i n d et er mi n at e b y 
m or p h ol o g y, it s h o ul d b e n e g ati v e
 b y 
i m m u n o hist oc h e mistr y. A s a m pl e t h at is n e g ati v e b y 
i m m u n o hist oc h e mistr y b ut t h at d e m o nstr at es a s m all 
p o p ul ati o n of cl o n al l y m p h oc yt es  b y fl o w c yt o m etr y will b e 
c o nsi d er e d a C R u ntil d at a b ec o m e  a v ail a bl e 
d e m o nstr ati n g a cl e ar diff er e nc e i n p ati e nt o utc o m e.  
 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 8 0  of 8 5  
C o m pl et e 
R e s p o n s e / U n c o nfi r m e d 
( C R u): 
T h e  us e  of  t h e  a b o v e  d efi niti o n  f or  C R  a n d  t h os e  b el o w  f or  P R  
eli mi n at es t he c at e g or y of C R u.  
 
 
P a rti al
 R e s p o n s e
 
( P R):  
 
T h e d esi g n ati o n of P R r e q uir es all of t h e f oll o wi n g:  
•  
At l e ast  a 5 0 % d ecr e as e i n s u m of t h e pr o d uct of t h e 
di a m et ers  ( S P D) of u p t o si x of t h e l ar g est d o mi n a nt n o d es or 
n o d al m ass es.  T h es e n o d es or m ass es s h o ul d b e s el ect e d 
acc or di n g t o all of  t h e f oll o wi n g: t h e y s h o ul d b e cl e arl y 
m e as ur a bl e i n at l e ast
 2 p er p e n dic ul ar di m e nsi o ns; if 
p ossi bl e t h e y s h o ul d b e fr o m  dis p ar at e r e gi o ns of t h e b o d y; 
a n d t h e y s h o ul d i ncl u d e m e di asti n al  a n d r etr o p erit o n e al 
ar e as of dis e as e w h e n e v er  t h es e sit es ar e i n v ol v e d. 
•  
N o i ncr e as e s h o ul d b e o bs er v e d i n t h e siz e of ot h er  n o d es, 
li v er, or s pl e e n.  
•  
S pl e nic a n d h e p atic n o d ul es m ust  r e gr ess b y ≥5 0 % i n t h eir 
S P D  or, f or si n gl e n o d ul es, i n t h e  gr e at est tr a ns v ers e 
di a m et er. 
•  
Wit h t h e e xc e pti o n of s pl e nic
 a n d h e p atic n o d ul es, 
i n v ol v e m e nt of ot h er or g a ns is us u all y  ass ess a bl e a n d n o 
m e as ur a bl e dis e as e
 s h o ul d b e pr es e nt. 
•  
B o n e  m arr o w ass ess m e nt is irr el e v a nt f or d et er mi n ati o n of a
 
P R if  t h e s a m pl e w as p ositi v e b ef or e tr e at m e nt. H o w e v er, if 
p ositi v e,  t h e c ell t y p e s h o ul d b e s p ecifi e d ( e. g., l ar g e-c ell  
l y m p h o m a or s m all n e o pl astic B c ells). P ati e nts w h o ac hi e v e  a 
C R b y t h e  a b o v e crit eri a, b ut w h o h a v e p ersist e nt 
m or p h ol o gic
 b o n e m arr o w  i n v ol v e m e nt will b e c o nsi d er e d 
p arti al r es p o n d ers.   
W h e n t h e
 b o n e m arr o w w as i n v ol v e d b ef or e t h er a p y a n d a 
cli nic al  C R w as  ac hi e v e d, b ut wit h n o b o n e m arr o w 
ass ess m e nt aft er tr e at m e nt,  p ati e nts s h o ul d b e c o nsi d er e d 
p arti al r es p o n d ers.  
•  
N o n e w sit es  of dis e as e s h o ul d b e o bs er v e d.  
•  
T y pic all y F D G -a vi d l y m p h o m a:  f or p ati e nts wit h n o 
pr et r e at m e nt  P E T sc a n or if t h e P E T sc a n  w as p ositi v e b ef or e 
t h er a p y, t h e p ost -tr e at m e nt P E T s h o ul d b e p ositi v e i n at l e ast 
o n e pr e vi o usl y  i n v ol v e d sit e. 
•  
V ari a bl y  F D G -a vi d l y m p h o m as / F D G -a vi dit y u n k n o w n: f or 
p ati e nts  wit h o ut  a pr etr e at m e nt P E T sc a n, or if a 
pr e tr e at m e nt P E T sc a n w as n e g ati v e,  C T crit eri a s h o ul d b e 
us e d.  
 
I n p ati e nts wit h f ollic ul ar l y m p h o m a or m a ntl e-c ell l y m p h o m a, a P E T 
sc a n is o nl y i n dic at e d wit h o n e or at m ost t w o r esi d u al m ass es t h at h a v e 
r e gr ess e d b y m or e t h a n 5 0 % o n C T; t h os e wit h m or e t h an t w o r esi d u al 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 8 1  of 8 5  
l esi o ns ar e u nli k el y t o b e P E T n e g ati v e a n d s h o ul d b e c o nsi d er e d p arti al 
r es p o n d ers. 
 
St a bl e Di s e a s e ( S D):   
 
St a bl e dis e as e ( S D) is d efi n e d as t h e f oll o wi n g:  
•  
A p ati e nt is  c o nsi d er e d t o h a v e S D w h e n h e or s h e f ails t o 
att ai n  t h e crit eri a n e e d e d f or a C R or P R, b ut d o es n ot f ulfill 
t h os e f or pr o gr essi v e dis e as e (s e e R el a ps e d Dis e as e [ aft er 
C R] / Pr o gr essi v e  Dis e as e  [ aft er P R, S D]). 
•  
T y pic all y F G D -a vi d l y m p h o m as: t h e P E T s h o ul d  b e p ositi v e at  
pri or sit es of dis e as e wit h n o n e w ar e as of i n v ol v e m e nt  o n 
t h e p ost -tr e at m e nt C T or P E T. 
•  
V ari a bl y F D G -a vi d l y m p h o m as / F D G -a vi dit y  u n k n o w n: f or 
p ati e nts  wit h o ut a pr etr e at m e nt P E T sc a n or if  t h e 
pr etr e at m e nt P E T w as  n e g ati v e, t h er e m ust b e n o c h a n g e i n  
t h e si z e of t h e pr e vi o us l esi o ns o n t h e p ost-tr e at m e nt 
C T  sc a n. 
R el a p s e d Di s e a s e 
( aft e r C R) / 
P r o g r e s si v e Di s e a s e 
( aft e r P R, S D):   
 
L y m p h n o d es s h o ul d be c o nsi d er e d a b n or m al if t h e l o n g axis is m or e 
t h a n 1. 5 c m r e g ar dl ess of t h e s h ort axis. If a l y m p h n o d e h as a l o n g axis 
of 1. 1 t o 1. 5 c m, it s h o ul d o nl y b e c o nsi d er e d a b n or m al if its s h ort axis is 
m or e t h a n 1. 0. L y m p h n o d es ≤1. 0 x ≤1. 0 c m will n ot b e c o nsi d er e d as 
a b n or m al f or r el a ps e or pr o gr essi v e dis e as e.  
•  
A p p e ar a nc e of a n y n e w l esi o n m or e t h a n  1. 5 c m i n a n y a xis 
d uri n g  or at t h e e n d of t h er a p y, e v e n if  ot h er  l esi o ns ar e 
d ecr e asi n g  i n si z e. I ncr e as e d F D G u pt a k e i n a pr e vi o usl y 
u n aff ect e d sit e  s h o ul d o nl y b e c o nsi d er e d r el a ps e d  or 
pr o gr essi v e dis e as e aft er  c o nfir m ati o n wit h ot h er m o d aliti es.  
I n p ati e nts wit h n o pri or hist or y of p ul m o n ar y l y m p h o m a, 
n e w  l u n g n o d ul es i d e ntifi e d b y C T ar e m ostl y b e ni g n. T h us, a 
t h er a p e utic d ecisi o n s h o ul d n ot  b e m a d e s ol el y o n t h e b asis 
of t h e P E T wit h o ut  hist ol o gic c o nfir m ati o n.  
•  
At l e ast a 5 0 % i ncr e as e fr o m n a dir  i n t h e S P D of a n y 
pr e vi o usl y  i n v ol v e d n o d es, or i n a si n gl e i n v ol v e d n o d e, or t h e 
si z e of  ot h er l esi o ns ( e. g., s pl e nic or  h e p atic n o d ul es). T o b e 
c o nsi d er e d  pr o gr essi v e dis e as e, a l y m p h  n o d e wit h a 
di a m et er of t h e s h ort  a xis of l ess t h a n 1. 0 c m m ust  i ncr e as e 
b y 5 0 % a n d t o a si z e  of 1. 5 x 1. 5 c m or m or e t h a n  1. 5 c m i n 
t h e lo n g a xis.  
•  
At l e ast a 5 0 % i ncr e as e i n t h e l o n g est  di a m et er of a n y si n gl e  
pr e vi o usl y i d e ntifi e d n o d e m or e t h a n  1 c m i n its s h ort a xis.  
•  
L esi o ns s h o ul d b e P E T p ositi v e if  o bs er v e d i n a t y pic al 
F D G -a vi d  l y m p h o m a or t h e l esi o n w as P E T p ositi v e b ef or e 
t h er a p y u nless  t h e l esi o n is t o o s m all t o b e d et ect e d wit h 
c urr e nt P E T s yst e ms  ( < 1. 5 c m i n its l o n g a xis  b y C T).  
 
M e as ur a bl e extr a n o d al dis e as e s h o ul d b e ass ess e d i n a m a n n er si mil ar t o t h at f or n o d al dis e as e. F or 
t h es e r ec o m m e n d ati o ns, t h e s pl e e n is c o nsi d er e d n o d al dis e as e.  Dis e as e t h at is o nl y ass ess a bl e ( e. g., 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 8 2  of 8 5  
pl e ur al eff usi o ns, b o n e l esi o ns) will b e r ec or d e d as pr es e nt or a bs e nt o nl y, u nl ess, w hil e a n a b n or m alit y 
is still n ot e d b y i m a gi n g st u di es or p h ysic al ex a mi n ati o n, it is f o u n d t o b e hist ol o gic all y n e g ati v e.  
I n cli nic al tri als w h er e P E T is u n a v ail a bl e t o t h e v ast m aj orit y of p artici p a nts, or w h er e P E T is n ot 
d e e me d n ec ess ar y or a p pr o pri at e f or us e ( e. g., a tri al i n p ati e nts wit h M A L T l y m p h o m a), r es p o ns e s h o ul d 
b e ass ess e d as a b o v e, b ut o nl y usi n g C T sc a ns.  H o we v er, r esi d u al m ass es s h o ul d n ot b e assi g n e d C R u 
st at us, b ut s h o ul d b e c o nsi d er e d p arti al r es p o ns es. 
R e s p o n s e A s s e s s m e nt:  
R e s p o n s e D efi niti o n s f or Cli ni c al T ri al s  
R e s p o n s e  
D efi niti o n  
N o d al M a s s e s  
S pl e e n, Li v e r  
B o n e M a r r o w  
C R  
Dis a p p e ar a nc e of 
all e vi d e nc e of 
dis e as e  
•  F D G -a vi d or 
P E T p ositi v e 
pri or t o 
t h er a p y; m ass 
of a n y siz e 
p er mitt e d if 
P E T n e g ati v e  
•  V ari a bl y 
F D G -a vi d or 
P E T n e g ati v e; 
r e gr essi o n t o 
n or m al siz e 
o n C T  
N ot p al p a bl e, 
n o d ul es 
dis a p p e ar e d  
I nfiltr at e cl e ar e d o n 
r e p e at bi o ps y; if 
i n d et er mi n at e b y 
m or p h ol o g y, 
i m m u n o hist oc h e mistr y 
s h o ul d b e n e g ati v e 
P R  
R e gr essi o n of 
m e as ur a bl e 
dis e as e a n d n o 
n e w sit es  
•  ≥5 0 % 
d ecr e as e i n 
S P D of u p t o 
6 l ar g est 
d o mi n a nt 
m ass es; n o 
i ncr e as e i n 
si z e of ot h er 
n o d es  
•  F D G -a vi d or 
P E T p ositi v e 
pri or t o 
t h er a p y; o n e 
or m or e P E T 
p ositi v e at 
pr e vi o usl y 
i n v ol v e d sit e 
•  V ari a bl y F D G -
a vi d or P E T 
n e g ati v e; 
r e gr essi o n o n 
C T  
≥5 0 % d ec r e as e 
i n S P D of 
n o d ul es (f or 
si n gl e n o d ul e i n 
gr e at est 
tr a ns v ers e 
di a m et er); n o 
i ncr e as e i n si z e 
of li v er or 
s pl e e n 
Irr el e v a nt if p ositi v e 
pri or t o t h er a p y; c ell 
t y p e s h o ul d b e 
s p ecifi e d 
 


U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 8 3  of 8 5  
Res p o nse Defi niti o ns f or Cli nic al Tri als (c o nti n ue d)  
Res p o nse  
Defi niti o n  
N o d al M asses  
S plee n, Li ver  
B o ne M arr o w  
S D  
Fail ure t o attai n 
C R/ P R or P D  
•  F D G -a vi d or 
P E T p ositi ve 
pri or t o t hera p y; 
P E T p ositi ve at 
pri or sites of 
disease a n d n o 
ne w sites o n C T 
or P E T  
•  Varia bl y F D G -
a vi d or P E T 
ne gati ve; n o 
c ha n ge i n size of 
pre vi o us lesi o ns 
o n C T 
— 
— 
Rela pse d 
disease or 
P D  
A n y ne w lesi o n or 
i ncrease b y ≥5 0 % 
of pre vi o usl y 
i n v ol ve d sites fr o m 
na dir 
•  A p peara nce of a 
ne w lesi o n(s) 
> 1. 5 c m i n a n y 
a xis, ≥5 0 % 
i ncrease i n S P D 
of m ore t ha n o ne 
n o de, or ≥5 0 % 
i ncrease i n 
l o n gest dia meter 
of a pre vi o usl y 
i de ntifie d n o de 
> 1  c m i n s h ort 
a xis 
•  Lesi o ns P E T 
p ositi ve if F D G -
a vi d l y m p h o ma 
or P E T p ositi ve 
pri or t o t hera p y 
> 5 0 % i ncrease 
fr o m na dir i n t he 
S P D of a n y 
pre vi o us lesi o ns  
Ne w or rec urre nt 
i n v ol ve me nt 
A b bre vi ati o ns:  C R, c o m plete re missi o n; F D G, [ 1 8F]fl u or o de o x y gl uc ose; P E T, p ositr o n e missi o n 
t o m o gra p h y; C T, c o m p ute d t o m o gra p h y; P R, partial re missi o n; S P D, s u m of t he pr o d uct of t he dia meters; 
S D, sta ble disease; P D, pr o gressi ve disease.  
 
S o urce:   C hes o n B D, Pfist ner B , J u wei d M E, Gasc o y ne R D, S pec ht L, H or ni n g SJ, et al. Re vise d Res p o nse 
Criteria f or Mali g na nt L y m p h o ma. J  Cli n O nc ol. 2 0 0 7; 2 5 ( 5): 5 7 9- 8 6. 
 
 




 
 
 
 
 
  
  
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
  
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
U T X -T G R -2 0 3  
 
 
D at e d: 2 0 D ec e m b er 2 0 1 8 ( V er 2. 0)  
 
P a g e 8 5  of 8 5  
2 0  A P P E N DI X F – H E P A TI TI S B S E R O L O GI C T E S T R E S U L T S